K. penomenue samples bacteria colonies. In addition, the effect of both stretching frequency and pulses numbers have been studied on the bacteria count, growth kinetics, and protein leakage. Our contribution here is to introduce an innovative way of the direct impact of the generated electric field from piezoelectric nanofibers on the reduction of bacteria growth, without depending on traditional anti-bacterial nanoparticles. This work can open a new trend of the usability of piezoelectric nanofibers through masks, filters, and wound curing mats within anti-bacterial biological applications.This paper introduces a new approach of testing piezoelectric nanofibers as antibacterial mat. In this work, both Polyvinylidene fluoride (PVDF) and PVDF embedded with thermoplastic polyurethane nanofibers are synthesized as nanofibers mat via electrospinning technique. Then, such mat is analyzed as piezoelectric material to generate electric voltage under different mechanical excitations. Furthermore, morphological and chemical characteristics have been operated to prove the existence of beta sheets piezoelectricity of the synthesized nanofibers mats. Then, the synthesized nanofibers surfaces have been cyclically stretched and exposed to bacteria specimen. It has been noticed that the generated voltage and the corresponding localized electric field positively affect the growth of bacteria and reduces the formation of  Electrospinning depends on the electric grounding of the collecting target and the stretching electric force produced by the charges delivered to the solution from high voltage power supply. Due to the entanglements in the polymer chain within the fluid, the charged jet does not disintegrate1. A droplet at the needle's tip forms a Tylor cone when the charges reach a critical point, and a fluid jet shoots from it in the direction of the grounded collector, which has a lower potential accordingly. Since several polymers whether natural, synthetic, biodegradable, and nondegradable polymers are used to create nanofibers2 with unique and creative characteristics including polyurethanes (PU), polylactic acid (PLA), collagen, cellulose, chitosan, silk fibroin, and many more5, this technique has been used in a wide variety of industries1, including pharmaceutical, nano-catalysis, biomedicine, healthcare, protective clothing, environmental engineering, filtration6, and many others. Clay, titanium dioxide, carbon nanotubes, silica, and other inorganic nanofillers are used to create nanofiber composites with improved thermal, magnetic, electrical, fluorescent, and catalytic characteristics.The groundbreaking discovery of electrospinning has attracted a lot of attention in both science and business. This mechanism can spin a wide variety of polymers into fibers with diameters ranging from several nanometers to sub-micrometers, along with the control of fibers’ characteristics like pore structure, morphology, and functionality8 as a result of the electric dipole moment of PVDF monomer units due to the β-phase which is responsible for the piezoelectric behavior, and can be enhanced via electric poling and mechanical stretching10. This property qualifies PVDF to be a promising materials for future manufacturing of several applications, due to the high piezoelectric properties as a result of the polar crystalline structure11. The processing of PVDF in the form of nanofibers, play a crucial role in developing a flexible, lightweight, and biocompatible films for several applications such as wearable devices, wound dressing, biosensors13, and nano-generators16.Some polymeric materials such as PVDF have a unique piezoelectric property with the ability to transform the mechanical energy to electrical energy without external inputs18. The use of nanofibers in tissue engineering19 and wound dressing20 to promote cell growth and proliferation21 is increasingly crucial as nanofibrous membranes are used in medication delivery systems22 to implant drug carriers inside of patients' bodies. By changing the composition, porosity, and shape of electrospun nanofibers, the release rate of a medicine may be controlled while still maintaining an effective drug concentration at the injured area23. The electrospun nanofibers, which are excellent transporters, prevent the medication from decomposing. The systemic absorption of the medicine as well as any negative side effects can both be considerably reduced when the nanofibers are utilized as carriers for drug delivery at the specific location of the wound. The theory behind drug delivery using polymer nanofibers is that as the surface area of the drug and the matching carrier increases, so does the rate at which the drug dissolves24. The release of a pharmaceutical dosage form can be planned as delayed, immediate, fast, or modified dissolution depending on the kind of polymer carrier used for the creation of nanofibers. Several proteins, polysaccharides, growth hormones, and some anticancer medicines have all been successfully delivered via nanofibers28. Numerous low-molecular-weight medication solutions have been electrospun by researchers, including lipophilic pharmaceuticals like rifampin, ibuprofen, Cefazolin, Paclitaxel29, and hydrophilic drugs including mefoxin and tetracycline hydrochloride30.In a correlated track, bioengineering is one of the industries with the fastest growth rates especially when nanofibers technology started to merge inside the field32, photonics35, and antibacterial medical applications37. Strong inhabitation and high antibacterial effect was recorded against several bacteria when using nanoparticles such as silver (Ag)38, Zinc oxide (ZnO)40, and copper oxide (CuO)41, which can be used in burns, cuts, and wounds treatment with significant properties43 for the elimination of bacteria, viruses, fungus46 and multi-resistant bacteria47. Because there is a greater surface area exposed to the germs due to the small fiber diameter, the antibacterial impact is boosted. The nanoparticles in the composite nanofibers begin by rupturing bacterial cell walls, which has the inhibitory effect of preventing bacterial growth and ultimately leads to bacterial death50. The interaction between the bacterial cell and the oxides is facilitated by the nanoparticles' tiny size51. The method of nanoparticle penetration into bacterial cells is described by osmosis, cell-destructing enzymes, and subsequent cell death.Strong impact can also be achieved through nanoparticles incorporation inside nanofibers in many applications such as lithography54. It has been proven that the electric field has a role in inactivating microorganisms under non-thermal conditions57. There are several parameters affecting the role of field interaction such as bacteria type, growing phase, and conditions of growth. Not only this but also, the field type, strength, frequency, time of application, and field proximity to exposed cells60. The metabolic process of bacterial cells possesses various intercommunication signals that acting between cells to complete the vitality process61. The application of external localized fields may cause disruption of cellular membrane charge distribution and hence lead to electrical stress on the bacterial bio-entity64. Even at very low energy electric fields, they have the ability to penetrate the biological systems with almost no attenuation and to modify the natural biorhythms and existing signal transduction processes in cell membranes65. The transmembrane receptors and vertebral macromolecules allocated through the cellular envelop are acting as a group of electric fields antennae that can differentiate, discern, and transform the wave energies into signals66. Consequently, the impact application of close proximity electric fields may lead to severe cellular structural changes that eventually lead to lethal effect and drive to cell lysis67.Along with the interest in finding alternatives to antibiotics, great attention has arisen to studying the effects of electromagnetic waves and their ability to control bacterial growth as an alternative technique rather than the use of antibiotics68. Then, different piezoelectric analysis has been operated to show the generated electric voltage under different mechanical excitations including cyclic tension, cyclic normal force, and impulse loading. In addition, beta phase analysis using both XRD and FTIR is carried out to prove the piezoelectric performance of the synthesized nanofibers mats. Therefore, the stretched piezoelectric nanofibers are exposed to a specimen of bacteria to check the effect of generated voltage and corresponding localized electric field on the life of the bacteria colonies and its kinetic growth. Different stretching frequencies and number of stretching cycles are examined on the antibacterial performance.In this work, we are introducing an innovative antibacterial impact of piezoelectric nanofibers to use the generated localized electric field from mechanical excitations, such as cyclic tension, into a direct effect on bacteria. The used nanofibers are composed of pure PVDF nanofibers and PVDF mixed with Thermoplastic polyurethane (TPU) to give more mechanical stretching capabilities. From a recent published work by the authors, the addition of TPU at certain optimum concentration can lead to enhance the piezoelectric sensitivity due to the higher mechanical stretchability that TPU can contribute−1 molecular weight and Polydispersity Index (PDI) of 1.83. Certain concentrations of the polymers were dispersed in dimethylformamide (DMF 98%) from .Polyvinylidene fluoride (PVDF) was purchased from ARKEMA , Thermoplastic polyurethane (TPU) was ordered from  with 107,020 g molPVDF polymer solution of 10 wt% was prepared by adding the polymer powder into DMF. Similar concentration of TPU polymer solution was prepared by dispersing the polymer pellets into DMF, and a blended ratio was prepared with total concentration of 10% for PVDF:TPU, but with a weight ratio equals to 85:15, respectively. Knowingly that, this ratio has been chosen according to previous study performed by the same research team (68). The prepared polymer solutions were stirred overnight before the spinning process. Electrospinning process was performed by adding the prepared polymer solutions of PVDF and PVDF/TPU into plastic syringes with stainless steel needles of gauge 21. A high voltage power supply provided 30 kV  to the syringe needle, and a constant feed rate of 1 mL/hr was fixed by NE1000 syringe pump . A distance of 10 cm was adjusted between the needle and the grounded drum collector.−1 over a range of 4000–400 cm−1. The mechanical tensile testing was performed through Texture Analyzer CTX  by cutting the produced nanofibrous membranes into rectangular (1 × 6 cm2) and placing each sample between two cardboards frames. The thickness was measured by spring-based micrometer. Strain rate of 10 mm/min and zero initial loads were fixed. The used load cell was equal to 50 N. Each sample was tested three times and then the average stress–strain curve has been analyzed, to detect maximum tensile strength and the breaking strain where the strain where the sample was cut.Scanning Electron Microscopy through  was performed to observe the surface morphology of PVDF and PVDF/TPU nanofibrous membranes with 15 kV acceleration voltage. The nanofiber membranes were fixed on a carbon tape over aluminum stubs and sputter coated with platinum. The nanofibers diameters were analyzed through Image-J software  and the fiber diameter distribution was detected manually at different imaging scales. The Fourier Transform Infra-Red Spectrometer (FT-IR)  was used to calculate the β phase content in ATR mode. The nanofibers were scanned 120 times at a resolution of 5 cmThe Piezoelectric characterizations for pure PVDF and PVDF: TPU 15% were measured using various testing such as impulse, frequency, and stretching responses. The impulse response has measured using a simple setup as shown in Fig. 2 and sandwiched between two stretchable metallic electrodes as shown in Fig. In another test, the cyclic load has been applied on nanofiber system for measuring the frequency response using a light-weight spring built-up vertically controlled by brash-less DC motor connected with an electronic speed controller as shown in Fig. K. pneumoniae (ATCC 70068) was collected from Alexandria University Hospital, Egypt. It is worthwhile clarifying that the chosen bacteria strain is based on recent findings in our lab which confirmed the antibacterial effect of exposure to electromagnetic fields as a stressor co-factor against K. pneumoniae70.The isolates were inoculated in MacConkey agar plates at 37 °C for 24 h. For maintaining fresh subcultures, every while three colonies were added into sterilized MacConkey broth media and incubated at 37 °C for 24 h. Then after, a cultured supernatant stock inoculated in MacConkey broth by approximately 105 CFU of K. pneumonia was prepared. Four groups of bacteria samples are collected after exposure to electric pulses generated from nanofibers at three different exposure conditions and one group of bacteria sample free of exposure is considered as a control one. It is worthy to state that the nanofiber sheets were stretched mechanically in three frequency bases  and every time the bacteria samples were sprayed over the sheets before stretching and collected by taking swaps after the mechanical stretches. The growth characteristics of bacteria samples were evaluated by measuring growing turbidity in broth media and plate counts in agar media. The optical density (OD) of turbid inoculated broths were monitored every 1 h by taking 1 ml from 25 ml transparent glass bottles of the supernatants under treatment in a semi-micro quartz cuvette (P.N. 035 127). The OD measurements were carried out by using a spectrophotometer  set at 600 nm and every 0.1 in OD reading scale is considered as 108 bacteria cells per cm371. Furthermore, the growth counts were measured by using plate counting technique to get CFU values confirming the obtained OD measurements. The growth curves between OD values and incubation times were graphed. The curves were analyzed and corresponding arbitrary rate constants were calculated according to the following formulae and graphed versus concentrations for each applied frequency72.o the initial cell count. In addition, the cytotoxicity was assessed by lactate dehydrogenase (LDH), nucleic acid and protein leakage into the culture medium. The levels of LDH values, protein leakage amounts and nucleic acid percentages were obtained by methods adapted by Kim et al.73, Li et al.74, and Riss et al.75, respectively. Results were analyzed and presented as a percentage of control values and graphed relative to it.Standard strain of 77.Figure 78. As shown in Fig. −1 corresponding to the rocking of CH2, C–C, and CF2 stretching, in addition to 1175 cm−1 for C–F and 1400 cm−1 for C–H vibrations80. Nevertheless, the main characteristic bands for TPU were observed at 3365, 2971, 1735, and 1533 cm−1, corresponding to N–H stretching, C–H, C = O, and CONH– asymmetrical bond, respectively82. The β-phase fraction was calculated as shown in Table Figure Aα and Aβ are the intensities of 764 cm−1 and 840 cm−1 absorbance bands, respectively. Table Aα and Aβ were reduced according to the addition of TPU, the β-phase fraction was increased within PVDF: TPU sample compared to pure PVDF membrane. Accordingly, the piezoelectric response can be developed for TPU added samples compared to the pure PVDF ones, as will be shown in a later section.where 85.Stress–strain curves of PVDF and PVDF/TPU nanofibrous membranes are shown in Fig. In this section, the generated peak-to-peak output voltages are detected under different applied mechanical excitations including impulse loading of free fallen masses with different weights, mechanical cyclic forces, and cyclic stretching/tension. Figure 87.From the previous discussion, the output peak-to-peak voltage of the blended PVDF: TPU mat is found to be larger than the pure PVDF for the impulse, cyclic, and stretching responses. In addition, the comparison between the impulse and frequency responses shows that the response of blended PVDF:TPU, according to the frequency increase is more effective than the incremented applied force as shown in both Fig. Klebsiella penomenue (k. penomenue) to piezoelectric field pulses (PEPs) generated from PVDF and PVDF-TPU nanofibers under application of mechanical stretches. The antibacterial effect of PEPs was obtained by measuring the growth kinetics over 20 h of incubation and by plate colony counts. Furthermore, bacterial cytotoxicity was investigated by measuring the percentage of protein leakage, the level of the lactate dehydrogenase enzyme (LDH), and nucleic acid changes in comparison to control samples. It is worth to note that the PEPs are generated from mechanical stresses applied over the PVDF nanofiber mats, and so, here we divided the groups of nanofiber samples based on the number of applied mechanical stretches. The applied mechanical stretches were adapted by time of application and represented as frequency “in terms of Hz” resulted from dividing different number of pulses per relevant sets of times . It is worthwhile clarifying that the generation of PEPs was done by applying different numbers of mechanical stretches within certain periods at the aforementioned frequencies to check the influence of pulse numbers and stretching times as an antibacterial agent. The bacterial log reduction values for k. penomenue samples treated by PEPs generated from PVDF and PVDF-TPU nanofibers at set of frequencies are tabulated in Table Now, it will be shown the effect of exposing gram-negative bacteria k. penomenue colonies grown in MacConkey media exposed to PEPs generated from PVDF and PVDF-TPU nanofibers at set of frequencies  in comparison to control one are represented in Fig. Furthermore, bacteria growing kinetics were studied and graphed under the application of PEPs generated from PVDF and PVDF-TPU nanofibers at set of frequencies  as shown in Fig. 87. It is worth to note that live cells possess intercommunication signals between each other to functionalize their metabolic activities61. The transmembrane specialized receptors and allocated protein molecules, acting as a group of electromagnetic antennas that can differentiate, discern, and transform the wave energies into signals88. In another way, the external electromagnetic fields have the ability to penetrate the biological systems without attenuation and they have the ability to modify the natural bio-rhythm even at very low energies89. Therefore, the train of applied pulses from PEPs generated from nanofibers has influenced the existing signal transduction processes in cell membranes by 0–1 field action because of its analogy to frequency resonance action90.To that end, the growing kinetics of bacteria exposed to PEPs, which were generated from nanofibers mats, were graphed together to compare the effect of time and the number of applied mechanical stretches as shown in Fig. 91. In addition, the LDH as bio-marker enzyme was studied to confirm cellular injury due to exposure to PEPs in percentages of changes relative to control samples. The reflections of loss bacterial cell membrane integrity could be monitored by LDH increase due to cell death and lysis of its inter-constituents. Figure 92. On the bases of heterogeneous macro and micro structure of the cell membrane and the presence of ion binding protein it may be presumed that the electrical alterations in cell envelop leaded to lose normal charge distribution95 and cause changes in the ion concentration gradient across the membrane. The changes in ionic concentration gradient caused remarkable variations in the membrane potential and hence loss of membrane molecular constituents97.The study was extended to include the intracellular protein leakage from bacterial membranes into the extracellular medium and then measured as percentage of leakage in relative to control samples. Figure 98. The cell membrane potential resulting from charge distribution is related to cell membrane composition and gives biological characteristics of the cell99. Membrane stability, dynamicity and ionic uptake are dependent on the charged macromolecular head groups as key elements in modulating channels functionalized in the cell metabolic activity101. Different field perturbations are resulted from interaction of localized piezoelectric fields with charged macromolecular heads due to differences in their charge amount and bond length. The induced electric moments across membrane bilayer have reoriented and dislocated peripheral membrane macromolecules that caused intracellular metabolism to cease to exist and hence cell death.Moreover, to check the quality of cell inner constituents; the nucleic acid percentages were measured in relative to control samples and graphed as shown in Fig. k. penomenue bacteria colonies due to the applied cyclic stretching, and the corresponding generated voltage of both studied nanocomposite mats. In addition, the cyclic piezoelectric performance shows a slower kinetic growth of the bacteria due to the generated electric voltage, and corresponding localized electric field exposed to bacteria. Generally, PVDF:TPU nanofibers show a slower kinetic growth of bacteria up to half the similar rate of pure PVDF nanofibers according to piezoelectric field pulses (PEPs) with a frequency up to 2 Hz. In addition, PVDF:TPU shows a relative change in the nucleic acid more than 30% and relative leakage of proteins close to 200%. In summary, The piezoelectric mechanism from both PVDF and enhanced-stretchable PVDF: TPU electrospun nanofibers positively acts as an effective anti-bacterial mats. This work is promising in applying the piezoelectricity characteristics in microbiological field within masks, filters, and wound curing applications, without depending on the traditional direct contact mechanism of anti-bacterial nanoparticles.In this work, we innovatively investigated the impact of piezoelectric electrospun nanofibers and its corresponding generated voltage on the reduction of bacteria growth. This paper introduced the fabrication of both piezoelectric PVDF and PVDF: TPU nanofibers mats via electrospinning process. The piezoelectric analysis of both mats, which contain beta-sheet concentrations up to 80%, shows the generation of voltages up to 1 V under stretching strain of more than 15% on cyclic basis. Furthermore, TPU enhanced the piezoelectric response, compared to pure PVDF, under different applied mechanical excitations according to a possible better dipoles’ alignment inside the nanofibers within the added stretchable TPU element. Then, we have used both studied nanofibers to check the antibacterial impact due to cyclic stretched piezoelectricity. The experimental results show the reduction of the formed


Females when compared to males reported stronger feeling of “drug effects” and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [ Dopamine signaling in the brain is responsible for modulating functions critical for survival, including attention, memory, motor control, motivation, and reward-guided behaviors , 2. SeveSimilarly, the prevalence of most substance use disorders (SUD) including that for stimulants is higher for males than females . However11C]raclopride, which binds to D2 and D3 [D2/3] receptors) and compare its binding after placebo and after a drug or a behavioral challenge. If the challenge increases dopamine levels, the endogenous dopamine occupies D2/3 receptors, decreasing their availability, and hence [11C]raclopride binding is reduced (the decrease in receptor availability is a marker of ‘dopamine release’). To our knowledge, three PET studies have examined sex differences in striatal dopamine release using the stimulant amphetamine as a challenge and [11C]raclopride or [18F]fallypride as D2/3 receptor radiotracers. One study using [11C]raclopride reported greater striatal dopamine release after intravenous amphetamine (0.3 mg/kg) in men than women  [18F]fallypride reported higher dopamine release in pallidum after oral ampethamine (0.43 mg/kg) in women than men  [18F]fallypride study did not observe consistent sex differences after oral amphetamine (0.43 mg/kg)  raclopride scans were performed on one of two scanners: a high-resolution research tomography (HRRT) scanner  or a Biograph PET/CT scanner . The methods for correcting differences between scanners are described in the PET analysis section below. Scans were conducted on two separate days: once 1 h after administration of an oral placebo pill (to assess baseline dopamine D2/3 receptor availability) and once 1 h after administration of 60 mg oral methylphenidate . All scans were conducted at the same time of day (1 PM) and in the same scanner for a given subject. Emission scans were started immediately after injection of 10 mCi (specific activity ≥500 mCi/µmol at end of bombardment). Twenty-two dynamic emission scans were obtained from time of injection up to 60 min after and arterial sampling was used to quantify total carbon-11 and unchanged [11C]raclopride in plasma. Dynamic emission scan images were evaluated before analyses to ensure that motion artifacts or misplacements were not included.Cohort A. [11C]raclopride scans were acquired on a Siemens HR + scanner and some of the data was reported previously for different study purposes [2/3 receptor availability) and once 2 min after 0.5 mg/kg intravenous methylphenidate . Details on this PET scanning protocol have been previously described [11C]raclopride in plasma. In addition, the dynamic emission scan images were evaluated before analyses to ensure that any motion artifacts or misplacements were not included.Cohort B. , p = 0.032). For full ANOVA results see Supplementary Table Differences in methylphenidate plasma levels did not drive the sex differences in dopamine release in NAc nor the subjective drug effects. The sex-by-time interaction was not significant: Cohort A: t = −2.387, p = 0.027), follicular stimulating hormone , and luteinizing hormone , as well as estimated cycle phase based on self-reported days since last menstruation  = 4.336, p = 0.047), all remained significant for sex differences in NAc dopamine release (Cohort A). Meanwhile, in all of these analyses, the effect of the sex hormone quantities and self-reported menstrual phase were not significant . Due to insufficient plasma sample volume for some participants, data on estradiol was only available for n = 17  participants, and we were thus insufficiently powered to do the same analysis with estradiol and the progresterone:estradiol ratio. However, the preliminary data suggests that these markers are also not strongly associated with methylphenidate-induced dopamine release in NAc. For visualization of individual datapoints showing the (lack of) association between all hormones and NAc dopamine release, see scatter plots in Supplementary Figure Likewise, differences in menstrual cycle phase did not appear to play a major role in the sex differences in dopamine release in NAc. Follow-up analyses that included the following additional covariates: plasma levels of progresterone  when challenged with methylphenidate whether it was given orally or intravenously whereas we found no differences in the dorsal striatum. These results provide evidence of sex differences in sensitivity of the dopamine reward system with females showing greater sensitivity than males. The replication of sex differences in dopamine release in NAc and of no sex differences in the dorsal striatum in two independent cohorts supports the robustness of the findings and indicate that the sex differences were specific for NAc.2/3 receptor availability fallypride [11C]raclopride and since these two radiotracers differ in their sensitivity to striatal and extra striatal dopamine this could have contributed to the differences across studies. More importantly, prior studies used amphetamine, whereas we used methylphenidate, and the differences in their mechanism of action could account for the discrepancies. Methylphenidate’s primary mechanism of action is to block dopamine transporters, whereas amphetamine directly releases dopamine from cell vescicles via deacidification into the synaptic cleft via reverse transport through dopamine transporters [18F]fallypride study that did not observe consistent sex differences included 39 females of whom 18 were on hormonal birth control, 10 were postmenopausal and 11 were studied during the luteal phase [11C]raclopride study that reported greater increases in males than females included 15 young women, six of whom were studied in the luteal phase and nine in the follicular phase raclopride we cannot determine where the location of the DA increases from methylphenidate occurred (synaptic or extrasynaptic) [Limitations. In Cohort A, PET data were collected on two different scanners, which could confound findings. However, there were no significant differences in participant demographics based on the scanner used; we used methods to correct for any average differences in scanners; and our primary findings were replicated in Cohort B, where all PET data were collected on the same scanner. In addition, our data were collected in a sample with a relatively wide age range (19–64), which could impact the findings since age is strongly associated with dopamine signaling , althougynaptic) .In summary, we showed that there are sex differences in methylphenidate-induced dopamine increases in NAc that might underlie the greater vulnerability of females to drug conditioning and to addiction. These findings also have implications for sex differences in other neuropsychiatric conditions associated with aberrant dopamine signaling in mesoaccumbens pathways, including ADHD and depression.Supplement


The realization of a semiconductor near-unity absorber in the infrared will provide new capabilities to transform applications in sensing, health, imaging, and quantum information science, especially where portability is required. Typically, commercially available portable single-photon detectors in the infrared are made from bulk semiconductors and have efficiencies well below unity. Here, we design a novel semiconductor nanowire metamaterial, and show that by carefully arranging an InGaAs nanowire array and by controlling their shape, we demonstrate near-unity absorption efficiency at room temperature. We experimentally show an average measured efficiency of 93% (simulated average efficiency of 97%) over an unprecedented wavelength range from 900 to 1500 nm. We further show that the near-unity absorption results from the collective response of the nanowire metamaterial, originating from both coupling into leaky resonant waveguide and transverse modes. These coupling mechanisms cause light to be absorbed directly from the top and indirectly as light scatters from one nanowire to neighbouring ones. This work leads to the possible development of a new generation of quantum detectors with unprecedented broadband near-unity absorption in the infrared, while operating near room temperature for a wider range of applications. A metaatom is considered the unit cell of a metamaterial, comprised of a single or many structures, whereby their unique arrangement leads to an optical response different from the individual structure. Their coordinated design and careful placement can lead to a near-unity absorber for a broader range of applications. It has been shown that the properties of propagating photons, such as polarization and refraction, through interaction with metamaterials can be exploited to create super-lenses, negative refraction, asymmetric transmission, and cloaking10. Early demonstrations of such metamaterial properties were achieved by exploiting plasmons  to control the interaction of light with the surface12. In this class of plasmonic metamaterials, the electric dipole response is controlled by the shape, size, and orientation of the metaatoms in the crystalline structure14. More recently, dielectric and semiconductor metamaterials were used to demonstrate light manipulation with lower losses than their plasmonic counterpart18. Indeed, the freedom to control the magnetic and electric field response in such structures leads to the realization of highly absorbing or transmissive metamaterials with unique qualities that are highly desired in sensing and imaging applications23.The field of optical metamaterials demonstrates promise because of the inherent advantages they exhibit over their bulk counterpart for enhanced absorption or realizing an exotic optical response, which originates from the specific arrangement and the collective interactions of the so-called metaatoms25. In this work, we overcome this narrow bandwidth limitation by designing a new semiconductor metamaterial made of indium gallium arsenide (InGaAs) nanowire metaatoms and precisely arranging them into an array. By optimizing the nanowire array geometry and shape, we design a near-unity absorber over an unprecedented wavelength range, from 400 to 1650 nm, with an average calculated absorptance of 92%. We fabricated the optimized metamaterial design and confirmed its infrared performance by Fourier-transform infrared (FTIR) spectroscopy. The metamaterial exhibited near-unity absorption over the wavelength range from 900 to 1500 nm, with a measured average absorption efficiency of 93% . We compare this measured absorption of the InGaAs nanowire metamaterial to bulk InGaAs of similar thickness and show that the absorptance is significantly enhanced by the nanowire shape and array geometry towards unity. This new class of semiconductor nanowire metamaterials meets the need for a near-unity absorber in the wavelength range where the quantum efficiencies of commercially available detectors are limited without the need for cryogenic cooling. The ability to realize a near-unity absorber in a semiconductor material over such a broad range of wavelengths is of particular interest for developing a next generation single-photon detector for a wider range of applications. Reaching impacts range from quantum technologies in imaging, sensing, communication and computing to biomedical applications such as dose monitoring for cancer treatment and imaging of the eye to identify potentially blinding diseases.Near-unity absorption in semiconductor metamaterials has been previously demonstrated by overlapping both electric- and magnetic-field components in the photonic nanostructure with Mie resonators and nanowires; however, this near-unity absorption efficiency could only be achieved over a narrow bandwidth in the range of tens of nanometers as reported in previous works28, the role of periodicity on achieving near-unity absorption has been largely unexplored until now. Figure 11 and EH11)27. Second, light can be indirectly absorbed by scattering from one nanowire to another one through excitation of transverse electric (TE) and transverse magnetic (TM) modes, thus, leading to further absorption. In this latter case, the leaky guided modes migrate towards the nanowire sidewall as they travel downwards. At the interface of the nanowire sidewall and the surrounding dielectric medium, the leaky modes decouple from the nanowire and subsequently emit into free-space. This emitted light then interacts with neighbouring nanowires within the array by coupling to both TE and TM modes. The strong interaction of the electric field between neighboring nanowires for metaatoms with diameter of 200 nm, periodicity of 833 nm and height of 1400 nm is illustrated in Fig. To design a broadband, near-unity absorber, we first investigate the role of periodicity on the absorption profile in cylindrical nanowires. Although high absorption in cylindrical nanowires has been previously investigated29. This eigenvalue equation supports the mechanisms of enhanced absorption in nanowire metamaterials as described previously and illustrated in Fig. The eigenvalue equation, which satisfies Maxwell’s equation for cylindrical boundary conditions, describes the angle dependence of the excited modes in the nanowires27. However, increasing the radius further results in multiple leaky modes to be supported. In this regime of large nanowire radius, multiple leaky modes overlap, and the spectral selectivity vanishes. Thus, the absorption profile broadens as a result. We note that for a larger nanowire radius (> 660 nm), the absorption profile is very similar to the bulk response of the same material. Although the spectral sensitivity in larger nanowire radii vanishes, the peak absorption efficiency of a single nanowire still remains far from unity.We further study the cylindrical nanowire case by analyzing the simulated absorptance of a single InGaAs metaatom as a function of its radius Fig. a. For naIn order to reach near-unity absorption efficiency we place the single nanowire in an array and optimize the periodicity. The role of the array periodicity on the absorption efficiency of a nanowire metamaterial has not yet been fully explored until now. Our analysis shows that the absorption efficiency of the cylindrical semiconductor nanowire metamaterial is directly linked to the array periodicity. The results of our analysis are summarized in Fig. To better understand the underlying mechanisms contributing to near-unity absorption in the nanowire metamaterial, we focus our attention on nanowires with dimensions: 200 nm diameter and 1400 nm height. A nanowire height of 1400 nm was selected since this was close to the smallest height where broadband near-unity absorptance was achieved  to coincide with the cylindrical nanowire radius that produced the highest resonant spectral response near the edge of the InGaAs bandgap (1650 nm). The bottom radius of the tapered nanowire was increased in size until the absorption was enhanced over a broad spectral range see Fig. a,b. The Next, the optimal nanowire metaatom from Fig. In Fig. Next, we fabricate the nanowire metamaterial absorber with dimensions as close as possible to the optimized structure using an InGaAs film (2250 nm thickness) grown by molecular beam epitaxy on an (100) InP substrate. We utilized a multistep nanofabrication process to realize a 100 μm × 100 μm metamaterial comprised of a tapered InGaAs nanowire array. See Supplementary Note A scanning electron micrograph of the fabricated optimized nanowire metatoms is shown in the inset of Fig. We now bring attention to the measured broadband near-unity absorption, as shown in Fig. To demonstrate the enhanced absorption in tapered nanowire metamaterials we compared it to an unprocessed bulk InGaAs film with a thickness of 2250 nm. The measured bulk InGaAs film absorptance is shown as a function of wavelength in Fig. We studied the theoretical mechanisms that govern the enhanced absorption in nanowire metamaterials, with emphasis in the infrared. We identified two prominent mechanisms that contribute to near-unity absorption in nanowire metamaterials. These include the free-space coupling of photons into the nanowires which excite leaky guided modes, followed by the strong interaction between neighbouring nanowires which excite transverse modes. We subsequently showed the importance of nanowire periodicity on achieving the maximum absorption efficiency of the metamaterial by manipulating the interaction between neighbouring nanowires. We optimized for near-unity absorption in cylindrical and tapered nanowire metamaterials, demonstrating a systematic approach to achieve narrowband and broadband characteristics. Furthermore, we fabricated a tapered InGaAs nanowire metamaterial with dimensions similar to the optimized structure. With this optimized structure, we experimentally demonstrated the near-unity absorption efficiency over an unprecedented wavelength range from 900 to 1500 nm, with an average efficiency of 93%. Although we demonstrated near-unity broadband absorption of the nanowire metamaterial in the near-infrared region, our approach is not limited to only InGaAs. The nanowire metamaterial can be tailored to achieve enhanced absorption in the mid-infrared and other spectral regions through the incorporation of appropriate semiconductor materials. Realizing this approach to achieve near-unity absorption efficiency over such a broad bandwidth for the first time will play a major role in the discovery of a new generation of photodetectors targeting a wider range of applications from biomedical to quantum information.Supplementary Information.


The strong coupling of molecules with surface plasmons results in hybrid states which are part molecule, part surface-bound light. Since molecular resonances may acquire the spatial coherence of plasmons, which have mm-scale propagation lengths, strong-coupling with molecular resonances potentially enables long-range molecular energy transfer. Gratings are often used to couple incident light to surface plasmons, by scattering the otherwise non-radiative surface plasmon inside the light-line. We calculate the dispersion relation for surface plasmons strongly coupled to molecular resonances when grating scattering is involved. By treating the molecules as independent oscillators rather than the more typically considered single collective dipole, we find the full multi-band dispersion relation. This approach offers a natural way to include the dark states in the dispersion. We demonstrate that for a molecular resonance tuned near the crossing point of forward and backward grating-scattered plasmon modes, the interaction between plasmons and molecules gives a five-band dispersion relation, including a bright state not captured in calculations using a single collective dipole. We also show that the role of the grating in breaking the translational invariance of the system appears in the position-dependent coupling between the molecules and the surface plasmon. The presence of the grating is thus not only important for the experimental observation of molecule-surface-plasmon coupling, but also provides an additional design parameter that tunes the system. Multiple recent reviews and perspectives exist on this emerging topic, see for example , 2. An aX + N model, where X is the number of photonic modes and N is the number of molecules. We first provide a reference point by employing our approach to a more familiar strong coupling system – molecules coupled to the cavity mode of a planar optical microcavity. We then discuss molecules coupled to a surface plasmon, then introduce the grating. We find the (X + N) × (X + N) Hamiltonian and corresponding dispersion relation of each system, and demonstrate that for molecules coupling to SPs on a grating, the spatial distribution of the molecules relative to the grating provides an additional control feature with which to tune the system. We contrast our results to those found by modelling the molecules via a single collective dipole mode (i.e. a X + 1 model) and rigorous coupled wave analysis (RCWA), and demonstrate that the X + N model is necessary to capture the full character of the system.Here, we make use of a microscopic quantum electrodynamics (QED) model to analyse in detail the strong coupling interaction between molecular resonances and surface plasmons in the presence of a periodically modulated (grating) surface. Throughout we use the full 2i with transition energy ℏωmol can be described in the low-excitation regime  that lies within the frequency range of interest. The excitation of molecule gime see  by a FocN uncoupled molecules (i.e. assuming no interactions between molecules) is given by,d and area A, of dielectric constant ɛ2, with the ith molecule positioned at . The molecules are randomly spaced with density N/V, where V = Ad. We place the slab containing the molecules in a cavity comprised of two mirrors  is given by,ith term we can rewrite kx(x − xi) ≪ 1, πz/Lcav) ≈ cos(πzi/Lcav). The interaction strength varies with the z position, as has been demonstrated experimentally [x position of the molecules does not.The Hamiltonian of mentally . This inkx-dependent Hamiltonian of the system is given byN molecules, N, which is a sensible assumption in most experimental situations. Representing the molecules as a single effective dipole is an elegant way to study the two polaritons expected in the system, however it misses out the remaining molecular dark states. In a cavity system this is not of great importance as the dark states are typically not seen owing to the high impedance mismatch that prevents much light entering the cavity around the resonance frequency [N individual molecular modes so as to accurately capture the multi-band features of the resulting system. However, to avoid unduly long computation times associated with diagonalising our X + N Hamiltonian we choose a value of A such that we can obtain molecular densities commensurate with typical experimental results. While N should be small enough to give a short calculation time, it must also be large enough to yield the expected bulk response, which is particularly important if the molecules are taken to have random spatial distribution. N should be larger than the number of distinct bands in the system, and values of N ≈ 100 qualitatively gives the bulk result, given randomly distributed molecules. Larger values of N can be taken to fully converge to the bulk system. We can write the Hamiltonian in matrix form as,H(kx) is a (1 + N) × (1 + N) matrix,We may write the transition dipole matrix element asnt(kx)=ℏωcav. The transition matrix dipole moment is oriented along the bond, and the resonance of this excitation occurs at H(kx), we find the dispersion relation of the coupled system. y direction, such that φi = ϑi = π/2. We see an avoided crossing at the resonance frequency, with the gap between the upper and lower hybrid modes gi is the interaction strength of the ith molecule at the crossing point of the two dispersion relations. The polariton modes demonstrate a mixing of photonic and molecular character, as shown by their colour projection (where green gives the projection of the hybrid state onto the unperturbed cavity mode and black gives the projection onto the molecular mode). In total, there are three distinct modes – two polariton modes and N − 1 degenerate molecular modes; modes that have not taken on any photonic properties. The interaction strength of each molecule can be tuned through the orientation of its transition dipole, with the maximal value for orientation along the y axis, and complete decoupling when oriented along the x-axis, i.e. when φi = ϑi = 0, as illustrated in z = 0. kx dependence of the interaction strength. kx enters the interaction strength via both the field strength (as mode frequency is kx-dependent), and also through a phase term. In practice, this dependence is often neglected, particularly in systems with losses, as it is the relative strengths of terms in the Hamiltonian which will dominate the characteristics of the system. In d = 2.26 μm, from which we see the dependence of the gap on the density of molecules.Diagonalising Having established our approach in the context of strong coupling for molecules within a planar cavity, in 31Strictly they are surface plasmon-polaritons . are highly confined electromagnetic modes which propagate at dielectric/metal interfaces. It is the negative permittivity of the metal  that enables this behaviour. For an SP launched in the x direction on a metallic slab  it cannot be experimentally observed without using one of a variety of experimental tricks to overcome this momentum mismatch. This will be discussed further in the next section.Surface plasmons (SPs)slab see , the SP z > 0 iskz is purely imaginary and ∼1/2Lz, where Lz is the penetration depth of the electric field into the dielectric. We consider a sample with dimensions smaller than the propagation length of the SPs in order to neglect the decaying amplitude of the SP in the direction of propagation. kx. The Hamiltonian matrix is given byAs only p-polarised light may excite an SP mode, and constrained by the boundary conditions at the interface, the electric field of the SP for N molecular modes, and the result is two hybrid modes and N − 1 unperturbed molecular modes. As in the previous case, the spatial distribution of the molecules in the z direction causes a reduction in the collective coupling strength. Spatial distribution in the x direction has no effect on the dispersion relation.Diagonalising this Hamiltonian, we find the dispersion relation. As for the planar cavity above, we assume a molecular orientation aligned with the maximal direction of the electric field. The uncoupled system is given in As the strong coupling described in this section occurs beyond the light line, it cannot be experimentally probed without the introduction of a tool such as a prism or grating. The addition of a grating is expected to alter the molecule–light interaction. This is what we explore in the next section, which encompasses the main results of this work.4The introduction of a grating to the system perturbs the plasmon dispersion relation inside the light-line. This adds some subtleties to the theoretical model, which we now discuss.x direction illustrated in kx → kx ± a2π/Λ, where Λ is the period of the grating, and a = 0, 1, 2, … The SP dispersion now presents multiple branches, parts of which will now have been shifted inside the light line. In ωmol (see q = 2π/Λ. We label the two solutions of ωSP corresponding to a = ±1 as ω∓. This labelling convention is chosen so that ω+(kx) > ω−(kx) for kx > 0. Coherent superpositions of the (±1) scattered SPs may take different spatial positions with relation to the peaks and troughs of the grating [ℏD(kx) away from the unperturbed frequency, where the analytical expression for D(kx) is given by [s = qh, k0 = ω0/c. This results in a total energy gap of 2ℏD(kx). For a grating with period Λ = 4.0 μm and h = 0.1 μm, ℏD(kx) ≈ 1.2 meV at kx = 0. This small splitting can be seen in A periodic structure at the dielectric/metal interface on the order of the photonic wavelength D(a = ±1) grating-scattered branches are of the modified form z > 0)ω+(kx) and ω−(kx) SPs, respectively. The interaction Hamiltonian of the coupled system is given by,The presence of the grating enforces a periodic boundary condition on the electric field of the SP, such that the plane wave expansions of the first-order (N) × (2 + N) matrix form,The Hamiltonian can be written in  we see five distinguishable bands, as in N − 2 dark molecular bands. D, g+, g− ≠ 0, which is very similar to Repeating the same procedure of the previous sections, we find the dispersion relation by diagonalising the Hamiltonian for an explicit example. We use a slab of PMMA of thickness xi = aiΛ + biS, where ai = 0, 1, 2…, 0 ≤ bi ≤ 1, and 0 ≤ S ≤ Λ. S parameterises how molecules are localised in each grating period. For S = Λ the molecules are found everywhere, while for S → 0 the molecules are concentrated in a small fraction of each grating period  to recover the approximate eigenvalues for the system of homogeneously distributed molecules on a grating. The variation in band positions as S is varied suggests that there are optimal ways in which one can choose the spatial distribution of the molecules with respect to the grating profile, in order to tune the band separation [To see the five-band dispersion relation, the molecular distribution and SPs must extend across the full grating profile. The spatial position of each molecule can be defined as g period . In Figuparation . For sysX + N model in which X photonic modes and N molecular resonances are individually included in the Hamiltonian, versus the results of a X + 1 model in which the molecules are treated via their collective behaviour as the collective coupling strength ϵ2 = 1.99, ω0 = 3.28 × 1014 rad s−1, γ = 2, 45 × 1012 rad s−1 and A = 0.0165 [N molecular modes are treated here via their collective mode. In the case of the cavity X + N model, but the dark modes are absent. In the case of the plasmon on a slab X + 1 model is thus a good description of what is seen in cavity experiments. For 2 of thickness 30 μm. We have plotted the imaginary component of the reflection in order to observe physics below the light line. The dark states can clearly be seen in the dispersion relation, and so the X + N model gives a more complete description of the system. In 2 of depth 30 μm, and the PMMA on top of the grating has thickness 0.9 μm. The X + N model gives good agreement, although the analytical result found for grating period Λ = 4.0 μm best fits to the calculated system with grating period of Λ = 4.7 μm, owing to the simplified description of the grating used in the analytical model.The final point of this paper is to compare the results of a is (RCWA ). For th= 0.0165 . The simTo see clearly what is happening in this system, we have assumed SPs exist only on one side of the grating. However, for a sufficiently thin metal film, we would expect coupled SPs on both the top and bottom of the grating, resulting in a more complex dispersion diagram and optical spectra of the system. We would expect to see additional plasmonic modes in the dispersion relation, which would couple to the molecular mode and result in an increase in the total number of polariton modes. This, as well as additional interesting and important features such as non-zero linewidths, molecular interactions and inhomogeneous broadening could all be added to the simple model, we have presented here. While molecular interactions would not be expected to significantly modify the dispersion relation, very strong dipole–dipole interactions would result in a lifting of degeneracy of the molecular band . SimilarX + N) × (X + N) representation of the Hamiltonian matrix. For large values of the molecular dipole moment  or particularly large mode volumes, the system moves into the intermediate strong coupling regime, and a (2XN) × (2XN) model2N + 1 versus 2N, where N is the number of photonic modes, coupled to a single molecular mode. The current work uses different notation, i.e. X photonic modes and N molecular modes.The two models are usually referred to as  is required to accurately reproduce the dispersion relation [The grating in this work has been treated as a simple periodic boundary condition on the plasmon electric field. While this approach gives good agreement with numerical simulations, the specific form of the grating profile will have an effect on plasmon-molecule coupling and should eventually be taken into account. The tuning of the electric near-field profile will provide an additional tool for controlling plasmon–molecule interactions. The work presented in this paper uses a  × (2 + N) Hamiltonian 29 of the system, with spatial- and grating-dependence, which when diagonalised gives a five-band dispersion relation. Of these five distinguishable bands, four bands are bright states and N − 2 are dark, collective molecular states. For a single electromagnetic mode coupled to molecules, we expect to see three distinct bands. For two electromagnetic modes coupling to molecules, we expect to see four distinct bands, and the breaking of translational invariance with the addition of a grating adds a fifth band. While it is already known that changing the grating period will change the dispersion relation of the system, by calculating the Hamiltonian of the system from a first principles approach using the full 2 + N system, we can calculate the full (2 + N)-band dispersion relation and also demonstrate the importance of the spatial distribution of the molecules. We show that an X + 1 model does not qualitatively or quantitatively describe the features of this system, as compared to RCWA simulations, as the full basis of states is required. With ever improving techniques to control the orientation and placement of molecules on surface, the spatial distribution of the molecules may be an additional tool in engineering the bands of molecule-light hybrid systems.In this work, we have developed the theoretical model of molecules interacting with surface plasmons in the presence of a grating. The main result of this work is the (2 + Data access statement: The research data supporting this publication are openly available from ORE at: https://doi.org/10.24378/exe.4105.Supplementary Material DetailsClick here for additional data file.


KMT2D and KDM6A. This review assesses our current understanding of KS, which was originally named Niikawa–Kuroki syndrome, and aims to guide surveillance and medical care of affected individuals as well as identify gaps in knowledge and unmet patient needs. Ovid MEDLINE and EMBASE databases were searched from 1981 to 2021 to identify reports related to genotype and systems-based phenotype characterization of KS. A total of 2418 articles were retrieved, and 152 were included in this review, representing a total of 1369 individuals with KS. Genotype, phenotype, and the developmental and behavioral profile of KS are reviewed. There is a continuous clinical phenotype spectrum associated with KS with notable variability between affected individuals and an emerging genotype–phenotype correlation. The observed clinical variability may be attributable to differences in genotypes and/or unknown genetic and epigenetic factors. Clinical management is symptom oriented, fragmented, and lacks established clinical care standards. Additional research should focus on enhancing understanding of the burden of illness, the impact on quality of life, the adult phenotype, life expectancy and development of standard-of-care guidelines.Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including  Kabuki syndrome (KS) (Niikawa–Kuroki syndrome) is a rare, congenital disorder that was first recognized as a distinct entity by two independent groups of clinicians in 1981 . KS has We now recognize that the clinical phenotype of KS follows a highly variable and continuous spectrum that additionally includes cardiac, renal, genitourinary and/or inner ear structural defects, dental anomalies, developmental delays, hypotonia, feeding difficulties, hearing loss, as well as involvement of the immune, neurologic, ophthalmologic, gastrointestinal, and endocrine systems ,5,7. AspUpdated international consensus diagnostic criteria were recently published . HistoriKMT2D are associated with autosomal dominant KS type 1  whereas heterozygous or hemizygous variants in KDM6A are associated with X-linked dominant KS type 2 .The identification of the molecular basis of KS ,10 allowKMT2D, whereas a much smaller number (6–10%) harbor pathogenic variants in the coding regions of KDM6A [RAP1A/RAP1B, HNRNPK and ZMZ1 [The vast majority of individuals (>80%) with a clinical diagnosis of KS harbor pathogenic variants in the coding regions of number 6–% harbor of KDM6A ,12,13. Pand ZMZ1 ,15,16. LKMT2D and KDM6A are, de novo, either associated with loss-of-function  resulting in haploinsufficiency or with missense variants, which may pose a challenge for variant classification [KMT2D present with a unique clinical phenotype that includes choanal atresia, athelia, thyroid abnormalities, abnormal pubertal development, and short stature [KMT2D variants may also be associated with isolated alobar holoprosencephaly [The majority of pathogenic variants in both fication ,10. Mosafication ,23,24,25 stature ,27. KMT2ncephaly ,29KMT2D encodes a lysine-specific methyltransferase, responsible for post-translational histone 3 lysine 4 (H3K4) mono-, di- and tri-methylation, which is exclusively associated with actively transcribed genes [KDM6A encodes an X-linked H3K27 demethylase that removes repressive epigenetic marks and interacts with KMT2D in regulating gene expression in the activating signal cointegrator-2 -containing complex (ASCOM) complex [ed genes . KDM6A e complex . TranscrThis review aims to appraise our current knowledge of Kabuki syndrome with specific attention to clinical presentation and associated genotypes to identify gaps in knowledge and unmet patient needs.A literature search was conducted using EMBASE and Ovid MEDLINE databases by two independent individuals (KB and MT). Search terms and inclusion and exclusion criteria are detailed in A total of 2418 citations matching the search terms were identified . After removal of duplicates and evaluation of abstracts for exclusion and inclusion criteria , 152 citA total of 1369 individuals with KS were identified in the published literature. When gender was reported (n = 582), 43% were male, and 57% were female. The average age at the time of publication was 9.97 years . Reported ethnicity (n = 475) was as follows: Scandinavian (18%), US-American (14%), British (14%), Italian (10%), Chinese (8%), Brazilian (5%), Korean (4%), Australian (4%), Turkish (4%), French (3%), German (3%), Japanese (3%), Canadian (2%), Czech (2%), Thai (2%), Welch (1%). Case reports from Taiwan, Spain, Ireland, Palestine, Iran, Morocco, Egypt, Columbia, and Ecuador were also identified.KMT2D were identified. The remaining 195 individuals carried a clinical diagnosis of KS without molecular confirmation. The majority of KMT2D variants were truncating (nonsense: n = 241 or frameshift: n = 137), followed by missense (n = 163), small deletions (n = 95), and splice site variants (n = 66). When recorded (n = 718), the relative frequency of variants correlated with the size of the exon and was the highest for exons 39 (20% of variants), 48 (15%), 31 (11%), 34 (7%), 11 (5%), and 10 (5%) of KMT2D. Five mosaic KMT2D cases were identified with reported levels of mosaicism of 68%, 40%, 32% and 37% in blood [A total of 1174 individuals with pathogenic or likely pathogenic variants in in blood . One stuKDM6A were identified. When described (n = 56), the majority of KDM6A variants were truncating , followed by splice site (n = 11), missense (n = 10), large deletions (n = 3), small insertions (n = 3), indel (n = 2), and small deletions (n = 2). In a recent study which evaluated 61 pathogenic KDM6A variants in patients with KS type 2, truncating variants were distributed across the entire gene whereas missense variants were primarily clustered in the TRP2, TRP3, TRP 7, and Jmj-C domains [KDM6A case was identified; the level of mosaicism was not reported [A total of 89 individuals with pathogenic or likely pathogenic variants in  domains . One mosreported KDM6A variants  and 5 inherited KMT2D variants  [In total, 19 cases of inherited pathogenic variants from affected parents were identified including 14 inherited herited) ,23,25,32herited) ,34,35,36herited) ,21. In therited) . Prenataherited) . In famiThe cardinal facial features associated with KS include long palpebral fissures; eversion of the lateral third of the lower eyelid; arched and broad eyebrows with a sparse lateral third; a broad/depressed nasal tip with short columella; and large, prominent, or cupped ears . DysmorpThe reported frequency of congenital heart defects in KS varies, ranging between 28 and 80%; most are diagnosed prenatally or at an early age ,39 and pImmune deficiency and autoimmune disorders manifest in 60–73% of KS patients. Hypogammaglobulinemia occurs in up to 58% and IgA deficiency in up to 80% ,48,49,50Autoimmune disorders typically manifest in late childhood between 4 and 13 years . The mosRare cases of premature death have been reported in severely immunologically impaired patients ,52,58,65Congenital central nervous system malformations and functional neurological abnormalities are common. Muscular hypotonia is highly prevalent (51–98%) and may lead to long-term sequelae including developmental delays and oromotor dysfunction . EmerginStructural central nervous system anomalies may have an ethnic association; most cases of cortical dysplasia were reported in Caucasian individuals, although reporting biases cannot be excluded . The repKMT2D are frequently implicated in tumorigenesis and depending on the biologic context, this methyltransferase may exert either tumor suppressive or promoting functions [KMT2D may be at an increased risk for developing cancer due to somatic second hit mutations [The incidence of cancer and whether individuals with KS have an increased predisposition for malignancy is unknown. Somatic mutations in the histone methyltransferase unctions ,81. It hutations ; neuroblutations ; low-grautations ; synoviautations ; aggressutations ; hepatocutations ; giant cutations ; spinal utations . Hematolutations ; acute lutations ; Burkittutations ,92. Notautations ,94. Piloutations ,96.KDM6A increased the release of insulin from pancreatic islet cells in murine models [Endocrine dysfunction is common in KS. Postnatal growth restriction occurs in 35–85% of individuals and is far more common than growth hormone deficiency ,98,99. Re models .Two cases of isolated central diabetes insipidus (DI) are described in the literature ,103. AltIn KS, the risk for diabetes mellitus type II may be as high as 20% in early adulthood . In suchIn total, 30–40% of individuals with KS have a genitourinary anomaly . Both reOcular abnormalities occur in 38–72% of KS patients ,114. In Feeding difficulty and reflux are highly prevalent in KS , but conThere is a paucity of information regarding fertility and reproductive health pertaining to KS. Familial transmission of KS both to and from affected males and females has been reported ,21,22,37There is a paucity of data concerning prenatal and perinatal complications of KS. One study reported abnormal second and third trimester ultrasounds and quad screens in 69% and 44% of cases, respectively . PolyhydPostnatal growth restriction (60–83%) and short stature (31–81%) ,97 are cThe natural history of KS is poorly characterized. In one Japanese study, childhood height ranged from −2.1 to −5 SD below the mean for healthy controls; 27% of children had height within the normal range; none were greater than +0.5 SD above the mean . KS1-speInterestingly, up to 50% of individuals with KS will become overweight or obese in late childhood or adolescence ,97,127. Developmental milestones are often delayed in children with KS. Cognitive impairment, hypotonia, skeletal anomalies, congenital heart defects, hearing loss, and gastrointestinal anomalies can cause delays in speech and language development, feeding and swallowing, walking, sitting upright, and toilet training ,132,133.In one study, the average age of acquisition of developmental milestones was as follows : sittingLanguage acquisition varies in KS ,135. AltKDM6A is similarly associated with more severe psychomotor developmental delays [KDM6A versus protein-altering variants may also display more severe intellectual disability [No clear pattern of psychomotor development has emerged, and data are limited to sporadic case reports ,138,139;l delays . In KS2,l delays . Patientsability .Intellectual disability (ID) is one of the cardinal features of KS, presenting in up to 90% of cases ,99. ID iSevere ID is rare and only described in a few cases ,76,146. A variable pattern of oromotor, speech, and language deficits reflects neurologic, orofacial, structural, hearing, and cognitive impairment.Receptive and expressive language delays present across multiple language sub-domains  ,119; howSome studies report improvements in speech, language, and oromotor function with age; however, others conclude the opposite, noting worsening language impairment over time ,152. RegAutistic-like behavior, hyperactivity, inattention, impulsivity, self-mutilation, sleep disturbances, multiple phobias, emotional dysregulation, impairment of adaptive skills, difficulty with communication and peer interactions, poor eye contact, and anxiety disorders are among the diverse behavioral phenotypes associated with KS ,154,155.Severe behavioral phenotypes  are rare, occurring only in patients with severe cognitive deficits . ChildreMore consistently, children with KS are socially outgoing, talkative, and affectionate, with good socialization skills and affable nature ,130. A sKMT2D and KDM6A in transcriptional regulation, growth, and development. Current literature lacks consistent clinical characterization of KS, posing challenges in drawing meaningful genotype–phenotype correlations. Limited long-term follow-up similarly restricts our understanding of the natural history of the disease. Unfortunately, clinical management is fragmented and remains largely symptom oriented.A broad and continuous spectrum of clinical phenotypes is associated with KS, with notable variability between affected individuals. Advancements in genetic sequencing improve our understanding of this disease and elucidate the role of This review holistically examines KS and details the natural history as described in current literature to guide the surveillance and expectant management of KS . Clinici


Living anionic polymerization enabled the synthesis of narrowly dispersed terpolymers with low average molecular weights and different composition ratios, as verified by multiple molecular characterization techniques. To evaluate their self-assembly behavior, transmission electron microscopy and small-angle X-ray scattering experiments were conducted, indicating the effect of asymmetric compositions and interactions as well as inversed segment sequence on the adopted morphologies. Furthermore, post-polymerization chemical modification reactions such as hydroboration and oxidation were carried out on the extremely low molecular weight PB1,2 in all three terpolymer samples. To justify the successful incorporation of –OH groups in the polydiene segments and the preparation of polymeric brushes, various molecular, thermal, and surface analysis measurements were carried out. The synthesis and chemical modification reactions on such triblock terpolymers are performed for the first time to the best of our knowledge and constitute a promising route to design polymers for nanotechnology applications.We report the synthesis of three (3) linear triblock terpolymers, two (2) of the ABC type and one (1) of the BAC type, where A, B and C correspond to three chemically incompatible blocks such as polystyrene (PS), poly(butadiene) of exclusively (~100% vinyl-type) -1,2 microstructure (PB The ability of polymers to self-assemble in bulk or thin films using solvents with different selectivity enables the formation of various well-defined morphologies at the nanoscale. This fundamental characteristic is of major importance, leading to their possible utilization in nano-lithographic applications as reported in the literature ,2,3. χAB, χBC, χBA) , termination agent [methanol (98%)], 1,2-dipiperidinoethane [dipip (98%)], and initiator [secondary-BuLi ] are documented elsewhere , monomers  for selective staining of the poly(butadiene) segment in order to increase the electron density through crosslinking and to improve the image contrast between PB, PS and PDMS segments.The specifics regarding TEM and SAXS measurements are provided elsewhere . The trib-PB1,2-b-PDMS and PB1,2-b-PS-b-PDMS sequences. All samples exhibited narrow dispersity indices, justifying the high standards of the living polymerization. The SEC chromatographs are presented in the 1,2 and intermediate diblock precursors are also given. The molecular characteristics of all blocks for the 3 triblock terpolymer samples were determined through VPO, and the results are summarized in Anionic polymerization enabled the synthesis of novel triblock terpolymers of the PS-1H-NMR spectra, the mass fractions of the three different segments were calculated and are also given in 1H-NMR, as indicated by the absence of any proton chemical shifts at 5.30 ppm. The complete absence of the two olefinic protons strongly suggests the successful synthesis of pure vinyl elastomers due to the use of 1,2-dipiperidinoethane, which is well elaborated in the literature [Through the characteristic chemical shifts evident from the terature . From thgs) of approximately −121 °C and 65 °C were recorded, corresponding exclusively to PDMS and PS blocks, respectively. The 1,2 in almost all cases were lower than or very close (sample 1) to the entanglement molecular weight (Me ~3.8 kg/mol) [g of the PS block is extensively analyzed in the literature [A DSC analysis was carried out to study the thermal behavior of the terpolymers. The thermographs are shown in the  kg/mol) , justifyterature ,42.4 stained samples for approximately 30 min [1,2 formed two-phase morphologies as expected [The as-cast OsOy 30 min  were morexpected . Complemχ values based on fundamental equations from literature are provided in our previous works [The interaction parameters between the different components have been theoretically calculated at room temperature and are presented in us works ,41. The 1,2 and increased molecular weight of the PDMS block were chosen. This strategy was followed to clarify the effect of the larger elastomeric end block on the overall morphology. The desired composition ratio for the individual segments was approximately 2/2/5, as evident in 1,2 and the gray areas to the PDMS segments. The dark color of the PB1,2 is attributed to the OsO4 staining. One could easily observe the molecular weight influence on the sheet thickness. Specifically, the dimensional approximation for the first three lamellar sheets (black/white/black) is attributed to the identical molecular weights between the two olefinic segments. The enhanced thickness of grey areas is induced by the almost doubled molecular weight of the PDMS block. The PDMS blocks due to the high incompatibility with the PS segments probably dictate the stretching of the PB1,2 blocks. The SAXS results further support the existence of lamellar morphology. The characteristic peak ratio of 1:2:3:4 is evident in In this triblock terpolymer similar b-PB1,4-b-PDMS sequence with approximate molecular characteristics and composition ratio. Even though the molecular weight of the blocks is quite low, especially for the intermediate elastomeric block, the system formed the structure that requires the lowest free energy. In 1,2 due to the enhanced electron density induced after staining, the white to the PS, and the grey to the PDMS. One would expect a different morphology to be derived from the asymmetric compositions, but the asymmetric interactions (χPS/PB≠χPB/PDMS≠χPS/PDMS) have a dominant role in the formation of a less frustrated structure [χ terpolymers results in different structures due to the three possible pairs of interactions.Taking into consideration the mass fraction ratio presented in tructure ,46. The 1,2/PS due to the low 1,2/PS and PDMS. Strikingly, real-space imaging and scattering results revealed the formation of a network phase where the PS corresponds to the matrix and PB1,2 and PDMS constitute the two independent networks  induced packing frustration that allowed the formation of the cubic network phase. The results were supported by the SAXS pattern, as can be clearly identified in q region, meaning √2, as can be observed in the relative SAXS pattern, is attributed to the distortion or deformation of the lattice [It is well established that the ability to manipulate the block sequences in triblock terpolymers provides different nanostructures ,46. Thisnetworks a. We spe lattice . The dom1,2 was kept extremely low in all terpolymers to facilitate the physical adsorption of a very thin layer on the surface of the preferred solid substrate after the chemical modification increased its binding capacity. It would therefore be used as a polymeric brush on a corresponding surface. The chemical modification reactions were exclusively performed on the PB1,2 segment of each triblock terpolymer. Note that the molecular characteristics of the PS and PDMS blocks remained unchanged while the introduction of the –OH group after the modification reactions (-CH2-CH2-OH instead of -CH=CH2 per monomeric unit) induced an alternation on the mass fraction ratios. This alternation on the molecular characteristics is attributed to the enhanced molecular weight of the modified polybutadiene monomeric unit for the different terpolymers. The results concerning the molecular characteristics of the modified samples are summarized in As evident from 1H-NMR , and one can clearly observe the differentiation between the two spectra where the different vibrations are illustrated for better understanding.The molecular characterization through OH group . IR expe spectra  presente1,2 were significant low , poly(butadiene) of exclusively (~100%) -1,2 microstructure (B) and poly(dimethylsiloxane) (C) were synthesized with anionic polymerization. The total average molecular weights were kept low to achieve as small dimensions as possible by adopting different microstructures due to the diverse composition ratios. The self-assembly behavior indicated the impact of asymmetric compositions, different interactions between the adjacent blocks, and segment sequence on the formed structures. Post-polymerization chemical modification reactions such as hydroboration and oxidation were conducted on the PB


Cutibacterium modestum was named in 2020. C. modestum was previously called Propionibacterium humerusii. Several implant-associated infections caused by Cutibacterium species have been previously reported, but native vertebral osteomyelitis due to these bacteria has rarely been reported.C. modestum by 16SrRNA gene sequencing. A diagnosis of vertebral osteomyelitis caused by C. modestum was made. Minocycline followed by oral amoxicillin was administered for 3 months. His symptom improved and did not recur after treatment completion.A 72-year-old man, who had previously received several nerve block injections for low back pain, was referred to our hospital for deterioration in back pain in the last 1 month. MRI findings were suggestive of L5-S1 vertebral osteomyelitis. Blood cultures and bone biopsy culture revealed the presence of Gram-positive bacilli. The isolate was identified as C. modestum was encountered. Although C. modestum is very similar to C. acnes, it could be accurately identified by 16SrRNA gene sequencing. This case represents the first documented C. modestum infection in humans.A case of vertebral osteomyelitis caused by  Cutibacterium was previously called Propionibacterium. Cutibacterium is a Gram-positive anaerobic bacterium that is a significant component of the human skin microbiota. A new species of Propionibacterium was reported in 2011 and named Propionibacterium humerusii [Cutibacterium modestum. Here, we report the first documented C. modestum infection not associated with implant or direct medical procedure.The genus A 72-year-old Japanese man was referred to our hospital for treatment of vertebral osteomyelitis. He had been followed by his primary care physician for lumber spinal canal stenosis and type 2 diabetes mellitus. He had received several nerve block injections for his low back pain. One month prior to admission the patient’s low back pain worsened when he visited his family physician. Magnetic resonance imaging (MRI) was performed, and findings were suggestive of L5-S1 vertebral osteomyelitis  semi-solid medium  of the biopsy culture. And Gram-positive bacilli from blood culture was also grown on the same medium. Non-hemolytic small colonies were observed on the Brucella HK agar from blood culture after 48 h of incubation under anaerobic conditions  for the 16S rRNA gene sequencing was performed using the taxonomy browser of the National Center for Biotechnology Information. The sequence result showed 100% similarity (1366/1366 bp) with a strain of Propionibacterium humerusii P08 (accession No. AFAM00000000.1); therefore, the isolate was identified as P. humerusii (C. modestum).To further characterize and identify the isolated organism, 16SrRNA gene sequencing using universal primers was performed as previously reported . A BasicC. acnes and Gram-positive anaerobes, we switched the antibiotics to oral amoxicillin. Hospitalist consulted to physical medicine and rehabilitation team. Patient was transferred to another hospital and continue physical therapy and rehabilitation. We continued amoxicillin for 3 months. The patient’s symptoms improved and did not recur 2 years after treatment completion.Prior to the precise identification of this organism with BLAST, the minimum inhibitory concentration of antibiotics was assessed with a broth microdilution method using Brucella broth (Eiken Co.) under anaerobic conditions Table . AccordiCutibacterium modestum was previously described as “Propionibacterium humerusii.” The DNA sequence of C. modestum is 89% similar to that of C. acnes [Cutibacterium modestum” in 2020 [C. acnes . PreviouC. acnes , 4. This in 2020 .C. acnes. However, the predominant peaks on mass spectrometry of C. modestum are different compared with those of C. acnes and its subspecies [C. acnes. However, the log score 1.62 of this species was not adequate to accurately identify the bacteria on either the species or genus level. In addition, the biochemical qualities of this isolate, in particular glycine arylamidase and indole levels, were not consisting with those of C. acnes and other Cutibacterim species [C. modestum from other Cutibacterium species.MALDI-TOF MS is widely used for bacterial identification and allows for the relatively easy and quick identification of microorganisms, including bspecies . MALDI-T species . We therPropionibacterium humerusii in 2011 and its new name C. modestum, no literature has reported a clinical C. modestum infection in humans. We were able to successfully treat this patient using antibiotics alone in accordance with the EUCAST breakpoint for C. acnes and Gram-positive anaerobes [C. modestum is required to answer this question.Since the description of naerobes . HoweverC. modestum infection was reported [C. acnes infections have been previously reported [Recently, an implant-associated reported . Our casreported , 11, as Growth of Cutibacterium species depends on the bacterial inoculum size. It took 7 days for blood culture growth in our case. This suggests low inoculum of bacteremia in this case. When Cutibacterium species is considered as causative pathogen, prolonged blood culture incubation might be feasible.C. modestum. C. modestum is very similar to C. acnes, and may be misidentified as C. acnes. The biochemical characteristics and inadequate results of MALDI-TOF were very important for distinguishing this bacterium from other Cutibacterium species. Further microbiological and clinical investigations are required to better describe the management of C. modestum infections.In conclusion, we reported the native vertebral osteomyelitis due to