In this paper, the full solar spectrum coverage with an absorption efficiency above 96% is attained by shell-shaped graphene-based hollow nano-pillars on top of the refractory metal substrate. The material choice guarantees the high thermal stability of the device along with its robustness against harsh environmental conditions. To design the structure, constitutive parameters of graphene material in the desired frequency range are investigated and its absorption capability is illustrated by calculating the attenuation constant of the electromagnetic wave. It is observed that broadband absorption is a consequence of wideband retrieved surface impedance matching with the free-space intrinsic impedance due to the tapered geometry. Moreover, the azimuthal and longitudinal cavity resonances with different orders are exhibited for a better understanding of the underlying wideband absorption mechanism. Importantly, the device can tolerate the oblique incidence in a wide span around 65°, regardless of the polarization. The proposed structure can be realized by large-area fabrication techniques. For this purpose, different geometrical and material combinations have been proposed, only some of them covering the whole spectrum. For instance, the relatively poor absorption efficiency of thin-film solar cells is the consequence of the indirect bandgap of silicon, where surface plasmon resonances of metallic nanoparticles can be used to enhance it3. In these solar cells, prolonged action of air and moisture affect the photocurrent generation due to the formation of oxide layers on metallic particles4. As an alternative approach, the front-sided integration of high-index dielectric particles has been proposed to enhance the power conversion efficiency of the thin-film solar cells5. Metasurface-based absorbers are another common category of solar cells, where metal–insulator–-metal (MIM) stacks have been widely used. In the aforementioned solar thermo-photovoltaic systems (STPV), the proper choice of the metal  to withstand high temperature is a key factor6. Refractory metals, possibly coated with protection layers, are good candidates for this purpose because of their heat-tolerant and large absorption capabilities9.Solar energy trapping, as the main source of renewable energy, has been the focus of extensive research for many years11. In this regard, a graphene\semiconductor heterostructure has been proposed for stable and efficient conversion of the light to electricity, being much thinner than its commercial silicon p–n junction counterparts12. Moreover, silicon photovoltaics can benefit from graphene as a semi-transparent electrode and an antireflection coating13. As another instance, by integrating Al nanoparticles and wrinkle-like graphene sheets, 7.2% enhancement in the photocurrent density of the solar cell is attained14. Moreover, broadband absorption of the un-polarized light is achieved using a 90-nm graphene dielectric stack which behaves as a hyperbolic metamaterial15. The aim of the present research is the design of a graphene-based ultra-broadband absorber covering the whole solar spectrum. A comprehensive review of graphene synthesis and functionalization for solar cells can be found in16.Because of their broadband absorption nature, excellent chemical stability, high thermal stability, and excellent thermal conductivity, carbon-based materials have gained lots of interest as photo-thermal materials17. In the non-resonant approach, the wideband absorption is the consequence of gradient impedance matching, and the energy is dissipated either in lossy conductors or lossy dielectrics18. For instance, in the Sierpinski carpet, MIM absorber, and metallic nano-wires filled pyramid dielectric medium absorber, the absorption spectrum is widened by merging multiple resonances20. The absorption enhancement mechanism of the wideband truncated-pyramid-based metamaterial absorber and truncated titanium/semiconductor cone absorber can be respectively understood by extracting the effective impedance and Fabry–Perot cavity like resonances of the high-index dielectric resonator22. Due to the inherent wideband nature of tapered structures, in the paper, the cone-shaped geometry is chosen as the building block and its absorption spectrum is further manipulated by truncating the tip and hollowing the nano-pillars. In the following paragraphs, after wisely choosing the materials, the optical performance of the shell-shaped truncated hollow cone solar cell will be discussed in detail. The paper is organized as follows. At first, the potential of graphene material in the solar cell design is investigated by introducing its constitutive parameters. Later, the attenuation constant of the electromagnetic wave illuminated to the graphene slab is calculated to confirm its absorption capability. Finally, using a shell-shaped graphene-based nano-pillar and refractory metal substrate, respectively the impedance matching and transmission blockage conditions are satisfied in the desired spectrum. Multiple parametric studies are conducted to better understand the performance.Ultra-broadband absorbers can be realized using different approaches. Combined narrowband resonances to form super-unit, multi-resonance structures, and multi-layered configurations are beneficial for resonant devicesIn the following sections, the design procedure and performance analysis of a graphene-based solar cell is investigated in detail. After exhibiting the absorption capability of graphene material in the solar spectrum, by wideband impedance matching and transmission elimination, a full-spectrum solar cell is proposed and its performance is discussed employing multiple simulations.9. In the infrared regime, graphene is commonly modeled by its surface conductivity calculated based on Kubo formulas. The outstanding feature of graphene in the plasmonic state is being reconfigurable through its chemical potential and relaxation time23. In this band, graphene surface conductivity can also be converted to the equivalent bulk permittivity with the negative real part using the Ampere’s low24. In the visible spectrum and beyond, graphene behaves as an ordinary dielectric. Thus, the Drude Lorentz model can be used to approximate the monolayer graphene dispersive permittivity using the measured data25. Hence26:27:a and b in (2) are defined as: ε) and permeability (μ). Graphene is a non-magnetic material, therefore the real and imaginary parts of its permeability are respectively one and zero.Let us initially investigate the equivalent permittivity of graphene material in the solar spectrum. The solar radiation covers the wavelength range of 295–2500 nm (~ 100–1200 THz), comprised of ultraviolet, visible, and infrared lighth1 = 100 nm and h2 = 1600 nm, respectively. The dispersive permittivity of TiN refractory metal is extracted from29 and that of the graphene is based on (1). The graphene nano-pillar is with a bottom radius of R1 = 120 nm and a top radius of R2 = 40 nm. Moreover, the periodicity is T = 2R1 + p = 240 nm (p = 0) and the thickness of the graphene shell is tg = 10 nm. The dispersive permittivity introduced in (1) is used for the layered graphene as well30. Note that 3D nano-pillars can be fabricated by hole-mask colloidal lithography31. The method can also be used for the large-scale fabrication of shaped high index dielectric patterns32. Tape-assist transfer and spin coating can be used for wrapping graphene on curved surfaces35. Moreover, the core template can be removed by immersing it in hydrofluoric acid (HF) solution with stirring to reach ultrathin-shell graphene hollow particle36.The unit cell of our proposed absorber for the full coverage of the solar spectrum is illustrated in Fig. 37:As Fig. 38. The geometrical parameters are comparable with the TiN-shell based nano-pillar solar cell31.Based on the figure, wideband impedance matching is observed in this spectrum. The results of the above figures show that the underlying mechanism of the absorption is wideband impedance matching and transmission blockage39, the impact of the height on optical absorption is further discussed in the last section to reach geometrically compact devices for high-frequency operation.The spatial components of the electric field at three different frequencies  are provided in Table 40 and the absorption rate above 90% can be attained for angles up to 65°.The sensitivity of the absorption to the incident angle of the radiating wave is shown in Fig. 2 material with a refractive index of 1.459. Based on the figure, the hollow nano-pillars have better low-frequency performance. Absorption rate enhancement by decreasing the core permittivity is expected since it is equivalent to the decrease in the size of the system41. The reader is referred to the experimental realization of carbon-based hollow particles for high power energy applications as further examples45 Moreover, in Fig. Figure 30. As Fig. 46. Using few-layer graphene films in the optical design, cost, scalability, and ultra-broadband absorption features can be attained but the effective transport of the photothermal energy generated on the surface and the possibility of performance manipulation become limited11. Moreover, Fig. The optical absorption of the proposed device with changes in different geometrical parameters is studied in this section. Initially, let us consider the impact of the thickness of the graphene shell on the absorption rate. The reported absorption manipulation by the increase in the number of wrapped graphene layers around a spherical resonator exhibit different performance for solid silver and dielectric-metal core–shell resonators, respectively increasing and decreasing for thicker shells47.The absorption rate of the proposed solar cell for different cone heights is investigated in Fig. 51. However, since the nanowire system is relatively easy to realize and control, two simpler geometries are analyzed in the following. Specifically, in Fig. Finally, the morphology-dependent behavior of the proposed structure is investigated in Fig. With the combined use of shell-shaped graphene-based hollow nano-pillars and a refractory metal substrate, a full-spectrum solar cell is designed. These two sections are respectively responsible for impedance matching and transmission blockage, leading to efficient energy absorption. Moreover, the performance is further explained by exhibiting the azimuthal and longitudinal cavity resonances with different orders in the spectrum. The polarization in-sensitive absorption of the solar cell is maintained up to 65°. Moreover, it is observed that tip truncation and using hollow particles are two key factors for the efficient absorption of the low-frequency waves. The proposed device is heat tolerant and environmentally robust and can be possibly realized by the current fabrication technology.52. The Floquet ports with two prorogating modes are considered during the simulations. The absorption rate (A) of the structure is calculated using the simulated reflectance (R) and transmittance (T) as37:S11 and S12 are the scattering parameters.The unit cell analysis of CST software is used for simulation


Introduction: In recent years, computer-assisted surgery has made it possible to undergo surgery with a high degree of precision. This study aimed to investigate the usefulness of computer-assisted surgery for femoral trochanteric fractures using the ADAPT (ADAptive Positioning Technology) system. Methods: A total of forty patients with femoral trochanteric fracture underwent intramedullary nailing for fracture fixation: in twenty patients, the ADAPT system (ADAPT group), and in the other twenty, it was not used (control group). The operative time, intraoperative fluoroscopy time, tip apex distance (TAD), and tip to head surface distance (TSD) were measured and compared between the two groups to assess the efficiency and accuracy of the surgery. Results: The operative time was significantly shorter (P < 0.05), intraoperative fluoroscopy time was significantly reduced (P < 0.01), and implant placement was significantly better in the ADAPT group (P < 0.01). Conclusion: Navigation systems have been developed to improve the efficiency of surgery. The ADAPT system was considered a very useful device for intramedullary nailing of femoral trochanteric fractures, as it reduced the intraoperative fluoroscopy time and improved the accuracy of implant placement, also reducing the operative time. Supplementary File 1) has been developed, which is expected to overcome this problem. ADAPT is a fluoroscopy-based navigation system that uses two-dimensions (2D) X-ray images taken with a C-arm device to construct three dimensions (3D) information. This computer-assisted surgery system has been described in detail in a previously published cadaver study [In recent years, navigation systems have increased, and their usefulness in orthopedic surgery is becoming increasingly important. Computer-assisted surgery (CAS) has been in development since the early 1990s. Thirty years on, CAS technology has been put to practical use in joint replacement, spinal surgery, tumor surgery, and trauma surgery, contributing to improved surgical accuracy . One of er study . In intrer study . ADAPT ier study . ADAPT iA total of forty patients in the study agreed to undergo computed tomography (CT) before participating in the study. There were four male and thirty-six female patients, with a mean age of 85.7 years. Fracture classification was carried out using the Jensen classification . There wSupplementary File 2). When using ADAPT, it is necessary to attach the FluoroDisc to the C-arm device, the ADAPT clip to the Gamma3 targeting device, and use the ADAPT Platform as an additional monitor  . The operative time was 28.3 ± 6.99 min in the ADAPT group and 35.1 ± 11.2 min in the Control group (The operative time was significantly shorter in the ADAPT group (ol group .P < 0.01). The intraoperative fluoroscopy time was 1.98 ± 1.40 min in the ADAPT group, and 6.46 ± 2.27 min in the Control group (The intraoperative fluoroscopy time was significantly reduced in the ADAPT group (ol group .P < 0.01). TAD was 12.6 ± 2.64 mm in the ADAPT group and 18.3 ± 1.63 mm in the Control group (TAD was significantly better in the ADAPT group (ol group .r = 0.81) . The correlation coefficient between the two groups is 0.81 ( = 0.81) .Conventional navigation systems improve the accuracy of implant placement but are time-consuming and require a long time to set up , 10–12. There are two limitations to this study. The first was that all the operations were undergone by experienced orthopedic surgeons. Secondly, there was always a trained computer operator present during the operation using ADAPT. Valsamis et al. state that the presence of a highly skilled surgeon and a trained computer operator in hip arthroplasty using a navigation system will certainly reduce the operative time . This liThe position of the lag screw has been reported to be important in the osteosynthesis of femoral trochanteric fractures . One of TAD is measured from 2D images and TSD from 3D images. It was impossible to determine TAD intraoperatively, as TAD was originally a criterion to assess postoperative radiographs. It is difficult to determine TSD intraoperatively because TSD is a criterion that is assessed in 3D. However, ADAPT can demonstrate TAD and TSD intraoperatively. In particular, when inserting a lag screw, the TSD can be displayed on the screen in 0.1 mm increments for each X-ray exposure. The position of the lag screw within the bone head is converted from 2D to 3D by ADAPT, allowing the TSD to be determined intraoperatively. Takai et al. and Kuhl and Beimel compared the intraoperative TAD values of the ADAPT system with the TAD values on postoperative radiographs and reported the high accuracy of the intraoperative measurements , 20. Ourhttps://www.sicot-j.org/10.1051/sicotj/2021056/olmSupplementary material is available at Supplementary File 1. SICOT-J ADAPT.mpgSupplementary File 2. G3_IN_1.mpeg4.ac3.aviT.M. certifies that he has no financial conflict of interest in connection with this article. K.Y. certifies that he has no financial conflict of interest in connection with this article. H.O. certifies that he has no financial conflict of interest in connection with this article.This research did not receive any specific funding.Ethical approval was not required.This article does not contain any studies involving human subjects.T.M. was involved in the conception and coordination of the study and contributed to the acquisition, analysis and interpretation of the data and drafted the manuscript.K.Y. and H.O. assisted in the conception and coordination of the study and helped with data analysis and preparation of the manuscript.


This study aims to analyze the relationship between the sociocognitive skills of a group of children and adolescents with autism spectrum disorder (ASD) at verbal level 1, the variability of the therapist’s heart rate (HRV), and the conversational turn-taking during online psychotherapy sessions. Initially, we assessed the intelligence, narrative, and behavioral characteristics of the participants. We videotaped the online sessions and recorded the therapist’s HRV via a smart wireless sensor. Finally, we analyzed the video sessions using an observation system and the therapist’s HRV using the Poincaré technique. The results show that the patients’ communicative intention was related to their narrative, intellectual and social competencies. Furthermore, the turn-taking between the therapist and the participant was associated with the patient’s emotional and behavioral difficulties. On the other side, the therapist’s heart rate variability (HRV) was related to the synchrony between the therapist and the participant with more significant stress on the therapist, when he shared and expanded the conversation with the patient, and when the patient broadened and shared the conversation with the therapist. The therapist–patient relationship is a specific intersubjective interaction environment, determined by a high level of confidentiality and emotional involvement ,2. It enFrom this perspective, the synchrony between therapist and young patients can be defined as “responsiveness” , “reciprThe dyadic interaction between any caregiver and child implies synchrony, a continuous, dynamic, reciprocal behavioral and emotional adaptation during shared activities ,2,8,9. TConsequently, reciprocal behavioral adaptation and turn-taking are interactive components required in the caregiver–child relationship and the therapeutic one, especially with children and adolescents with social impairments such as autism spectrum disorder. Moreover, turn-taking includes cognitive, behavioral, emotional, and physiological components ,15,16.Therefore, quantifying the turn-taking and physiological activity during psychotherapy allows one to understand how the therapist recognizes, regulates, and reorganizes cognitive activity for reciprocal emotional attunement , adaptinIntersubjectivity, social interaction and turn-taking allow the development of affective bonds, attachment ,19 and tOne of the primary intervention approaches with dysregulation and disruptive behaviors in children and adolescents with ASD focuses on communication , on the From this perspective, ecological and mainstreaming psychotherapy promotes language adaptation and social skills, always considering interlocutors ,35,36,37From a novel perspective, online psychotherapy offers a flexible patient–therapist setting for synchronic conversations, including the child and adolescent’s daily environment, especially with people with verbal-level ASD . The effAutism spectrum disorders (ASD) are neurodevelopmental disorders with different quantitative and qualitative impairments in communication, interaction, and restricted behaviors/interests ,42,43,44This sensory particularity and perceptual weak central coherence bias in ASD can generate high levels of anxiety and, consequently, an increase in the manifestation of obsessive and compulsive behaviors . MoreoveUltimately, understanding the relationship between self-esteem, personal resources, emotional and behavioral difficulties , narrative, and social skills of young people with ASD, the turn-taking and the therapist’s physiological variability during discursive dialogic psychotherapy, can be useful to explore the communication, representation, and social adaptation in ASD.Moreover, given the importance of turn-taking and patient-therapist synchrony, it is crucial to analyze the therapist’s reactions during psychotherapy to make explicit and optimize the interventions with young people with verbal-level ASD.In this way, the psychotherapy can be calibrated to improve self-awareness and behavioral–emotional self-regulation, optimizing, and promoting more flexible and balanced representations .The study’s design is cross-sectional, and explores behavioral and emotional characteristics of a group of children and adolescents with ASD, the turn-taking, and the therapist’s heart rate variability (HRV) during 26 online discursive dialogic therapy sessions with 16 Spanish children and adolescents with verbal-level ASD. Several participants’ characteristics were explored, including age, narrative, social skills, and emotional and behavioral difficulties . Moreover, we analyzed the turn-taking between the therapist and patient during the online session through sequential observational analysis of video recordings, with minimum intervals of one second. Finally, we defined two different conditions based on the therapist’s electrocardiogram (ECG) signal: condition A (low heart rate variability—HRV), defined by a low sympathetic activity (low-stress), and condition B (high HRV), defined by a high sympathetic activity (high-stress).Three hypotheses were explored:Hypothesis 1 (H1).The communicative intention during the turn-taking of children/teenagers with ASD and therapist can be related to participants’ intelligence, age, narrative, and social skills.Hypothesis 2 (H2).The turn-taking between the therapist and the young patients with ASD can be related to the participant’s emotional and behavioral difficulties, according to self-report, family, and school.Hypothesis 3 (H3).During the psychotherapeutic session, the therapist’s heart rate variability (HRV) can be related to the patient’s turn-taking synchrony, with more significant stress on the therapist throughout shared and broadened activities.The study involved 16 Spanish boys between 6 and 18 years  with verbal-level autism spectrum disorder (ASD), level 1. The participants were selected from a Spanish psychological center with verbal skills to perform a narrative task . All theA trained researcher assessed participants’ intelligence, narrative, and behavioral characteristics, in person, using the Reynolds RIAS intelligence test , the SENskype.com) was video-recorded  and analyzed by two independent researchers, blinded to the study hypothesis, using a turn-taking sequential observation system [Each online psychotherapy session , a smartphone Xiaomi Redmi Note 3, a signal acquisition software (physiolitix.fbk.eu) and an ECG signal processing system [The therapist’s heart rate activity was recorded through a smart wireless sensor  is a textile type sensor that allows continuous and non-invasive heart rate variability (HRV) monitoring, reflecting the therapist’s emotional stress level. It measures the ECG signal in mV, through two electrodes  that captures 128 samples per second (128 Hz), representing the first ECG lead. This measurement provides the voltage between the left arm electrode and the right arm electros Lead I = LA − RA. The ECG sensor requires both, a signal acquisition and a signal processes. The signal acquisition process pairs the ECG sensor with a smartphone via Bluetooth connection and runs the PhysioREC application (physiolitix.fbk.eu). PhysioREC is a smart software based on an open-source algorithm called “Pyphysio” [The Comftech CozyBaby ECG sensor .The behavioral and functional data were obtained from families and teachers through the SENA questionnaire (family and school forms) in previous sessions.In the first 45-min individual session with each participant, the first part of the RIAS intelligence test and the Bears Family Projective Test were administered. In a second individual session, the second part of the RIAS intelligence test and the SENA questionnaire (self-report form) were administered.For the stories told by the participants using the Bears Family Projective Test, two trained researchers, blinded to the research hypotheses, coded the video-recorded story sessions using the Bears Family Test Manual . The relThe discursive dialogic online therapy sessions were offered during SARS-CoV-2 pandemic lockdown in Spain (March–June 2020), collecting data from two different sources: 1—he video recording through OBS software (obsproject.com) of each online psychotherapy session via Skype Video Call (skype.com); and 2—the therapist’s heart rate activity recording through the Comftech CozyBaby ECG sensor (comftech.com), the signal acquisition PhysioREC software (physiolitix.fbk.eu), a smartphone Xiaomi RedmiNote 3, and the ECG signal processing system Pyphysio .The protocol used during the sessions to capture both recordings was: 1- the smartphone was connected to the ECG sensor using Bluetooth; 2- the application PhysioREC was opened to upload ECG data to a web platform; 3- the electrodes were moistened to improve sensibility; 4- the sensor’s band was set on the therapist’s chest between the manubrium and the body sternum; 5- the recording of the camera and ECG sensor were started.For the analysis of the turn-taking exchange between the therapist and each patient during the online therapy sessions, two independent researchers, blinded to the study hypothesis, coded the video recorded sessions using the turn-taking sequential observation system, considering minimum sequences of one second. The reliability was evaluated in 65% of the sample using Cohen’s kappa index , which wFor the analysis of the turn-taking exchange between the therapist and each patient during the online therapy sessions, two independent researchers, blinded to the study hypothesis, coded the video-recorded sessions using the turn-taking sequential observation system, considering minimum sequences of one second. The reliability was evaluated in 65% of the sample using Cohen’s kappa index, which was statistically acceptable (kappa = 0.87).For the analysis of the therapist’s heart rate variability (HRV), proceeding from the ECG sensor during each session, a researcher, blinded to the study hypothesis, analyzed the ECG signal, and extracted some key features  to detect high and low heart HRV. The RR interval, also known as the interbeat interval (IBI), is the time between one beat and the next using the ECG signal’s R peak as a reference . The PoiWe used this measurement’s mean and standard deviation to calculate the Poincaré SD1 and SD2 that associate HRV to stress levels. HRV reflects the variation of the beat-to-beat (RR) intervals and is an indicator of the autonomic nervous system activity . SD1 repPreviously to calculate the features shown above, the signal’s quality was checked morphologically, looking for noise or fragments of the corrupted recording. From a total of the 33 recordings, seven were discarded due to the presence of noise or corrupted fragments. The final number of samples was 26, with enough quality to be analyzed. We obtained all the features using a time window of 24 s. Each second of the ECG signal it was ranged from current time point ±12 s.To study the therapist’s different stress levels, we clustered the different sessions in two groups (low and high stress level), according to the SD1 and SD2 parameters, related inversely to the sympathetic activity. Some authors also use the activity stress score SS based on SD2   and, forConsequently, a low HRV reflects a low sympathetic activity (low-stress), while a high HRV reflects a high sympathetic activity (high-stress). To analyze the relationships between the communicative intention during the turn-taking of children/teenagers with ASD and therapist (Hypotheses 1 and 2), we run Pearson correlation (95% and 99% confidence levels with a two-tailed test of significance).To explain the differences between the heart rate variability (HRV) of the therapist and patients’ events (Hypotheses 3). First, we performed Shapiro–Wilk normality tests on the two categories of study variables . Then, we performed a t-test to determine the equality of means on those variables that meet the normality assumption in both categories (high and low HRV) and a nonparametric test (Mann–Whitney) on those variables that do not meet the normality criterion in both categories.Additionally, to study the impact—both on the patient and the therapist—of the different events during the session on the SD2 parameter, we used the nonparametric test hypothesis for k independent samples  grouped by therapist and patient events.Concerning Hypothesis 1, according to which the communicative intention during the turn-taking in the therapeutic session can be related to participants’ intelligence, age, narrative, and social skills, the results confirm it . below dDescriptive statistics about session duration, the number of turn-taking events, and the turn-taking frequency per second are shown in p = 0.05), considering the frequency of changes in turn-taking per second  and structure  of the patient’s story with the Bears Family Projective Test ; meanwhile older patients expands (patient Expands—NAm) more on the therapist’s conversation during the session   the therapist’s initial conversation topic proposal for a longer time  .p = 0.05).Concerning narrative competence, patients who told stories with a more significant number of propositions at the Bears Family Projective Test, spent more time expanding (patient expands—NAm) the therapist’s conversation during the session .Patients who reached a greater story cohesion index in the Bears Family Projective Test spent less time, during the session, not sharing and continuing with their activity , less integration and social competence perceived by the patient  corresponded a mayor frequency of times with the patient not accepting the initial proposal of the therapist (patient does not accept—NNA).At a low perception of self-esteem .A lower perception of personal resources at home corresponded with longer time, during the session, that the patient did not share and propose a topic to the therapist  and who perceive and show at home fewer personal resources .On the one hand, the therapist takes more time to start the online therapy session (therapist proposes—T*) with patients who perceive and show at school more behavioral problems , show more global problems  and emotional regulation difficulties at home . Moreover, the therapist stays for a longer time co-oriented (co-oriented therapist-TMC) with patients who perceive and show at home more aggressive behaviors .The therapist sustains (therapist holds—TS) for a longer time the patient’s conversation topic with patients who perceive more aggressive behaviors , and show, at school, more global problems , emotional problems , behavioral problems , difficulties in executive functions , depressive features , hyperactivity , anger , aggressiveness , challenging behavior , unusual behaviors , emotional regulation difficulties , and rigidity .The therapist directs for a longer time attention (therapist directs attention—TDAt) when interacting with patients who perceive more behavioral problems , less emotional regulation at home  and, at school, more global problems , behavioral problems , executive dysfunctions , depressive features , attention difficulties , hyperactivity , anger , aggressiveness , behavior challenging , unusual behaviors , and emotional regulation problems .The therapist interrupts the conversation for a longer time and proposes a new conversation topic (therapist interrupts—TI) when interacts with patients who perceive more antisocial behaviors , and anger .Finally, the therapist takes longer to finish the online session (therapist ends—TT) with patients who perceive and show at home and school more behavioral problems , and he perceive and show at home fewer emotional problems . Despite it, patients who proposes a topic to the therapist for a longer time also perceive more antisocial behaviors , and show at home more aggressive behaviors .On the other hand, the patient proposes a topic to the therapist (child proposes—N*) for a longer time when they perceive more aggressive behaviors , and expands (child Expands—NAm) the conversation longer when they perceive more difficulties with peers , executive dysfunction , depressive features , hyperactivity , challenging behavior , stiffness , isolation , and fewer personal resources .The patients who did not share with therapist and continued with their conversation or action for longer (child does not share and continues with his activity—NNcC) were those who used to show at school more global problems , emotional problems  can be related to the patient’s turn-taking synchrony, with more significant stress on the therapist throughout shared and broadened activities, the results confirm it.Considering the global average of the SD2 ECG parameter (HRV) of the therapist  during tHence, we analyzed the relationship between the SD2 parameter, and the different actions taken, by therapist and patient, during the turn-taking interactions in the whole session, searching for significant differences. Once it is verified that the data do not follow a normal distribution , we perfThe SD2 values are then sorted for a better understanding and interpretation of their meaning. We grouped the therapist’s SD2 parameter by the therapist’s turn-taking interactive behavior. Considering that a lower SD2 corresponds to a higher therapist HRV , we listed in Similarly, we grouped the therapist’s SD2 parameter by the patient’s turn-taking interactive behavior . So, we These results indicate that there is a more significant stress on the therapist both when they shares (TMC) and expand (TA) the conversation with the patient both when the patient expands (Nam) and shares (NC) the conversation with the therapist.The study aimed to analyze the therapist’s physiological reactions and conversational turn-taking during online psychotherapy with a group of children and adolescents with ASD at verbal level 1. We considered the patient’s intellectual and narrative skills, emotional and behavioral difficulties from a multi-informant perspective .Hypothesis 1 hypothesized that the communicative intention during the turn-taking of children/teenagers with ASD and therapist could be related to participants’ intelligence, age, narrative, and social skills.According to Hypothesis 1, the results confirmed that the communicative intention during the turn-taking between patient and therapist was related to the patient’s age and socio-cognitive skills. The older the patient was, and the more he told stories with more proposition and adaptive behaviors in the narrative baseline using the Bears Family Projective, the more conversation he expanded during the online session with the therapist. Moreover, the patients who self-reported several personal resources and greater self-esteem, expanded more, and shared the conversation during the online session, producing the therapist’s most physiological activation (HRV) in the therapist.At a lower equivalent and chronological age, the patient accepted the initial therapist proposal for longer at the beginning of the session; meanwhile, at a lower self-esteem perception, integration, and social competence, the patient did not accept the initial therapist proposal as long.Generally, according to self-report, acceptance in turn-taking during all the psychotherapeutic sessions was longer with patients who perceived fewer emotional and contextual problems, depressive features, and anxious symptoms; according to the family perception, with fewer emotional problems, difficulties in executive function, depressive, anxiety, rigidity, isolation, but more significant behavioral and challenging problems; and, according to the teacher perception, with more challenging behavior, learning problems, and difficulties in emotional regulation.In highly charged cognitive and emotional circumstances, the person’s capacity to manage and regulate their behavior is minimized ,99,100. These findings indicate that the mental health specialist must promote balanced positive and negative representations in the conversation about oneself and the patient, past, present, and future experiences, alternating and balancing own and other representations, a primary objective in dialogic psychotherapy, especially with children and adolescents with ASD at the verbal level ,104,105.Hypothesis 2 hypothesized that the turn-taking between the therapist and the young patients with ASD could be related to the participant’s emotional and behavioral difficulties, according to self-report, family, and school.For Hypothesis 2, the results confirmed that conversational turn-taking between therapist and patient was related to the patient’s emotional and behavioral difficulties. Indeed, the therapist spent more time starting online therapy sessions, sustaining, co-orienting, directing attention, interrupting the conversation, proposing a new topic, and finishing the session with patients with more behavioral problems and fewer personal resources. On the other hand, patients with more behavioral problems spent more time proposing a topic to the therapist, expanding, and not sharing his conversational topic or action.These findings indicate that it is more challenging to open and alternate therapist’s own and patient’s representations when the patient shows more behavioral difficulties. The specialist’s objective must be to share an argument in conversation to balance positive and negative representations, facilitating both metacognitive and executive skills. In this case, a more active role for the therapist is necessary, interrupting and directing the conversation to promote coherence between the patient’s dialogic representations and his owns, promoting a shared communicative exchange that actively involves both interlocutors ,107,108.Hypothesis 3 hypothesized that, during the psychotherapeutic session, the therapist’s heart rate variability (HRV) could be related to the patient’s turn-taking synchrony, with more significant stress on the therapist throughout shared and broadened activities.Concerning Hypothesis 3, the results confirmed that the therapist’s heart rate variability (HRV) was related to turn-taking during the interactions with the patient, with more significant stress on the therapist both when he shared and expanded the conversation with the patient both when the patient expanded and shared the conversation with the therapist.This result underlines that the therapist must adapt to the patient’s peculiarities, looking for an active strategy to support and expand the patient’s conversation and topic proposals in a balanced and coherent way. Like a mirror of the patient’s effort to enter and remain in the shared dialogic contact, the therapist experiences a heart rate stress, probable reflex of emotional resonance that he must recognize, regulate, and reorganize to return to the therapeutic relationship in a modulated and understandable way, operating an emotional attunement with the patient ,17. DuriSynchrony is a social signal, and synchrony improvement can lead to cognitive and behavioral improvement in young patients with ASD ,109. DurThe psychophysiological response is triggered in interpersonal interactions, where cognitions, emotions, and empathy feed physiological responses of approach or flight ,110. NeuSo emotional fluctuations can be shared and linked in a relational scaffolding through emotional and cognitive-relational exchanges during specific relationship experiences such as dialogic psychotherapy. Psychotherapy, presential or online, represents a particular intersubjective interaction context. The high level of confidentiality and affective involvement allows synchronous interlocutors to visit past/present experiences and anticipating future situations, looking to balance positive and negative representations, being an active emotionally involved part in a turn-taking interaction process ,17.Several therapeutic approaches with ASD aim to develop the patient’s functional speech . Some ofThis study contributes to the lack of knowledge about the turn-taking and communicative processes between therapists and young patients with ASD. However, synchrony is an essential aspect for the prognosis of the child and adolescent with ASD ,104, feeThus, it is essential to promote the child’s communication because of its functional nature. Communication that occurs naturally always has a goal and is therefore closely related to the motivation of the person who wants to communicate. Children and adolescents with ASD show specific difficulties interacting with other people because they often experience these interactions as frustrating and not always successful. Therefore, the therapist or person who fosters a successful interaction must be sensitive and not hostile with children and adolescents with ASD  sharing


Dimethyl sulfide (DMS) is the dominant volatile organic sulfur in global oceans. The predominant source of oceanic DMS is the cleavage of dimethylsulfoniopropionate (DMSP), which can be produced by marine bacteria and phytoplankton. Polar oceans, which represent about one fifth of Earth’s surface, contribute significantly to the global oceanic DMS sea-air flux. However, a global overview of DMS and DMSP cycling in polar oceans is still lacking and the key genes and the microbial assemblages involved in DMSP/DMS transformation remain to be fully unveiled.Tara Ocean dataset. Our analyses suggest that intense DMS/DMSP cycling occurs in the polar oceans. DMSP demethylase (DmdA), DMSP lyases , and trimethylamine monooxygenase  were the most prevalent bacterial genes involved in global DMS/DMSP cycling. Alphaproteobacteria  and Gammaproteobacteria appear to play prominent roles in DMS/DMSP cycling in polar oceans. The phenomenon that multiple DMS/DMSP cycling genes co-occurred in the same bacterial genome was also observed in metagenome assembled genomes (MAGs) from polar oceans. The microbial assemblages from the polar oceans were significantly correlated with water depth rather than geographic distance, suggesting the differences of habitats between surface and deep waters rather than dispersal limitation are the key factors shaping microbial assemblages involved in DMS/DMSP cycling in polar oceans.Here, we systematically investigated the biogeographic traits of 16 key microbial enzymes involved in DMS/DMSP cycling in 60 metagenomic samples from polar waters, together with 174 metagenome and 151 metatranscriptomes from non-polar Overall, this study provides a global overview of the biogeographic traits of known bacterial genes involved in DMS/DMSP cycling from the Arctic and Antarctic oceans, laying a solid foundation for further studies of DMS/DMSP cycling in polar ocean microbiome at the enzymatic, metabolic, and processual levels.Video AbstractThe online version contains supplementary material available at 10.1186/s40168-021-01153-3. The volatile organosulfur compound dimethyl sulfide (DMS) is the main source of marine sulfate aerosols , a key pThe predominant source of oceanic DMS is bacterial cleavage of dimethylsulfoniopropionate (DMSP). DMS can also be produced by direct cleavage of intracellular DMSP in DMSP-producing phytoplankton . DMSP clBacterial oxidation is the primary process for DMS removal in the marine environment . MicrobidsyB gene encoding a MTHB methyltransferase in the transamination pathway [mmtN gene encoding a Met methyltransferase in the methylation pathway [Roseobacter and SAR11 clades [The biosynthesis of DMSP is initiated from methionine (Met) through four different pathways, including two methylation pathways, a transamination pathway, and a decarboxylation pathway . It is g pathway  and the  pathway  have bee pathway . It is e pathway . In addi pathway . It is e pathway . The fir pathway , 35. Dmd1 clades , 38. Mos1 clades . HoweverRuegeria pomeroyi DSS-3 has 3 different DMSP lyases, DddQ [Pelagibacter sp. HTCC1062 contains DddK [Labrenzia aggregata LZB033 possessing methyltransferase DsyB can also carry out DMSP cleavage using the DMSP lyase DddL [Although historically, each pathway in DMS/DMSP cycling is discovered independent, many of these genes co-exist in bacteria. For example, it is reported that es, DddQ , DddW [1es, DddQ , and Dddes, DddQ , the DMSes, DddQ  as well es, DddQ . The SARins DddK , DmdA [4ins DddK , and Tmmins DddK . It is ains DddK  and DMS ins DddK . The DMSThe Arctic and Antarctic are two of the most geographically separated bioregions on Earth with extreme environmental conditions. High concentrations of DMS/DMSP have been detected in both the Arctic Ocean and the Southern Ocean Table . Indeed,n = 16), Arctic-Deep , Antarctic-Surface , and Antarctic-Deep . For comparison, metagenomes of 174 non-polar seawater samples (Table Tara Oceans project [http://www.pangaea.de/). Additionally, 151 metatranscriptomes  or the IMG/M database [http://hmmer.org). The cutoff values used were selected based on established stringency cutoff values from previous reports  were retrieved from the metagenomes/metatranscriptomes and aligned by MUSCLE. Maximum-likelihood phylogenetic trees were created via FastTree  and visuSecond, for those enzymes involved in DMSP/DMS cycling whose structures are available , DddP (2 sequences), DddK (2 sequences), DmdA (1 sequence), and Tmm (2 sequences) (Table Escherichia coli BL21 (DE3). These proteins were purification as described previously [Tara Oceans datasets are usually short and do not always contain the full open reading frame, making it difficult for gene synthesis and overexpression in E. coli for functional validation.Finally, to validate the function of predicted hits of the top 5 most abundant enzymes from our datasets, we randomly selected several environmental sequences from each group, chemically synthesized these genes, and overexpressed them in recombinant s) Table . The nuceviously  and theieviously , 72, 80.eviously . DddX hoThe amino acid sequences of predicted DMS/DMSP cycling-related genes from these metagenomes/metatranscriptomes were extracted using scripts compiled in Python code and aligned against the non-redundant protein sequences (nr) database using BLASTP . The beshttps://cran.r-project.org/web/packages/geosphere/index.html). The relationship between Bray-Curtis dissimilarity of microbial communities [https://www.originlab.com/). The average abundance of DMS/DMSP-related genes in metagenomic and metatranscriptomic samples from polar and non-polar oceans was used for Pearson correlation analysis. Pearson correlation coefficients and P values were calculated using ‘ggcorrplot’ packages [The geographical distribution of sampling locations was constructed by Ocean Data View . DMS/DMSmunities  involvedpackages . Data prTara Ocean datasets  for each protein involved in DMSP/DMS cycling using ratified sequences obtained from literature Table . These Hts Table . Homologts Table  were fouts Table a althougts Table .Fig. 3RE. coli. Indeed, these proteins retrieved from environmental samples were functional  did not appear to be prevalent in these polar samples (Table S1). In contrast, the DmdA-mediated DMSP demethylation pathway was more prevalent, consistent with previous reports of high abundance of DmdA from other oceans [Tara Oceans project were analysed. Among the 16 proteins analysed, DmdA, DddD, and DddP were also the most abundant genes involved in DMS/DMSP cycling in non-polar metagenomic samples  and polar metagenomic samples , respectively  and redundancy analysis (RDA) were performed. These metagenomic samples were broadly grouped into three independent coordinates: polar surface waters, Tara surface waters, and deep waters Fig. b. Polar Further RDA analysis demonstrated that the divergence of the ordinations is mostly driven by the differences of relative abundance of certain genes in DMS/DMSP cycling in surface and deep waters Table . DddK waTo reveal the taxonomic diversity of DMS/DMSP cycling-related proteins in polar oceans, 17,189 protein sequences from polar oceans obtained through our pipeline were aligned against the NCBI-nr database, and the taxon of each best hit with the highest accuracy to species level was extracted. Thirty phyla  spanning over 38 classes, 72 orders, and 107 families were involved in polar DMS/DMSP cycling Table . Among tRegardless of the abundance of the potential genes, DddD, DddP, and MddA exhibited high phylogenetic diversities Fig. d. In conIn the majority of the metagenomic samples from both polar and non-polar oceans, the cumulative relative abundance of DMS/DMSP-related genes exceeded 1 Fig. a, b, sugTo uncover the co-occurrence of these genes in DMS/DMSP metabolism, we carried out a comprehensive co-occurrence network analysis of all microbial genomes in the IMG/M database, which contained genomes of 10285 isolates, 2120 Single cell Amplified Genomes (SAGs) and 5267 MAGs. At the time of the analysis , IMG/M included 2428 genomes, of which 412 genomes had more than one gene involved in DMS/DMSP metabolism Table . At the Tara Ocean datasets. The relative abundance and phylogenetic analyses of these potential genes involved in DMS/DMSP cycling in polar oceans suggested that there appears to be an intense and integrated DMS/DMSP cycle in polar oceans  [Similarly, the relative abundance of Tmm and DMSOR in polar oceans suggested that the production DMS and DMSO were likely unbalanced, which may result in DMSO accumulation. Indeed, high concentrations of DMSO have been detected in both polar oceans waters and sea ice , 47, 101e (TMAO)  and the e (TMAO) , which sOverall, the relative abundance of genes involved in DMS/DMSP cycling in polar oceans appears to be higher than that in non-polar oceans Fig. . InteresOverall, this study provides a global overview of the biogeographic traits of known bacterial genes involved in DMS/DMSP cycling from the Arctic and Antarctic oceans, laying a solid foundation for further studies of DMS/DMSP cycling in polar ocean microbiome at the enzymatic, metabolic, and processual levels.Additional file 1: Figure S1. Analysis of conserved amino acid residues involved in substrate binding and catalysis of DddK (a), DddQ (b), DddY (c), Tmm (d), DddP (e), DmdA (f) and DMSOR (g) retrieved from polar metagenomic samples. Figure S2. Maximum likelihood trees of the predicted hits of the top five most abundant genes  involved in DMSP/DMS cycling which were retrieved from the polar metagenomes, Tara metagenomes/metatranscriptomes datasets. Figure S3. Correlation between dissimilarity of DMS/DMSP related bacterial community and water depth in polar oceans.Additional file 2: Table S1. Raw abundances of DMS/DMSP related genes in Arctic and Antarctic seawater samples. Table S2. A list of enzymes selected as outgroups for phylogenetic analyses. Table S3. Raw abundances and taxonomic composition of DMS/DMSP related genes in MAGs. Table S4. Raw abundances of DMS/DMSP related genes in Tara Ocean samples. Table S5. Raw abundances of DMS/DMSP related genes in metatranscriptomes. Table S6. The predicted hits with enzymatic activity. Table S7. Biplot scores for constraining variables. Table S8. Taxonomy composition of DMS/DMSP related genes in polar ocean samples. Table S9. Occurrence of DMS/DMSP related genes in genomes from IMG/M database. Table S10. Raw abundances of MTO in metagenomic and metatranscriptomic samples.


Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial lung disease, of which the etiology has been poorly understood. Several studies have focused on the relationship between IPF and diabetes mellitus (DM) in the past years but have failed to reach a consensus. This meta-analysis aimed to examine the association between diabetes to IPF.I2 statistics. We also performed subgroup analysis, meta-regression, and Egger’s test for bias analysis.We accumulated studies investigating the association between DM and IPF from databases including Medline, Cochrane Library, Embase, Web of Science, and China National Knowledge Infrastructure. RevMan 5.3 and the Newcastle–Ottawa Scale (NOS) were utilized to analyze the data and assess the quality of the included studies. The value of odds ratio (OR) with 95% confidence interval (CI) was used as the measure to estimate the risk of DM in IPF. Heterogeneity was assessed by P < 0.0001). Meta-regression and subgroup analysis negated the influence of covariates like cigarette smoking, age and gender, but the heterogeneity existed and could not be fully explained.Nine case–control studies with 5096 IPF patients and 19,095 control subjects were included in the present meta-analysis, which indicated a positive correlation between DM and IPF (OR 1.65, 95% CI 1.30–2.10; IPF and DM may be associated, but the causal relationship remains indeterminate till now. Further rigorously designed studies are required to confirm the present findings and investigate the possible mechanisms behind the effect of DM on IPF. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal pulmonary disease with an annual cumulative prevalence of 18.2 cases per 100,000 persons in America . IPF is In recent years, it has been observed that IPF patients are often additionally diagnosed with diabetes mellitus (DM), resulting in increased research interest in the correlation between these two diseases. Firstly, two earlier case-controls studies , 8 were Due to the conflicting results in the existing studies, it remains controversial whether DM is truly correlated with IPF. Hence, in the present study, we conducted a meta-analysis and systematic review, aiming to assess the association between DM and the incidence of IPF.We performed meta-analysis and wrote this report referring to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) proposal  and the We searched databases including Medline, Cochrane Library, Embase, Web of Science and China National Knowledge Infrastructure. The following items were searched in databases as keywords or random words: “pulmonary fibrosis”, “diabetes”, “risk factors” and such searches were additionally filtered for articles published in any language leading up to September 30, 2020 (Complete search strategy presented in Appendix 1).Case–control studies or cohort studies were selected. The case groups were all diagnosed with IPF in accordance with clinical history, High-Resolution Computed Tomography (HRCT), and when available, lung biopsy. Also, a calculated measure of association between DM and IPF was required. Studies focusing on progression or prognosis of IPF and studies lacking general information about control groups were excluded.Two researchers (L.B. and L.Z.) managed data extraction independently, reviewing the title, abstract, and full text of each article, and discussed or consulted a third researcher (T.P.) when disputations arose. The following are included: (1) basic information of each study including author, publication year, study design, etc.; (2) characteristics of case and control groups; (3) diagnostic methods of DM and IPF; (4) the number of diabetics in case and control groups; and (5) potential sources of biases.The Newcastle–Ottawa Scale (NOS) was used for quality assessment of included studies, covering three domains: selection of groups, comparability of groups and ascertainment of exposure . The NOSI2 statistics and random effect model was chosen when heterogeneity was significant (I2 > 50%), otherwise, fixed effect model was selected. Forest plots were used to display the results from individual studies and pooled estimates, and P < 0.05 were regarded as statistically significant. Trial Sequential Analysis (TSA) was used for estimate of evidence size and reliability of the conclusion [In our meta-analysis, odds ratio with 95% confidence interval (95% CI) was used as the effect measure. Heterogeneity was assessed by nclusion , 22. We nclusion  were utiAs is briefly illustrated in Fig. P < 0.0001), based on statistical reliability verified by the subsequent trial sequential analysis  with no obvious sources of biases found among the sensitivity analyses , which coincided with the outcome of the meta-regression , suggesting that smoking was unlikely to distort the final results. Next, considering that age and gender are related to IPF despite inexplicable reasons [P = 0.0007). Still, there remained two potential sources of biases that the included literatures did not sufficiently address (Table P = 0.016 < 0.05) judged by the Egger’s test , HRCCO , 40) andCO , 42, incCO , etc.), −), potentially giving rise to damage of lung tissue and ultimately pulmonary fibrosis [Therefore, understanding the exact pathological mechanisms is crucial; namely, how persistent hyperglycemia, a known characteristic of diabetes, gradually contributes to the pulmonary lesions. Studies found that a high glucose concentration could result in nonenzymatic glycation with the ultimate formation of advanced glycation end products (AGEs), which may target type IV collagen in the alveolar basement membrane, thicken the basal lamina both in epithelial and capillary of alveoli and eventually lead to a decrease in pulmonary elasticity and compliance –46. Thisfibrosis , 52. In fibrosis –57, all fibrosis  and a mefibrosis  inferredAlthough the possible pathophysiologic mechanisms do explain the disease process, we acknowledge that multiple factors may induce pulmonary fibrosis and that it is also indeterminate to what extend IPF is affected by diabetes. Thus, to solidify the association between DM and IPF, the beneficial effect of antidiabetic therapy should be established. Rangarajan et al.  demonstrIn our meta-analysis, we screened literatures in strict accordance with inclusion and exclusion criteria, designed the study with high quality, and finally demonstrated that DM and IPF are very likely interrelated. Nevertheless, there remain several limitations in our study. Firstly, the heterogeneity was significant, and a reasonable interpretation is still absent. The wide range of prevalence of DM (from 10 to 61% in IPF groups and from 3 to 43% in control groups) in the studies has attracted our attention, which could be responsible for major heterogeneity; we assumed this to be secondary to multiple factors including diagnostic criteria of diabetes (subjective or objective methods) and IPF (differences of diagnostic criteria in different guidelines), selection of populations (with or without underlying diseases), and regional differences. However, the internal causal relationship has not been established to date. Secondly, given that the result is based on case–control studies, which are susceptible to confounding factors, the potential sources of biases have always been a focus. Even though influence of smoking, age, and gender was ruled out in our bias analysis, other covariates such as genetic factor might also cloud the association between DM and IPF, especially considering that at least 30% of patients have predisposing genetic factors which could increase the risk of pulmonary fibrosis –64. BesiThe association between diabetes and IPF was briefly referred to in ATS/ERS clinical practice guideline updated in 2011 , but not


The current status, ongoing challenges, and potential future outlooks of nanocellulose-graphene hybrids in multi-sensing applications are highlighted.The fundamentals of synthetization, interfacial interactions, functionalization, and green fabrication techniques of nanocellulose-graphene hybrids are described.The most advanced novel nanocellulose-graphene hybrids implementation as a multifunctional sensing platform is discussed. Naturally derived nanocellulose with unique physiochemical properties and giant potentials as renewable smart nanomaterials opens up endless novel advanced functional materials for multi-sensing applications. However, integrating inorganic functional two-dimensional carbon materials such as graphene has realized hybrid organic–inorganic nanocomposite materials with precisely tailored properties and multi-sensing abilities. Altogether, the affinity, stability, dispersibility, modification, and functionalization are some of the key merits permitting their synergistic interfacial interactions, which exhibited highly advanced multifunctional hybrid nanocomposites with desirable properties. Moreover, the high performance of such hybrids could be achievable through green and straightforward approaches. In this context, the review covered the most advanced nanocellulose-graphene hybrids, focusing on their synthetization, functionalization, fabrication, and multi-sensing applications. These hybrid films exhibited great potentials as a multifunctional sensing platform for numerous mechanical, environmental, and human bio-signals detections, mimicking, and in-situ monitoring. Figure 50 thin film (400 nm), which refers to the strong interfacial bonding during deposited-washed cycles. The high GO content and multilayer number, as demonstrated in Fig. –4 S m−1), which makes it a promising candidate for sensors and electrochemical devices. The applicability of multilayer spraying assembly was reported by Sadasivuni et al. [n layers (n ≈ 40) through cyclical spraying-coating assembly on polymer substrate has a significant impact on the electrical conductivity with an inverse relationship between the optical transparency and resistivity of fabricated hybrid film  thermal conductivity [12.6 W m−1 K−1] and inferior cross-plane (λZ) thermal conductivity [0.042 W m−1 K−1] values at 40 deposition cycles  or environmental  and other human bio-signals (human motion and breathing). Also, combined NCs and GO/rGO are used as one of the components that accompany by other stimuli-responsive compounds used in the fabrication of sensors. The multifunctional NCs-GO/rGO hybrid films exhibit a wide multi-sensing range in responding to diverse stimuli through different sensing mechanisms , which will be discussed in the following subsections.Rrel) changing under strain with cyclic loading 1 mm min−1 up to fracture. Remarkably, to some extent, the hybrid NCs-rGO film shows a linear strain response (4.7% Rrel at 2.9% strain) until the fracture, as illustrated in Fig. R/R0)  Fig. b. Noticerel) changing when applied for RH variations of (30–90%) and temperature sweeps [280 →  ← 380 K] of warming up and cooling down cycles  mechanism at constant T 23 °C, RH 35%values can be referring to NCs matrix swelling behavior because of water molecules absorption at the rGO surface, which leads to change the distance and destruct the conductivity pathways between rGO nanosheets.Recently, NCs-GO/rGO hybrid film sensitivity toward changing environmental conditions like temperature and relative humidity (RH) correlated with relative resistance–capacitance has confirmed based on the GO/rGO nanosheets high electrical conductivity , 31, 37 les Fig. a, b. TheAC–CR)  results in Fig. Comprehensive work in the Jaehwan Kim group has demonstrated the high temperature and relative humidity sensitivity of NCs-GO/rGO hybrid films based on their dielectric behavior Fig. a and absCR) Fig. c–f. The rel) changes. Interestingly, the NCs-rGO hybrid film was found to be a multifunctional liquids-solvents sensor during immersion and drying cycles with different solvents, temperatures, and salt concentrations  and different salt concentration solutions (0.5–2%)  Fig. c, d. TheRrel) fluctuation  evolution, which allows it to detect human breathing during inhalation and exhalation cycles  and rGO nanosheets conjugated structures have elucidated the flexibility and conductivity of the NCs-rGO hybrid film. Moreover, rGO hydrophobicity prevents the fabricated hybrid film sensor from bio-signals interference, achieving simultaneous in-situ monitoring. More profoundly, the electrical resistivity (–/ + ΔR/R0) consistently changed with microstrain deformation variations and multidirectional human motions (under compressive and tensile state) with small hysteresis and reliability , improved functionality of NCs-GO/rGO hybrid nanocomposites are possible. After that, through eco-friendly and facile approaches, different techniques have been applied to fabricate NCs-GO/rGO hybrid films and enhanced their properties. Finally, to well understand of these NCs-GO/rGO hybrid films’ characteristics and outstanding desirable properties, their multi-sensing applications were discussed.Significantly, in this review, we have demonstrated the nanocellulose abilities to act as a multifunctional green dispersant, stabilizer, filler, and reductant agent for graphene derivatives, resulting in superior rheological, mechanical, electrical, thermal, and optical properties. Also, the nanocellulose surface was proven to act as a unique functional platform with controlling the self-assembly of graphene sheets, which in turn considered a promising accomplishment for multi-sensing applications. However, some critical challenges should be addressed and taken into consideration to fully realize nanocellulose-graphene hybrid films as realistic multi-sensing platforms in practical aspects. The first and foremost challenges refer to the nanocellulose and graphene origin sources top-down synthesis standardization and characterization of nanoscale dimension structures, surface functional groups, and assembling behaviors. Nevertheless, the large-scale empirical development of NCs-GO/rGO hybrid films can provide a deeper understanding and detail technical datasheets for commercial aspects in the near future. Consequently, practical applications of such advanced hybrid functional materials can open prospective and attract more attention as next-generation advanced functional materials with high performance, eco-effective, and cost-effective. Also, graphene derivatives are commonly considered non-cytotoxic and biocompatible. However, their synthetization routes extremely influence the in vivo and in vitro assessments as results of the residual reagents/solvents (i.e. hydrazine) utilized during synthetization process, which can interact with tissues/cells and induced cytotoxicity. Hence, NCs with multifunctional eco-synthesis routes abilities, besides the eco-friendliness merits such as non-toxicity, biocompatibility, and biodegradability can significantly eliminate and diminish these induced cytotoxicity and adverse side effects.Future outlooks consist of the collaboration of engineers and biomaterial scientists to elaborate marketable and accessible products of such promising hybrids for multi-sensing applications. For instance, a multifunctional wearable NCs-GO/rGO hybrid film sensor exhibited excellent high strain response and wide detection range of various human body motions, including finger, wrists, throat motions, and head rotations, besides the human sweat ion concentrations during the motion. These multifunctional-integrated smart sensors can closely measure, mimic, and in-situ monitor a broad range of bio-physical, bio-chemical, and environmental signals that offer critical insights into overall human health status and driven innovations in digital healthcare like multifunctional wearable healthcare monitors and so forth.


In utero PFAS exposure is associated with neurodevelopmental effects; however, the mechanism is poorly understood. Brain-derived neurotrophic factor (BDNF) signaling is critical to fetal neurodevelopment during pregnancy and maintains important regulatory roles later in life. This study aims to characterize placental BDNF signaling and investigate whether PFAS exposure disrupts the signaling pathway in placental trophoblast cells.Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. NTR and TrkB–in first trimester and term human placentas and trophoblast cells were investigated by immunofluorescence staining. To assess the effects of PFAS exposure on the BDNF pathway, BeWo cells were treated with PFAS mixtures that mimicked blood levels in a highly exposed population and major PFAS compounds in the mixture at 0.01, 0.1, 1, and 10 µM concentrations. Changes in pro-BDNF levels and phosphorylation of TrkB receptors were examined by Western blot.The expression and localization of BDNF receptors–p75NTR receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75NTR receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75NTR receptor staining was negative. TrkB receptors were confined to the nuclear and perinuclear spaces, and phosphorylation occurred at the Tyr816 residue in BeWo cells. Exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly affect BDNF levels or activation (phosphorylation) of TrkB. Treating cells with 1 μM and 10 μM of PFNA resulted in increased TrkB phosphorylation compared to unexposed controls, but BDNF levels were unchanged.In first trimester human placentas, TrkB and p75BDNF receptors are present in different regions of human placental villi, indicating diverse functions of BDNF signaling in placental development. Our findings suggest that the BDNF pathway in placental trophoblast cells is not disrupted by exposures to PFOS, PFOA, PFBS, and a PFAS mixture, but may be affected by PFNA exposures. Further investigation is needed on how PFAS affects other critical signaling pathways during fetal neurodevelopment. Biomand soil . Previouand soil –9. One sConcern surrounding PFAS has risen among affected North Carolina residents due to the potential deleterious human health effects associated with exposure. A growing body of robust laboratory and epidemiologic data link PFAS to increased risk of cancer, immune system dysfunction, poor antibody response to vaccines, hormone disruption, kidney disease, thyroid disorders, high cholesterol, pregnancy-induced hypertension, preeclampsia, asthma, and decreased fertility . FetusesNTR and tropomyosin sensitive receptor kinase B (TrkB) . BDNF is essential to mammalian nervous system development and function . BDNF prB (TrkB) , 32. AbnB (TrkB) , 33–38. B (TrkB) . NeurotrB (TrkB) –42. BDNFB (TrkB) , 43, 44.B (TrkB) –48. BDNFB (TrkB) . ChangesB (TrkB) , 53. Howxposures , 37, 54.xposures –59.This study aims to characterize the BDNF pathway in human placental tissues and trophoblast cell lines. Further, we seek to investigate how the BDNF pathway in placental trophoblast cells is affected by exposures to a PFAS mixture—which models the exposure of Pittsboro, North Carolina residents (based on blood levels)—and major PFAS compounds in this mixture.Potassium nonafluoro-1-butanesulfonate , tridecafluorohexane-1-sulfonic acid potassium salt (K+PFHxS), and heptadecafluorooatanesulfonic acid potassium salt (K+PFOS) were purchased from Sigma-Aldrich . Oerfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were purchased from Synquest Laboratories . Product purity is above 95%. Stock solutions of PFAS at 10, 1, 0.1, 0.01 mM were prepared by dissolving PFAS compounds in ultrapure distilled water. A PFAS mixture was made based on the PFAS levels in blood samples collected from people living in Pittsboro, NC, in 2019  was cultured in Dulbecco’s Modified Eagle Medium-Hams/F12 (DMEM/F12) media supplemented with 10% Fetal Bovine Serum (FBS) and 1x antibiotic-antimycotic solution (Thermo Fisher Scientific). Cell culture and treatment conditions are described in our previous publications , 61. In han LD10 .First trimester placental tissues were collected from elective pregnancy termination patients without notifiable complications at 8-10 gestational weeks. The study protocol was approved by the Ethics Committees of Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine (IRB# XHEC-C-2018-089) with the consent waiver to obtain de-identified tissue that was not to be used for clinical purposes. Term placental tissues were collected under the Duke University Institutional Review Board approval (IRB# PRO00014627) with the consent waiver to obtain de-identified tissue that was not to be used for clinical purposes. The placentas were collected from women who underwent planned cesarean delivery at term , without labor and current or previous pregnancy complications.Sections of placental tissues were fixed and paraffin embedded. Tissue slides were deparaffinized with xylene followed by graded rehydration in ethanol and distilled water. Subsequently, the sections were subjected to heat-induced epitope retrieval by heating in antigen unmarking solution  preheated to boiling for 20 minutes, followed by a 20-minute cool-down period at room temperature. Slides were permeabilized and blocked with 1% BSA, 10% normal goat serum and 0.01% tween-20 in PBS for 60 min at room temperature. After blocking, the slides were incubated with primary antibodies in blocking buffer overnight at 4°C in humidified chambers. Primary rabbit anti-human syndecan 1 (SDC-1) antibody , mouse anti-human TrkB antibody , or p75NTR antibody  was used at a 1:200 dilution. Goat anti-rabbit Alexa Fluo 488 secondary antibody and Goat anti-mouse Alexa Fluo 594 secondary antibody  were used at 1:300 dilution. Nuclei were stained using NucBlue Fixed Cell ReadyProbes Reagent . Slides were mounted using ProLong Diamond Antifade Mountant (Invitrogen) and examined with a Leica SP5 inverted confocal fluorescence microscope.4 cells per well in glass chamber slides  then incubated for 24 hours. Cells were fixed with cold methanol for 10 minutes and blocked with 1% BSA, 5% goat serum, and 0.1% Tween-20 in PBS for 1 hour at room temperature. Next, cells were incubated at 4°C overnight with primary antibodies in humidified chambers. 1:100 dilutions of primary rabbit anti-human TrkB antibodies  and p75NTR antibodies  were used. Anti-rabbit IgG antibodies served as a negative control . 1:300 dilutions of goat anti-rabbit secondary antibodies and Alexa Fluo 594  were used. F-actin was stained using fluorescein Phalloidin  at 1:300 dilution. Nuclei were stained using NucBlue Fixed Cell ReadyProbes Reagent . Slides were mounted using ProLong Diamond Antifade Mountant (Invitrogen) and examined with a Leica SP5 inverted confocal fluorescence microscope.BeWo cells were seeded at a density of 2 x 104 cells per well in 96-well plates and incubated for 24 hours. The cells were then treated with each individual PFAS compound at 0, 0.01, 0.1, 1, 10 μM or a PFAS mixture . The optical density at 490 nm (OD490) was used to quantitatively compare cell viability between treatments after incubating the cells with MTS reagents for 4 hours. These experiments were repeated five times (N=5).BeWo cells were seeded at a density of 1 x 10To harvest cell lysates after treatment, we used RIPA buffer  with the complete mini-protease inhibitor cocktail . Protein concentrations were determined with the Bradford assay . 25μg of total protein samples were loaded onto 10% sodium dodecyl sulfate polyacrylamide gels, separated, and transferred to a polyvinylidene difluoride membrane. The membranes were blocked with 5% milk in Tris-Buffered Saline and Tween-20 (TBST) buffer. Membranes were probed in blocking buffer at 4°C with primary antibodies overnight. The following primary antibodies were used in the experiments: rabbit anti-human TrkB antibody , phosphor-TrkB (Tyr816) antibody , and rabbit anti-human pro-BDNF antibody  at 1:1000 dilution; rabbit anti-human GAPDH antibody at 1:20 000 dilution. The secondary antibody was diluted at a ratio of 1:2000. To visualize and photograph the membranes, we used the ChemiDoc MP Imaging System with Image Lab Software . Band intensity was quantified with ImageJ . Data were normalized to the internal control (GAPDH) and are presented as ratios. Experiments were repeated four times (N=4).Data are presented as means ± SD. Multiple comparisons between treatments were performed with a one-way ANOVA and the post-hoc Dunnett’s test using GraphPad Prism 6.0 . Results from treatment groups are compared to unexposed control cells. A p-value smaller than 0.05 is considered statistically significant.NTR receptors were stained red, and nuclei were stained blue (NTR staining were most pronounced in the STB and cytotrophoblast cells (CTBs) , a biomarker for syncytiotrophoblast (STB) was stained green on their epical membrane, TrkB and p75NTR receptors were primarily observed in the placental villous stroma distinguished it from the first trimester placenta  was widely detected in these cells with and without forskolin treatment. Finally, Western blot results demonstrated that exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly alter BDNF production or activation of TrkB, manifested by the constant ratio of phospho-TrkB (Tyr816) to total TrkB at any given dose  to total TrkB. Exposure to other PFAS compounds  and the PFAS mixture did not significantly alter BDNF signaling, as evidenced by unchanged levels of BDNF and phospho-TrkB. Thus, the impacts of PFAS exposure on fetal neurodevelopment previously observed in cohort studies  and in vivo  observations of the BDNF pathway upon PM2.5 exposure [unpublished data]. Finally, our findings are based on a single cell model due to the limited availability of STB cell models. JAR, JEG-3—other in vitro models of the trophoblast barrier—were unsuitable for this study because they fail to undergo substantial syncytial fusion . Three individually tested PFAS compounds  and a six-PFAS mixture mimicking residential exposure in Pittsboro, North Carolina, did not induce increased TrkB phosphorylation or alter pro-BDNF levels. Additionally, our results showed that in cells exposed to high concentrations of PFNA, phosphorylation of TrkB receptors increased while pro-BDNF levels remained stable. Although BDNF plays a critical role in brain development throughout all stages of life, it is unlikely to be primarily responsible for the observed neurodevelopmental consequences associated with The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committees of Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine and the Duke University Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.MM drafted the manuscript. SL performed research and data analysis. JZ contributed to the study design and drafting the manuscript. LF designed research, performed experiments and data analysis, and revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Fogarty International Center of the National Institutes of Health under Award Number 1K01TW010828-01 (PI: LF). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


There was a significant positive correlation between smoking history and ACE2 expression in the IPF cohort for SAE  and alveolar areas . This, to our knowledge, is the first study to compare ACE2, TMPRSS2, and Furin expression in patients with IPF and LAM compared to HC. Descriptive images show that α-SMA and TGF-β1 increase in the IPF and LAM tissue. Our data suggests that patients with ILDs are at a higher risk of developing severe COVID-19 infection and post-COVID-19 interstitial pulmonary fibrosis. Growth factors secreted by the myofibroblasts, and surrounding tissue could further affect COVID-19 adhesion proteins/cofactors and post-COVID-19 interstitial pulmonary fibrosis. Smoking seems to be the major driving factor in patients with IPF.We previously reported higher ACE2 levels in smokers and patients with COPD. The current study investigates if patients with interstitial lung diseases (ILDs) such as IPF and LAM have elevated ACE2, TMPRSS2, and Furin levels, increasing their risk for SARS-CoV-2 infection and development of COVID-19. Surgically resected lung tissue from IPF, LAM patients, and healthy controls (HC) was immunostained for ACE2, TMPRSS2, and Furin. Percentage ACE2, TMPRSS2, and Furin expression was measured in small airway epithelium (SAE) and alveolar areas using computer-assisted Image-Pro Plus 7.0 software. IPF and LAM tissue was also immunostained for myofibroblast marker α-smooth muscle actin (α-SMA) and growth factor transforming growth factor beta1 (TGF-β1). Compared to HC, ACE2, TMPRSS2 and Furin expression were significantly upregulated in the SAE of IPF ( The coronavirus disease 2019 (COVID-19) outbreak has caused more than 240 million infections so far with approximately 4.9 million deaths worldwide until October 2021 . SmokingHigh expression of ACE2 is also a potential risk factor for severe COVID-19 outcomes in patients with interstitial lung diseases (ILD) . Among tDuring the COVID-19 pandemic, patients with ILDs, such as IPF and LAM who had severe COVID-19 infection, experienced severe and fatal complications ,23. Thern = 12) from the James Hogg Lung Registry (Ethics ID: H00-50110), patients with end-stage IPF (n = 6) from the Alfred Health (Ethics ID: 336-13) and patients with LAM (n = 6) undergoing lung transplant provided from the National Disease Research Interchange (NDRI) Protocol DVES2   . All IPFv/v)  for 15 min and with protein block solution  for 30 min at ambient temperature before applying the primary antibodies. The sections then were immunohistochemically stained using primary antibodies: ACE2 , TMPRSS2 , Furin , α-SMA  and TGF-β1 . The tissue slides were incubated in an IHC humidity chamber for 1 h at ambient temperature, followed by peroxidase-conjugated polymer backbone-carried secondary antibodies and visualized by 3,3′-diaminobenzidine (DAB) staining .Lung tissue sections (3 µm) were cut from paraffin-embedded blocks individually. Tissue sections were treated with target retrieval solution  in a Decloaking chamber at 110 °C for 15 min, followed by 3% hydrogen peroxide in water . The quantification of ACE2, TMPRSS2 and Furin positive expression in small airway epithelium and alveolar regions was carried through imaging software Image-Pro Plus 7.0 . Images of small airway epithelium and alveolar regions were taken as many as possible to cover the whole tissue section; overlapping of tissue areas were strictly avoided. Further, a minimum of five images of each subject’s small airway epithelium and alveolar regions were randomly selected using excel random number selection formula for the quantification measurement. All measurements were carried out using tissue imaging software Image-Pro Plus 7.0 and data presented here as the percentage of ACE2, TMPRSS2, and Furin expression in the small airway and alveolar regions.p < 0.05 is considered significant.Following normality check, all data represented here were analyzed using non-parametric Kruskal–Wallis analysis of variance followed by multiple group comparisons Dunn’s test. Further, correlation analysis was performed with nonparametric Spearman correlation using GraphPad Prism V9.2, Overall, increased remodeling changes were observed in small airways and alveolar septal thickening in both IPF and LAM tissues, albeit higher expression in IPF patients than in LAM and HC tissues . We obsep < 0.01)) and LAM ) patients (p < 0.001)) and LAM ) patients compared to HC  , ACE2, TMPRSS2, and Furin expression were significantly upregulated in the airway epithelium of SAs of IPF  iv–vi. ThIn addition, in IPF patients, the fibrotic lesions showed less expression of TMPRSS2 and Furin, and moderate expression of ACE2 compared to the normal areas within the alveolar region  and alveoli (r = 0.941, p < 0.01; Compared to non-smokers, smokers are more vulnerable to respiratory infections . IPF patThis study, to our knowledge, is the first study that compares the ACE2, TMPRSS2, and Furin in resected lung tissue from IPF, LAM, and HC. We identified here that ACE2, TMPRSS2, and Furin are highly expressed on small airway epithelium and alveolar region in both IPF and LAM patients, especially high in IPF, which indicates that LAM and IPF patients could be more vulnerable to COVID-19 infections, and this could further exaggerate due to smoking history and comorbidities. Our findings provide the first histopathological evidence supporting the recent observational study from Lee et al.  The studCurrent clinical evidence shows that IPF patients who were COVID-19 positive, developed severe fatal complications due to inflammation and lung injury, increasing their mortality from the virus-induced hyperinflammation . This inACE2 is the first step for the virus to attach to the host cell membrane ,33. CofaOn the other hand, LAM sections showed relatively lower expression of ACE2 and other co-factors in the alveolar epithelium than IPF. This reduction might be due to the established role of estrogens in downregulating ACE2 expression, as LAM is almost specific to females . But intInterestingly, we previously noted that the elevated endosomal protein markers expression and ACE2 expression were concomitant in small airways, type II pneumocytes and alveolar macrophages in smokers and COPD patients. These findings suggest that the endocytosis process is elevated in smokers and patients with chronic respiratory diseases, which means endocytic machinery could also play a critical role in assisting with the virus replication and release. In addition, due to smoking history with IPF in our cohort, we believe that endocytic vacuoles could also be active in this disease pathology, but this warrants further work.There are limitations to the study. First, the sample size was small; however, the stats were robust. Therefore, we believe it is unlikely to be a type-2 error. Second, LAM patients have other respiratory comorbidities and received various treatments, such as Sirolimus, Armour Thyroid, Oxybutynin, Rapmine, Lyrica, and Pramipexole. These comorbidities and treatments may affect LAM patients’ ACE2, TMPRSS2, and Furin expression. Further studies are needed to investigate whether the comorbidities and treatments affect these markers’ expression ,37,38,39This is the first study to our knowledge that compares the ACE2, TMPRSS2, and Furin in resected lung tissue in IPF and LAM. We identified that ACE2, TMPRSS2, and Furin are highly expressed on small airway epithelium and alveolar regions in IPF and LAM patients. Notably, we observed the increased expression of these markers in type II pneumocytes and alveolar macrophages in IPF patients, indicating that LAM and IPF patients could be more vulnerable to COVID-19 infections, which could further exaggerate due to smoking history and comorbidities. It also indicates that more than one cell type is involved in these markers. Growth factors such as TGF-β1 could also be playing an essential role in upregulating these COVID-19-related biomarkers, further exaggerating fibrotic pathology; however, further work is needed to illustrate such changes. Other environmental factors such as air pollution and the use of electronic cigarettes could also be involved but further work is required in this space ,41,42,43