TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching.

The AAA+ family ATPase TRIP13 is a key regulator of meiotic recombination and the spindle assembly checkpoint, acting on signaling proteins of the conserved HORMA domain family. Here we present the structure of the Caenorhabditis elegans TRIP13 ortholog PCH-2, revealing a new family of AAA+ ATPase protein remodelers. PCH-2 possesses a substrate-recognition domain related to those of the protein remodelers NSF and p97, while its overall hexameric architecture and likely structural mechanism bear close similarities to the bacterial protein unfoldase ClpX. We find that TRIP13, aided by the adapter protein p31(comet), converts the HORMA-family spindle checkpoint protein MAD2 from a signaling-active 'closed' conformer to an inactive 'open' conformer. We propose that TRIP13 and p31(comet) collaborate to inactivate the spindle assembly checkpoint through MAD2 conformational conversion and disassembly of mitotic checkpoint complexes. A parallel HORMA protein disassembly activity likely underlies TRIP13's critical regulatory functions in meiotic chromosome structure and recombination

Transcranial alternating current stimulation for the treatment of major depressive disorder: from basic mechanisms toward clinical applications

Non-pharmacological treatment is essential for patients with major depressive disorder (MDD) that is medication resistant or who are unable to take medications. Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that manipulates neural oscillations. In recent years, tACS has attracted substantial attention for its potential as an MDD treatment. This review summarizes the latest advances in tACS treatment for MDD and outlines future directions for promoting its clinical application. We first introduce the neurophysiological mechanism of tACS and its novel developments. In particular, two well-validated tACS techniques have high application potential: high-definition tACS targeting local brain oscillations and bifocal tACS modulating interarea functional connectivity. Accordingly, we summarize the underlying mechanisms of tACS modulation for MDD. We sort out the local oscillation abnormalities within the reward network and the interarea oscillatory synchronizations among multiple MDD-related networks in MDD patients, which provide potential modulation targets of tACS interventions. Furthermore, we review the latest clinical studies on tACS treatment for MDD, which were based on different modulation mechanisms and reported alleviations in MDD symptoms. Finally, we discuss the main challenges of current tACS treatments for MDD and outline future directions to improve intervention target selection, tACS implementation, and clinical validations

A conserved filamentous assembly underlies the structure of the meiotic chromosome axis.

The meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that 'axis core proteins' from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify 'closure motifs' in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core proteins form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture, and likely also plays conserved roles in meiotic chromosome axis assembly and recombination control

Identification and Characterization of Key Chemical Constituents in Processed Gastrodia elata Using UHPLC-MS/MS and Chemometric Methods

© The Author(s) 2019. Background. Obesity is a major medical issue nationally, with rates continually increasing. In obese patients, minimal data exist for appropriate dosing of acyclovir to decrease the rates of nephrotoxicity. The purpose of this study was to determine the prevalence of and risk factors associated with acyclovir-induced nephrotoxicity. Methods. A retrospective case-control of patients who received intravenous acyclovir for \u3e48 hours at University of Mississippi Medical Center over a 4-year period were evaluated to elucidate the prevalence of acyclovir-induced nephrotoxicity. Additionally, risk factors for the development of nephrotoxicity, including the effect of obesity and dosing strategy, were assessed. Results. One hundred fifteen patients were included in the study. A total of 24 (21%) patients developed nephrotoxicity after acyclovir exposure and were in the Risk (9.6%), Injury (4.3%), and Failure (7%) categories, defined by the RIFLE criteria. Neither acyclovir dosage, fluid status, nor baseline characteristics, other than obesity, varied between those who developed nephrotoxicity vs those who did not. Independent predictors of nephrotoxicity were obesity (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.19-8.67) and receipt of vancomycin (OR, 4.73; 95% CI, 1.57-14.25). No differences in vancomycin dosing or concentrations were observed between the patients who developed nephrotoxicity and those who did not. Conclusions. In this study, nephrotoxicity occurred in 21% of patients receiving acyclovir. Concomitant vancomycin receipt and obesity led to higher rates of toxicity. Efforts should be made to target obese patients on acyclovir plus vancomycin and discontinue therapy in patients not warranting antiviral coverage to minimize chances of toxicity

Re-analysis of gene mutations found in pituitary stalk interruption syndrome and a new hypothesis on the etiology

BackgroundPituitary stalk interruption syndrome (PSIS) is a complex clinical syndrome characterized by varied pituitary hormone deficiencies, leading to severe manifestations across multiple systems. These include lifelong infertility, short stature, mental retardation, and potentially life-threatening pituitary crises if not promptly diagnosed and treated. Despite extensive research, the precise pathogenesis of PSIS remains unclear. Currently, there are two proposed theories regarding the pathogenic mechanisms: the genetic defect theory and the perinatal injury theory.MethodsWe systematically searched English databases (PubMed, Web of Science, Embase) and Chinese databases (CNKI, WanFang Med Online, Sinomed) up to February 24, 2023, to summarize studies on gene sequencing in PSIS patients. Enrichment analyses of reported mutated genes were subsequently performed using the Metascape platform.ResultsOur study included 37 articles. KEGG enrichment analysis revealed mutated genes were enriched in the Notch signaling pathway, Wnt signaling pathway, and Hedgehog signaling pathway. GO enrichment analysis demonstrated mutated genes were enriched in biological processes such as embryonic development, brain development, axon development and guidance, and development of other organs.ConclusionBased on our summary and analyses, we propose a new hypothesis: disruptions in normal embryonic development, partially stemming from the genetic background and/or specific gene mutations in individuals, may increase the likelihood of abnormal fetal deliveries, where different degrees of traction during delivery may lead to different levels of pituitary stalk interruption and posterior lobe ectopia. The clinical diversity observed in PSIS patients may result from a combination of genetic background, specific mutations, and variable degrees of traction during delivery

A conserved filamentous assembly underlies the structure of the meiotic chromosome axis

The meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that 'axis core proteins' from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify 'closure motifs' in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core proteins form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture, and likely also plays conserved roles in meiotic chromosome axis assembly and recombination control