Tractability

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in MASLD. METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored...

Electron pairs have an illustrious history in chemistry, from powerful concepts to understanding structural stability and reactive changes to the promise of serving as building blocks of quantitative descriptions of the electronic structure of complex molecules and materials. However, traditionally, two-electron wavefunctions (geminals) have not enjoyed the popularity and widespread use of the more standard single-particle methods. This has changed recently, with a renewed interest in the development of geminal wavefunctions as an alternative to describing strongly correlated phenomena...

Deciphering the regulatory code of gene expression and interpreting the transcriptional effects of genome variation are critical challenges in human genetics. Modern experimental technologies have resulted in an abundance of data, enabling the development of sequence-based deep learning models that link patterns embedded in DNA to the biochemical and regulatory properties contributing to transcriptional regulation, including modeling epigenetic marks, 3D genome organization, and gene expression, with tissue and cell-type specificity...

The equations governing gas flow dynamics are computationally challenging for energy network optimization. This paper proposes an efficient solution procedure to enable tractability for an hourly resolved yearly decision horizon. The solution procedure deploys linear and second-order cone gas flow models alternatively based on the length-diameter ratio of pipes, achieving maximum efficiency within accuracy limits. Moreover, it addresses the computational complexity of bidirectional pipe flows by fixing the associated integer variables according to a preceding optimization with a static flow approximation...

Identifying the molecular origins by which new morphological structures evolve is one of the long standing problems in evolutionary biology. To date, vanishingly few examples provide a compelling account of how new morphologies were initially formed, thereby limiting our understanding of how diverse forms of life derived their complex features. Here, we provide evidence that the large projections on the Drosophila eugracilis phallus that are implicated in sexual conflict have evolved through co-option of the trichome genetic network...

Wound healing is impaired by infection; however, how microbe-induced inflammation modulates tissue repair remains unclear. We took advantage of the optical transparency of zebrafish and a genetically tractable microbe, Listeria monocytogenes , to probe the role of infection and inflammation in wound healing. Infection with bacteria engineered to activate the inflammasome, Lm-Pyro, induced persistent inflammation and impaired healing despite low bacterial burden. Inflammatory infections induced il1b expression and blocking IL-1R signaling partially rescued wound healing in the presence of persistent infection...

BACKGROUND: The epididymis has long been of interest owing to its role in promoting the functional maturation of the male germline. More recent evidence has also implicated the epididymis as an important sensory tissue responsible for remodeling of the sperm epigenome, both under physiological conditions and in response to diverse forms of environmental stress. Despite this knowledge, the intricacies of the molecular pathways involved in regulating the adaptation of epididymal tissue to paternal stressors remains to be fully resolved...

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy...

Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has established the precision oncology paradigm in lung cancer. Most patients with EGFR -mutated lung cancer respond but eventually acquire resistance. Methods: Patients exhibiting the EGFR p.T790M resistance biomarker benefit from sequenced targeted therapy with osimertinib. We hypothesized that metabolic response as detected by 18 F-FDG PET after short-course osimertinib identifies additional patients susceptible to sequenced therapy...

Research into learning and memory over the past decades has revealed key neurotransmitters that regulate these processes, many of which are evolutionarily conserved across diverse species. The monoamine neurotransmitter dopamine is one example of this, with countless studies demonstrating its importance in regulating behavioural plasticity. However, dopaminergic neural networks in the mammalian brain consist of hundreds or thousands of neurons, and thus cannot be studied at the level of single neurons acting within defined neural circuits...

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies...

Missense mutations in the RAS family of oncogenes (HRAS, KRAS, and NRAS) are present in approximately 20% of human cancers, making RAS a valuable therapeutic target (Prior et al., Cancer Res 80:2969-2974, 2020). Although decades of research efforts to develop therapeutic inhibitors of RAS were unsuccessful, there has been success in recent years with the entrance of FDA-approved KRASG12C -specific inhibitors to the clinic (Skoulidis et al., N Engl J Med 384:2371-2381, 2021; Jänne et al., N Engl J Med 387:120-131, 2022)...

IMPORTANCE: The restricted Net Treatment Benefit (rNTB) is a clinically meaningful and tractable estimand of the overall treatment effect assessed in randomized trials when at least one survival endpoint with time restriction is used. Its interpretation does not rely on parametric assumptions such as proportional hazards, can be estimated without bias even in presence of independent right-censoring and can include a pre-specified threshold of minimal clinically relevant difference. OBJECTIVE: To demonstrate that the rNTB, corresponding to the NTB during a predefined time interval, is a meaningful and adaptable measure of treatment effect in clinical trials...

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass...

Traumatic brain injury (TBI) is a major global health concern and is increasingly recognized as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Repetitive TBIs (rTBIs), commonly observed in contact sports, military service, and intimate partner violence (IPV), pose a significant risk for long-term sequelae. To study the long-term consequences of TBI and rTBI, researchers have typically used mammalian models to recapitulate brain injury and neurodegenerative phenotypes...

Ammonia availability has a crucial role in agriculture as it ensures healthy plant growth and increased crop yields. Since diazotrophs are the only organisms capable of reducing dinitrogen to ammonia, they have a great ecological importance and potential to mitigate the environmental and economic costs of synthetic fertilizer use. Rhizobia are especially valuable being that they can engage in nitrogen-fixing symbiotic relationships with legumes, and they demonstrate great diversity and plasticity in genomic and phenotypic traits...

In electroreceptive jawed vertebrates, embryonic lateral line placodes give rise to electrosensory ampullary organs as well as mechanosensory neuromasts. Previous reports of shared gene expression suggest that conserved mechanisms underlie electroreceptor and mechanosensory hair cell development and that electroreceptors evolved as a transcriptionally related "sister cell type" to hair cells. We previously identified only one transcription factor gene, Neurod4 , as ampullary organ-restricted in the developing lateral line system of a chondrostean ray-finned fish, the Mississippi paddlefish ( Polyodon spathula )...

An important consideration in drug discovery is the prioritization of tractable protein targets that are not only amenable to binding small molecules, but also alter disease biology in response to small molecule binding. Covalent fragment-based drug discovery has emerged as a powerful approach to aid in the identification of such protein targets. The application of irreversible binding mechanisms enables the identification of fragment hits for challenging-to-target proteins, allows proteome-wide screening in a cellular context, and makes it possible to determine functional effects with modestly potent ligands without the requirement for extensive compound optimization...

Neonicotinoid insecticides, the fastest-growing class in recent decades, interfere with cholinergic neurotransmission by binding to the nicotinic acetylcholine receptor. This disruption affects both targeted and non-targeted insects, impairing cognitive functions such as olfaction and related behaviors, with a particular emphasis on olfactory memory due to its ecological impact. Despite the persistent presence of these chemicals in the environment, significant research gaps remain in understanding the intricate interplay between cognitive function, development, neuronal activity, and neonicotinoid-induced toxicity...

The zebrafish (Danio rerio) is an important model organism for basic as well as applied bio-medical research. One main advantage is its genetic tractability, which was greatly enhanced by the introduction of the CRISPR/Cas method a decade ago. The generation of loss-of-function alleles via the production of small insertions or deletions in the coding sequences of genes with CRISPR/Cas systems is now routinely achieved with high efficiency. The method is based on the error prone repair of precisely targeted DNA double strand breaks by non-homologous end joining (NHEJ) in the cell nucleus...