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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative diseases sharing clinical and pathological features. Both involve complex neuron-glia interactions, but cell-type-specific alterations remain poorly defined. We performed single-nucleus RNA sequencing of the frontal cortex from C9orf72-related ALS (with and without FTLD) and sporadic ALS (sALS). Neurons showed prominent changes in mitochondrial function, protein homeostasis, and chromatin...

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in superoxide dismutase 1 (SOD1). Diagnosis based on SOD1 sequencing can not only be definitive but can also indicate specific therapies available for SOD1-associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance"...

Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with pathogenic variants in the SCN1A gene. The neuropathological features of adult DS remain poorly understood. We report the postmortem findings of a 55-year-old woman with DS due to a confirmed SCN1A pathogenic variant leading to Nav1.1 loss of function. Clinically, she developed pharmacoresistant seizures, intellectual disability, progressive ataxia, parkinsonism, and cognitive decline. Neuropathological...

Cancer drug resistance remains a major barrier to durable treatment success, often leading to relapse despite advances in precision oncology. While combination therapies are being increasingly investigated, such as chemotherapy with small molecule inhibitors, predicting drug response and identifying rational drug combinations based on resistance mechanisms remain major challenges. Therefore, a proteome-wide, single-gene overexpression screening platform is essential for guiding rational therapy...

CONCLUSIONS: Our findings underscore the previously unrecognized role of STR sequence variability in modulating gene expression and contributing to human phenotypic diversity.

CONCLUSION: In non-cirrhotic patients with ECOG2 performance status, minimally invasive minor liver resection may be considered with an acceptable complication rate similar to ECOG1 patients.

Reproductive isolation and genomic divergence both accumulate over time in the formation and persistence of distinct biological species. The pace of "speciation clocks" quantified with pre-zygotic and post-zygotic reproductive isolation, however, differs among taxa, with pre-zygotic isolation tending to evolve sooner in some but not all taxa. To address this issue in nematodes for the first time, here we infer the species tree and divergence times across the phylogeny of 51 species of...

Chronic urinary tract infections are persistent bacterial infections with the potential to drive antibiotic resistance. Like other persistent bacterial infections, intracellular bacterial reservoirs and biofilm formation hinder the clearance of pathogens despite long courses of antibiotic therapy. New strategies for treatment of these persistent infections are needed. Here we describe the results of an open-label individual patient study using bacteriophage therapy to treat a chronic urinary...

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CONCLUSION: These findings indicate the potential of magnetic targeting to direct gene therapy following systemic delivery, paving the way for future applications in the treatment of HL.

BACKGROUND: Antimicrobial resistance is a globally recognised public health threat. In rural China, antibiotic use is common for acute respiratory infections (ARIs), which include symptoms such as coughing and fever that are most likely viral infections but with a small proportion as bacterial infections. This study aims to evaluate the effectiveness of a comprehensive intervention based on C-reactive protein and serum amyloid A point-of-care testing (CRP&SAA POCT) in reducing the inappropriate...

CONCLUSIONS: Patient-reported diary data revealed early and sustained improvements in depressive symptom severity during 8 weeks of adjunctive brexpiprazole treatment. 'Word of the day' may be an effective qualitative tool for future trials.

An exciting feature of nanopore sequencing is its ability to record multi-omic information on the same sequenced DNA molecule. Well-trained models allow the detection of nucleotide-specific molecular signatures through changes in ionic current as DNA molecules translocate through the nanopore. Thus, naturally occurring DNA modifications, such as DNA methylation and hydroxymethylation, may be recorded simultaneously with the genetic sequence. Additional genomic information, such as chromatin...

Digital self-guided single-session interventions (SSIs) provide a structured psychological intervention within one interaction. We crowdsourced 66 diverse 10-minute SSIs for depression and selected 11 for testing in a pre-registered "megastudy" (ClinicalTrials.gov ID: NCT06856668). American adults (N = 7,505) experiencing elevated depressive symptoms were recruited online and randomly assigned to one of the 11 crowdsourced SSIs, a previously-validated active comparison SSI, or a control without...

CONCLUSIONS: Mortality was relatively common after pediatric SCI and was associated with CCJ dissociation or concomitant nonspinal injuries. Among surviving patients who were admitted to the hospital with neurological impairment, a majority experienced improvement by ≥ 1 AIS grade at the 12-month follow-up.

SC05-UT is an anaerobic, heterogenous microbial enrichment culture that reduces chloroform to dichloromethane through reductive dechlorination, which it further mineralizes to carbon dioxide. This dichloromethane mineralization yields electron equivalents that are used to reduce chloroform without the addition of exogenous electron donor. By studying this self-feeding chloroform-amended culture and a dichloromethane-amended enrichment subculture (named DCME), we previously found the genomic...

Single-cell fluorescence characterization has gained much attention for studying the dynamics of individual cells in human diseases such as cancer. Despite the abundance of literature on quantitative fluorescence microscopy and its advantages in measuring cell-to-cell variation and spatial variation over other high-throughput instruments, there lacks a concise model that one can follow to maximize the quality of images. Here, we used the signal-to-noise ratio (SNR) model to verify marketed...

The ingression of neural crest cells from an ectodermal to a mesodermal layer is regulated by instructive, directional cues and potentially stochastic, biophysical parameters such as differential cell adhesion and tension heterogeneity. However, a cohesive framework in which to consider how various influences contribute to ingression remains elusive. Here, we observe the cell behaviors of the murine neural crest in three dimensions over time and apply a free energy framework to more wholly...

Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes¹. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains¹. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into...

Host cells provide intracellular bacteria with protection from harsh environmental conditions and immune responses, but for many intracellular pathogens, this protection does not appear to be absolute as once thought. Bacteriophages that can kill bacteria inside host cells have been identified for pathogens including Salmonella, Mycobacterium, and Chlamydia species. Even in pathogens for which no stable phages have been isolated, such as Legionella pneumophila, the presence of phage defense...