Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify. We describe KS clinical presentation in a large Italian cohort.This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution.We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients.2, and 25.5% of KS had metabolic syndrome (MetS). LH and FSH were increased, and mean total testosterone were 350 ± 9.1 ng/dl. A descriptive analysis showed that 329 KS patients were evaluated in Northern Italy, 76 in Central and 204 in Southern Italy. Analysis of variance demonstrated significant statistical differences (p < 0001) between the age at diagnosis of the three geographical groups. Compared with the expected number among male patients matched for age in Italy, only 16% of KS patients received a diagnosis.Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/mThese data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory. Klinefelter syndrome (KS) is the most frequent chromosomal disorder associated to male infertility, occurring in 1:500 to 1:1000 live male births. Men with KS typically present tall stature, small and firm testes, and a progressive testicular secretion impairment leading to infertility and hypergonadotropic hypogonadism. Without timely replacement, testosterone deficiency can lead to delayed or incomplete puberty, gynecomastia, decreased muscle mass, decreased bone density, and a reduced amount of facial and body hair . HoweverMulticenter observational study of 609 KS was performed among the patients regularly attending the centers of the national network of academic or general hospitals named KING , between January 2014 and June 2018, after written informed consent had been obtained (the supplementary table lists the KING centers involved in the study). The participants were consecutively selected in order of appearance according to their convenient accessibility at the KING centers. In 594 KS age at diagnosis was reported. The study, accomplishing the Declaration of Helsinki, was approved by the Ethics Committee of the coordinating institution , and all patients or their tutors gave a written informed consent. The local Ethics Committees of each center approved the study. Anonymous patient data, referred to the time of diagnosis, before any further therapy, were collected and a clinical database was created. Inclusion criteria were (i) a verified KS karyotype  and (ii) a written informed consent.KS patients with mosaic forms of chromosomal aneuploidy or any other structural or numerical karyotype anomaly, with AZF microdeletions, were excluded.Patients and/or their parents underwent standard interviews on family history. Data collected included: (1) pubertal development (Tanner stages) and (2) testicular volume (TV) by Prader orchidometer, the physical examination was performed by the same blinded investigator in each center of the KING group. Body weight was measured (with the participants wearing underwear) to the nearest 0.1 kg, height was measured to the nearest 0.5 cm, BMI was calculated.Venous blood (2 ml) from participants was collected by blood banks of the hospitals of the KING centers during the same period of KS recruitment. All basal blood samplings were performed before 09:00 h, after an adequate fasting period, and the low hormonal levels were always confirmed at least twice. Samples were immediately sent for analysis of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), total testosterone (T), 17ß-estradiol, sex-hormone binding globulin (SHBG), to the laboratory facility in each hospital institution of the KING groups. As we recruited patients from different centers, different methods were used. In most of the cases FSH, LH were determined by IRMA, using commercial kits (12). Serum E2 levels and total testosterone were measured by immunoassay using a commercial Kit, automated immunoassays . The normal male reference for the parameters studied were the following: total testosterone 249–836 ng/dl, estradiol 20–80 ng/ml. LH and FSH assays had a lower limit of detection of 0.1 IU/L and a functional sensitivity of 0.2 IU/L. The inter- or intra-assay coefficients of variation were < 5% in all assays since 2008. Free testosterone was calculated using Vermeulen Eq. (20).Metabolic syndrome (MetS) was diagnosed according to the definition of the National Cholesterol Education Program (NCEP)/Adult Treatment Panel III (ATPIII), criteria (21). The study population was classified for the presence of abdominal obesity (waist circumference > 102 cm), hypertriglyceridemia , hypercholesterolemia , hypertension  and impaired fasting glucose . Patients currently receiving antihypertensive drug, statins or oral hypoglycemic drugs were considered as having those components of the metabolic syndrome. Smoking status was defined by two dichotomous categories: smoker and non-smoker. The presence of the metabolic syndrome was defined by the coexistence of ≥ 3 among abdominal obesity, hypertriglyceridemia, hypercholesterolemia, hypertension, and impaired fasting glucose (21).p Value less than 0.05 was considered statistically significant.This is multicenter observational cohort study conducted from 2014 to 2018. No longitudinal data were collected in the present study. Continuous data were represented as mean ± standard deviation (SD) or median (interquartile range—IQR). Categorical data were represented as absolute and relative frequencies. Group comparison was performed using the appropriate statistical test, in accordance with the number of groups and the type of variable . The population-based prevalence was estimated as the annual number of cases being alive in Italy each year during the study period (2014–2018). Incidence was estimated as the average number of diagnosed cases per million males (KS) in the background population each year during the study period. With the aim to test the association between metabolic syndrome and therapy, a logistic regression model was used. The odds ratio (OR) and its 95% confidence interval (95%CI) was calculated. The model was further adjusted for related clinical variable. All statistical analysis was performed using STATA v16 . 2 and TESE was performed in 68 patients out of 402 (16.9%). Twenty five percent (25.5%) of the patients with KS developed MetS  and 28.5 IU/L (median and IQR: 17.5–39), respectively . The mean age at diagnosis was 37.4 ± 13.4 years (median IQR 28–46). There was no change in age at diagnosis during 2014–2018 among all KS. Diagnosis of KS before 18 years of age was made only in 46 out of 594 patients (7.7%) (Table4 to 2018p < 0.0001) between KS age at diagnosis in the three geographical areas. In particular, age at diagnosis was significantly lower in Southern Italy (33.3 ± 13 SD) compared to Central and Northern Italy (40.2 ± 12.5 SD and 39.2 ± 13.3 SD)  were identified. A descriptive analysis was performed and showed that 329 KS were referred to KING centers in Northern Italy, 76 and 204 KS to KING facilities in Central and Southern Italy, respectively  , 25, whiFinally, our data indicate the only generally shared clinical manifestation is the low bitesticular volume and the increased serum FSH and LH levels. The most surprising fact is that the KS patients in our cohort present MetS in a lower percentage compared to other finding.In conclusion, the results of the first baseline data of the Klinefelter Italian Group (KING) cohort study have clearly shown that although KS has been known for over 70 years, there is still much work to be done for early diagnosis and proper management of these patients. The KING database will allow the introduction of data on the same patient over time, compared to register studies. Longitudinal studies of this cohort will give us important clues on the management and follow-up of KS, also in terms of quality of life and life expectancy. However, still too many patients escape the diagnosis and that delay in identifying the presence of KS can have a detrimental effect on the quality-of-life of these men, impeding the start of replacement treatment and the evaluation on the associated disorders . Therefo


Nonetheless, KS-58 demonstrated reasonable stability in blood (t1/2 ≈ 30 min) and no obvious systemic adverse effects, suggesting clinical potential as a lead molecule against colorectal cancer.Mutations in the cell proliferation regulator K-Ras are found with a variety of cancer types, so drugs targeting these mutant proteins could hold great clinical potential. Very recently, a drug targeting the K-Ras(G12C) mutant observed in lung cancer gained regulatory approval and several clinical trials are currently underway to examine the efficacy of this agent when combined with other drugs such as a monoclonal antibody inhibitor of programmed cell death 1 receptor (anti-PD-1). Alternatively, there are currently no approved drugs targeting K-Ras(G12D), the most common cancer-associated K-Ras mutant. In 2020, we described the development of the K-Ras(G12D) inhibitory bicyclic peptide KS-58 and presented evidence for anticancer activity against mouse xenografts derived from the human pancreatic cancer cell line PANC-1 stably expressing K-Ras(G12D). Here, we show that KS-58 also possess anticancer activity against mouse tumors derived from the colorectal cancer cell line CT26 stably expressing K-Ras(G12D). Further, KS-58 treatment reduced phosphorylation of ERK, a major downstream signaling factor in the Ras pathway, confirming that KS-58 inhibits K-Ras(G12D) function. Unexpectedly; however, KS-58 did not show additive or synergistic anticancer activity with mouse anti-PD-1. Morphological analysis and immunostaining demonstrated no obvious differences in CD8 Therefore, molecular inhibitors targeting these mutants may be broadly effective antitumor agents. Recently, an irreversible covalent inhibitor against K-Ras(G12C), a mutation detected mainly in lung cancer, was granted regulatory approval based on clinical trial data showing efficacy as monotherapy3. In addition, several ongoing clinical trials are examining the efficacy of K-Ras(G12C) inhibitor in combination with other drugs, including immune checkpoint inhibitors  and various Ras pathway inhibitors 5, as K-Ras(G12C) inhibitor plus anti-PD-1 exerted synergistic anticancer effects in preclinical studies6.The Ras/MAPK signaling pathway protein K-Ras is a highly conserved molecular switch regulating cell proliferation, and several mutations in the K-Ras amino acid sequence, including K-Ras(G12D), K-Ras(G12V), and K-Ras(G12C), and have detected in various types of human cancer8, but attempts to produce proteins that inhibit these mutants via irreversible covalent binding have been unsuccessful10. In 2017, the first K-Ras(G12D)-selective inhibitory peptide KRpep-2d was reported13, and subsequently demonstrated to reversibly bind K-Ras(G12D) and suppress in vitro proliferation of human A427 lung carcinoma cells expressing K-Ras(G12D). In 2020, an optimized KRpep-2d was described, the bicyclic peptide KS-58  (data not shown).However, the therapeutic spectrum of K-RasG12C) inhibitor is limited because this mutation is found in only a minority of non-small cell lung cancers and rarely in other cancer types. In contrast, K-Ras(G12D) and K-Ras(G12V) are frequently detected in intractable tumors of the pancreas, colon, and rectum2C inhibiIn the current study, we examined the anticancer activity of KS-58 against mouse colorectal tumors derived from the murine cell line CT26 stably expressing K-Ras(G12D), both when administered alone and with the immune checkpoint inhibitor mouse PD-1 antibody (anti-PD-1). We also examined the pharmacokinetics of KS-58 in mice and K-Ras(G12D) targeting in tumors by measuring changes in the phosphorylation of ERK, a downstream signal in the Ras-Raf-MEK pathway.14. The CT26.WT (CRL-2638) mouse colorectal cancer cell line was purchased from American Type Cell Collection (ATCC) , and maintained in RPMI-1640 supplemented with 10% fetal bovine serum (growth medium) at 37 °C under a humidified 5% CO2 atmosphere according to the manufacturer’s recommended protocol.KS-58 was produced by SCRUM Inc.  using Fmoc-based solid phase peptide synthesis as previously described14. Briefly, cells were seeded at 1,000/well in 96-well tissue culture plates with growth medium and allowed to adhere overnight (day 0). For cell treatment, KS-58 was first solved in DMSO and then diluted in growth medium to a constant final DMSO concentration of 0.5%. Cells were incubated in the indicated treatment medium for 3 days with daily medium replacement. Relative cell numbers were estimated using a SpectraMax i3x luminescence detector . Cell proliferation rate (%) was calculated relative to baseline on day 0 (0%) and day 3 without peptide treatment (100%).Cell proliferation was measured using the CellTiter-Glo assay kit  according to the manufacturer’s instructions as previously describedFor evaluation of suppressing effects of KS-58 on Ras-ERK pathway in CT26 cells, phosphorylated ERK (pERK) was measured by Phospho-ERK1 (T202/Y204)/ERK2 (T185/Y187) DuoSet IC ELISA  according to the protocol supplied by the manufacture. CT26 cells were starved for 16 h, treated with KS-58 which was first solved in DMSO and then diluted in FBS-free medium for 1 h , and then treated with peptide diluted in FBS-containing medium for 1 h . Phosphorylation rate of ERK (%) was calculated based on no serum stimulation as 0% and serum stimulation without peptide as 100%.For colony growth assay, CT26 cells were seeded at 500 cells/well in 96-well plates  for 3D-culture. After 24 h incubation, the initial size (day 0) of colonies was measured as area using ImageJ . For colony treatment, KS-58 was first solved in DMSO and then diluted in growth medium to a constant final DMSO concentration of 0.5%. Colonies were incubated in the indicated treatment medium for 3 days with daily medium replacement. The size changes of colonies were measured at day 3 and the size changes rate (%) was calculated relative to initial on day 0 (0%) and day 3 without peptide treatment (100%).For apoptosis assay, RealTime-Glo Annexin V Apoptosis Assay reagent  was used according to the protocol supplied by the manufacture. PANC-1 (ATCC CRL-1469) and CT26 cells were seeded at 10,000 cells/well in 96-well tissue culture white plates with 10% FBS culture mediums. After 16 h incubation, KS-58 and apoptosis assay reagents diluted in FBS-containing medium were added to the wells. Luminescence  were measured at 0, 2, 4, 8, 24 and 32 h after KS-58/reagents addition. THFα (10 ng/mL)  was used as a positive control of apoptosis inducer.Guide for the Care and Use of Laboratory Animals15 and ARRIVE guidelines17. Animal experiments were approved by Animal Care and Use Committee of UNITECH Co. Ltd.   and conducted at UNITECH in accordance with the guidelines. To establish subcutaneous allograft tumors, 1 × 106 CT26 cells/100 µL were subcutaneously injected into the left groin region of BALB/cCrSlc female mice . Immediately before treatment, KS-58 was dissolved in DMSO and then diluted tenfold in normal saline. Tumor-baring mice in vehicle control, KS-58 (low), and KS-58 (high) groups were injected intravenously with vehicle , 10 mg/kg KS-58 solution, or 40 mg/kg KS-58 solution, respectively, once every 2 days for 17 days   = major axis × minor axis2 × 0.5. Tumors (with surrounding skin), liver, and kidneys were collected from satellite groups on day 15, fixed in formalin, and then maintained in 70% ethanol for histological analyses. Tumor, liver, and kidneys were collected from major groups on day 17 within 3 h of the last injection and weighed. The tumors were subsequently frozen in liquid nitrogen and stored at − 80 °C until homogenization for Western blotting.Experimental procedures that involved animals and their care were conducted in compliance with the Experiments were conducted at UNITECH. Briefly, frozen tumors excised as described were homogenized in cold RIPA buffer  supplemented with cOmplete mini EDTA-free Protease Inhibitor Cocktail  and PhosSTOP using a BioMasher II disposable homogenizer , incubated on ice for 30 min, and then centrifuged. The supernatant containing target proteins was collected and total protein concentration was measured. Supernatant proteins (30 μg per gel lane) were separated by SDS-PAGE using Laemmli mini gels (90 mm × 80 mm) and electrophoretically transferred onto polyvinylidene difluoride membranes. Membranes were blocked in TBS containing 0.1% Tween 20 (TBST) plus 3% BSA for 1 h at room temperature (RT) and then incubated with a rabbit monoclonal antibody against phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (1000-fold dilution)  in TBST plus 1% BSA for 1 h at RT. Blotted membranes were then incubated with horseradish peroxidase (HRP)-conjugated mouse anti-rabbit IgG (4000-fold dilution)  in TBST plus 1% BSA for 1 h at RT. The reactions were detected with ImmunoStar Zeta (FUJIFILM Wako) and Hyperfilm ECL . After detection, membranes was incubated with stripping buffer  for 30 min at 50 °C and then washed five times with TBST for measurement of total ERK as described above using p44/42 MAPK (Erk1/2) rabbit monoclonal antibody (1000-fold dilution) . After detection, membranes was incubated with stripping buffer  for 30 min at 50 °C and then washed five times with TBST for measurement of GAPDH as described above using anti-GAPDH antibody (1000-fold dilution) . Protein bands were quantified using ImageJ . Full length blots are shown in Supplementary Fig. Guide for the Care and Use of Laboratory Animals15 and ARRIVE guidelines17. Animal experiments were approved by the Animal Care and Use Committee of Osaka University  and conducted at Osaka University in accordance with the guidelines. LC–MS/MS data were obtained using a Xevo TQ-S mass spectroscopy system  connected to an ACQUITY UPLC system (Waters) equipped with a BEH C18 column . Mobile phase A was 0.1% formic acid in water and mobile phase B was 0.1% formic acid in acetonitrile. The gradient elution profile was 2% B at 0 min to 98% B at 1.8 min, and the flow rate was 0.5 mL/min.Experimental procedures that involved animals and their care were conducted in compliance with the For pharmacokinetics studies, KS-58 was dissolved in saline and administered intravenously to female BALB/c mice at 10 mg/kg. Serial blood samples (20 μL) were collected from the tail vein using heparinized tips at 7.5, 15, 30, 60, 120, 240, 320, and 1440 min after KS-58 administration. Aliquots (5 μL) of plasma obtained from each blood sample were treated with 50 μL acetonitrile and the organic layer was injected onto the LC–MS/MS system. Pharmacokinetic parameters were obtained by fitting the plasma concentration–time data to a noncompartmental model using PKPlus software .For evaluation of stability, KS-58 was incubated with commercial hepatic microsomes  in X medium supplemented with nicotinamide adenine dinucleotide phosphate for 10 and 60 min at 37 °C. The fraction (%) remaining in the medium was determined using the LC–MS/MS system (Waters). We also examined the fraction (%) remaining in fresh mouse blood after 60 and 120 min of incubation at 37 °C using the same LC–MS/MS system.For evaluation of plasma protein binding, the plasma compartment containing KS-58 was dialyzed against PBS (pH 7.4) for 5 h at 37 °C and the concentrations remaining in each compartment were quantified by LC–MS/MS.Tumors, livers, and kidneys were harvested from mice and fixed with 10% neutral-buffered formalin. After 24 h, tissues were transferred to 70% ethanol and stored at RT until analyses. Tissues were subsequently paraffinized, sectioned at 5-μm thickness, deparaffinized in xylene, dipped in 100% ethanol, washed in water, and then stained with antibodies or HE.2O2 in PBS to quench endogenous peroxidase activity and incubated with Simple Stain MAX PO  for 60 min at RT. Sections were then stained with DAB solution (Nichirei Bioscience Inc.), washed thoroughly with PBS, counterstained with hematoxylin for 1 min, washed with water, dehydrated, mounted, and scanned using a VS-120 Slide Scanner .For immunostaining, the sections were autoclaved for 10 min at 121 °C in 10 mM Tris/1 mM EDTA (pH 9.0) for antigen retrieval, blocked with 5% skim milk in PBS for 60 min at RT, and incubated with specific primary antibodies against the effector T-cell marker CD8  and PD-L1 (E1L3N) XP  for 60 min. Subsequently, the sections were treated with 3% HFor morphological analysis, sections cut at 5 μm were stained with hematoxylin and eosin. Histopathological analysis was conducted by a board-certified veterinary and toxicologic pathologist .p < 0.05).Software used for the statistical analysis was JMP8 (SAS Institute Inc.) The level of significance was set at 5% 18, have not been reported. Here we demonstrate that KS-58 dose-dependently suppresses the proliferation of murine CT26 colorectal cancer cells stably expressing K-Ras(G12D), with about 50% inhibition at 30 μM   inhibition, we evaluated phosphorylation of ERK (pERK), a downstream components of the K-Ras signaling cascade. Possible methods to evaluate pERK in tumors are (1) homogenizing tumor and evaluating the pERK by ELISA or Western blotting, and (2) preparing tissue sections of tumor and evaluating the pERK by immunohistochemical (IHC) staining. We first attempted to examine by Western blotting. Three tumors were randomly selected from each of the four major treatment groups  , homogenized, and subjected to Western blotting to quantify pERK, total ERK and GAPDH Fig. . The pERD inhibit14, we demonstrated the serum protease resistance of KS-58 and estimated the half-life in whole blood (~ 60 min) using RP-HPCL. Here, we evaluated the pharmacokinetics of KS-58 in greater detail using LC–MS/MS. The estimated limit of detection was ~ 250 nM. Following injection of 10 mg/kg, the plasma concentration decreased to ~ 50% of the initial concentration after about 30 min and was below the limit of detection after 4 h , and the volume of distribution at steady-state (Vdss) are shown in Fig. In our previous studyThe stability of KS-58 was evaluated in human and mouse liver microsomes as well as in whole blood Fig. B,C. Afte+ cells infiltration among treatment groups  inhibitor KS-58 can suppress the growth of tumors derived from PANC-1 pancreatic cancer cells and CT26 colorectal cancer cells expressing K-Ras(G12D) without serious side effects such as weight gain/loss, liver pathology, or kidney dysfunction. Further, these results provide proof of principle for the wider application of reversible K-Ras inhibitor to include cancers associated with other K-Ras mutations such as K-Ras(G12C), K-Ras(G12V).The findings presented here and in our previous report6. This K-Ras(G12C) inhibitor is reported to enhance tumor infiltration of effector T-cells and to downregulate PD-L1 expression6. Moreover, other Ras pathway inhibitors have shown additive anticancer efficacy when used in combination with immune checkpoint inhibitors22. Based on these reports, we expected that the anticancer efficacy of KS-58 would be enhanced by an immune checkpoint inhibitor, but unexpectedly, KS-58 plus anti-PD-1 was no more effective than KS-58 alone despite the confirmed inhibitory activity of KS-58 against K-Ras(G12D) function in vivo and the demonstrated non-interference of this effect by anti-PD-1. KS-58 was also relatively stable in liver microsomes and whole blood, which should enhance bioavailability of KS-58 in tumor and thus the potential for therapeutic interactions with anti-PD-1. However, a large fraction of KS-58 in whole blood eventually bound to the surface or accumulated within blood cells, which could have limited potential interactions with anti-PD-1. One possibility is that the additive or synergistic effects of KS-58 plus anti-PD-1 are mediated by antitumor immunity and that KS-58 entry into leukocytes disrupts this process, but immunostaining of CT26 tumors revealed that KS-58 did alter effector T-cell (CD8+) tumor infiltration or PD-L1 expression levels. Therefore, the reason for this lack of combined activity with anti-PD-1 remains unclear. It is still possible that KS-58 reduces the antitumoral lymphocyte response after infiltration, a potential mechanism requiring further study.A covalent inhibitor of K-Ras(G12C) recently granted regulatory approval for clinical use has demonstrated high target selectivity and shown to possess substantial therapeutic activity against lung cancer, especially when combined with an immune checkpoint inhibitor1/2 of KS-58 in mice was relatively short (~ 30 min) despite the relatively high degree of plasma protein binding  with slower off-rates are required24. Although the detailed metabolic pathway is not clear, histomorphological analysis suggested that KS-58 is metabolized in liver. While this relatively short t1/2 limits the exposure time to target tumor tissue, it also reduces exposure to healthy tissue, thereby decreasing the risks of potentially serious side effects. We previously reported that the cell membrane permeability of KS-58 may be enhanced in weakly acidic environments such as tumor tissues14, a property that could contribute to the selective anticancer activity and limited side effects profile observed in this study.The ting Fig. E, which 14. Further studies are required to determine if the anticancer efficacy of KS-58 is additive or synergistic with other Ras pathway inhibitors.Combination treatments consisting of a K-Ras inhibitor plus an immune checkpoint inhibitor like anti-PD-1 or Ras pathway inhibitor  are expected to have additive or synergistic anticancer activities. Unfortunately, KS-58 did not show additive or synergistic anticancer activity in combination with anti-PD-1 in this animal study. On the other hand, KS-58 has demonstrated additive anticancer activity in combination with the therapeutic DNA synthesis inhibitor gemcitabineIn summary, the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 dose-dependently inhibited the proliferation of CT26 colorectal cancer cells expressing K-Ras(G12D) and suppressed the growth of CT26-cell-derived tumors in mice, consistent with previous reports that this compound can inhibit the proliferation of a pancreatic cancer cell line expressing K-Ras(G12D). Unfortunately, the combination of KS-58 and anti-PD-1 was no more effective than KS-58 alone. Further studies are required to assess possible additivity or synergy with other immune checkpoint inhibitors, chemotherapeutics, and Ras pathway inhibitors.Supplementary Figures.


Based on these lines, one can easily predict the molecular polarizabilities of larger peptides, even proteins as long as the total molecular wavefunction is available, rather than solving the computationally demanding coupled-perturbed Hartree–Fock (CPHF) equation or its DFT counterpart coupled-perturbed Kohn–Sham (CPKS) equation. Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For base pairs, we have dissected the relative importance of energetic components by using two energy partition schemes in DFT. Our results convincingly show that the exchange-correlation effect predominantly governs the molecular stability of base pairs while the electrostatic potential plays a minor but indispensable role, and the steric effect is trivial. Furthermore, we have revealed that simple density-based ITA functions are in good relationships with molecular polarizabilities for a series of 30 hydrogen-bonded base pairs and all 20 natural  Rather, one can easily delve into their building blocks, base pairs of nucleic acids and amino acids of proteins or peptides, respectively.Nucleic acids and proteins are important biological polymers in living organisms. Proteins are responsible for the catalysis of biological processes, while nucleic acids or base pairs play a role as carriers of the genetic information. However, For base pairs, there exists a type of important noncovalent interaction: hydrogen-bonding interactions, which could stabilize the two strands of nucleic acids (DNA and RNA). To figure out the origin and nature of hydrogen-bonding interactions in base pairs is still of heated discussion and an ongoing task in the literature ,2,3,4,5.α-amino acids, 400 dipeptides and 8000 tripeptides. A few simple density-based ITA functions, such as Shannon entropy [Besides energetics, we have also explored the molecular polarizabilities of 30 base pairs and 20 natural  entropy , Ghosh−B entropy , Onicesc entropy , relativ entropy , informa entropy , and rel entropy ,14 are u entropy ,16,17 by entropy ,19,20 an entropy .MUE) and mean signed error (MSE), are employed to gauge the quality of the method. The experimental values [αiso are taken as reference to obtain MUE and MSE values. It is clearly shown that the combination of 6-311G with 5 functionals from this work or MP2 (MSE = ~16 Bohr3) from the literature [MSE dramatically decreases, for example from 18.4 (Def2-SVP) to 8.9 Bohr3 for M06-2X. If an even better basis set aug-cc-pVTZ is used, the MSE is only 3.8 Bohr3. Of note, the relative deviation of 5 density functionals should be comparable when combined with, for example, Def2-TZVP. In addition, though B3LYP performs well in predicting molecular polarizabilities here, its failure in delineating dispersion will undoubtedly hinder the wide applicability of ITA quantities for various kinds of inorganic, organic and biological systems. The results will be presented in our forthcoming publication. Collectively, with both accuracy and efficiency taken into consideration, we selected M06-2X/Def2-TZVP for predicting molecular polarizabilities.Hait et al.  have verl values  of αiso terature  leads tos), exchange-correlation (ΔExc), electrostatic potential (ΔEe), steric hindrance (ΔEs), and quantum effect (ΔEq), are obtained at the M06-2X/Def2-TZVP level, as collected in xc), electrostatic potential (ΔEe), and steric hindrance (ΔEs) all make positive contributions to the total energy difference. However, the large negative values of steric hindrance are compensated by the positive Fermionic quantum effect in the new scheme. In the conventional scheme, the positive kinetic energy also cancels out part of the exchange-correlation effect and electrostatic potential. Next, we will figure out the relative importance of these three components. Shown in s, ΔEe, and ΔExc. These lines indicate that single-variable linear regression cannot distinguish the relative importance of these three energetic components. To resolve this issue, two-variable fits are used to make that happen. Shown in To determine the nature of hydrogen bonding interactions in base pairs is of heated discussion in the literature. In this work, we aim to use two energy decomposition schemes as mentioned above to dictate which energetic component is responsible for the hydrogen bonding interactions. Using the supramolecular approach, the interaction energy (ΔE) and its components, including kinetic  between the molecular polarizabilities and molecular volumes and ITA quantities. One can observe that Shannon entropy (SS), Fisher information (IF), 2nd and 3rd relative Reényi entropy (rR2 and rR3), and G3 are in strong linear relationships with molecular polarizabilities, with R2 > 0.8. It is intriguing to note that the absolute values of G3 are very close to molecular polarizabilities. However, the reason is unknown at present. In 3 data, and those predicted on top of the molecular wavefunctions obtained at the M06-2X/Def2-TZVP level. One can easily observe that the G3 data are very accurate in comparison to conventional polarizability data with MSE(%) to 1.5. However, the two sets of predicted data employing the original Tkatchenko–Scheffler (TS) formula [In  formula  on top o formula  or Hirsh formula  partitiocurately . Thus, tformance . Yet, th2 = 0.992) between the two sets of calculated molecular polarizabilities. The gap between the two methods is only 11.95 Bohr3, indicating that one can use a relatively cheaper theoretical method to obtain accurate results. In addition, we have found some strong correlations for a total of 20 amino acids, 400 dipeptides, and 8000 tripeptides between molecular polarizabilities and molecular volumes, GBP entropy (SGBP), 2nd relative Rényi entropy (rR2), and G3 as shown in We first cross-validate the accuracy of the molecular polarizabilities of 8000 tripeptides. The two theoretical levels are M06-2X/Def2-TZVP//M06-2X/Def2-SVP and B3LYP/6-31+G//B3LYP/6-31G level, respectively. Shown in We have systematically investigated the energetics of 30 base pairs and molecular polarizabilities of 30 base pairs and 20 amino acids, 400 dipeptides, and 8000 tripeptides. It is the first time that ITA quantities have been applied to correlate with molecular polarizabilities. Though at present, in theory we have not verified the existence of such a linear correlation between ITA quantities and molecular polarizabilities, they are both related to electron density and its derivatives. Additionally, our results presented here demonstrate that one can determine the molecular polarizability by numerically integrating the simple density-based functions when the molecular wavefunction of a given system is obtained from single-point calculations, rather than resorting to iteratively obtaining the molecular orbital derivatives. The implication of our work is straightforward, that one can use the linear relationships as shown in the text to predict molecular polarizabilities of relatively larger peptides, or even larger proteins. Can the ITA quantities be widely applied to various inorganic, organic and biological systems? More work along this line is required.We have to point out that we are not the first to predict the molecular polarizabilities just as employing the electron density as the input. Jayatilaka et al.  has castE) can be decomposed into its components via [Ts, Ee, and xcE are the noninteracting kinetic, electrostatic, and exchange-correlation terms, respectively. The electrostatic potential eE has three components: the nuclear−electron attraction, (Vne), the classical Coulombic repulsion, (J), and the nuclear−nuclear repulsion (Vnn). The last term, Exc, consists of exchange (xE) and correlation (Ec) components. In Equation (2), Es stands for the steric hindrance, and Eq signifies the contribution from Fermionic quantum effect. The steric effect Es has been proved to be simply the Weizsäcker kinetic energy,In Kohn–Shan DFT, the total energy difference ΔE[qE, which readsCombining Equations (1)–(3), one can simply define This new formulation has its own distinct physical meaning with a corresponding physical state. It has been applied to a number of molecular systems and phenomena, whose results are consistent with our chemical intuition and conventional wisdom .SS [IF [Shannon entropy SS  is a meaSS [IF  measuresIF has an equivalent expression [2ρ(r).Additionally, for atoms and molecules, pression  in termsSGBP [t is the kinetic energy density, which is related to the total kinetic energy TS viatTF is the Thomas−Fermi (TF) kinetic energy density given byK as the Boltzmann constant (set to be unity for convenience in this work), c = (5/3) + ln(4Kπc/3), and cK = (3/10)(3π2)2/3, the specific form of the local kinetic energyGhosh−Berkowitz−Parr (GBP) entropy SGBP (8)SGBP=nnIG is given in Equation (14)ρ0(r) is the reference-state density satisfying the same normalization condition as ρ(r). More recently, additional ITA quantities have been introduced as new reactivity descriptors in conceptual density functional theory (CDFT) . One exa entropy  of ordernEn=1n−1∫ G1, G2, and G3, whose analytical forms as shown below:Very recently ,14, we hG2 function involves Laplacian contribution and can be regarded as the relative Laplacian contribution to the steric potential. The quantifications and applications of Equations (15)–(17) can be found in [The found in . Sufficefound in . For exafound in ,57, whicFollowing the notation of , we buil+ and Cl− ions. We performed a total of 1 ns MD simulations with the ff19SB [γ = 5 ps−1 [Shown in e ff19SB  force fie ff19SB  for the = 5 ps−1 . The pre= 5 ps−1 ,63. Peri= 5 ps−1 . Covalen= 5 ps−1 . All cla= 5 ps−1 ,67 CUDA = 5 ps−1  level, aAll density functional theory (DFT) calculations were conducted with the Gaussian 16  package iso = (αxx + αyy + αzz)/3 is reported in this work. Total energy components were obtained via the keyword iop(5/33 = 1). The Multiwfn 3.8 [3 contour surface of electronic density. The stockholder Hirshfeld partition scheme of atoms in molecules was employed when atomic contributions were concerned. The reference density was the neutral atom calculated at the same level of theory as molecules.A full geometric optimization at the M06-2X/Def2-SVP level without any symmetry constraint was conducted for 30 base pairs and 8420 peptides. The optimized Cartesian coordinates are supplied in the iwfn 3.8  program In this work, we have explored the interaction energy of base pairs and molecular properties of both base pairs and amino acids, dipeptides, and tripeptides. Using the total energy decomposition schemes, one can find that the exchange-correlation effect makes the predominant contribution to the molecular stability, followed by the electrostatic potential, and steric hindrance plays a trivial role. We further revealed that molecular polarizabilities can be linearly correlated with ITA quantities. These strong linear correlations can be used to predict the molecular polarizabilities of larger peptides and even proteins. We mention in passing that two directions merit further studies. (i) Verification of the wide applicability of ITA quantities to various systems needs intensive work. (ii) When a fragment-based method, such as the linear-scaling generalized energy-based fragmentation (GEBF) approach, is taken into consideration, one can directly predict the subsystem  polarizabilities rather than solving the derivatives of molecular orbitals and obtain the molecular polarizability of macromolecular systems via a linear combination of subsystem polarizabilities. More work along this line is ongoing, and results will be presented elsewhere in the very near future.


There is an absorption peak –N=C=O– which is not shown near 2268 cm−1, which proves that the structure of TPU contains the molecular structure of capping agent, PTMG and MDI. When the DMAA concentration in the capping agent was increased from 3.0 wt% to 10 wt%, the –C=O (H-bond) area percentage of hydrogen bonds formed at 1711 cm−1 increased from 41.7% to 57.6%, while the –NH (H bond) produced at 3330 cm−1 increased from 70% to 81%. These phenomena suggest that increasing the concentration of DMAA capping agent can effectively promote the formation of complex supramolecular network structures by hydrogen bonding in TPU. The content and concentration of the capping agent affects the molecular weight of the TPU. Chain growth is terminated when molecular weight growth can be effectively controlled and reduced. It was observed in thermal analysis that with increasing DMAA concentration in the molecular structure, the concentration of capping agent in TPU, hydrogen bonding force between hard segments, melting point (Tmh) and melting enthalpy (ΔH) all increased the capping agent. The pyrolysis temperature of TPU is increased by 10–20 °C.This series of studies aims to design acrylate-terminated polyurethanes for use in nylon seamless bonded fabrics. The first part used N,N-dimethylacrylamide (DMAA) and methyl methacrylate (MMA) to replace the chain extender in polyurethane synthesis as end-capping agent to synthesize thermoplastic polyurethane (TPU) adhesive. The molecular weight of the TPU is controlled to further influence the mechanical and processing properties of the polyurethane. Here, polytetramethylene ether glycol (PTMG) and 4,4-methylene diphenyl diisocyanate (MDI) were polymerized, and then a blocking agent was added thereto. The results show that the characteristic peaks of benzene ring and carbamate of TPU adhesive are at 1596 cm Thermoplastic polyurethanes (TPUs) are (AB)n linear block polymers. Molecular segments with better softness endow TPU with ductility and flexibility, so they are called soft segments, while hard segments provide rigidity to TPU . TPU canThe purpose of this study is to investigate the influence of the molecular structure and hydrogen bonding of the end-capping agent, and to analyze the enhanced degree of hydrogen bonding of the TPU molecular segments, thereby improving the tensile strength, peel strength and shear strength. This modified TPU is used in nylon to reinforce the fibers.The end-capping agent was synthesized using methyl methacrylate (MMA) and N,N-dimethylacrylamide (DMAA) as the main raw materials. Azobisisobutyronitrile (AIBN) and 2-mercaptoethanol (ME) were used as initiator and chain transfer agent, respectively. The capping agent was synthesized by a radical chain transfer reaction mechanism. Using polybutylene glycol, 4,4′-diphenylmethane diisocyanate and end-capping agent as raw materials, TPU is synthesized by bulk polymerization process. The content of the capping agent is adjusted to control the molecular weight of the TPU, and the DMAA concentration of the capping agent is adjusted to control the mechanical properties of the TPU. After TPU is compounded with nylon fabric, different characterization techniques such as FT-IR, GPC, TGA, DSC, DMA, etc., are used to analyze the functional group, hydrogen bond state, molecular weight state, pyrolysis state, melting point, melting enthalpy and glass transition of TPU temperature.Methyl methacrylate (MMA), molecular weight: 110.12 g/mole, from: Sigma-Aldrich . N,N-dimethylacrylamide (DMAA), molecular weight: 99.13 g/mole, from: Sigma-Aldrich. Azobisisobutyronitrile (AIBN), molecular weight: 164.21 g/mole, from: Sigma-Aldrich. 2-Mercaptoethanol (ME), molecular weight: 262 g/mole, from: Sigma-Aldrich. Ethyl acetate (EAc), molecular weight: 118 g/mole, from: Sigma-Aldrich. 4,4′-diphenylmethane diisocyanate (MDI), molecular weight: 250 g/mole, from: Sigma-Aldrich. Polytetramethylene glycol (PTMG), molecular weight: 1000 g/mole, from: Sigma-Aldrich.A solution was prepared by dissolving methyl methacrylate (MMA) in ethyl acetate (EAC). In this solution, N,N-dimethylacrylate (DMMA) and 2-mercaptoethanol (ME) were added as polymerization terminators, and the reaction temperature was fixed at 70 °C. The azobisisobutyronitrile (AIBN) was used as a catalyst to complete the reaction. Eventually, the capping agent based on methyl methacrylate (MMA) and N,N-dimethacrylate (DMAA) was synthesized after 24 h of polymerization. The structure of the capping agent is shown in The MMA obtained by polymerization is 37 wt%, 35 wt%, 33 wt% and 30 wt%, respectively.The PTMG and MDI were put in the reaction bulb in turn and heated to 80 °C in nitrogen environment, and polymerized by the mechanical agitator at speed of 200 rpm. After 1 h of polymerization, the end-capping agent was put in the reaction bulb. The TPU prepolymer was formed after 1 h of reaction . The TPU prepolymer was ripened at room temperature for 24 h, and put in the oven at 80 °C to remove the solvent. The generated data are shown in The compounding end-capping agents D  were added to the polyurethane prepolymer, respectively. The addition amount was shown in (a)Bonding temperature: 150 °C.(b)2.Bonding pressure: 1.0 kg/cm(c)Bonding time: 20 s.(d)Standing time after bonding: 20 min for cooling and stabilization.Afterwards, the TPU was cut into a 1.0 cm × 15 cm strip (thickness: 150 μm), and the nylon fabric was cut to the size of 2.54 cm × 18 cm. They were bonded according to the following processing conditions, and the bonding conditions included:−1 to 650 cm−1, and the resolution was 2 cm−1. The average of 16 scans was taken.The functional group and H-bond state of TPU were measured by using the Fourier transform infrared spectroscopy . The range of wave number scanned by ATR was 4000 cmThe molecular weight and molecular weight distribution of TPU were measured by using the gel permeation chromatography , including a reflective index (RI) detector  and two tubular columns in a series of Jordi gel DVB mixed beds and measuring the molecular weight distribution in relation to PS standard on 30 °C 10,000 Å bed. The carrier solvent was tetrahydrofuran, and the flow velocity was 1.0 mL/min.The pyrolysis temperature of TPU was measured by using the thermogravimetric analysis . The amount of sample was 5.0 mg to 8.0 mg, in N2, the temperature increased from 50 °C to 700 °C, the heating rate was 10 °C/min, and the TGA was performed.The melting point and melting enthalpy of TPU were measured by using the differential scanning calorimeter . The test specimen was 5.0 mg–8.0 mg and sealed in an Al tray. The test conditions are described below, (a) heating condition: from −40 °C to 240 °C, the heating rate is 10 °C/min; and (b) cooling condition: from 240 °C to −40 °C, the cooling rate is 10 °C/min.The glass transition temperature and storage modulus of TPU were measured by using the dynamic mechanical analyzer . In stretching mode, the frequency was 1 Hz, the temperature rose from −80 °C to 50 °C, the heating rate was 2.0 °C/min. The sample size was 20 × 5 × 0.2 mm (L × W × H).−1 and 1413 cm−1. The –C–H showed the bending vibration absorption peak at 1529 cm−1. The –C–N showed the stretching vibration absorption peak at 1308 cm−1. The –C–O showed the stretching vibration absorption peak at 1218 cm−1 [−1 and 1642 cm−1 [−1 [−1 and split into double peak, meaning the H bonding strength of –NH is very high. It is observed in the FT-IR spectra that the –N=C=O– stretching vibration absorption peak near 2268 cm−1 of the TPU sample with end-capping agent completely disappears, but the –NH absorption peak and Amide I absorption peak of DMAA occurred. This suggested that the TPU structure contained the molecular structures of end-capping agent, PTMG and MDI. In the FT-IR spectra, the absorption peak regions of –C=O group and –NH group are 1650 cm−1–1780 cm−1 (–C=O) and 3200 cm−1–3500 cm−1 (–NH), respectively, which are used as the feature regions for observing the hydrogen bonding. During hydrogen bonding, the two groups are disintegrated into two absorption peaks and move towards low wave number. The FT-IR spectra in −1 and 1711 cm−1. −1 to 3200 cm−1 [−1 increases from 41.7% to 57.6%; the free –C=O (free) at 1732 cm−1 decreased from 58.3% to 42.4%; (b) when the DMAA concentration of end-capping agent increased from 3.0 wt% to 10 wt%, the –NH (H-bond) of H-bond generated at 3330 cm−1 increased from 70% to 81%; the free –NH (free) at 3440 cm−1 decreased from 30% to 19%. As the DMAA concentration in the end-capping agent increased, the ability of –C=O group to receive protons and form H-bond is enhanced. The formation of H-bond is promoted, and a complex supermolecular network structure is formed in the TPU. However, the –C=O group in the molecular structure of DMAA has relatively strong ability to attract protons. The –NH of carbamate has relatively strong ability to give protons, so that more H-bonds are generated. It means that the stronger the ability of the proton donor to give protons, the higher is the electronegativity of proton acceptor, and the H-bond is likely to be formed due to difference of polarity, which ultimately increased the bond energy [This study used PTMG and MDI as the base of synthesizing TPU, and used D03, D05, D07 and D10 as end-capping agents, respectively, to synthesize TPU. The functional groups of TPU were analyzed by FT-IR. As shown in cm−1 [−1 . The abs3)2 of DMAA, which inhibits the formation of covalent bonds between –OH of the capping agent and isocyanate [2 leads to the uneven molecular weight distribution. In addition, the Mw and Mn of TPU varied with the content of capping agent, as described below: (a) TPU synthesized with capping agent D03, the content of capping agent was increased from 5.0 phm to 15 phm, the Mw of TPU decreased from 82,000 g/mole to 52,480 g/mole, and the Mn decreased from 35,520 g/mol to 27,960 g/mole Moore; (b) TPU synthesized with capping agent D05, the content of capping agent was increased from 5.0 phm to 15 phm, the Mw of TPU decreased from 86,810 g/mole to 55,080 g/mole, and the Mn decreased from 41,530 g/mol to 26,020 g/mole Moore; (c) TPU synthesized with capping agent D07, the content of capping agent was increased from 5.0 phm to 15 phm, the Mw of TPU was decreased from 96,330 g/mole to 64,730 g/mole, and the Mn was decreased from 47,980 g/mole to 28,300 g/mole; (d) synthesis of TPU with end-capping agent D10 series, the content of end-capping agent was increased from 5.0 phm to 15 phm, the Mw of TPU decreased from 111,580 g/mole to 68,080 g/mole, and the Mn decreased from 56,100 g/mol to 37,940 g/mol. The results show that the –OH of the blocking agent and the isocyanate group form a covalent bond, thus achieving the purpose of blocking.The relative molecular weight and molecular weight distribution of TPU have important effects on mechanical properties and post-processing properties. The tensile strength of TPU increases with increasing molecular weight of TPU. When the molecular weight exceeds a certain molecular weight range, the processing temperature of TPU increases, which affects the later processability of TPU. In this study, TPU was synthesized based on PTMG and MDI, and TPU was synthesized with D03, D05, D07 and D10 as capping agents, respectively. The weight average molecular weight (Mw), number average molecular weight (Mn) and molecular weight distribution coefficient (PDI) of TPU were analyzed by GPC. ocyanate ,21. The 3)2 grafted copolymer is decomposed at 300–550 °C. When the DMAA is admitted in the polymer, the pyrolysis temperature of the polymer rises. Because the –C=O group and polar group, such as –OH group, of DMAA form strong H-bond, the thermal stability of the polymer is improved [This study used PTMG and MDI, which are the bases for the synthesis of TPU, and used D03, D05, D07 and D10 as end-capping agents, respectively, to synthesize TPU. The temperature of pyrolyzing 5.0 wt% (Td5) and the temperature of pyrolyzing 10 wt% (Td10) and maximum decomposition rate of TPU were analyzed by using TGA as described in improved ,25. In Timproved ,27. Addiimproved , describThis study used PTMG and MDI as the base of synthesizing TPU, and used D03, D05, D07 and D10 as end-capping agents, respectively, to synthesize TPU. The hard segment melting point (Tmh) and melting enthalpy (ΔH) of TPU were analyzed by DSC. The DMA demonstrated the glass transition of various components of block polymer, provided the dynamic modulus of polymer and the law of variation of loss factor with temperature, and reflected the degree of microphase separation of the internal structure of polymer. The loss factor is the most effective method to judge the glass transition temperature of materials. The glass transition temperature of TPU generally referred to the glass transition temperature of soft segment (Tgs) ,31. ThisBased on the above discussion, this study used the end-capping agent to reduce the molecular weight of TPU and to adjust the DMAA concentration in the end-capping agent, which ultimately promoted the degree of H-bonding of TPU. Moreover, the contradictory problem in molecular weight control, mechanical properties and coating temperature of TPU is solved successfully. The findings showed that the FT-IR spectra verified the TPU having end-capping agent, PTMG and MDI, which completely reacted with each other. The DMAA in the end-capping agent effectively promoted the hydrogen bonding degree of TPU. However, the steric hindrance effect of DMAA influenced the chain termination reaction, so that the molecular weight of TPU is changed. In terms of thermal property, the DMAA promoted the molecule segment of TPU to synthesize the complex hydrogen bonding network. It was observed that when pyrolysis temperature of TPU is increased, the melting point and ΔH of the hard segment are also increased. Due to the polarity difference between the hard segment and soft segment with end-capping agent, the hard segment is difficult to be mixed in the soft segment phase, and the Tgs temperature remains stationary. When the temperature is low, the hard segments with relatively strong intermolecular force are gathered together, arranged in order and stacked closely. The crystals are formed, and the storage modulus increased continuously. The AFM verifies that the micro phase separation degree increases with the end-capping agent content, and irregularly shaped hard domains are generated and connected to each other. Finally, the hydrogen-bond acceptor (DMAA) concentration in the molecular structure of end-capping agents was adjusted in this study, which is an effective strategy for good mechanical properties of low molecular weight polymers. The mechanical properties of seamless bonding with nylon substrate will be analyzed and various application sides will be tested in subsequent research.


G) in different regions of fluorinated molecular patterns exhibited a strong correlation with a noise power spectral density of SI/I2 like SI/I2 ∝ G−2, which can be explained by enhanced barrier fluctuations produced by the dipoles of fluorinated molecules. Furthermore, we observed that the noise power spectral density of fluorinated molecules showed an anomalous frequency (f) dependence like SI/I2 ∝ 1/f1.7, possibly due to the slowing down of the tunneling of carriers from increased barrier fluctuations. In rather high bias conditions, conductions in both hydrogenated and fluorinated molecules showed a transition from tunneling to thermionic charge transports. Our results provide important insights into the effects of dipoles on mesoscopic transport and resistance-fluctuation in molecules and could have a significant impact on the fundamental understanding and applications in this area.We demonstrate a strategy to directly map and quantify the effects of dipole formation on electrical transports and noises in the self-assembled monolayers (SAMs) of molecular wires. In this method, the SAM patterns of fluorinated molecules with dipole moments were prepared on conducting substrates, and a conducting probe in contact-mode atomic force microscopy was utilized to map currents and noises through the probe on the molecular patterns. The maps were analyzed to extract the characteristic parameters of dipolar noises in SAMs, and the results were compared with those of hydrogenated molecular patterns without dipole moments. At rather low bias conditions, the fluorinated molecular junctions exhibited a tunneling conduction and a resistance value comparable to that of the hydrogenated molecules with a six-times-longer length, which was attributed to stronger dipoles formation in fluorinated molecules. Interestingly, conductance ( Howese model ,52. In sse model .φ(t) ~ePSD takes the form of S(f) ~1/f2−γ [α (Equation (2)) is significantly affected in a FSAM.In principle, 1−γ could take a value between 0 and 1. In the presence of such a distribution function, the noise  ~1/f2−γ ,56,57. FPSD values were measured in the frequency range of 17.3−1732 Hz at each point of the SAM surface and utilized to estimate the scaling factors. We fitted the PSD spectra with a function of A/fβ to obtain the scaling parameter β. The PSD spectra on the molecular monolayer exhibited the scaling behavior. The HSAM exhibited a scaling factor (β) close to 2, whereas the FSAM exhibited a scaling factor of 1.7. Note that the scaling factor map shows a clear contrast between the SAM regions and the ITO regions (β ~ 1.0). We could consistently obtain the scaling parameter from different molecular wire samples in this study, supporting the notion that measured noise signals in a molecular monolayer were from the molecular parts rather than other conducting parts in the sample. These results show that the scaling parameter analysis could be utilized to discriminate between molecular species present on a nanoscale junction.I(0.5 V)/I(−0.5 V)) was ~3.5. Presumably, the presence of fluorine atoms induced the formation of dipoles at terminal groups and backbone on the FSAM, resulting in the asymmetric I–V curve [A high electric field in one-dimensional molecular wires can significantly affect their transport and noise characteristics. –V curve ,59,60. O–V curve . Previou–V curve . In our –V curve ,62. We o–V curve ,64,65.PSD dependence on voltage for the HSAM and FSAM, plotted with blue and red colors, respectively. The noise PSD was measured at 17.32 Hz along with the currents, while the voltage was swept from −0.5 to 0.5 V on the ITO surface. We observed symmetric noise PSD in the HSAM, while the noise PSD in the FSAM was asymmetric, with high values at negative biases. The increased noise in the FSAM at a negative bias on the ITO substrate could be associated with the stronger effective dipole formation at an applied negative bias. Previous studies showed that a stronger dipole could lead to a more substantial fluctuation in the tunneling width and tunneling barrier, resulting in high noise levels, which is also consistent with our results [ results ,63,64,65logI versus logV curves for the HSAM and FSAM at a rather low bias below 0.1 V. Note that both data can be fitted by a curve with a slope of ~1, indicating a linear dependence of a current on the bias voltage at a low bias regime. Previous works showed that at small biases, electrical currents in a molecular junction can be explained by a tunneling current with a linear dependence on V like  results .logI versus V1/2 curves for the HSAM and FSAM at high biases (above 0.1 V) plotted with blue and red colors, respectively. In both the curves, logI showed a linear dependence on V1/2, which is consistent with previously reported results of thermionic conduction in molecular wires at a large bias voltage [On the other hand, the electrical currents at a rather high bias exhibited quite different behavior.  voltage ,67. It i voltage ,67.PSDSI/I2 and conductance G at 0.5 V on a log-log scale for the HSAM and FSAM, respectively. The graphs were obtained by statistical weightage plotting of the conductance and noise PSD data at 0.5 V on the x and y axes, respectively. The noise PSD showed a strong and positive correlation with conductance in both HSAM and FSAM, following scaling behavior of SI/I2 ∝ G2. This dependence is opposite to the low bias scaling behavior of PSD on conductance, where we observed a negative correlation like SI/I2 ∝ −G2 (see Equation (2)). The positive correlation could be explained by electrical noises in the thermionic emission at a high bias. A previous report showed that, in the thermionic emission, the carriers diffuse due to thermal energy by Joule heating, and the noise due to thermal diffusion of carriers is proportional to the square of a change in temperature like SI/I2 ∝ (ΔT)2 [G, the temperature change ΔT by Joule heating should be proportional to the power generated by electrical currents such as ΔT ∝ GV2. Since the bias voltage V was kept constant during the scanning, the noise PSD can be written as SI/I2 ∝ G2 at a high bias condition where the thermionic noise dominates. These results show that, at a rather high bias, a thermionic fluctuation can be a dominant noise source at molecular wire junctions. ∝ (ΔT)2 . At a moPSD scaled as the inverse of the square of the conductance like PSD ∝ G−2, which was explained by stronger dipolar interactions affecting the tunneling barrier in the FSAM. In addition, the frequency dependence of noise PSD showed 1/f2 behavior in the HSAM, whereas the FSAM showed a deviation, exhibiting 1/f1.7 dependence that could be attributed to the strong dipole formation slowing down the tunneling process. We observed asymmetrical current and noise only in the FSAM, owing to the strong dipole formation. Interestingly, at high biases, the conduction in HSAM and FSAM molecular wires showed the transition from tunneling to thermionic transports, which was reflected in the positive correlation of the noise PSD with conductance like PSD ∝ G2. Our results provide valuable insights about dipole noise generations in molecular wires with polarization, which could be helpful in understanding the charge transports and noise properties of molecular devices. Furthermore, we can expect that this strategy may be extended to the development of new methods for the analyses of other molecular wires with versatile non-linear behaviors such as memory effects and phonons.In summary, we report a strategy to directly map the effects of dipolar interactions on electrical transport and noise in the self-assembled monolayers (SAMs) of molecular wires. In this strategy, the current and noise images were measured simultaneously on molecular wire patterns by using a conducting probe. Then, the maps were analyzed to extract characteristic parameters of dipolar noises. The FSAM molecular junctions exhibited the molecular resistance comparable with the HSAM of nearly six times longer in length, which could be due to the strong dipole formations in the FSAM obstructing the charge conduction. Furthermore, in the FSAM, the normalized noise-


Endometrial cancer (EC) is one of the most common gynecological malignancies in Western countries. Traditionally, loco-reginal dissemination and histological characteristics are the main prognostic factors. Nowadays, molecular and genomic profiling showed exciting results in terms of prognostication. According to the data provided by The Cancer Genome Atlas and other studies, molecular and genomic profiling might be useful in identifying patients al low, intermediate, and high risk of recurrence. However, data regarding the therapeutic value are scant. Several prospective studies are ongoing to identify the most appropriate adjuvant strategy in EC patients, especially for those with positive nodes and low volume disease. The molecular classification has offered the possibility to improve the risk stratification and management of EC. The aim of this review is to focus on the evolution of molecular classification in EC and its impact on the research approach and on clinical management. Molecular and genomic profiling might be useful to tailor the most appropriate adjuvant strategies in apparent early-stage EC. In developed countries, endometrial cancer (EC) is the most common gynecological malignancy ,2 and onCurrently, the gold standard of therapy includes extrafascial hysterectomy with bilateral salpingo-oophorectomy (BSO) with eventual adjuvant therapy decided based on the class of the risk of developing recurrences (chemotherapy and/or radiotherapy and/or brachytherapy). Moreover, in recent years, there has been widespread agreement on the evaluation of lymph node status through the removal of the first lymph node that drains the tumor  ,6.Molecular classification and traditional clinicopathological prognostic factors represent the mainstay of risk classification and are correlated with prognosis, clinical management, and the personalization of patient therapy ,8,9.Therapies that target molecules responsible for carcinogenesis have been elaborated for several decades, and to this day, the use of treatments that focus on molecular aberrations of the malignant tumors is considered one of the best treatment options for promising outcomes ,8,9. RecWe provide a critical assessment of the impact of molecular/genomic profiling in EC, focusing on current implications and further perspectives.In November 2022, an extensive literature search was conducted by different authors to identify relevant trials on various databases . We selected all articles including the following key criteria: “carcinoma”, “endometrial cancer”, “molecular”, “genetics”, “target therapy”, and “personalized treatment”. No filter on the year of publication was set. The selected articles were rigorously reviewed and evaluated to identify studies that potentially meet the aims of this review.Key criteria for inclusion were: (1) articles in English, (2) original studies that dealt with the molecular classification of endometrial cancer, (3) studies evaluating EC management based on molecular classification, (4) studies analyzing the prognostic role of new molecular markers, and (5) studies comparing different adjuvant therapy in four molecular subclasses.Letters, editorials, and case reports were excluded from this review. The studies that met the inclusion and exclusion criteria were further analyzed, and relevant data were extracted and analyzed for each paper. Any discrepancies between the investigators were resolved through a consensus approach.In 1983, Bokhman introduced the historic pathogenetic classification of endometrial cancer that divided EC into type I and type II . Type 1 Now, EC can be divided into four prognostically relevant groups based on the type of mutations and somatic copy-number variations, genome, and exome sequencing, and microsatellite instability (MSI) assay:  polymeraWhile the TCGA study was innovative and extremely precise in characterizing patient with EC, the main drawbacks were complexity, cost and impracticality in clinical practice. Over the years, practical methodologies were developed to create a model called ProMisE  based on the Institute of Medicine (IOM) guidelines. This model, validated on a large cohort of patients, includes several steps in creating a molecular decision tree analysis.The first step is the determination through immunohistochemistry (IHC) of the presence or absence of two mismatch repair (MMR) proteins: mutS homolog 6 (MSH6) and PMS2. If the analysis does not detect the presence of these proteins, EC is classified into a MMR-deficient (dMMR) subgroup. If MMR proteins are physiologically expressed, the sample is further analyzed, using PCR to identify POLE exonuclease domain mutation (“POLE EDM”). If these mutations are present, the analysis stops and is classified within the POLE ultramutated group.In case of the absence of these mutations, the last step is to use IHC for the p53 status, wild type, or null/missense mutations ,22,23.To date, it is recommended to perform molecular analysis on all endometrial carcinomas according to the algorithm described. The decision to perform molecular testing depends on the resources and arrangements of each center’s disciplinary team . The maiMutations in the following genes were analyzed: B-Raf proto-oncogene (BRAF), cyclin-dependent kinase inhibitor 2A (CDKNA2), catenin beta 1 (CTNNB1), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), forkhead box L2 (180 FOXL2), HRAS, KRAS, NRAS, PIK3CA, protein phosphatase 2 scaffold subunit alpha (PPP2R1A), PTEN; also the expression of ER, PR, β-catenin, AT-rich interaction domain 1A (ARID1a) and L1 cell adhesion molecule (L1CAM) were studied. The main differences between the four molecular subgroups are clinicopathological and molecular features that reflect different clinical outcomes. The tumor with P53 mutation had unfavorable prognosis, with more than 10% L1CAM expression, PPP2R1a, and FBXW7 mutations, and histologic grade 3, without hormone receptor expression. MSI tumors and no specific molecular profile (NSMP) group tumors have an intermediate prognosis. The first presented more frequently LVSI and ARID1a abnormal expression. The second was frequently graded 1 with CTNNB1 mutant. The last group with POLE mutations had a favorable prognosis that occurred more frequently in younger women, even if associated with grade 3 and PTEN mutations. Univariable analysis and multivariable analyses showed that p53-mutant, substantial LVSI, and more than 10% L1CAM expression were the strongest prognostic factors for increased risk of recurrence and decreased overall survival. In addition, EC patients carrying CTNNB1 exon 3 mutations had an increased risk of distant recurrence. Estrogen receptor (ER) positivity, phosphatidylInositol 3-Kinase/protein-kinase B (PI3K/AKT) mutations, progesterone receptor (PR) positivity, and L1CAM positivity are molecular characteristics found in tumors with worse prognosis, respectively, in 78%, 65%, 61%, and 28% and less frequently mutation of FBXW7 and FGFR2 genes in 9% and 7% of cases. These subgroups with precise molecular subtyping are particularly useful in G3 ECs and all high-risk ECs ,27,28. BHigh-risk endometrial cancers are a heterogeneous group of tumors, including non-endometrioid histotypes, with different molecular alterations and clinical outcomes. In addition to classifying these tumors into the four molecular subgroups, identifying other alterations in potentially target pathways, such as in PI3K-AKT or FBXW7-FGFR2 pathways, is useful, especially those with the worst prognosis such as p53-mutant or NSMP and the non-endometrid histotype. Further studies with a large cohort of patients are needed to determine whether these additional target pathways can have a validated clinical–therapeutic role and improve survival ,32,33.A topic still debated today is the role of breast cancer gene 1 (BRCA1) and BRCA2 mutations on the developing EC. The women who carried a pathogenic variant of BRCA1 and BRCA2 had a lifetime risk of breast and ovarian cancer of 40–80% and 11–40%, respectively . Data avStarting from this strong scientific evidence, in recent years, EC therapy is increasingly becoming personalized for the various subclasses. Indeed, as demonstrated by a phase III study, patients classified in the low-risk category (POLE-mutated) with early-stage disease (FIGO stage I–II) do not need adjuvant treatment because of the low recurrence rate recorded, while inconclusive data are available for advanced stages ,40; inteAlthough various studies are ongoing, no level A evidence supported the use of mutational and genomic profiling in selecting adjuvant treatments in patients with early-stage disease. To date, the MSI status has implications in selecting the most appropriate therapies in the metastatic setting ,43.Programmed Death Ligand1 (PD-L1) and Programmed Death-1 (PD-1) are two of the immune checkpoint-associated proteins, and these are targets of immunotherapy drugs used in various types of cancer. These proteins are expressed at high levels within the tumor microenvironment and help cancer cells escape immunosurveillance. Drugs against these proteins make cancer cells susceptible to immune system response . A PhaseFrom data of the KEYNOTE-028, Patrick et al. and O’Malley et al. confirmed these results encouraging survival outcomes ,47. OtheOakin et al. reported preliminary data from the phase I GARNET trial, currently ongoin, which is investigating the efficacy of dostarlimab in both dMMR/MSI-H AND proficient/stable (MMRp/MSS) EC patients. The ORR is 43.1% with a good duration of response (DCR) and a manageable safety profile . TherapyThere is a growing unmet need to identify the most appropriate adjuvant strategy in EC patients, especially for those with positive nodes and low-volume disease ,59. SeveAmong the most important clinical trials, there is the RAINBO—umbrella program, which investigating new adjuvant therapies in EC patients. In this trial, EC patients are set in one of the four RAINBO trials depending on their cancer’s molecular profile. The p53abn-RED is an international, multicenter, phase III randomized trial that comprises the p53-mut treated with adjuvant chemoradiation and Olaparib for two years versus adjuvant chemoradiation only. The MMRd-GREEN trial is an international, multicenter, phase III randomized study for MMRd EC patients that brings into comparison adjuvant pelvic external beam radiotherapy and Durvalumab for one year with adjuvant pelvic external beam radiotherapy alone. The NSMP-ORANGE trial is for no specific molecular profile EC patients that are treated with adjuvant pelvic external beam radiotherapy followed by oral progestins (medroxyprogesterone acetate or megestrol acetate) for two years. The last is a POLEmut-BLUE trial for POLE mutant EC patients. The POLEmut-BLUE trial is an international, multicenter, single-arm, phase II trial that investigates the safety of de-escalation of adjuvant therapy. In particular, patients with stage I and II no receive adjuvant therapy and patients with stage III receive pelvic external beam radiotherapy or no receive adjuvant therapy. The aim of the whole RAINBO research is to associate data and tumor material of the four RAINBO clinical trials to make translational research and compare molecular profile-based adjuvant therapy to standard adjuvant therapy according to means of effectiveness, toxicity, quality of life, and cost-utility .Additionally, PORTEC-4a is investigating various treatment modalities in stage I–II high-intermediate risk EC patients based on their molecular profile . Other pEndometrial carcinoma has an altogether favorable prognosis. The surgical approach, when applicable, depending on the tumor extent and on the preoperative evaluation of the patient’s fragility is the mainstay of early treatment for EC ; on the Since endometrial carcinoma represents an emerging disease, also in patients in pre-menopause and where the age of the first pregnancy tends to be older, molecular analysis could also be used to choose the therapeutic strategy for the conservative treatment of lesions that anticipate EC. Zhang et al. in a retrospective analysis of 59 patients with EC and endometrial atypical hyperplasia/endometrial intraepithelial neoplasia (EAH/EIN) evaluated how molecular classification might predict response to conservative treatment and which subclasses are at the highest risk of evolution. The complete response was 100% in the POLEmut group and 71.43% in copy number-low mutation (CNL), demonstrating a good prognosis for these subgroups. However, the prognosis of copy number-high mutation (CNH) and the MSI-H group was significantly worse with 33.3% and 25% of complete response, respectively . In anotThe molecular classification has offered the possibility to improve the risk stratification and management of EC. In recent years, various treatments, including chemotherapy, radiation therapy, immune checkpoint, and molecular targeting therapy, have been studied to obtain tailored therapy according to clinical data and molecular-genetics characteristics. High response rates are observed from the results of various trials about the efficacy of immune checkpoint inhibitors, especially in patients with dMMR. Therefore, in recent years, various agents have been studied in monotherapy and combination with chemotherapy or other molecules, confirming their good effectiveness. Perhaps in the next few years, the results of ongoing studies will define these agents as the new first-line treatment standard in advanced or recurrent EC and compare radiation therapy with radiation therapy plus checkpoint inhibition.The p53 group has the worst prognosis among all EC subgroups, although it represents a small percentage of cases. Therefore, new therapeutic strategies have shown promising results. PARP inhibitors act on homologous recombination deficits, and specific antibodies may act in tumors with the overexpression of human epidermal growth factor receptor 2 (HER2) . Ongoing


Kabuki Syndrome (KS) is a rare genetic disorder characterized by dysmorphic facial features, skeletal anomalies, dermatoglyphic abnormalities, intellectual disability, and short stature. Autoimmune disease can be seen more frequently in this patient population. Vitiligo is an autoimmune disease that is uncommonly reported in patients with KS. This report describes a case of vitiligo manifesting in a patient with KS and discusses the use of Janus kinase inhibitors as treatment. Kabuki Syndrome (KS), also known as Niikawa-Kuroki syndrome, is a rare genetic disorder characterized by dysmorphic facial features, skeletal anomalies, dermatoglyphic abnormalities, intellectual disability, and short stature . The chaThe estimated prevalence of KS varies between 1:32,000 births in Japan and 1:86,000 births in New Zealand and Australia . VitiligA 5-year-old female presents to dermatology for a one-year duration of increasing, asymptomatic light patches on her skin. Further history reveals the patient has Kabuki Syndrome discovered by whole exome sequencing which found a pathogenic variant in the KMT2D gene Table . This muUpon examination, there are many coalescing depigmented patches on the patient’s neck, trunk, and extremities Figures -4. The fAt a four-month follow-up visit, there was no improvement in the vitiligo lesions Figures -8. TreatIn 2018, Adam et al. published the diagnostic criteria for KS in collaboration with an international group of experts. This group established that a definite diagnosis of KS can be made in patients with a history of infantile hypotonia, developmental delay, and/or intellectual disability with at least one of the following major criteria: a pathogenic or likely pathogenic variant in KMT2D or lysine-specific demethylase 6 A (KDM6A) or typical dysmorphic facial features . The typWhile KMT2D is the most common mutation, KDM6A is mutated in about five percent of KS individuals. These genes are involved in a complex of proteins associated with COMPASS, or complex of proteins associated with Set1, which modifies epigenetic marks on histones during chromatin remodeling ,6.Autoimmune disorders have been reported with an increased frequency in patients with KS. The most common autoimmune disease reported is ITP . AutoimmVitiligo is commonly treated with topical corticosteroids and calcineurin inhibitors, both of which promote re-pigmentation. Systemic steroids are effective to stabilize an uncontrolled disease. Light therapy can also be used, with narrow-band ultraviolet B (nbUVB) being shown to decrease vitiligo lesions with fewer adverse effects compared to psoralen plus ultraviolet A (PUVA) phototherapy. NbUVB phototherapy can also be used in combination with topical therapies for an additive effect . The dowJanus kinase (JAK) inhibitors have recently been researched in the treatment of vitiligo. JAK inhibitors target the JAK/signal transducer and activator of transcription (STAT)-1 signaling pathway. The JAK/STAT pathway is involved in interferon-gamma and chemokine secretion by keratinocytes which recruit CXCR3+ CD8+ T cells that promote melanocyte detachment and apoptosis. Targeting this pathway has been shown to be effective in blocking interferon-gamma signaling, contributing to re-pigmentation of vitiligo lesions. Ruxolitinib is a selective JAK1 and JAK2 inhibitor. Oral ruxolitinib was first approved in 2011 for the treatment of polycythemia vera, essential thrombocytopenia, and myelofibrosis. Systemic effects of JAK inhibitors include an increased incidence of malignancy, serious infections, and thrombosis based on data from oral use in rheumatoid arthritis. When applied topically, ruxolitinib has resulted in higher medicinal concentrations in the epidermis and dermis with minimum systemic effects . ResultsIn conclusion, KS is a rare genetic disorder with a variety of clinical manifestations. Autoimmune conditions such as vitiligo are seen more frequently in KS patients. In a patient presenting with vitiligo and dysmorphic facial features, healthcare providers should have a clinical suspicion for KS and perform a thorough review of symptoms. More research is needed on the use of topical JAK inhibitors in children as this medication has minimal systemic adverse effects and has worked in patients that failed standard treatment methods.


Communications Chemistry.Hear from Professor Nathalie Katsonis on her academic journey and passions, her thoughts on the future directions of chemical research, and her experience of being an Editorial Board Member for  Nathalie Katsonis received her MSc (2001) and PhD (2004) degrees from the University Pierre et Marie Curie . Her investigations of the interplay between motion, light and molecular machines started in the group of Ludovic Jullien, where she synthesized an analogue of the chromophore that initiates the flagellar movement of purple bacteria, and studied its photochemistry. For her postdoctoral research she moved to the group of Ben Feringa to investigate chirality and order in supramolecular assemblies.Her independent career started in 2007 as Associate Researcher for the French National Center for Scientific Research. In 2008 she was invited back to Groningen to work with Feringa on artificial molecular motors and switches. In 2011 she took up a tenure-track position at the MESA + Institute for Nanotechnology at the University of Twente (the Netherlands), where she was promoted to Associate Professor in 2014 and to Full Professor in ‘Bio-inspired and Smart Materials’ in 2017. In March 2020 she joined the Stratingh Institute of Chemistry of the University of Groningen (the Netherlands), as Professor of chemistry, founding the group ‘Active Molecular Systems and Materials’.Katsonis has led the way in transmitting directed molecular motion across length scales, with a special focus on the role of chirality and on the effects of mechanically relevant motion of molecular machines. She has recently developed an interest in the motion of supramolecular compartments in fluids. A central objective of this program is to create droplets, vesicles, and other microcompartments that can move autonomously by using metabolic energy. Her achievements have provided the underpinnings for increasingly complex functionalities in dynamic and ultimately life-like supramolecular materials.Why did you choose to be a scientist?Becoming a scientist has always been evident for me, so I don’t believe it was a conscious decision on my part. I did, however, choose chemistry deliberately. My mother is both a mathematician and economist, and my father is a physicist, so I believe that by choosing chemistry I demonstrated originality! Chemistry was my strongest subject, but I also enjoyed it more because I felt that if I created the objects of my own study, I would have more room for creativity. This impression was ultimately confirmed.In the French system at the time, engineering schools, known as “Grandes Ecoles”, were the typical entry point for students interested in science. I succeeded the entrance examinations of Chimie Paris, which is luckily for me a very research-oriented school. The focus suited me well, and I made some excellent friends there. I felt truly fulfilled after enrolling in the Master of condensed matter at the University that was at the time called “Université Pierre et Marie Curie”. Among other teachers, I had a special appreciation for Ludovic Jullien; his views have irreversibly shaped the way I see chemistry and I published my first paper with him too.What scientific development are you currently most excited about?There are so many exciting things happening now — I feel it’s a golden age for chemistry. Developing RNA vaccines and all the associated research and development would be my most obvious response. There is a great deal of chemistry involved, as the RNA is fragile and must be enclosed in a synthetic lipid-based fat bubble. The need for lipid transfer bubbles has prompted a wealth of exciting research on the synthesis and self-assembly features of lipids.Active and passive mass transport properties—at the molecular level and above—are also the focus of new research sparked by this development. Mass transport has, of course, been extensively studied at the macroscopic level and in bulk systems. In contrast, using molecular design allows controlling mass transport in supramolecular systems and guiding interactions between large ensembles of molecules with specific functions—what we refer to as complex molecular systems. My personal feeling is that controlling active mass transport at intermediate length scales offers tremendous opportunities for the future.What direction do you think your research field should go in?I believe that the development of artificial intelligence will have a significant impact on all research fields, including chemistry. We are currently experiencing a paradigm shift, where we go from a traditional way of doing chemistry, towards automatized laboratories where the production of large data sets will be coupled to artificial intelligence, to aid discovery. The effectiveness of these approaches will also facilitate major steps towards sustainable formulations and a circular chemical industry. Such a change of paradigm impacts academic research, chemical industries, and also education – it implies that we will change the minds of educators, and altogether it’s a very exciting time for the chemistry community. We can’t be sure where it will lead us, but there is a general trend and every day we discover new things along the way.Communications Chemistry? What have you gotten out of the experience?What attracted you to becoming an Editorial Board Member for Communications Chemistry after being asked by a former PhD student of Steve Fletcher, who was Associate Editor at the time. I always have had relations of trust with Andrew and therefore I was inclined to accept the invitation. I see my task as contributing to building a community in the fields of molecular machines and systems chemistry and bringing people together, so they can become more than the sum of their parts.I view my position on the Editorial Board as a chance to contribute to shaping the future of chemistry, if only on a small scale. I specifically chose to contribute to How do your editorial responsibilities integrate with your academic role?As scientists we bear responsibility towards society—we educate, we communicate, and also we work on scientific problems that are relevant for both chemistry and society. If one is isolated, it is not always easy to have a feeling for what is relevant. Editorial responsibilities keep you alert in terms of broader interests, what is relevant, where chemistry should go. Beyond my own community, the work keeps me engaged with the whole chemistry community.Communications Chemistry in the scientific community?What do you see as the role of Communications Chemistry embraces the possibility to do things differently—it promotes open access publication, maintains close collaboration between Editorial Board Members and professional editors to exchange good practices and different ways of doing things, offers the possibility to publish valuable, solid and sound chemistry. The journal also tries original initiatives, like supporting young investigators financially to attend conferences or acknowledging reviewer’s work with reviewer of the month nominations.Within the Nature Portfolio, This interview was conducted by the editors of Communications Chemistry.