Artificial Neurons on Flexible Substrates: A Fully Printed Approach for Neuromorphic Sensing.

Printed electronic devices have demonstrated their applicability in complex electronic circuits. There is recent progress in the realization of neuromorphic computing systems (NCSs) to implement basic synaptic functions using solution-processed materials. However, a fully printed neuron is yet to be realised. We demonstrate a fully printed artificial neuromorphic circuit on flexible polyimide (PI) substrate. Characteristic features of individual components of the printed system were guided by the software training of the NCS. The printing process employs graphene ink for passive structures and In2O3 as active material to print a two-input artificial neuron on PI. To ensure a small area footprint, the thickness of graphene film is tuned to target a resistance and to obtain conductors or resistors. The sheet resistance of the graphene film annealed at 300 °C can be adjusted between 200 Ω and 500 kΩ depending on the number of printed layers. The fully printed devices withstand a minimum of 2% tensile strain for at least 200 cycles of applied stress without any crack formation. The area usage of the printed two-input neuron is 16.25 mm2, with a power consumption of 37.7 mW, a propagation delay of 1 s, and a voltage supply of 2 V, which renders the device a promising candidate for future applications in smart wearable sensors.

Supporting Underrepresented in Medicine (UIM) and non-UIM Trainees Applying into Dermatology: A Qualitative Analysis.

BACKGROUND: Recently, there have been calls to improve diversity among the dermatology workforce, with emphasis placed on the resident selection process and trainee pipeline. However, there is limited data on the perspectives of dermatology applicants, especially among UIM trainees, and the support that they need and want to successfully apply in dermatology. METHODS: To assess trainee perspectives, we disseminated a survey to medical students, interns (matched into dermatology), and dermatology residents asking how dermatology residency programs can best support trainees through the dermatology application process. We developed a codebook drawing upon grounded theory methodology, and consensus coded all qualitative responses. RESULTS: We received 224 qualitative responses from underrepresented in medicine (UIM) (65, 29.0%) and non-UIM trainees (159, 70.9%). UIM trainees were more likely to mention diversity and inclusion initiatives (46.2% vs 3.8%, P<0.001), transparency in program information (40.0% vs 24.5%, P=0.021), holistic review (30.8% vs 6.3%, P<0.001), UIM student outreach/pipeline programs (23.1% vs 0.6%, P<0.001), and mentorship (21.5% vs 8.2%, P=0.009). CONCLUSION: Improving programmatic efforts to address unique challenges UIM trainees face when applying into dermatology is instrumental to mitigating barriers. We highlight opportunities for dermatology residency programs to create a more fair and equitable dermatology application process and support a more diverse pipeline of future dermatologists. J Drugs Dermatol. 2021;20(7):795-797. doi:10.36849/JDD.6043.

Light-controlled modulation of gene expression by chemical optoepigenetic probes.

Epigenetic gene regulation is a dynamic process orchestrated by chromatin-modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small-molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatiotemporal control. Here we present a generalizable approach, referred to as 'chemo-optical modulation of epigenetically regulated transcription' (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may be translated into new therapeutic strategies for diseases where conditional and selective epigenome modulation is required.

Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation.

Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease.

Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors.

The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications.

Monoalkoxy BODIPYs--a fluorophore class for bioimaging.

Small molecule fluorophores are indispensable tools for modern biomedical imaging techniques. In this report, we present the development of a new class of BODIPY dyes based on an alkoxy-fluoro-boron-dipyrromethene core. These novel fluorescent dyes, which we term MayaFluors, are characterized by good aqueous solubility and favorable in vitro physicochemical properties. MayaFluors are readily accessible in good yields in a one-pot, two-step approach starting from well-established BODIPY dyes, and allow for facile modification with functional groups of relevance to bioconjugate chemistry and bioorthogonal labeling. Biological profiling in living cells demonstrates excellent membrane permeability, low nonspecific binding, and lack of cytotoxicity.

Entropy for q-rung linear diophantine fuzzy hypersoft set with its application in MADM.

A notable advancement in fuzzy set theory is the q-rung linear diophantine fuzzy set. The soft set theory was expanded into the hypersoft set theory. By combining both the q-rung linear diophantine fuzzy set and hypersoft set, this study describes the notion of q-rung linear diophantine fuzzy hypersoft set that can handle multi sub-attributed q-rung linear diophantine fuzzy situations in the real world. Furthermore, some of its algebraic operations such as union, intersection and complement are described in this study. In addtion, the entropy measure of the q-rung linear diophantine fuzzy hypersoft set is established as it is helpful in determining the degree of fuzziness of q-rung linear diophantine fuzzy hypersoft sets. A multi-attribute decision making algorithm based on suggested entropy is presented in this study along with a numerical example of selecting a suitable wastewater treatment technology to demonstrate the effectiveness of the proposed algorithm in real-life situations. A comparative study was undertaken that describes the validity, robustness and superiority of the proposed algorithm and notions by discussing the advantages and drawbacks of existing theories and algorithms. Overall, this study describes a novel fuzzy extension that prevails over the existing ones and contributes to the real world with a valid real-life multi-attribute decision making algorithm that can cover many real-world problems that are unable to be addressed by the existing methodology.

Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia.

Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.

Antibiotic adherence in dermatologic surgery: a Multicenter prospective cohort study.

Understanding patient non-adherence to prescribed antibiotics can inform clinical practices, patient counseling, and antibiotic efficacy study design in dermatology. The primary objective was to determine the rate of and reasons for antibiotic non-adherence in the dermatologic surgery setting. The secondary objective was to test the applicability of previously studied survey questions for antibiotic non-adherence screening in the dermatologic surgery setting. Five academic outpatient dermatologic surgery centers across the United States conducted one multicenter prospective cohort study. Dermatologic surgery patients ≥ 18 years of age who were prescribed an antibiotic were included as part of this study. 15.2% (42/276) of patients did not adhere to their antibiotic regimen after dermatologic surgery. Most common reasons for incomplete antibiotic courses included forgotten antibiotics (42.9%,18/42) and side effects (28.6%, 12/42). Previously evaluated questions to identify and predict non-adherence had modest performance in the dermatologic surgery setting (Area under the curve of 0.669 [95% CI (0.583-0.754)]). Antibiotic non-adherence after skin surgery is prevalent and commonly due to reasons that physicians can address with patients.

Striatal neurons expressing full-length mutant huntingtin exhibit decreased N-cadherin and altered neuritogenesis.

The expanded CAG repeat that causes striatal cell vulnerability in Huntington's disease (HD) encodes a polyglutamine tract in full-length huntingtin that is correlated with cellular [ATP] and [ATP/ADP]. Since striatal neurons are vulnerable to energy deficit, we have investigated, in Hdh CAG knock-in mice and striatal cells, the hypothesis that decreased energetics may affect neuronal (N)-cadherin, a candidate energy-sensitive adhesion protein that may contribute to HD striatal cell sensitivity. In vivo, N-cadherin was sensitive to ischemia and to the effects of full-length mutant huntingtin, progressively decreasing in Hdh(Q111) striatum with age. In cultured striatal cells, N-cadherin was decreased by ATP depletion and STHdh(Q111) striatal cells exhibited dramatically decreased N-cadherin, due to decreased Cdh2 mRNA and enhanced N-cadherin turnover, which was partially normalized by adenine supplementation to increase [ATP] and [ATP/ADP]. Consistent with decreased N-cadherin function, STHdh(Q111) striatal cells displayed profound deficits in calcium-dependent N-cadherin-mediated cell clustering and cell-substratum adhesion, and primary Hdh(Q111) striatal neuronal cells exhibited decreased N-cadherin and an abundance of immature neurites, featuring diffuse, rather than clustered, staining for N-cadherin and synaptic vesicle markers, which was partially rescued by adenine treatment. Thus, mutant full-length huntingtin, via energetic deficit, contributes to decreased N-cadherin levels in striatal neurons, with detrimental effects on neurite maturation, strongly suggesting that N-cadherin-mediated signaling merits investigation early in the HD pathogenic disease process.

Patient Preferences for Pain Control After Mohs Micrographic Surgery: A Single-Center Discrete Choice Experiment.

Importance: Patient preferences for pain medications after Mohs micrographic surgery are important to understand and have not been fully studied. Objective: To evaluate patient preferences for pain management with only over-the-counter medications (OTCs) or OTCs plus opioids after Mohs micrographic surgery given varying levels of theoretical pain and opioid addiction risk. Design, Setting, and Participants: This prospective discrete choice experiment was conducted in a single academic medical center from August 2021 to April 2022 among patients undergoing Mohs surgery and their accompanying support persons (≥18 years). A prospective survey was administered to all participants using the Conjointly platform. Data were analyzed from May 2022 to February 2023. Main outcome and measure: The primary outcome was the pain level at which half of the respondents chose OTCs plus opioids equally to only OTCs for pain management. This pain threshold was determined for varying opioid addiction risk profiles (low, 0%; low-moderate, 2%; moderate-high, 6%; high, 12%) and measured via a discrete choice experiment and linear interpolation of associated parameters (pain levels and risk of addiction). Results: Of the 295 respondents (mean [SD] age, 64.6 [13.1] years; 174 [59%] were female; race and ethnicity were not considered) who completed the discrete choice experiment, 101 (34%) stated that they would never consider opioids for pain management regardless of the pain level experienced, and 147 (50%) expressed concern regarding possible opioid addiction. Across all scenarios, 224 respondents (76%) preferred only OTCs vs OTCs plus opioids after Mohs surgery for pain control. When the theoretical risk of addiction was low (0%), half of the respondents expressed a preference for OTCs plus opioids given pain levels of 6.5 on a 10-point scale (90% CI, 5.7-7.5). At higher opioid addiction risk profiles (2%, 6%, 12%), an equal preference for OTCs plus opioids and only OTCs was not achieved. In these scenarios, patients favored only OTCs despite experiencing high levels of pain. Conclusion and relevance: The findings of this prospective discrete choice experiment indicate that the perceived risk of opioid addiction affects the patient's choice of pain medications after Mohs surgery. It is important to engage patients undergoing Mohs surgery in shared decision-making discussions to determine the optimal pain control plan for each individual. These findings may encourage future research on the risks associated with long-term opioid use after Mohs surgery.