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Synaptic dysfunction is a key feature of SHANK-associated disorders such as autism spectrum disorder, schizophrenia, and Phelan-McDermid syndrome. Since detailed knowledge of their effect on synaptic nanostructure remains limited, we aimed to investigate such alterations in ex11|SH3 SHANK3-KO mice combining expansion and STED microscopy. This enabled high-resolution imaging of mosaic-like arrangements formed by synaptic proteins in both human and murine brain tissue. We found distinct shape-profiles as fingerprints of the murine postsynaptic scaffold across brain regions and genotypes, as well as alterations in the spatial and molecular organization of subsynaptic domains under SHANK3-deficient conditions. These results provide insights into synaptic nanostructure in situ and advance our understanding of molecular mechanisms underlying synaptic dysfunction in neuropsychiatric disorders., (© 2024. The Author(s).)

Myeloid phagocytes are essential for antifungal immunity against pulmonary Aspergillus fumigatus and systemic Candida albicans infections. However, the molecular mechanisms underlying fungal clearance by phagocytes remain incompletely understood. In this study, we investigated the role of perforin-2 ( Mpeg1 ) in antifungal immunity. We found that Mpeg1 -/- mice generated on a mixed C57BL/6J-DBA/2 background exhibited enhanced survival, reduced lung fungal burden, and greater neutrophil fungal killing activity compared to wild-type C57BL/6J (B6) mice, suggesting that perforin-2 may impair antifungal immune responses. However, when we compared Mpeg1 -/- mice with co-housed Mpeg +/+ littermate controls, these differences were no longer observed, indicating that initial findings were likely influenced by differences in the murine genetic background or the microbiota composition. Furthermore, perforin-2 was dispensable for antifungal immunity during C. albicans bloodstream infection. These results suggest that perforin-2 is not essential for host defense against fungal infections in otherwise immune competent mice and highlight the importance of generating co-housed littermate controls to minimize murine genetic and microbiota-related factors in studies of host defense mechanisms., Importance: Aspergillus fumigatus is the leading cause of invasive aspergillosis (IA), which is associated with significant mortality, particularly in immunocompromised patients such as those with acute leukemia or undergoing hematopoietic stem cell transplants, where death rates reach 40-50% despite standard care. Treatments for IA remain limited and resistance to antifungals is emerging, leading the World Health Organization to recently classify A. fumigatus as a critical priority fungal pathogen. A greater understanding of how the immune system clears A. fumigatus could lead to host-directed therapies that could complement our current armamentarium of antifungal drugs and improve patient outcomes. Our findings reveal that perforin-2 is not essential for antifungal immunity against A. fumigatus in otherwise immune-competent mice and underscore the necessity of using co-housed littermate controls to avoid confounding factors in immunological studies.

Background and Objectives: Although ventriculoperitoneal (VP) shunts are a common treatment for hydrocephalus, there are complication risks including infections. Late complications such as ventriculitis from ascending abdominal infections can have severe consequences. However, the incidence of central nervous system (CNS) infections in VP shunt patients with abdominal infections is not well understood. We aimed to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections., Methods: Using the National Inpatient Sample, we studied patients from 2016 to 2019 to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. Results were compared with VP shunt patients admitted for primary pneumonia., Results: Among 725 VP shunt patients presenting with abdominal infections, 20 (2.8%) had CNS infections. Chronic obstructive pulmonary disease, hypertension, older age, and a smoking history were more common in patients with CNS infections and primary abdominal infection (P < .05). Patients who developed CNS infection had a significantly higher likelihood of both blood transfusion and coma but a lower likelihood of seizures. VP shunt patients with CNS infections were more likely to undergo shunt removal (odds ratio [OR] = 23.167, P < .001). 4.1% of VP shunt patients with primary abdominal infections died during admission. In a population of primary abdominal infection and pneumonia patients with VP shunts, a multivariate logistic regression analysis controlling for age, sex, and comorbidities identified abdominal infection as an independent risk factor for both CNS infection (OR = 51.208, P < .001) and inpatient death (OR = 3.417, P < .001). Among 6620 VP shunt patients admitted with primary pneumonia, only 5 (0.1%) had CNS infection compared with 20 (2.8%) in those with a primary abdominal infection (OR = 37.532, P < .001), and mortality was 1.6% vs 4.1% for those with a primary abdominal infection (P < .05)., Conclusion: CNS infections in VP-shunted patients with abdominal infections are relatively rare but may lead to increased risks of death and other serious adverse outcomes., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Astronomical precision spectroscopy underpins searches for life beyond Earth, direct observation of the expanding Universe and constraining the potential variability of physical constants on cosmological scales. Laser frequency combs can provide the required accurate and precise calibration to the astronomical spectrographs. For cosmological studies, extending the calibration with such astrocombs to the ultraviolet spectral range is desirable, however, strong material dispersion and large spectral separation from the established infrared laser oscillators have made this challenging. Here, we demonstrate astronomical spectrograph calibration with an astrocomb in the ultraviolet spectral range below 400 nm. This is accomplished via chip-integrated highly nonlinear photonics in periodically-poled, nano-fabricated lithium niobate waveguides in conjunction with a robust infrared electro-optic comb generator, as well as a chip-integrated microresonator comb. These results demonstrate a viable route towards astronomical precision spectroscopy in the ultraviolet and could contribute to unlock the full potential of next-generation ground-based and future space-based instruments., (© 2024. The Author(s).)

Geometric morphometrics (GMM) have been applied to understand morphological variation in biological structures. However, research studying cortical bone through geometric histomorphometrics (GHMM) is scarce. This research aims to develop a landmark-based GHMM protocol to depict osteonal shape variation in the femoral diaphysis, exploring the role of age and biomechanics in bone microstructure. Proximal, midshaft, and distal anatomical segments from the femoral diaphysis of six individuals were assessed, with 864 secondary intact osteons from eight periosteal sampling areas being manually landmarked. Observer error was tested using Procrustes ANOVA. Average osteonal shape and anatomical segment-specific variation were explored using principal component analysis. Osteon shape differences between segments were examined using canonical variate analysis (CVA). Sex differences were assessed through Procrustes ANOVA and discriminant function analysis (DFA). The impact of osteonal size on osteonal shape was investigated. High repeatability and reproducibility in osteon shape landmarking were reported. The average osteon shape captured was an elliptical structure, with PC1 reflecting more circular osteons. Significant differences in osteon shape were observed between proximal and distal segments according to CVA. Osteon shape differed between males and females, with DFA showing 52% cross-validation accuracies. No effect of size on shape was reported. Osteonal shape variation observed in this study might be explained by the elderly nature of the sample as well as biomechanical and physiological mechanisms playing different roles along the femoral diaphysis. Although a larger sample is needed to corroborate these findings, this study contributes to the best of our knowledge on human microanatomy, proposing a novel GHMM approach., (© 2024 The Author(s). Journal of Forensic Sciences published by Wiley Periodicals LLC on behalf of American Academy of Forensic Sciences.)

Blood plasma is one of the most commonly analyzed and easily accessible biological samples. Here, we describe an automated liquid-liquid extraction platform that generates accurate, precise, and reproducible samples for metabolomic, lipidomic, and proteomic analyses from a single aliquot of plasma while minimizing hands-on time and avoiding contamination from plasticware. We applied mass spectrometry to examine the metabolome, lipidome, and proteome of 90 plasma samples to determine the effects of age, time of day, and a high-fat diet in mice. From 25 μl of mouse plasma, we identified 907 lipid species from 16 different lipid classes and subclasses, 233 polar metabolites, and 344 proteins. We found that the high-fat diet induced only mild changes in the polar metabolome, upregulated apolipoproteins, and induced substantial shifts in the lipidome, including a significant increase in arachidonic acid and a decrease in eicosapentaenoic acid content across all lipid classes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The majority of Plasmodium spp infections in endemic countries are asymptomatic and a source of onward transmission to mosquitoes. We aimed to examine whether Plasmodium falciparum transmission and malaria burden could be reduced by improving early detection and treatment of infections with active screening approaches., Methods: In this 18-month cluster randomised study in Sapone, Burkina Faso, households were enrolled and randomly assigned (1:1:1) to one of three groups: group 1 (control) received standard of care only, group 2 received active weekly, at home, fever screening by a community health worker regardless of symptoms, participants with a fever received a rapid diagnostic test (RDT) and treatment if RDT positive, and group 3 received active weekly fever screening (as in group 2) plus a monthly RDT regardless of symptoms, and treatment if RDT positive. Eligible households had a minimum of three eligible residents, one in each age group (<5 years, 5-15 years, and >15 years). The primary outcome was parasite prevalence by quantitative PCR (qPCR) in the end-of-study cross-sectional survey. Secondary outcomes included parasite and gametocyte prevalence and density in all three end-of-season cross-sectional surveys, incidence of infection, and the transmissibility of infections to mosquitoes. This trial was registered at ClinicalTrials.gov (NCT03705624) and is completed., Findings: A total of 906 individuals from 181 households were enrolled during two phases, and participated in the study. 412 individuals were enrolled between Aug 9 and 17, 2018, and participated in phase 1 and 494 individuals were enrolled between Jan 10 and 31, 2019, in phase 2. In the end-of-study cross-sectional survey (conducted between Jan 13 and 21, 2020), Pfalciparum prevalence by qPCR was significantly lower in group 3 (29·26%; 79 of 270), but not in group 2 (45·66%; 121 of 265), when compared with group 1 (48·72%; 133 of 273; risk ratio 0·65 [95% CI 0·52-0·81]; p=0·0001). Total parasite and gametocyte prevalence and density were also significantly lower in group 3 in all surveys. The largest differences were seen at the end of the dry season, with gametocyte prevalence 78·4% and predicted transmission potential 98·2% lower in group 3 than in group 1., Interpretation: Active monthly RDT testing and treatment can reduce parasite carriage and the infectious reservoir of P falciparum to less than 2% when used during the dry season. This insight might inform approaches for malaria control and elimination., Funding: Bill & Melinda Gates Foundation, European Research Council, and The Netherlands Organization for Scientific Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: A growing interest in renal normothermic machine perfusion (NMP) has resulted in more clinically available perfusion devices. While all perfusion systems have the same aim, there are significant differences in their circuits, pumps, sensors, and software. Therefore, our objective was to assess the impact of different perfusion protocols and devices on kidney function and perfusion parameters during NMP., Methods: Porcine kidneys were subjected to 30 min of warm ischemia, 24 h of static cold storage, and subsequently perfused for 6 h using (1) the Kidney Assist (KA) machine with a pressure of 75 mm Hg, (2) the KA device incorporating several adjustments and a pressure of 85 mm Hg (modified KA), or (3) the Perlife (PL) perfusion device (n = 4). Consecutively, discarded human kidneys were perfused using the KA or modified KA (n = 3) protocol., Results: The PL group quickly reached the device's upper flow limit and consequently received a significantly lower pressure compared to the KA groups. The arterial pO 2 was significantly lower in the PL group. Yet, hemoglobin concentration increased over time, and oxygen consumption was significantly higher compared to the KA groups. Fractional sodium excretion was significantly lower in the PL group. Tissue ATP levels, urine production, and creatinine clearance rates did not differ between groups. In human kidneys, the modified KA group showed significantly lower vascular resistance, higher oxygen delivery, and lower levels of lactate in the perfusate compared to the KA group., Conclusions: This study shows that perfusion characteristics and kidney function are significantly influenced by the perfusion protocol and the device and its settings during normothermic machine perfusion and therefore should be interpreted with caution., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13 +/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13 +/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population., (© 2024. The Author(s).)

Breakthrough fungal infections in patients on antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT) represent a major and often unexplained cause of morbidity and mortality. Candida parapsilosis is a common cause of invasive candidiasis and has been classified as a high-priority fungal pathogen by the World Health Organization. In high-risk allo-HCT recipients on micafungin prophylaxis, we show that heteroresistance (the presence of a phenotypically unstable, low-frequency subpopulation of resistant cells (~1 in 10,000)) underlies breakthrough bloodstream infections by C. parapsilosis. By analyzing 219 clinical isolates from North America, Europe and Asia, we demonstrate widespread micafungin heteroresistance in C. parapsilosis. Standard antimicrobial susceptibility tests, such as broth microdilution or gradient diffusion assays, which guide drug selection for invasive infections, fail to detect micafungin heteroresistance in C. parapsilosis. To facilitate rapid detection of micafungin heteroresistance in C. parapsilosis, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible using a maximum of ten genomic features. These results connect heteroresistance to unexplained antifungal prophylaxis failure in allo-HCT recipients and demonstrate a proof-of-principle diagnostic approach with the potential to guide clinical decisions and improve patient care., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Epithelial cells orchestrate immune responses against fungal pathogens. This review highlights advances in integrating epithelial cells in immune responses against inhaled molds and dimorphic fungi, and against Candida species that colonize mucosal surfaces. In the lung, epithelial cells respond to interleukin-1 (IL-1) and interferon signaling to regulate effector cell influx and fungal killing. In the alimentary and vulvovaginal tracts, epithelial cells modulate fungal commensalism, invasive growth, and local immune tone, in part by responding to damage caused by candidalysin, a C. albicans peptide toxin, and through IL-17-dependent release of antimicrobial peptides that contribute to Candida colonization resistance. Understanding fungal-epithelial interactions in mammalian models of disease is critical to predict vulnerabilities and to identify opportunities for immune-based strategies to treat fungal infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Ex vivo normothermic machine perfusion (NMP) is a promising tool for assessing an isolated kidney prior to transplantation. However, there is no consensus on the perfusate's optimal oxygen-carrying capacity to support renal function. To investigate the association of hemoglobin levels with renal function parameters, a retrospective analysis of isolated, normothermically, perfused porcine kidneys was performed., Methods: Between 2015 and 2021, a total of 228 kidneys underwent 4 h of NMP with perfusates that varied in hemoglobin levels. A generalized linear model was used to determine the association of hemoglobin levels with time-weighted means of renal function markers, such as fractional sodium excretion (FENa) and creatinine clearance (CrCl). Stratified by baseline hemoglobin level (<4.5, 4.5-6, or >6 mmol/L), these markers were modeled over time using a generalized linear mixed-effects model. All models were adjusted for potential confounders., Results: Until a hemoglobin level of around 5 mmol/L was reached, increasing hemoglobin levels were associated with superior FENa and CrCl. Thereafter, this association plateaued. When hemoglobin levels were categorized, hemoglobin <4.5 mmol/L was associated with worse renal function. Hemoglobin levels were neither significantly associated with proteinuria during NMP nor with ATP levels at the end of NMP. Hemoglobin levels >6 mmol/L showed no additional benefits in renal function., Conclusion: In conclusion, we found an association between baseline hemoglobin levels and superior renal function parameters, but not injury, during NMP of porcine kidneys. Furthermore, we show that performing a retrospective cohort study of preclinical data is feasible and able to answer additional questions, reducing the potential use of laboratory animals., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

At altitude, factors such as decreased barometric pressure, low temperatures, and acclimatization might affect lung function. The effects of exposure and acclimatization to high-altitude on lung function were assessed in 39 subjects by repetitive spirometry up to 6022 m during a high-altitude expedition. Subjects were classified depending on the occurrence of acute mountain sickness (AMS) and summit success to evaluate whether lung function relates to successful climb and risk of developing AMS. Peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) increased with progressive altitude (max. +20.2 %pred, +9.3 %pred, and +6.7 %pred, all p<0.05). Only PEF improved with acclimatization (BC1 vs. BC2, +7.2 %pred, p=0.044). At altitude FEV1 (p=0.008) and PEF (p<0.001) were lower in the AMS group. The risk of developing AMS was associated with lower baseline PEF (p<0.001) and longitudinal changes in PEF (p=0.008) and FEV1 (p<0.001). Lung function was not related to summit success (7126 m). Improvement in PEF after acclimatization might indicate respiratory muscle adaptation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Motivation: Acute kidney injury (AKI) is a syndrome that affects a large fraction of all critically ill patients, and early diagnosis to receive adequate treatment is as imperative as it is challenging to make early. Consequently, machine learning approaches have been developed to predict AKI ahead of time. However, the prevalence of AKI is often underestimated in state-of-the-art approaches, as they rely on an AKI event annotation solely based on creatinine, ignoring urine output., We construct and evaluate early warning systems for AKI in a multi-disciplinary ICU setting, using the complete KDIGO definition of AKI. We propose several variants of gradient-boosted decision tree (GBDT)-based models, including a novel time-stacking based approach. A state-of-the-art LSTM-based model previously proposed for AKI prediction is used as a comparison, which was not specifically evaluated in ICU settings yet., Results: We find that optimal performance is achieved by using GBDT with the time-based stacking technique (AUPRC = 65.7%, compared with the LSTM-based model's AUPRC = 62.6%), which is motivated by the high relevance of time since ICU admission for this task. Both models show mildly reduced performance in the limited training data setting, perform fairly across different subcohorts, and exhibit no issues in gender transfer., Following the official KDIGO definition substantially increases the number of annotated AKI events. In our study GBDTs outperform LSTM models for AKI prediction. Generally, we find that both model types are robust in a variety of challenging settings arising for ICU data., Availability and Implementation: The code to reproduce the findings of our manuscript can be found at: https://github.com/ratschlab/AKI-EWS., (© The Author(s) 2024. Published by Oxford University Press.)

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles., (© 2024. The Author(s).)

Ice XIX and ice XV are both partly hydrogen-ordered counterparts to disordered ice VI. The ice XIX → XV transition represents the only order-to-order transition in ice physics. Using Raman and dielectric spectroscopies, we investigate the ambient-pressure kinetics of the two individual steps in this transition in real time (of hours), that is, ice XIX → transient ice VI (the latter called VI‡) and ice VI‡ → ice XV. Hydrogen-disordered ice VI‡ appears intermittent between 101 and 120 K, as inferred from the appearance and subsequent disappearance of the ice VI Raman marker bands. A comparison of the rate constants for the H2O ices reported here with those from D2O samples [Thoeny et al., J. Chem. Phys. 156, 154507 (2022)] reveals a large kinetic isotope effect for the ice XIX decay, but a much smaller one for the ice XV buildup. An enhancement of the classical overbarrier rate through quantum tunneling for the former can provide a possible explanation for this finding. The activation barriers for both transitions are in the 18-24 kJ/mol range, which corresponds to the energy required to break a single hydrogen bond. These barriers do not show an H/D isotope effect and are the same, no matter whether they are derived from Raman scattering or from dielectric spectroscopy. These findings favor the notion that a dipolar reorientation, involving the breakage of a hydrogen bond, is the rate determining step at the order-to-order transition., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Methyl esters are an important component of combustion and atmospheric systems. Reaction with the OH radical plays an important role in the removal of the simplest methyl ester, methyl formate (MF, CH 3 OCHO). In this paper, the overall rate coefficients for the reactions of OH and OD with MF isotopologues, studied under pseudo-first-order conditions, are reported using two different laser flash photolysis systems with the decay of OH monitored by laser-induced fluorescence. The room-temperature rate coefficient for OH + MF, (1.95 ± 0.34) × 10 -13 cm 3 molecule -1 s -1 , is in good agreement with the literature. The rate coefficient exhibits curved Arrhenius behavior, and our results bridge the gap between previous low-temperature and shock tube studies. In combination with the literature, the rate coefficient for the reaction of OH with MF between 230 and 1400 K can be parametrized as k OH+MF = (3.2 × 10 -13 ) × (T/300 K) 2.3 × exp(-141.4 K/ T ) cm 3 molecule -1 s -1 with an overall estimated uncertainty of ∼30%. The reactions of OD with MF isotopologues show a small enhancement (inverse secondary isotope effect) compared to the respective OH reactions. The reaction of OH/OD with MF shows a normal primary isotope effect, a decrease in the rate coefficient when MF is partially or fully deuterated. Experimental studies have been supported by ab initio calculations at the CCSD(T)-F12/aug-cc-pVTZ//M06-2 X /6-31+G** level of theory. The calculated, zero-point-corrected, barrier heights for abstraction at the methyl and formate sites are 1.3 and 6.0 kJ mol -1 , respectively, and the ab initio predictions of kinetic isotope effects are in agreement with experiment. Fitting the experimental isotopologue data refines these barriers to 0.9 ± 0.6 and 4.1 ± 0.9 kJ mol -1 . The branching ratio is approximately 50:50 at 300 K. Between 300 and 500 K, abstraction via the higher-energy, higher-entropy formate transition state becomes more favored (60:40). However, experiment and calculations suggest that as the temperature increases further, with higher energy, less constrained conformers of the methyl transition state become more significant. The implications of the experimental and theoretical results for the mechanisms of MF atmospheric oxidation and low-temperature combustion are discussed.

T helper 1 (T H 1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated T H 1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the T H 2 lineage: T-bet quantities were inversely correlated with the ability to express the T H 2 lineage-specifying transcription factor GATA-3 and T H 2 cytokines. Reprogramed T H 1 cells acquired graded mixed T H 1 + T H 2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated T H 1 cells was essential to ensure T H 1 cell stability. Thus, innate cytokine signals regulate T H 1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.

Background: After posterior cruciate ligament reconstruction (PCLR), functional deficits at the knee can persist. It remains unclear if neighboring joints compensate for the knee during demanding activities of daily living., Purpose: To assess long-term alterations in lower limb mechanics in patients after PCLR., Study Design: Descriptive laboratory study., Methods: A total of 28 patients who had undergone single-bundle unilateral isolated or combined PCLR performed stair navigation, squat, sit-to-stand, and stand-to-sit tasks at 8.2 ± 2.2 years after surgery. Motion capture and force plates were used to collect kinematic and kinetic data. Then, 3-dimensional hip, knee, and ankle kinematic data of the reconstructed limb were compared with those of the contralateral limb using statistical parametric mapping., Results: Side-to-side differences at the knee were primarily found during upward-driven movements at 8 years after surgery. The reconstructed knee exhibited lower internal rotation during the initial loading phase of stair ascent versus the contralateral knee ( P = .005). During the sit-to-stand task, higher flexion angles during the midcycle ( P = .017) and lower external rotation angles ( P = .049) were found in the reconstructed knee; sagittal knee ( P = .001) and hip ( P = .016) moments were lower in the reconstructed limb than the contralateral limb. In downward-driven movements, side-to-side differences were minimal at the knee but prominent at the ankle and hip: during stair descent, the reconstructed ankle exhibited lower dorsiflexion and lower external rotation during the midcycle versus the contralateral ankle ( P = .006 and P = .040, respectively). Frontal hip moments in the reconstructed limb were higher than those in the contralateral limb during the stand-to-sit task ( P = .010); during squats, sagittal hip angles in the reconstructed limb were higher than those in the contralateral limb ( P < .001)., Conclusion: Patients after PCLR exhibited compensations at the hip and ankle during downward-driven movements, such as stair descent, squats, and stand-to-sit. Conversely, residual long-term side-to-side differences at the knee were detected during upward-driven movements such as stair ascent and sit-to-stand., Clinical Relevance: After PCLR, side-to-side differences in biomechanical function were activity-dependent and occurred either at the knee or neighboring joints. When referring to the contralateral limb to assess knee function in the reconstructed limb, concentric, upward-driven movements should be prioritized. Compensations at the hip and ankle during downward-driven movements lead to biases in long-term functional assessments., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: G.N.D. has received consulting fees from Pluristem, DePuy Synthes, Implantec, Implantcast, and Stryker; has grants or grants pending with Pluristem, DePuy Synthes, Implantec, Implantcast, Smith & Nephew, Stryker, and Zimmer; and has patents (planned, pending, or issued) with Pluristem and B&C for work unrelated to this particular study. T.M.J. has received support for education and hospitality payments from Smith & Nephew, Richard Wolf, and DJO Global. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

The detection of oral bacteria in faecal samples has been associated with inflammation and intestinal diseases. The increased relative abundance of oral bacteria in faeces has two competing explanations: either oral bacteria invade the gut ecosystem and expand (the 'expansion' hypothesis), or oral bacteria transit through the gut and their relative increase marks the depletion of other gut bacteria (the 'marker' hypothesis). Here we collected oral and faecal samples from mouse models of gut dysbiosis (antibiotic treatment and DSS-induced colitis) and used 16S ribosomal RNA sequencing to determine the abundance dynamics of oral bacteria. We found that the relative, but not absolute, abundance of oral bacteria increases, reflecting the 'marker' hypothesis. Faecal microbiome datasets from diverse patient cohorts, including healthy individuals and patients with allogeneic haematopoietic cell transplantation or inflammatory bowel disease, consistently support the 'marker' hypothesis and explain associations between oral bacterial abundance and patient outcomes consistent with depleted gut microbiota. By distinguishing between the two hypotheses, our study guides the interpretation of microbiome compositional data and could potentially identify cases where therapies are needed to rebuild the resident microbiome rather than protect against invading oral bacteria., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Histopathological assessment of tissue samples after prolonged formalin fixation has been described previously, but currently there is only limited knowledge regarding the feasibility of molecular pathology on such tissue. In this pilot study, we tested routine molecular pathology methods (DNA isolation, DNA pyrosequencing/next-generation sequencing, DNA methylation analysis, RT-PCR, clonality analysis and fluorescence in situ hybridization) on tissue samples from 11 tumor entities as well as non-neoplastic brain tissue from 43 body donors during the gross anatomy course at Ulm University (winter semester 2019/20 and 2020/21). The mean post mortem interval until fixation was 2.5 ± 1.6 days (range, 1-6 days). Fixation was performed with aqueous formaldehyde solution (formalin, 1.5-2%). The mean storage time of body donors was 12.8 ± 5.6 months (range, 7-25 months). While most diagnostic methods were successful, samples showed significant variability in DNA quality and evaluability. DNA pyrosequencing as well as next-generation sequencing was successful in all investigated samples. Methylation analyses were partially not successful in some extend due to limited intact DNA yield for these analyses. Taken together, the use of prolonged formalin-fixed tissue samples from body donors offers new avenues in research and education, as these samples could be used for morpho-molecular studies and the establishment of biobanks, especially for tissue types that cannot be preserved and studied in vivo. Pathological ward rounds, sample collection, and histopathological and molecular workup have been integrated in the gross anatomy course in Ulm as an integral part of the curriculum, linking anatomy and pathology and providing medical students early insight into the broad field of (molecular) pathology., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization., (© 2024 Pal et al.)

Ice XIX is a partly hydrogen-ordered polymorph related to disordered ice VI, similar to ice XV. We here investigate the order-order-disorder sequence ice XIX→ice XV→ice VI based on calorimetry at ambient pressure both for D 2 O and H 2 O-ice XIX. From these data we extract configurational entropy differences between ice XIX, ice XV and ice VI. This task is complex because, unlike for all other ices, the order-disorder transition from ice XIX to ice VI takes place in two steps via ice XV. Even more challenging, these two steps take place in an overlapping manner, so that careful separation of slow kinetics is necessary. This is evidenced best by changing the heating rate in calorimetry experiments: For fast heating experiments the second step, disordering of ice XV, is suppressed because the first step, formation of ice XV from ice XIX, is too slow. The transient state ice VI ‡ that is initially produced upon ice XIX decay then does not have enough time to convert to ice XV, but remains disordered all along. In order to tackle the challenge to determine the entropy difference between ice XIX and VI as well as the entropy difference between ice XV and VI we employ two different approaches that allow assessing the impact of kinetics on the entropy change. "Single peak integration" defines a kinetically limited result, but "combined peak integration" allows estimation of the true thermodynamic values. Our best estimate for the true value shows ice XIX to be much more ordered than ice XV (25 ± 3% vs 9 ± 4% of the Pauling entropy). For D 2 Oice XIX samples we obtain 28% of order, but only when a small number of fast H-isotope defects are used. In the second part we use these results to estimate the location of the ice XIX phase boundary both for protiated and deuterated ice XIX. The initial Clapeyron slope at ambient pressure is determined from the combination of neutron powder diffraction volume differences and calorimetry entropy differences data to be 21 K GPa -1 with an order-disorder transition temperature T o-d (0.0 GPa) = 103 ± 1 K. An in situ bracketing experiment at 1.8 GPa yields T o-d (1.8 GPa) = 116 ± 3 K, i.e., the phase boundary slope flattens at higher pressures. These data allow us to determine the region of thermodynamic stability of ice XIX in the phase diagram and to explain the surprising isotope shift reversal at 1.6 GPa compared to 0.0 GPa, i.e., why D 2 O-ice XIX disorders at lower temperatures than H 2 O-ice XIX at 1.6 GPa, but at higher temperatures at ambient pressures., (© 2024. The Author(s).)

We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

This study integrates leadership process models with process models of personality and behavioral personality science to examine the behavioral-perceptual pathways that explain interpersonal personality traits' divergent relation to group leadership evaluations. We applied data from an online group interaction study ( N = 364) alternately assigning participants as leaders conducting brief tasks. We used four variable types to build the pathways in multiple mediator models: (a) Self-reported personality traits, (b) video recordings of expressed interpersonal behaviors coded by 6 trained raters, (c) interpersonal impressions, and (d) mutual evaluations of leadership emergence/effectiveness. We find interpersonal big five traits to differently relate to the two leadership outcomes via the behavioral-perceptual pathways: Extraversion was more important to leadership emergence due to impressions of assertiveness evoked by task-focused behavior being strongly valued. Agreeableness/emotional stability were more important to leadership effectiveness due to impressions of trustworthiness/calmness evoked by member-focused/calm behavior being stronger valued., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Liquid-liquid phase separation (LLPS) plays a key role in the compartmentalization of cells via the formation of biomolecular condensates. Here, we combined atomistic molecular dynamics (MD) simulations and terahertz (THz) spectroscopy to determine the solvent entropy contribution to the formation of condensates of the human eye lens protein γD-Crystallin. The MD simulations reveal an entropy tug-of-war between water molecules that are released from the protein droplets and those that are retained within the condensates, two categories of water molecules that were also assigned spectroscopically. A recently developed THz-calorimetry method enables quantitative comparison of the experimental and computational entropy changes of the released water molecules. The strong correlation mutually validates the two approaches and opens the way to a detailed atomic-level understanding of the different driving forces underlying the LLPS.

Purpose: Peritoneal surface malignancies (PSM) are commonly known to have a dismal prognosis. Over the past decades, novel techniques such as cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been introduced for the treatment of PSM which could improve the overall survival and quality of life of patients with PSM. The decision to proceed with CRS and HIPEC is often challenging due the complexity of the disease, the extent of the procedure, associated side effects, and potential risks. Here, we present our experience with CRS and HIPEC to add to the ongoing discussion about eligibility criteria, technical approach, and expected outcomes and contribute to the evolution of this powerful and promising tool in the multidisciplinary treatment of patients with primary and secondary PSM., Methods: A single-center retrospective chart review was conducted and included a total of 40 patients treated with CRS and HIPEC from April 2020 to September 2022 at the University Hospital Münster Department of Surgery. All patients had histologically confirmed primary or secondary peritoneal malignancies of various primary origins., Results: Our study included 22 patients with peritoneal metastases from gastric cancer (55%), 8 with pseudomyxoma peritonei (20%), 4 with mesothelioma of the peritoneum (10%), and 6 patients with PSM originating from other primary tumor locations. Median PCI at time of cytoreduction was 4 (0-25). Completeness of cytoreduction score was 0 in 37 patients (92.5%), 1 in two patients (5%), and 2 in one patient (2.5%). Median overall survival across all patients was 3.69 years., Conclusion: Complete cytoreduction during CRS and HIPEC can be achieved for patients with low PCI, for patients with high PCI in low-grade malignancies, and even for patients with initially high PCI in high-grade malignancies following a significant reduction of cancer burden due to extensive preoperative treatment with PIPAC and systemic chemotherapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing., (© 2023. The Author(s).)

Introduction: Mushroom toxicity is an important etiology of acute liver injury in a patient with gastrointestinal symptoms., Case Report: We present the case of a male patient presenting to the emergency department (ED) with gastrointestinal distress who was placed under ED observation for elevated liver function tests. During his hospital course, it was revealed he had consumed wild mushrooms believed to be Amanita phalloides ., Conclusion: While mushroom ingestion and subsequent toxicity are rare, a high index of suspicion in foraging hobbyists is essential to arriving at the correct diagnosis and directing the patient to the appropriate management., Competing Interests: Conflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

Objectives: To attain a collective expert opinion on the use of air powder waterjet technology (APWT) with erythritol and glycine powders in the prophylaxis and therapy of periodontal and peri-implant diseases., Material and Methods: In the first step, a modified one-round online Delphi survey including 44 five-point Likert scale questions was conducted among a group of 10 expert clinicians and researchers with thorough knowledge and experience in this topic. In the second step, the single questions and the survey results were discussed during a meeting, and consensus statements were formulated, respectively., Results: An agreement was reached on most items, especially opinions supporting glycine and erythritol powders as favorable with respect to efficiency, safety, and comfort. More scientific evidence is needed to support the improvement in clinical attachment on teeth and implants, especially when APWT with erythritol is used. In addition, APWT needs more long-term evaluation and studies in terms of microbiome/microbiological effects as well as effects on the inflammatory response on natural teeth and implants, also in light of a guided biofilm therapy concept., Conclusions: In line with the expert opinions and supported by the evidence, it was concluded that the use of APWT with erythritol and glycine powders in nonsurgical periodontal and peri-implant therapy and prophylaxis is patient compliant and efficient., (© 2024 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases., (© 2024. The Author(s).)

Solid-state quantum emitters embedded in circular Bragg resonators are attractive due to their ability to emit quantum light with high brightness and low multiphoton probability. As for any emitter-microcavity system, fabrication imperfections limit the spatial and spectral overlap of the emitter with the cavity mode, thus limiting their coupling strength. Here, we show that an initial spectral mismatch can be corrected after device fabrication by repeated wet chemical etching steps. We demonstrate an ∼16 nm wavelength tuning for optical modes in AlGaAs resonators on oxide, leading to a 4-fold Purcell enhancement of the emission of single embedded GaAs quantum dots. Numerical calculations reproduce the observations and suggest that the achievable performance of the resonator is only marginally affected in the explored tuning range. We expect the method to be applicable also to circular Bragg resonators based on other material platforms, thus increasing the device yield of cavity-enhanced solid-state quantum emitters., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Effective decision-making requires the evaluation of several criteria rather than a single, preferred criterion. The best decision options (alternatives) are recommended to decision-makers when a multi-criteria decision problem is addressed. This study develops a multi-criteria selection method for the assessment of small-scale anaerobic digester technology by combining two existing methods. The Simple Multi-Attribute Rating Technique (SMART) and the Analytical Hierarchy Process (AHP) approaches of multiple-criteria decision analysis were used as a decision support tool, and the preferred anaerobic digester technology was selected from a list of eleven potential small-scale digester technologies used in low to middle-income countries. These techniques were applied under two scenarios for a case study in the South African smallholder farmers. Scenario 1 involves a subsistence smallholder farming context, while scenario 2 involves a commercially oriented smallholder farming context. The overall results revealed that the DIY Biobag and Puxin digester design models achieved 82.1 and 73.7 % preference in comparison to other digester technologies for scenarios 1 and 2, respectively. The Biobag digester technology achieved the highest ranking, which is consistent with the significant cost advantage and technical characteristics of the technology. However, for those households with sufficient access to funds for the initial expenditure, the method identifies the Puxin digester as the most appropriate alternative, excluding cases where underground construction is not possible. The AGAMA BiogasPro digester was ranked in the second position in both scenarios. A sensitivity analysis was conducted to determine the effect of changes in the assessment criteria weights and found the selected alternatives stable and robust. Finally, it can be concluded that the developed technology selection model contributed a knowledge-based framework to be used in various situations by different decision-makers, thereby providing a method applicable to particular local conditions to identify the most suitable technology choices., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (©2024PublishedbyElsevierLtd.)

A 51-year-old woman showed structural epilepsy following an atypical, nontraumatic intracranial hemorrhage in the right frontal area. Despite successful seizure control with lamotrigine, she developed severe morning anxiety and panic attacks, leading to agoraphobia, social withdrawal, and psychogenic nonepileptic seizures. Neuropsychiatric and psychological assessments confirmed an anxiety disorder with no significant symptoms of depression. The patient received various psychopharmacological treatments with limited success. This case report illustrates that managing panic disorder in patients with structural epilepsy requires a comprehensive treatment approach that includes pharmacotherapy and psychotherapy. Differential diagnosis and accurate treatment are crucial because of the symptom overlap between panic attacks and peri -ictal fear. Screenings instruments such as the Panic and Agoraphobia Scale (PAS) can aid in assessing anxiety-related symptoms. First-line pharmacotherapy with selective serotonin reuptake inhibitors, especially sertraline, or venlafaxine can effectively reduce panic attacks and can be recommended in patients with epilepsy. Psychotherapy, particularly cognitive-behavioral therapy, is the treatment of choice. Referral to a psychiatrist is indicated when symptoms are severe or refractory to treatment., Competing Interests: CB has received support from and/or has served as a paid consultant for Angelini, Arvelle, Eisai, GW Pharmaceuticals, Jazz Pharmaceuticals, Johnson & Johnson, Marinus, UCB Pharma, and Xenon. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Bispecific antibodies (BsAbs) capable of recognizing two distinct epitopes or antigens offer promising therapeutic options for various diseases by targeting multiple pathways. The favorable pharmacokinetic (PK) properties of monoclonal antibodies (mAbs) are crucial, as they directly influence patient safety and therapeutic efficacy. For numerous mAb therapeutics, optimization of neonatal Fc receptor (FcRn) interactions and elimination of unfavorable molecular properties have led to improved PK properties. However, many BsAbs exhibit unfavorable PK, which has precluded their development as drugs. In this report, we present studies on the molecular determinants underlying the distinct PK profiles of three IgG1-scFv BsAbs. Our study indicated that high levels of nonspecific interactions, elevated isoelectric point (pI), and increased number of positively charged patches contributed to the fast clearance of IgG1-scFv. FcRn chromatography results revealed specific scFv-FcRn interactions that are unique to the IgG1-scFv, which was further supported by molecular dynamics (MD) simulation. These interactions likely stabilize the BsAb FcRn interaction at physiological pH, which in turn could disrupt FcRn-mediated BsAb recycling. In addition to the empirical observations, we also evaluated the impact of in silico properties, including pI differential between the Fab and scFv and the ratio of dipole moment to hydrophobic moment (RM) and their correlation with the observed clearance. These findings highlight that the PK properties of BsAbs may be governed by novel determinants, owing to their increased structural complexity compared to immunoglobulin G (IgG) 1 antibodies.

A quantum-light source that delivers photons with a high brightness and a high degree of entanglement is fundamental for the development of efficient entanglement-based quantum-key distribution systems. Among all possible candidates, epitaxial quantum dots are currently emerging as one of the brightest sources of highly entangled photons. However, the optimization of both brightness and entanglement currently requires different technologies that are difficult to combine in a scalable manner. In this work, we overcome this challenge by developing a novel device consisting of a quantum dot embedded in a circular Bragg resonator, in turn, integrated onto a micromachined piezoelectric actuator. The resonator engineers the light-matter interaction to empower extraction efficiencies up to 0.69(4). Simultaneously, the actuator manipulates strain fields that tune the quantum dot for the generation of entangled photons with corrected fidelities to a maximally entangled state up to 0.96(1). This hybrid technology has the potential to overcome the limitations of the key rates that plague QD-based entangled sources for entanglement-based quantum key distribution and entanglement-based quantum networks., Supplementary Information: The online version contains supplementary material available at 10.1186/s43593-024-00072-8., Competing Interests: Competing interestsThe authors declare no competing financial or non-financial interests., (© The Author(s) 2024.)

Background: The association between surgical volume and patient outcome is well established, with higher case volume associated with a lower risk of complications. We hypothesized that the geographic distribution of endocrine/head and neck surgeons with an endocrine focus in the United States and Puerto Rico may limit access to many potential patients, particularly in rural areas., Methods: We used web-based directories from the American Association of Endocrine Surgeons, American Head and Neck Society, and the American Academy of Otolaryngology-Head and Neck Surgery to identify endocrine surgery specialists in the United States and Puerto Rico. Using geographic coordinates and OpenStreetMap and Valhalla software, we calculated the areas within a 60-, 90-, or 120-minute driving distance from specialist offices. We used 2020 U.S. Census Data to calculate census tract populations inside or outside the accessible areas., Results: Excluding duplicate providers across organizations, we geocoded 603 specialist addresses in the United States and Puerto. We found that 23.76% (78.3 million) of Americans do not have access to a society-affiliated endocrine/head and neck surgeon with an endocrine focus within a 60-minute drive, 14.37% (47.4 million) within a 90-minute drive, and 8.38% (27.6 million) within a 120-minute drive. We observed that the areas of coverage are primarily focused on metropolitan areas., Conclusion: Nearly one-third of Americans do not have access to a society-affiliated endocrine/head and neck surgeon with an endocrine focus within a 1-hour drive, highlighting a concerning geographic barrier to care. Further work is needed to facilitate patient access and mitigate disparities in quality care., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Aspergillus fumigatus can cause a life-threatening infection known as invasive pulmonary aspergillosis (IPA), which is marked by fungus-attributable mortality rates of 20%-30%. Individuals at risk for IPA harbor genetic mutations or incur pharmacologic defects that impair myeloid cell numbers and/or function, exemplified by bone marrow transplant recipients, patients that receive corticosteroid therapy, or patients with chronic granulomatous disease (CGD). However, treatments for Aspergillus infections remain limited, and resistance to the few existing drug classes is emerging. Recently, the World Health Organization classified A. fumigatus as a critical priority fungal pathogen. Our cell death research identifies an important aspect of fungal biology that impacts susceptibility to leukocyte killing. Furthering our understanding of mechanisms that mediate the outcome of fungal-leukocyte interactions will increase our understanding of both the underlying fungal biology governing cell death and innate immune evasion strategies utilized during mammalian infection pathogenesis. Consequently, our studies are a critical step toward leveraging these mechanisms for novel therapeutic advances., Competing Interests: The authors declare no conflict of interest.

Background: Fractional flow reserve (FFR) is an established method to guide decisions on revascularization; however, in patients with diabetes mellitus (DM), FFR-negative lesions carrying an optical coherence tomography-detected thin-cap fibroatheroma (TCFA) remain at high risk for adverse cardiac events., Methods: In this prespecified subanalysis of the COMBINE OCT-FFR trial, DM patients with ≥1 FFR-negative, TCFA-positive medically treated target lesions referred to as vulnerable plaque (VP group), were compared to patients with exclusively FFR-positive target lesions who underwent complete revascularization (CR group). The primary endpoint was first and recurrent event analysis for target lesion failure and the secondary endpoint was a composite of cardiac death, target vessel myocardial infarction, target lesion revascularization, or hospitalization due to unstable angina., Results: Among 550 patients enrolled, 98 belonged to the VP group while 93 to the CR group and were followed up to 5 years. The VP group had a higher occurrence of the primary endpoint (20.4% vs 8.6%; HR, 2.22; 95% CI, 0.98-5.04; P = .06). Recurrent event analysis showed that the VP group had significantly higher rates of the primary and secondary endpoints (9.17 vs 3.76 events per 100 PY; RR, 2.44; 95% CI, 1.16-5.60; P = .01 and 13.45 vs 5.63 events per 100 PY; RR, 2.39; 95% CI, 1.30-4.62; P < .01)., Conclusions: In a population with DM, medically treated nonischemic, TCFA-carrying target lesions were associated with higher risk of reoccurring adverse cardiac events compared to target lesions that underwent complete revascularization, opening the discussion about whether a focal preventive revascularization strategy could be contemplated for highly vulnerable lesions., (© 2023 The Author(s).)

Effective treatment of orthopedic implant-associated infections (IAIs) remains a clinical challenge. The in vitro and in vivo studies presented herein evaluated the antimicrobial effects of applying cathodic voltage-controlled electrical stimulation (CVCES) to titanium implants inoculated with preformed bacterial biofilms of methicillin-resistant Staphylococcus aureus (MRSA). The in vitro studies showed that combining vancomycin therapy (500 µg/mL) with application of CVCES at -1.75 V (all voltages are with respect to Ag/AgCl unless otherwise stated) for 24 h resulted in 99.98% reduction in the coupon-associated MRSA colony-forming units (CFUs) (3.38 × 10 3 vs. 2.14 × 10 7 CFU/mL, p < 0.001) and a 99.97% reduction in the planktonic CFU (4.04 × 10 4 vs. 1.26 × 10 8 CFU/mL, p < 0.001) as compared with the no treatment control samples. The in vivo studies utilized a rodent model of MRSA IAIs and showed a combination of vancomycin therapy (150 mg/kg twice daily) with CVCES of -1.75 V for 24 h had significant reductions in the implant associated CFU (1.42 × 10 1 vs. 1.2 × 10 6 CFU/mL, p < 0.003) and bone CFU (5.29 × 10 1 vs. 4.48 × 10 6 CFU/mL, p < 0.003) as compared with the untreated control animals. Importantly, the combined 24 h CVCES and antibiotic treatments resulted in no implant-associated MRSA CFU enumerated in 83% of the animals (five out of six animals) and no bone-associated MRSA CFU enumerated in 50% of the animals (three out of six animals). Overall, the outcomes of this study have shown that extended duration CVCES therapy is an effective adjunctive therapy to eradicate IAIs., (© 2023 Orthopaedic Research Society.)

Myeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity to Aspergillus fumigatus , the most common etiologic agent of mold pneumonia worldwide. Following the engulfment of A. fumigatus conidia, fusion of the phagosome with the lysosome is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti- Aspergillus immunity during infection. We found that lung neutrophils express TFEB and TFE3, and their target genes were upregulated during A. fumigatus lung infection. In addition, A. fumigatus infection induced nuclear accumulation of TFEB and TFE3 in macrophages in a process regulated by Dectin-1 and CARD9. Genetic deletion of Tfeb and Tfe3 impaired macrophage killing of A. fumigatus conidia. However, in a murine immune-competent Aspergillus infection model with genetic deficiency of Tfeb and Tfe3 in hematopoietic cells, we surprisingly found that lung myeloid phagocytes had no defects in conidial phagocytosis or killing. Loss of TFEB and TFE3 did not impact murine survival or clearance of A. fumigatus from the lungs. Our findings indicate that myeloid phagocytes activate TFEB and TFE3 in response to A. fumigatus , and while this pathway promotes macrophage fungicidal activity in vitro , genetic loss can be functionally compensated in the lung, resulting in no measurable defect in fungal control and host survival., Competing Interests: Andrea Ballabio is co-founder of CASMA Therapeutics and advisory board member of Next Generation Diagnostics and Avilar and Coave Therapeutics.

Background: SHANKs are major scaffolding proteins at postsynaptic densities (PSDs) in the central nervous system. Mutations in all three family members have been associated with neurodevelopmental disorders such as autism spectrum disorders (ASDs). Despite the pathophysiological importance of SHANK2 and SHANK3 mutations in humans, research on the expression of these proteins is mostly based on rodent model organisms., Results: In the present study, cellular and neuropil SHANK2 expression was analyzed by immunofluorescence (IF) staining of post mortem human brain tissue from four male individuals (19 brain regions). Mouse brains were analyzed in comparison to evaluate the degree of phylogenetic conservation. Furthermore, SHANK2 and SHANK3 isoform patterns were compared in human and mouse brain lysates. While isoform expression and subcellular distribution were largely conserved, differences in neuropil levels of SHANK2 were found by IF staining: Maximum expression was concordantly measured in the cerebellum; however, higher SHANK2 expression was detected in the human brainstem and thalamus when compared to mice. One of the lowest SHANK2 levels was found in the human amygdala, a moderately expressing region in mouse. Quantification of SHANK3 IF in mouse brains unveiled a distribution comparable to humans., Conclusions: In summary, these data show that the overall expression pattern of SHANK is largely conserved in defined brain regions; however, differences do exist, which need to be considered in the translation of rodent studies. The summarized expression patterns of SHANK2 and SHANK3 should serve as a reference for future studies., (© 2023. The Author(s).)

Bimetallic nanoparticles have been extensively studied as electrocatalysts due to their superior catalytic activity and selectivity compared to their monometallic counterparts. The properties of bimetallic materials depend on the ordering of the metals in the structure, and to tailor-make materials for specific applications, it is important to be able to control the atomic structure of the materials during synthesis. Here, we study the formation of bimetallic palladium indium nanoparticles to understand how the synthesis parameters and additives used influence the atomic structure of the obtained product. Specifically, we investigate a colloidal synthesis, where oleylamine was used as the main solvent while the effect of two surfactants, oleic acid (OA) and trioctylphosphine (TOP) was studied. We found that without TOP included in the synthesis, a Pd-rich intermetallic phase with the Pd 3 In structure initially formed, which transformed into large NPs of the CsCl-structured PdIn phase. When TOP was included, the syntheses yielded both In 2 O 3 and Pd 3 In. In situ X-ray total scattering with Pair Distribution Function analysis was used to study the formation process of PdIn bimetallic NPs. Our results highlight how seemingly subtle changes to material synthesis methods can have a large influence on the product atomic structure., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: To investigate current abortion access in the United States based on geographic location and to forecast access according to the landscape of abortion care in the year after the Dobbs v Jackson Women's Health Organization decision., Methods: Addresses of abortion-providing clinics were identified using web-based directories from Planned Parenthood, the National Abortion Foundation, Abortion Finder, and Power to Decide. Using geographic coordinates and the OpenStreetMap road network, Valhalla's Isochrone application programming interface was used to calculate the areas within a 30-, 60-, and 90-minute driving distance from these clinics. The population of reproductive-aged women (15-49 years) in the tracts inside or outside the accessible areas was determined using the U.S. Census American Community Survey for 2020. Review of legislative and judicial actions for 2023 determined at-risk states. Clinic locations and laws are accurate as of June 2, 2023., Results: The addresses of 750 abortion facilities were geocoded. Currently, 41.4% (30.8 million) of women do not have access to an abortion clinic within a 30-minute drive, and 29.3% and 23.6% do not have access within a 60-minute and 90-minute drive, respectively. When accounting for the combined population with no access, severely limited access, and at-risk of losing access, 53.5% of women do not have access within a 30-minute drive, and 45.6% and 43.0% do not have access within a 60-minute and 90-minute drive, respectively., Discussion: Two of every five American women do not have access to an abortion facility within a 30-minute drive, and one in four lack access within a 90-minute drive. These proportions could significantly increase if access is restricted further with state bans proposed in 2023., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Bis(trifluoromethylated)benziodoxoles (Bx) are broadly used cyclic hypervalent iodine reagents due to their stability and unique chemical properties. However, current methods to access them require several steps and long reaction times, making their synthesis tedious. Herein, a direct one-pot synthesis of bis(trifluoromethylated) Bx reagents from iodine(I) precursors is reported, enabling the synthesis of functionalized reagents.

The thalamus acts as an interface between the periphery and the cortex, with nearly every sensory modality processing information in the thalamocortical circuit. Despite well-established thalamic nuclei for visual, auditory, and tactile modalities, the key thalamic nuclei responsible for innocuous thermosensation remains under debate. Thermosensory information is first transduced by thermoreceptors located in the skin and then processed in the spinal cord. Temperature information is then transmitted to the brain through multiple spinal projection pathways including the spinothalamic tract and the spinoparabrachial tract. While there are fundamental studies of thermal transduction via thermosensitive channels in primary sensory afferents, thermal representation in the spinal projection neurons, and encoding of temperature in the primary cortical targets, comparatively little is known about the intermediate stage of processing in the thalamus. Multiple thalamic nuclei have been implicated in thermal encoding, each with a corresponding cortical target, but without a consensus on the role of each pathway. Here, we review a combination of anatomy, physiology, and behavioral studies across multiple animal models to characterize the thalamic representation of temperature in two proposed thermosensory information streams., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Leva and Whitmire.)

The ambigols are cyanobacterial natural products characterized by three polychlorinated aromatic building blocks connected by biaryl and biaryl ether bridges. All ambigols known to date possess promising biological activities. Most significantly, ambigol A was reported to have antibacterial activity against Gram-positive bacteria, such as Bacillus megaterium and B. subtilis . We established a diverse compound library for in-depth biological evaluation building on our previous bio- and total synthetic research on this natural product family. To explore the antimicrobial potential in detail and to determine initial structure-activity relationships of this product class, a large set of dimeric and trimeric compounds were screened against selected bacterial and Candida target strains. Our results reveal exceptional antibiotic activity of the ambigols, especially against challenging clinical isolates.