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Failures, errors, and bugs can corrupt file systems and cause data loss, despite the presence of journals and similar preventive techniques. While consistency checkers such as fsck can detect corruption and repair a damaged image, they are generally created as an afterthought, to be run only at rare intervals. Thus, checkers operate slowly, causing significant downtime for large scale storage systems. We address this dilemma by treating the checker as a key component of the overall file system, rather than a peripheral add-on. To this end, we present a modified ext3 file system, rext3, to directly support the fast file-system checker, ffsck. Rext3 colocates and self-identifies its metadata blocks, removing the need for costly seeks and tree traversals during checking. These modifications allow ffsck to scan and repair the file system at rates approaching the full sequential bandwidth of the underlying device. In addition, we demonstrate that rext3 generally performs competitively with ext3 and exceeds it in handling random reads and large writes. Finally, we apply our principles to FreeBSD's FFS file system and its checker, doing so in a lightweight fashion that preserves the file-system layout while still providing some of the performance gains from ffsck. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion and conclusion HENMT1 encodes a small RNA methyltransferase that plays a crucial role in mouse spermatogenesis through the methylation of the 3′ end of PIWI‐interacting RNAs.Our study aims to elucidate the relationship between HENMT1 and male infertility in humans.A consanguineous family, having a single non‐obstructive azoospermia patient was recruited for pathogenic variants screening. The research includes genetic analysis and experimental validation using mouse models. The patient was diagnosed with non‐obstructive azoospermia. Whole‐exome sequencing and subsequent bioinformatic analyses were performed to screen for candidate pathogenic variants. The pathogenicity of the identified variant was assessed and studied in vivo using a mouse model that mimicked the patient's mutation.Through whole‐exome sequencing, we identified a homozygous nonsense variant (c.555G > A, p.Trp185*) in HENMT1 in the patient. The presence of the mutant HENMT1 mRNA was detected in the patient's blood, and the truncated HENMT1 protein was observed in transfected HEK293T cells. The mutant mice modeling this HENMT1 variant displayed an infertile phenotype similar to that of the patient, characterized by spermiogenesis arrest. Further analysis revealed a significant derepression of retrotransposon LINE1 in the testes of the Henmt1 mutant mice, and increased apoptosis of spermatids.Our findings provide the evidence of pathogenicity of the identified HENMT1 variant, thus shedding light on the indispensable role of HENMT1 in human spermatogenesis. [ABSTRACT FROM AUTHOR]

Reaction coordinates (RCs) are the few essential coordinates of a protein that control its functional processes, such as allostery, enzymatic reaction, and conformational change. They are critical for understanding protein function and provide optimal enhanced sampling of protein conformational changes and states. Since the pioneering work in the late 1990s, identifying the correct and objectively provable RCs has been a central topic in molecular biophysics and chemical physics. This review summarizes the major advances in identifying RCs over the past 25 years, focusing on methods aimed at finding RCs that meet the rigorous committor criterion, widely accepted as the true RCs. Importantly, the newly developed physics-based energy flow theory and generalized work functional method provide a general and rigorous approach for identifying true RCs, revealing their physical nature as the optimal channels of energy flow in biomolecules.

Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia (OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T, p.Arg306*) in the coiled-coil domain containing 146 ( CCDC146 ) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein (amino acids 1-305), retaining only two out of five coiled-coil domains. To validate the pathogenicity of the CCDC146 mutation, we generated a mouse model ( Ccdc146 mut/mut ) with a similar mutation to that of the patient. Consistently, the Ccdc146 mut/mut mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm of Ccdc146 mut/mut mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20 (IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20. This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

Objective: To investigate the long-term changes in nutritional status in children with solid tumors during treatment and the relationship between nutritional status and clinical outcomes., Methods: This study was a retrospective medical records review of data from children who were diagnosed with solid tumors and followed up for more than 3 months from January 2016 to December 2021 in China. Patient demographics and clinical information, including nutritional status, parenteral nutrition use, intensive care unit (ICU) transfers, infection during hospitalization, hospitalization frequency, length of stay, hospitalization costs and antibiotic costs, were collected to analyze the nutritional status of children with different types of solid tumors, the dynamic changes in nutritional status during treatment, and the relationship between nutritional status and clinical outcomes., Results: Among the 764 patients (383 males (50.1%); 381 females (49.9%); mean age: 2.58 years), 41.6% of the solid tumors were neuroblastomas, 17.1% were hepatoblastomas, and Wilms tumors as the third most common solid tumors (8.9%). The median follow-up duration was 6 months (range: 3-40 months). At diagnosis, the proportion of children who were undernourished (underweight and wasting) versus overweight or obese were 26.71% versus 5.21% (25.86% vs. 2.89% in the third month; 29.77% vs. 2.28% in the sixth month; 24.77% vs. 3.27% in the 12th month). The body mass index Z scores decreased from the initial values after the first month (-0.56 (-1.47, 0.23) vs. -0.44 (-1.29, 0.41)) but improved later and decreased again at 6 months. The children in the undernutrition group had longer hospital stays (p < 0.001), higher hospitalization costs (p < 0.001), higher antibiotic costs (p < 0.001), a higher risk of neutropenia (OR = 4.781 (95% CI: 1.571-14.553), p = 0.006), and a higher risk of ICU transfers (OR = 1.498 (95% CI: 1.010-2.224), p = 0.044). No significant differences in those associations by malnutrition and infection, ICU duration, or length of parenteral nutrition were observed., Conclusion: There is a considerable prevalence of malnutrition in children with solid tumors. Malnutrition is related to adverse clinical outcomes and increases in total hospital expenses and antibiotic costs., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The DSB machinery, which induces the programmed DNA double-strand breaks (DSBs) in the leptotene and zygotene stages during meiosis, is suppressed before the onset of the pachytene stage. However, the biological significance and underlying mechanisms remain largely unclear. Here, we report that ZFP541 is indispensable for the suppression of DSB formation after mid-pachytene. The deletion of Zfp541 in mice causes the aberrant recruitment of DSB machinery to chromosome axes and generation of massive DSBs in late pachytene and diplotene spermatocytes, leading to meiotic arrest at the diplotene stage. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data indicate that ZFP541 predominantly binds to promoters of pre-pachytene genes, including meiotic DSB formation-related genes (e.g., Prdm9 and Mei1) and their upstream activators (e.g., Meiosin and Rxra), and maintains their repression in pachytene spermatocytes. Our results reveal that ZFP541 functions as a transcriptional regulator in pachytene spermatocytes, orchestrating the transcriptome to ensure meiosis progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Most functional processes of biomolecules are rare events. Key to a rare event is the rare fluctuation that enables the energy activation process that precedes and powers crossing of the activation barrier. However, the physical nature of this rare fluctuation and how it enables energy activation and subsequently barrier crossing are unknown. We developed a novel metric, the reaction capacity p C , that rigorously defines the beginning and parameterizes the progress of energy activation. This enabled us to identify the rare fluctuation as a special phase-space condition that is necessary and sufficient for initiating systematic energy flow from the non-reaction coordinates into the reaction coordinates. The energy activation of a prototype biomolecular isomerization reaction is dominated by kinetic energy transferring into and accumulating in the reaction coordinates, administered by inertial forces alone. This mechanism for energy activation is fundamentally different from the mechanism suggested by Kramers theory.

Microtubules are the backbone of the cytoskeleton and vital to numerous cellular processes. The central dogma of microtubules is that all their functions are driven by dynamic instability, but its mechanism has remained unresolved for over 30 years because of conceptual difficulties inherent in the dominant GTP-cap framework. We present a physically rigorous structural mechanochemical model: dynamic instability is driven by non-equilibrium transitions between the bent (B), straight (S), and curved (C) forms of tubulin monomers and longitudinal interfaces in the two-dimensional lattice of microtubule. All the different phenomena (growth, shortening, catastrophe, rescue, and pausing) are controlled by the kinetic pathways for B↔S↔C transitions and corresponding energy landscapes. Different kinetics at minus end are due to different B↔S↔C pathways imposed by the polarity of microtubule lattice. This model enables us to reproduce all the observed phenomena of dynamic instability of purified tubulins in kinetic simulations., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Drug discovery for neurodegenerative diseases is particularly challenging because of the discrepancies in drug effects between in vitro and in vivo studies. These discrepancies occur in part because current cell culture systems used for drug screening have many limitations. First, few cell culture systems accurately model human aging or neurodegenerative diseases. Second, drug efficacy may differ between dividing and stationary cells, the latter resembling nondividing neurons in the CNS. Brain aggregates (BrnAggs) derived from embryonic day 15 gestation mouse embryos may represent neuropathogenic processes in prion disease and reflect in vivo drug efficacy. Here, we report a new method for the production of BrnAggs suitable for drug screening and suggest that BrnAggs can model additional neurological diseases such as tauopathies. We also report a functional assay with BrnAggs by measuring electrophysiological activities. Our data suggest that BrnAggs could serve as an effective in vitro cell culture system for drug discovery for neurodegenerative diseases., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Paradoxical embolization can occur when a right-to-left shunt allows a venous thromboembolus to escape filtration by the lungs. Venous collateral pathways draining into the left heart incited by superior vena cava obstruction are a rare acquired right-to-left shunt. Herein, the authors report on a case of transient ischemic attack in a patient with vena caval occlusion secondary to histoplasmosis-related fibrosing mediastinitis, with subclavian vein thrombosis and a right-to-left extracardiac shunt diagnosed with echocardiography. Despite the complexity of the collateral network, this shunt was successfully eradicated with coil embolization.

We describe the implementation of a general and flexible Monte Carlo (MC) module for the program CHARMM, which is used widely for modeling biomolecular systems with empirical energy functions. Construction and use of an almost arbitrary move set with only a few commands is made possible by providing several predefined types of moves that can be combined. Sampling can be enhanced by noncanonical acceptance criteria, automatic optimization of step sizes, and energy minimization. A systematic procedure for improving MC move sets is introduced and applied to simulations of two peptides. The resulting move sets allow MC to sample the configuration spaces of these systems much more rapidly than Langevin dynamics. The rate of convergence of the difference in free energy between ethane and methanol in explicit solvent is also examined, and comparable performances are observed for MC and the Nosé-Hoover algorithm. Its ease of use combined with its sampling efficiency make the MC module in CHARMM an attractive alternative for exploring the behavior of biomolecular systems., (Copyright 2005 Wiley Periodicals, Inc.)

Lowering the overall morbidity rate of peripheral vascular disease requires a systematic approach to the patient with atherosclerosis. This includes comprehensive assessments of risk factors, appropriate modifications of diet and lifestyle as well as an effective and sustaining exercise regimen. The role of new pharmacologic agents is discussed.

Although activation of the endocrine renin-angiotensin system with consequent vasoconstriction and salt retention have long been known as the hallmarks of the early phase of renovascular hypertension, the recent recognition of a local vascular angiotensin system and the understanding of the process of vascular remodeling provide new insights into the pathophysiology of this form of hypertension. New pathophysiologic insights as well as technological advances are beginning to alter longstanding clinical approaches to this disease. For example, the captopril renogram has emerged as the screening test of choice in diagnostic evaluation. In addition, new imaging modalities such as magnetic resonance angiography and spiral computed tomography show promise for providing noninvasive anatomical characterization of renovascular disease. Moreover, therapeutic strategies have advanced as a result of better understanding of the natural history of the disease, more effective pharmacologic therapy, and advances in revascularization techniques, such as intravascular stents. This review focuses on these intriguing new developments.