Changes in source contributions to the oxidative potential of PM2.5 in urban Xiamen, China.

The toxicity of PM2.5 does not necessarily change synchronously with its mass concentration. In this study, the chemical composition (carbonaceous species, water-soluble ions, and metals) and oxidative potential (dithiothreitol assay, DTT) of PM2.5 were investigated in 2017/2018 and 2022 in Xiamen, China. The decrease rate of volume-normalized DTT (DTTv) (38%) was lower than that of PM2.5 (55%) between the two sampling periods. However, the mass-normalized DTT (DTTm) increased by 44%. Clear seasonal patterns with higher levels in winter were found for PM2.5, most chemical constituents and DTTv but not for DTTm. The large decrease in DTT activity (84%-92%) after the addition of EDTA suggested that water-soluble metals were the main contributors to DTT in Xiamen. The increased gap between the reconstructed and measured DTTv and the stronger correlations between the reconstructed/measured DTT ratio and carbonaceous species in 2022 were observed. The decrease rates of the hazard index (32.5%) and lifetime cancer risk (9.1%) differed from those of PM2.5 and DTTv due to their different main contributors. The PMF-MLR model showed that the contributions (nmol/(min·m3)) of vehicle emission, coal + biomass burning, ship emission and secondary aerosol to DTTv in 2022 decreased by 63.0%, 65.2%, 66.5%, and 22.2%, respectively, compared to those in 2017/2018, which was consistent with the emission reduction of vehicle exhaust and coal consumption, the adoption of low-sulfur fuel oil used on board ships and the reduced production of WSOC. However, the contributions of dust + sea salt and industrial emission increased.

O-glycosylation contributes to mammalian glycoRNA biogenesis.

There is an increasing appreciation for the role of cell surface glycans in modulating interactions with extracellular ligands and participating in intercellular communication. We recently reported the existence of sialoglycoRNAs, where mammalian small RNAs are covalently linked to N-glycans through the modified base acp3U and trafficked to the cell surface. However, little is currently known about the role for O-glycosylation, another major class of carbohydrate polymer modifications. Here, we use parallel genetic, enzymatic, and mass spectrometry approaches to demonstrate that O-linked glycan biosynthesis is responsible for the majority of sialoglycoRNA levels. By examining the O-glycans associated with RNA from cell lines and colon organoids we find known and previously unreported O-linked glycan structures. Further, we find that O-linked glycans released from small RNA from organoids derived from ulcerative colitis patients exhibit higher levels of sialylation than glycans from healthy organoids. Together, our work provides flexible tools to interrogate O-linked glycoRNAs (O-glycoRNA) and suggests that they may be modulated in human disease.

Where do neurodevelopmental conditions fit in transdiagnostic psychiatric frameworks? Incorporating a new neurodevelopmental spectrum.

Features of autism spectrum disorder, attention-deficit/hyperactivity disorder, learning disorders, intellectual disabilities, and communication and motor disorders usually emerge early in life and are associated with atypical neurodevelopment. These "neurodevelopmental conditions" are grouped together in the DSM-5 and ICD-11 to reflect their shared characteristics. Yet, reliance on categorical diagnoses poses significant challenges in both research and clinical settings (e.g., high co-occurrence, arbitrary diagnostic boundaries, high within-disorder heterogeneity). Taking a transdiagnostic dimensional approach provides a useful alternative for addressing these limitations, accounting for shared underpinnings across neurodevelopmental conditions, and characterizing their common co-occurrence and developmental continuity with other psychiatric conditions. Neurodevelopmental features have not been adequately considered in transdiagnostic psychiatric frameworks, although this would have fundamental implications for research and clinical practices. Growing evidence from studies on the structure of neurodevelopmental and other psychiatric conditions indicates that features of neurodevelopmental conditions cluster together, delineating a "neurodevelopmental spectrum" ranging from normative to impairing profiles. Studies on shared genetic underpinnings, overlapping cognitive and neural profiles, and similar developmental course and efficacy of support/treatment strategies indicate the validity of this neurodevelopmental spectrum. Further, characterizing this spectrum alongside other psychiatric dimensions has clinical utility, as it provides a fuller view of an individual's needs and strengths, and greater prognostic utility than diagnostic categories. Based on this compelling body of evidence, we argue that incorporating a new neurodevelopmental spectrum into transdiagnostic frameworks has considerable potential for transforming our understanding, classification, assessment, and clinical practices around neurodevelopmental and other psychiatric conditions.

Nanoporous amorphous carbon nanopillars with lightweight, ultrahigh strength, large fracture strain, and high damping capability.

Simultaneous achievement of lightweight, ultrahigh strength, large fracture strain, and high damping capability is challenging because some of these mechanical properties are mutually exclusive. Here, we utilize self-assembled polymeric carbon precursor materials in combination with scalable nano-imprinting lithography to produce nanoporous carbon nanopillars. Remarkably, nanoporosity induced via sacrificial template significantly reduces the mass density of amorphous carbon to 0.66 ~ 0.82 g cm-3 while the yield and fracture strengths of nanoporous carbon nanopillars are higher than those of most engineering materials with the similar mass density. Moreover, these nanopillars display both elastic and plastic behavior with large fracture strain. A reversible part of the sp2-to-sp3 transition produces large elastic strain and a high loss factor (up to 0.033) comparable to Ni-Ti shape memory alloys. The irreversible part of the sp2-to-sp3 transition enables plastic deformation, leading to a large fracture strain of up to 35%. These findings are substantiated using simulation studies. None of the existing structural materials exhibit a comparable combination of mass density, strength, deformability, and damping capability. Hence, the results of this study illustrate the potential of both dense and nanoporous amorphous carbon materials as superior structural nanomaterials.

In Vivo Raman Spectroscopy of Muscle Is Highly Sensitive for Detection of Healthy Muscle and Highly Specific for Detection of Disease.

Raman spectroscopy of muscle provides a molecular fingerprint to identify the disease. Previous work has demonstrated effectiveness in differentiating between two groups of equal sizes (e.g., healthy vs disease) but imbalanced multiclass scenarios are more common in medicine. We performed in vivo Raman spectroscopy in a total of 151 mice across four different histopathologies (healthy, acute myopathy, chronic myopathy, neurogenic), with variable numbers in each (class "imbalance"). Using hierarchical modeling and synthetic data generation, we demonstrate high sensitivity (94%) for detection of healthy muscle and high specificity (≥97%) for disease. Further, we demonstrate the potential for unique biomarker development by demonstrating variations in the protein structure across different pathologies. The findings demonstrate the potential of Raman spectroscopy to provide accurate disease identification and unique molecular insights.

Mass Spectrometry-Based Direct Sequencing of tRNAs De Novo and Quantitative Mapping of Multiple RNA Modifications.

Despite the extensive use of next-generation sequencing (NGS) of RNA, simultaneous direct sequencing and quantitative mapping of multiple RNA nucleotide modifications remains challenging. Mass spectrometry (MS)-based sequencing can directly sequence all RNA modifications without being limited to specific ones, but it requires a perfect MS ladder that few tRNAs can provide. Here, we describe an MS ladder complementation sequencing approach (MLC-Seq) that circumvents the perfect ladder requirement, allowing de novo MS sequencing of full-length heterogeneous cellular tRNAs with multiple nucleotide modifications at single-nucleotide precision. Unlike NGS-based methods, which lose RNA modification information, MLC-Seq preserves RNA sequence diversity and modification information, revealing new detailed stoichiometric tRNA modification profiles and their changes upon treatment with the dealkylating enzyme AlkB. It can also be combined with reference sequences to provide quantitative analysis of diverse tRNAs and modifications in total tRNA samples. MLC-Seq enables systematic, quantitative, and site-specific mapping of RNA modifications, revealing the truly complete informational content of tRNA.

Theory-Driven Behavioral Obesity Treatment and Carry-Over of Exercise-Related, to Eating-Related, Self-Regulation: Effects on Short- and Long-Term Weight/Waist Circumference Reductions.

The predominant method for treating obesity has been suggesting and providing information on a controlled diet and, to a lesser extent, increased exercise. That approach has largely failed beyond the short term for many decades as obesity rates continue to rise. Therefore, leveraging improvements in psychosocial correlates of weight-loss behaviors has sometimes been suggested instead. The aim of this study was evaluation of targeted improvements in self-regulation and self-efficacy within a theoretically derived weight-loss program. Women with obesity (N = 103) participated in a year-long community-based program emphasizing self-regulatory skills development to counter lifestyle barriers/challenges to first exercise, then controlled eating. Within a structured treatment protocol administered by community facility employees-and based on tenets of social cognitive theory, self-regulation theory, self-efficacy theory, and coaction theory-self-regulatory skills were initially developed to foster adherence to exercise. Those skills were then adapted to promote eating-behavior changes, emphasizing fruit and vegetable intake. Improvements in measures of exercise self-regulation, eating self-regulation, and self-efficacy for controlling eating, their corresponding behaviors, and weight and waist circumference were significant. Greater within-participant carry-over of changes in exercise self-regulation to eating self-regulation was significantly associated with more weight and waist circumference reductions over both 6 and 12 months. Change in eating-related self-efficacy significantly mediated those relationships. The mean weight reduction of approximately 6% indicated positive effects on obesity-related health risks. The community-based setting indicated potentials for large-scale dissemination of theory- and evidence-driven behavioral obesity treatments focused primarily on self-regulatory skills development.

Discrimination of double-click synthetic echoes by bottlenose dolphins: Effects of inter-highlight interval and phasea).

Two bottlenose dolphins (Tursiops truncatus) were trained to discriminate double-click synthetic "echoes" differing in inter-highlight interval (IHI). In the first experimental task, dolphins passively listened to background (S-) stimuli with constant IHI and responded on discriminating a change to target (S+) stimuli with a slightly increased IHI. The second task was similar, but the highlights were assigned random, frequency-independent phase angles. This phase randomization was designed to interfere with potential auditory cues from characteristic spectral interference patterns linked to IHI changes. Discrimination thresholds were higher with randomized phase when the S- stimuli had IHIs of 50-250 µs. Thresholds were highest and comparable at the longest S- IHIs of 375 and 500 µs and were independent of phase condition. Although dolphin detection of changes in highlight envelope timing can explain threshold patterns at 375 and 500 µs, this cue did not explain performance at IHIs less than the dolphin auditory temporal window of ∼250 µs. Modeling results suggested that phase manipulations eliminated the availability of a simple difference in spectral magnitudes at the shortest IHIs, but the perception of a time separation pitch cue may still explain the dolphins' observed threshold patterns.

Predicting Health Misperceptions: The Role of eHealth Literacy and Situational Perceptions.

This study sought to understand how health misperceptions develop among individuals after exposure to misinformation messages, and how eHealth literacy and situational motivation in problem solving are associated with the negative effects of misinformation exposure. We also sought to understand the differentiated effects of misinformation exposure on the four misinformation-susceptible publics. Results from two studies revealed that situational motivation was positively associated with the formation of misperceptions after misinformation exposure as well as individuals' likelihood of amplifying the misinformation message. However, eHealth literacy does not reduce misperceptions, as had been hypothesized. In fact, eHealth literacy was not significantly associated with misperceptions or with misinformation amplification likelihood. Results also provide support for the typology of misinformation-susceptible publics as misinformation-amplifying publics were the most susceptible to misinformation messages.

Comparison of Four Body Composition Methods: Circumference Measurements, Eight-Point Bioelectrical Impedance Analysis up to 500 and 1000 kHz to Dual-Energy X-Ray Absorptiometry to Measure Body Fat Percentage.

INTRODUCTION: A comparison of body composition assessments using military circumferences to bioelectrical impedance analysis (BIA) and the reference standard dual-energy X-ray absorptiometry (DEXA) can gauge effectiveness of assessments. High-frequency (500 KHz) direct segmental multifrequency bioelectrical impedance analysis (DSM-BIA) accurately calculates total water mass and body fat% (BF%), but it is unknown whether higher frequencies (1,000 KHz) increase measurement accuracy. The purpose was to compare DSM-BIA 500, DSM-BIA 1000, the DoD Circumference Method (CM), and the reference-standard DEXA. MATERIALS AND METHODS: Design: Cross sectional, observational study. Participants/Setting: A total of 62 participants from the military healthcare system (n = 25 males, 38.8 ± 11.4 years, n = 37 females 43.7 ± 15.95 years) were measured in an outpatient clinic setting. Statistical Analysis: BF% was estimated via DEXA, DSM-BIA 500, DSM-BIA 1000, and CM to identify the relationship between methods using Pearson correlation, intraclass correlation coefficients (ICCs), and Bland-Altman plots. The study was approved by the IRB from Walter Reed National Military Medical Center at Bethesda and Concordia University Chicago. RESULTS: Circumference Method BF% was moderately correlated with DSM-BIA 500 (males r = 0.63, ICC = 0.76; females r = 0.77, ICC = 0.85), DSM-BIA 1000 (males r = 0.59, ICC = 0.74; females r = 0.77, ICC = 0.85), and DEXA (males r = 0.62, ICC = 0.62; females r = 0.73, ICC = 0.82). DSM-BIA 500 BF% was strongly correlated with DSM-BIA 1000 (males r = 0.99, ICC = 0.99; females r = 0.99, ICC = 0.99) and DEXA (males r = 0.93, ICC = 0.94; females r = 0.89, ICC = 0.89). Lastly, DSM-BIA 1000 BF% was also strongly correlated with DEXA (males r = 0.93, ICC = 0.94; females r = 0.84, ICC = 0.90) (P for each reported r < 0.01). Bland-Altman analysis confirmed an overall mean bias of -1.72% CM vs. DEXA in females, indicating the tendency of CM to underestimate BF% compared to DEXA limits of agreement from -14.24 to 10.8. There was an upward slope of the linear relationship between the bias and mean of the measures (Beta = 0.34, P = 0.01). In the full cohort, there was an overall mean bias of 1.14% of CM vs. DSM BIA 1000, with CM tending to overestimate BF% compared to DSM BIA 1000 with limits of agreement -11.13 to 13.41%. There is an upward slope line of the linear relationship between the bias and the mean of the measures (Beta = 0.17, P = .03). CONCLUSION: This study found that CM BF% was moderately correlated with DSM-BIA 500 kHz, DSM-BIA 1,000 kHz BIA, and DEXA. Both DSM-BIA 500 and DSM-BIA 1,000 kHz strongly correlated well with DEXA implying that there was no further increase in correlation with increased frequency. Additionally, there was proportional bias in BF% in the female group between CM and DEXA and in the total group between CM and DSM BIA 1000.

Simultaneous modulation of pulse charge and burst period elicits two differentiable referred sensations.

Objective To investigate the feasibility of delivering multidimensional feedback using a single channel of peripheral nerve stimulation by complementing intensity percepts with flutter frequency percepts controlled by burst period modulation. Approach Two dimensions of a distally referred sensation were provided simultaneously: intensity was conveyed by the modulation of the pulse charge rate inside short discrete periods of stimulation referred to as bursts and frequency was conveyed by the modulation of the period between bursts. For this approach to be feasible, intensity percepts must be perceived independently of frequency percepts. Two experiments investigated these interactions. A series of two alternative forced choice tasks (2AFC) were used to investigate burst period modulation's role in intensity discernibility. Magnitude estimation tasks were used to determine any interactions in the gradation between the frequency and intensity percepts. Main Results The 2AFC revealed that burst periods can be individually differentiated as a gradable frequency percept in peripheral nerve stimulation. Participants could correctly rate a perceptual scale of intensity and frequency regardless of the value of the second, but the dependence of frequency differentiability on charge rate indicates that frequency was harder to detect with weaker intensity percepts. The same was not observed in intensity differentiability as the length of burst periods did not significantly alter intensity differentiation. These results suggest multidimensional encoding is a promising approach for increasing information throughput in sensory feedback systems if intensity ranges are selected properly. Significance This study offers valuable insights into haptic feedback through the peripheral nervous system and demonstrates an encoding approach for neural stimulation that may offer enhanced information transfer in virtual reality applications and sensory-enabled prosthetic systems. This multidimensional encoding strategy for sensory feedback may open new avenues for enriched control capabilities.

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. METHODS AND FINDINGS: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. INTERPRETATION: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

Cognitive outcomes following unilateral magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: findings from two cohorts.

Magnetic resonance-guided, focused ultrasound thalamotomy is a neurosurgical treatment for refractory essential tremor. This study examined cognitive outcomes following unilateral magnetic resonance-guided, focused ultrasound thalamotomy, targeting the ventral intermediate nucleus of the thalamus for essential tremor. The research was conducted at two sites: Sunnybrook Research Institute in Toronto, Canada, and West Virginia University School of Medicine Rockefeller Neuroscience Institute in West Virginia, USA. The study focused on cognitive changes at both the group and individual levels. Patients with refractory essential tremor completed cognitive testing before and after magnetic resonance-guided, focused ultrasound thalamotomy at both sites. The cognitive testing assessed domains of attention, processing speed, working memory, executive function, language and learning/memory. Postoperative changes in cognition were examined using paired t-tests and Wilcoxon signed-rank tests, as appropriate. Reliable change indices were calculated to assess clinically significant changes at the individual level. A total of 33 patients from Toronto and 22 patients from West Virginia were included. Following magnetic resonance-guided, focused ultrasound thalamotomy, there was a significant reduction in tremor severity in both cohorts. At the group level, there were no significant declines in postoperative cognitive performance in either cohort. The reliable change analyses revealed some variability at the individual level, with most patients maintaining stable performance or showing improvement. Taken together, the results from these two independent cohorts demonstrate that unilateral magnetic resonance-guided, focused ultrasound thalamotomy significantly reduces tremor severity without negatively impacting cognition at both the group and individual levels, highlighting the cognitive safety of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor.

Quality of interaction between clinicians and artificial intelligence systems. A systematic review.

Introduction: Artificial intelligence (AI) has the potential to improve healthcare quality when thoughtfully integrated into clinical practice. Current evaluations of AI solutions tend to focus solely on model performance. There is a critical knowledge gap in the assessment of AI-clinician interactions. We systematically reviewed existing literature to identify interaction traits that can be used to assess the quality of AI-clinician interactions. Methods: We performed a systematic review of published studies to June 2022 that reported elements of interactions that impacted the relationship between clinicians and AI-enabled clinical decision support systems. Due to study heterogeneity, we conducted a narrative synthesis of the different interaction traits identified from this review. Two study authors categorised the AI-clinician interaction traits based on their shared constructs independently. After the independent categorisation, both authors engaged in a discussion to finalise the categories. Results: From 34 included studies, we identified 210 interaction traits. The most common interaction traits included usefulness, ease of use, trust, satisfaction, willingness to use and usability. After removing duplicate or redundant traits, 90 unique interaction traits were identified. Unique interaction traits were then classified into seven categories: usability and user experience, system performance, clinician trust and acceptance, impact on patient care, communication, ethical and professional concerns, and clinician engagement and workflow. Discussion: We identified seven categories of interaction traits between clinicians and AI systems. The proposed categories may serve as a foundation for a framework assessing the quality of AI-clinician interactions.

The phosphorus challenge: biotechnology approaches for a sustainable phosphorus system.

Phosphorus (P) is essential for growing crops, but the supply of high-quality phosphate rock reserves used for fertilizer production is finite while losses of P from the food/waste system cause considerable environmental damage. A variety of emerging approaches in biotechnology are reviewed that hold promise for improving the sustainability of P use in the food/water systems. These include improved sensors, cell culture approaches to meat production, bio-based P adsorption and transformation strategies, advancements in understanding of polyphosphate-accumulating organisms, and new approaches involving biomineralization and anaerobic treatment. By advancing these technologies to scale, progress can be made in developing a circular phosphorus economy that improves food security while protecting drinking water and aquatic ecosystems.

Self-Assembled Antibody-Oligonucleotide Conjugates for Targeted Delivery of Complementary Antisense Oligonucleotides.

Antibody-oligonucleotide conjugate (AOC) affords preferential cell targeting and enhanced cellular uptake of antisense oligonucleotide (ASO).  Here, we have developed a modular AOC (MAOC) approach based on accurate self-assembly of separately prepared antibody and ASO modules. Homogeneous multimeric AOC with defined ASO-to-antibody ratio were generated by L-DNA scaffold mediated precise self-assembly of antibodies and ASOs. The MAOC approach has been implemented to deliver exon skipping ASOs via transferrin receptor (TfR1) mediated internalization. We discovered an anti-TfR1 sdAb that can greatly enhance nuclear delivery of ASOs. Cryo-EM structure of the sdAb-TfR1 complex showed a new epitope that does not overlap with the binding sites of endogenous TfR1 ligands. In vivo functional analyses of MAOCs with one ASO for single exon skipping and two ASOs for double exon skipping showed that both ASO concentration and exon skipping efficacy of MAOC in cardiac and skeletal muscles are dramatically higher than conventional ASOs in the transgenic Duchenne muscular dystrophy (DMD) mouse model. MAOC treatment was well tolerated in vivo and not associated with any toxicity-related morbidity or mortality. Collectively, our data suggest that the self-assembled MAOC is a viable option for broadening the therapeutic application of ASO via multi-specific targeting and delivery.

Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism.

Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory binders indicated a novel, Ca2+ competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context.

Altered bile acid and coproporphyrin-I disposition in patients with autosomal dominant polycystic kidney disease.

AIMS: Serum, liver and urinary bile acids are increased, and hepatic transport protein levels are decreased in a non-clinical model of polycystic kidney disease. Similar changes in patients with autosomal dominant polycystic kidney disease (ADPKD) may predispose them to drug-induced liver injury (DILI) and hepatic drug-drug interactions (DDIs). Systemic coproporphyrin-I (CP-I), an endogenous biomarker for hepatic OATP1B function and MRP2 substrate, is used to evaluate OATP1B-mediated DDI risk in humans. In this clinical observational cohort-comparison study, bile acid profiles and CP-I concentrations in healthy volunteers and patients with ADPKD were compared. METHODS: Serum and urine samples from healthy volunteers (n = 16) and patients with ADPKD (n = 8) were collected. Serum bile acids, and serum and urine CP-I concentrations, were quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS: Patients with ADPKD exhibited increased serum concentrations of total (1.3-fold) and taurine-conjugated (2.8-fold) bile acids compared to healthy volunteers. Specifically, serum concentrations of six bile acids known to be more hydrophobic/hepatotoxic (glycochenodeoxycholate, taurochenodeoxycholate, taurodeoxycholate, lithocholate, glycolithocholate and taurolithocholate) were increased (1.5-, 2.9-, 2.8-, 1.6-, 1.7- and 2.7-fold, respectively) in patients with ADPKD. Furthermore, serum CP-I concentrations were elevated and the renal clearance of CP-I was reduced in patients with ADPKD compared to healthy volunteers. CONCLUSIONS: Increased exposure to bile acids may increase susceptibility to DILI in some patients with ADPKD. Furthermore, the observed increase in serum CP-I concentrations could be attributed, in part, to impaired OATP1B function in patients with ADPKD, which could increase the risk of DDIs involving OATP1B substrates compared to healthy volunteers.

Inherited Basaloid Neoplasms Associated With SUFU Pathogenic Variants.

Importance: Germline SUFU pathogenic variants (PVs) have previously been associated with basal cell nevus syndrome (BCNS) and multiple infundibulocystic basal cell carcinoma syndrome; however, a broader spectrum of cutaneous findings in patients with SUFU PVs has not been well delineated. Objective: To define the clinical and histopathologic spectrum of cutaneous findings in patients with germline SUFU PVs. Design, Setting, and Participants: This case series was conducted in multiple US academic dermatology, medical genetics, and medical oncology clinics between July 2014 and July 2022. The study included patients with confirmed germline SUFU PVs who were evaluated by a dermatologist. The analysis took place from March to September 2023. Main Outcomes and Measures: Histopathologic evaluation of skin biopsies with or without immunohistochemical staining, and targeted next-generation sequencing (NGS) on tumor specimens. Results: All 5 patients were women. The mean (range) age at presentation was 50.2 (31-68) years, with skin manifestations initially appearing in the fourth to sixth decades of life. None had keratocystic odontogenic tumors. A total of 29 skin pathology specimens from the 5 patients were reviewed; of these, 3 (10.3%) were diagnosed as basaloid follicular hamartomas (BFHs), 10 (34.5%) classified as infundibulocystic basal cell carcinomas (iBCCs), 6 (20.7%) classified as nodular basal cell carcinomas (nBCCs), and 1 (3.4%) as infiltrative basal cell carcinoma (BCC). Targeted NGS studies on tumor specimens suggest that an increased number of UV-signature variants is associated with basal cell carcinomas compared with more indolent basaloid follicular hamartomas. Conclusions and Relevance: Patients with germline SUFU PVs may present with multiple indolent basaloid neoplasms in addition to conventional basal cell carcinomas, typically appearing in the fourth to sixth decades of life. Although there are overlapping clinical manifestations, these findings help to differentiate the clinical syndrome associated with SUFU PVs from PTCH1 BCNS. Awareness of the clinicopathologic spectrum of SUFU-associated basaloid neoplasms is important for dermatologists and dermatopathologists because many (although not all) of these lesions are indolent and do not require aggressive surgical treatment. Importantly, because SUFU lies downstream of the protein smoothened, vismodegib and other smoothened inhibitors are unlikely to be effective therapies in this subset of patients.

Two-dimensional silk.

Despite the promise of silk-based devices, the inherent disorder of native silk limits performance. Here, we report highly ordered two-dimensional silk fibroin (SF) films grown epitaxially on van der Waals (vdW) substrates. Using atomic force microscopy, nano-Fourier transform infrared spectroscopy, and molecular dynamics, we show that the films consist of lamellae of SF molecules that exhibit the same secondary structure as the nanocrystallites of native silk. Increasing the SF concentration results in multilayers that grow either by direct assembly of SF molecules into the lamellae or, at high concentrations, along a two-step pathway beginning with a disordered monolayer that then crystallizes. Scanning Kelvin probe measurements show that these films substantially alter the surface potential; thus, they provide a platform for silk-based electronics on vdW solids.