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We further show that some but not all of these CD38-induced phenotypes could be rescued by exogenous NAM. Treatment of cells with NAM rescued CD38-induced apoptosis and mitochondrial stress but did not restore intracellular NAD+ levels. We also found that NAM demonstrated biphasic effect on mitochondria function, a finding that can be explained by the dual role of NAM as both a precursor of NAD+ and also as a suppressor of a number of NAD+-dependent enzymes. Collectively, these findings provide additional insight supporting the functional relevance of CD38 loss in prostate cancer by linking cell-autonomous regulation of mitochondrial function and prostate cancer.Aromatic aldehydes are important industrial raw materials mainly synthesized by anti-Markovnikov (AM) oxidation of corresponding aromatic olefins. The AM product selectivity remains a big challenge. P450 aMOx is the first reported enzyme that could catalyze AM oxidation of aromatic olefins. Here, we reported a rational design strategy based on the "butterfly" model of the active site of P450 aMOx. Constrained molecular dynamic simulations and a binding energy analysis of key residuals combined with an experimental alanine scan were applied. As a result, the mutant A275G showed high AM selectivity of >99%. The results also proved that the "butterfly" model is an effective design strategy for enzymes.The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora of vital physiological processes. Consequently, GPCRs are an attractive drug target class. This is underlined by the fact that approximately 40% of marketed drugs modulate GPCRs. Intriguingly 60% of non-olfactory GPCRs have no drugs or candidates in clinical development, highlighting the continued potential of GPCRs as drug targets. The discovery of small molecules targeting these GPCRs by conventional high throughput screening (HTS) campaigns is challenging. Although the definition of success varies per company, the success rate of HTS for GPCRs is low compared to other target families (Fujioka and Omori, 2012; Dragovich et al., 2022). Beyond this, GPCR structure determination can be difficult, which often precludes the application of structure-based drug design approaches to arising HTS hits. GPCR structural studies entail the resource-durposes. In order to demonstrate the potential impact of ConfoBodies on translational research, examples are presented of their role in active state screening campaigns and structure-informed rational design to identify de novo chemical space and, subsequently, how such matter can be elaborated into more potent and selective drug candidates with intended pharmacology.Infection of mammalian cells by SARS-CoV-2 coronavirus requires primary interaction between the receptor binding domain (RBD) of the viral spike protein and the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) glycoprotein. Several mutations in the RBD of SARS-CoV-2 spike protein have been reported for several variants and resulted in wide spread of the COVID pandemic. For instance, the double mutations L452R and E484Q present in the Indian B.1.617 variant have been suggested to cause evasion of the host immune response. The common RBD mutations N501Y and E484K were found to enhance the interaction with the ACE2 receptor. In the current study, we analyzed the biosynthesis and secretion of the RBD double mutants L452R and E484Q in comparison to the wild-type RBD and the individual mutations N501 and E484K in mammalian cells. Moreover, we evaluated the interaction of these variants with ACE2 by means of expression of the S protein and co-immunoprecipitation with ACE2. Our results revealed that the double RBD mutations L452R and E484Q resulted in a higher expression level and secretion of spike S1 protein than other mutations. In addition, an increased interaction of these mutant forms with ACE2 in Calu3 cells was observed. Altogether, our findings highlight the impact of continuous S1 mutations on the pathogenicity of SARS-CoV-2 and provide further biochemical evidence for the dominance and high transmissibility of the double Indian mutations.Lipid-based nanosystems enable intracellular delivery of drugs in the oral cavity for the treatment of local diseases. To rationally design such systems, suitable matrix compositions and particle properties need to be identified, and manufacturing technologies that allow reproducible production have to be applied. This is a prerequisite for the reliable and predictable performance of in-vitro biological studies. Here, we showed that solid lipid nanoparticles (SLN, palmitic acid) and nanostructured lipid carriers (NLC, palmitic acid and oleic acid in different ratios) with a size of 250 nm, a negative zeta potential, and a polydispersity index (PdI) of less than 0.3 can be reproducibly prepared by high-pressure homogenization using quality by design and a predictive model. SLN and NLC were colloidally stable after contact with physiological fluid and did not form agglomerates. The in-vitro studies clearly showed that besides particle size, surface charge and hydrophobicity, matrix composition had a significant effect. More specifically, the addition of the liquid lipid oleic acid increased the cellular uptake capacity without changing the underlying uptake mechanism. Regardless of the matrix composition, caveolin-mediated endocytosis was the major route of uptake, which was confirmed by particle localization in the endoplasmic reticulum. Thus, this work provides useful insights into the optimal composition of lipid carrier systems to enhance the intracellular uptake capacity of drugs into the oral mucosa.

ECT is a rapid and effective treatment for depression. While efficacy is often remarkable over the initial 3-4 sessions, the efficacy of later sessions is less rapid, and the side-effects, especially cognitive impairment limit its use. To preliminarily compare the efficacy and acceptability of a novel hybrid-ECT (HECT) protocol for patients with major depressive disorder (MDD) with standard ECT, we conducted this pilot trial.

Thirty patients were randomly assigned to ECT or HECT. Both arms received three ECT sessions (phase 1) but, in phase 2, the HECT arm received low-charge electrotherapy instead of ECT. The primary outcome was the change in 24-item Hamilton depression rating scale (HAMD-24) scores between baseline and the end of treatment. Cognitive function was assessed by repeatable battery for the assessment of neuropsychological status (RBANS), Stroop color word, and orientation recovery tests (ORT). Safety was measured by the drop-out rate and adverse events (AEs). Four visits were conducted at baseline, post-phase 1, post-phase 2, and at 1-month follow-up. Trial registration Chinese Clinical Trial Registry (http//www.chictr.org.cn/), identifier ChiCTR1900027701.

Patients in both arms showed significant within-group improvements in HAMD-24, but the between-group differences were non-significant. Participants in the HECT arm outperformed ECT patients for most cognitive tests at the end of treatment or at follow-up. Bulevirtide chemical structure There was a significantly lower AE rate and shorter ORT in phase 2 of the HECT ar.

In this pilot trial, HECT was associated with fewer AEs and better cognitive function including executive and memory function, but its possible similar antidepressive efficacy needs to be further investigated in future.

In this pilot trial, HECT was associated with fewer AEs and better cognitive function including executive and memory function, but its possible similar antidepressive efficacy needs to be further investigated in future.

The external clinical manifestations (psychopathology) and internal subjective experience (phenomenology) of catatonia are of clinical importance but have received little attention. This study aimed to use a large dataset to describe the clinical signs of catatonia; to assess whether these signs are associated with underlying diagnosis and prognosis; and to describe the phenomenology of catatonia, particularly with reference to fear.

A retrospective descriptive cross-sectional study was conducted using the electronic healthcare records of a large secondary mental health trust in London, United Kingdom. Patients with catatonia were identified in a previous study by screening records using natural language processing followed by manual validation. The presence of items of the Bush-Francis Catatonia Screening Instrument was coded by the investigators. The presence of psychomotor alternation was assessed by examining the frequency of stupor and excitement in the same episode. A cluster analysis and principal tic variables. Fear appears in a large minority of patients with catatonia, but narrative explanations are varied and possibly more common.

Disruptions in rest and activity patterns are core features of bipolar disorder (BD). However, previous methods have been limited in fully characterizing the patterns. There is still a need to capture dysfunction in daily activity as well as rest patterns in order to more holistically understand the nature of 24-h rhythms in BD. Recent developments in the standardization, processing, and analyses of wearable digital actigraphy devices are advancing longitudinal investigation of rest-activity patterns in real time. The current systematic review aimed to summarize the literature on actigraphy measures of rest-activity patterns in BD to inform the future use of this technology.

A comprehensive systematic review using PRISMA guidelines was conducted through PubMed, MEDLINE, PsycINFO, and EMBASE databases, for papers published up to February 2021. Relevant articles utilizing actigraphy measures were extracted and summarized. These papers contributed to three research areas addressed, pertaining to the nature oll number of studies assessing longitudinal changes over days. Thus, there is an urgent need to extend this work to examine patterns of rhythmicity and regularity in BD. Actigraphy research holds great promise to identify a much-needed specific phenotypic marker for BD that will aid in the development of improved detection, treatment, and prevention options.

The use of actigraphy provides valuable information about rest-activity patterns in BD. Although results suggest that variability in rhythms over time may be a specific feature of BD, definitive conclusions are limited by the small number of studies assessing longitudinal changes over days. Thus, there is an urgent need to extend this work to examine patterns of rhythmicity and regularity in BD. Actigraphy research holds great promise to identify a much-needed specific phenotypic marker for BD that will aid in the development of improved detection, treatment, and prevention options.

With the development of quantitative electroencephalography (QEEG), an increasing number of studies have been published on the clinical use of QEEG in the past two decades, particularly in the diagnosis, treatment, and prognosis of neuropsychiatric disorders. However, to date, the current status and developing trends of this research field have not been systematically analyzed from a macroscopic perspective. The present study aimed to identify the hot spots, knowledge base, and frontiers of QEEG research in neuropsychiatric disorders from 2000 to 2021 through bibliometric analysis.

QEEG-related publications in the neuropsychiatric field from 2000 to 2021 were retrieved from the Web of Science Core Collection (WOSCC). CiteSpace and VOSviewer software programs, and the online literature analysis platform (bibliometric.com) were employed to perform bibliographic and visualized analysis.

A total of 1,904 publications between 2000 and 2021 were retrieved. The number of QEEG-related publications in neuropsychiatric disorders increased steadily from 2000 to 2021, and research in psychiatric disorders requires more attention in comparison to research in neurological disorders.