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A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.

BACKGROUND: Known genetic causes of congenital heart disease (CHD) explain

The experiment was conducted during kharif (July–October, 2023) at Centre for Forage Research, S. D. Agricultural University, Sardarkrushinagar, Gujarat, India to study to appraise genetic variability in pearl millet genotypes for fodder yield and associating traits. Thirty forage pearl millet genotypes were evaluated for genetic parameters in terms of days to flowering, days to maturity, plant height (cm), number of tiller plant-1, stem thickness (cm), number of leaf plant-1, leaf length (cm), leaf: stem ratio, dry fodder content (%), dry fodder yield plant-1 (g), crude protein content (%), green forage yield plant-1 (g). Range, mean, phenotypic coefficient of variation (PCV), genotypic coefficient of variation (GCV), heritability, and genetic advance as per cent of mean were studied. The phenotypic coefficient of variation was higher than the genotypic coefficient of variation for all the traits indicating slight dominance of environment in the expression as compared to genetic contribution. Genotypic and phenotypic coefficient of variation were high for green forage yield plant-1, dry fodder yield plant-1, plant height, and number of tiller plant-1. The high heritability with high genetic advance as a per cent of mean has been observed for green forage yield plant-1, crude protein content, dry fodder yield plant-1, leaf: stem ratio, leaf width, number of leaves plant-1, plant height, number of tiller plant-1, and stem thickness. This indicated that there is a lesser influence of environment in the expression of these traits and are predominantly governed by additive genes in their inheritance and selection for these traits will be effective for improvement of both forage yield and quality.

Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt+ Tregs) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt+ Tregs. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt+ Tregs. T cell-specific Ddx5 knockout (DDX5ΔT) mice have augmented RORγt+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5ΔT mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.

The Solanaceae or nightshade family is an economically important group with remarkable diversity. To gain a better understanding of how the unique biology of the Solanaceae relates to the familys small RNA (sRNA) genomic landscape, we downloaded over 255 publicly available sRNA data sets that comprise over 2.6 billion reads of sequence data. We applied a suite of computational tools to predict and annotate two major sRNA classes: (1) microRNAs (miRNAs), typically 20- to 22-nucleotide (nt) RNAs generated from a hairpin precursor and functioning in gene silencing and (2) short interfering RNAs (siRNAs), including 24-nt heterochromatic siRNAs typically functioning to repress repetitive regions of the genome via RNA-directed DNA methylation, as well as secondary phased siRNAs and trans-acting siRNAs generated via miRNA-directed cleavage of a polymerase II-derived RNA precursor. Our analyses described thousands of sRNA loci, including poorly understood clusters of 22-nt siRNAs that accumulate during viral infection. The birth, death, expansion, and contraction of these sRNA loci are dynamic evolutionary processes that characterize the Solanaceae family. These analyses indicate that individuals within the same genus share similar sRNA landscapes, whereas comparisons between distinct genera within the Solanaceae reveal relatively few commonalities.

Abstract Background Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). Methods In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0–11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. Results Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (− 1.64) vs. MS (− 1.32); between groups was [− 0.32% (95% CI, − 0.59, − 0.05)], P = 0.0208. Similar reductions were found in FPG [− 13.2 mg/dL (95% CI, − 22.86, − 3.71)], P = 0.0068, and PPG [− 20.83 mg/dL (95% CI, − 34.11, − 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. Conclusion The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. Trial registration Clinical Trials Registry of India, CTRI/2021/10/037461.

RAR-related orphan receptor-γ (RORγt) is an essential transcription factor for thymic T cell development, secondary lymphoid tissue organogenesis, and peripheral immune cell differentiation. Serine 182 phosphorylation is a major post-translational modification (PTM) on RORγt. However, the in vivo contribution of this PTM in health and disease settings is unclear. We report that this PTM is not involved in thymic T cell development and effector T cell differentiation. Instead, it is a critical regulator of inflammation downstream of IL-1β signaling and extracellular signal regulated kinases (ERKs) activation. ERKs phosphorylation of serine 182 on RORγt serves to simultaneously restrict Th17 hyperactivation and promote anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells. Phospho-null RORγtS182A knockin mice experience exacerbated inflammation in models of colitis and experimental autoimmune encephalomyelitis (EAE). In summary, the IL-1β-ERK-RORγtS182 circuit protects against T cell-mediated inflammation and provides potential therapeutic targets to combat autoimmune diseases.

ObjectiveIt is unknown how patients prioritize gadolinium-based contrast media (GBCM) benefits (detection sensitivity) and risks (reactions, gadolinium retention, cost). The purpose of this study is to measure preferences for properties of GBCM in women at intermediate or high risk of breast cancer undergoing annual screening MRI.MethodsAn institutional reviewed board-approved prospective discrete choice conjoint survey was administered to patients at intermediate or high risk for breast cancer undergoing screening MRI at 4 institutions (July 2018-March 2020). Participants were given 15 tasks and asked to choose which of two hypothetical GBCM they would prefer. GBCMs varied by the following attributes: sensitivity for cancer detection (80-95%), intracranial gadolinium retention (1-100 molecules per 100 million administered), severe allergic-like reaction rate (1-19 per 100,000 administrations), mild allergic-like reaction rate (10-1000 per 100,000 administrations), out-of-pocket cost ($25-$100). Attribute levels were based on published values of existing GBCMs. Hierarchical Bayesian analysis was used to derive attribute "importance." Preference shares were determined by simulation.ResultsResponse (87% [247/284]) and completion (96% [236/247]) rates were excellent. Sensitivity (importance = 44.3%, 95% confidence interval = 42.0-46.7%) was valued more than GBCM-related risks (mild allergic-like reaction risk (19.5%, 17.9-21.1%), severe allergic-like reaction risk (17.0%, 15.8-18.1%), intracranial gadolinium retention (11.6%, 10.5-12.7%), out-of-pocket expense (7.5%, 6.8-8.3%)). Lower income participants placed more importance on cost and less on sensitivity (p < 0.01). A simulator is provided that models GBCM preference shares by GBCM attributes and competition.ConclusionsPatients at intermediate or high risk for breast cancer undergoing MRI screening prioritize cancer detection over GBCM-related risks, and prioritize reaction risks over gadolinium retention.Key points• Among women undergoing annual breast MRI screening, cancer detection sensitivity (attribute "importance," 44.3%) was valued more than GBCM-related risks (mild allergic reaction risk 19.5%, severe allergic reaction risk 17.0%, intracranial gadolinium retention 11.6%, out-of-pocket expense 7.5%). • Prospective four-center patient preference data have been incorporated into a GBCM choice simulator that allows users to input GBCM properties and calculate patient preference shares for competitor GBCMs. • Lower-income women placed more importance on out-of-pocket cost and less importance on cancer detection (p < 0.01) when prioritizing GBCM properties.

PurposeThe SARS-CoV-2 pandemic has drastically disrupted radiology in-person education. The purpose of this study was to assess the implementation of a virtual teaching method using available technology and its role in the continuity of education of practicing radiologists and trainees during the pandemic.MethodsThe authors created the Online Liver Imaging Course (OLIC) that comprised 28 online comprehensive lectures delivered in real-time and on-demand over six weeks. Radiologists and radiology trainees were asked to register to attend the live sessions. At the end of the course, we conducted a 46-question survey among registrants addressing their training level, perception of virtual conferencing, and evaluation of the course content.ResultsOne thousand four hundred and thirty four radiologists and trainees completed interest sign up forms before the start of the course with the first webinar having the highest number of live attendees (343 people). On average, there were 89 live participants per session and 750 YouTube views per recording (as of July 9, 2020). After the end of the course, 487 attendees from 37 countries responded to the postcourse survey for an overall response rate of (33%). Approximately (63%) of participants were practicing radiologists while (37%) were either fellows or residents and rarely medical students. The overwhelming majority (97%) found the OLIC webinar series to be beneficial. Essentially all attendees felt that the webinar sessions met (43%) or exceeded (57%) their expectations. When asked about their perception of virtual conferences after attending OLIC lectures, almost all attendees (99%) enjoyed the virtual conference with a majority (61%) of the respondents who enjoyed the virtual format more than in-person conferences, while (38%) enjoyed the webinar format but preferred in-person conferences. When asked about the willingness to attend virtual webinars in the future, (84%) said that they would attend future virtual conferences even if in-person conferences resume while (15%) were unsure.ConclusionThe success of the OLIC, attributed to many factors, indicates that videoconferencing technology provides an inexpensive alternative to in-person radiology conferences. The positive responses to our postcourse survey suggest that virtual education will remain to stay. Educational institutions and scientific societies should foster such models.

Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and Fabp1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate (DSS)-induced colitis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.

fMRI has the potential of being able to differentiate between false memory and deception, but to apply this ability to real life situations, such as court cases or in neurodegenerative studies involving the brain's ability to recognize memory, it is vital that fMRI can detect the differences between general memory1 and deception, as false memory is often mixed in with true memory during recollection. To determine whether fMRI can do this, the prior study, “Can fMRI discriminate between deception and false memory? A meta-analytic comparison between deception and false memory studies” (Yu et al., 2019) [18] was extended. Yu et al., 2019 found that true memory and false memory, independently, could be distinguished from deception. This extension aims to determine if brain activity resulting from deception can be distinguished from activity caused by general memory as opposed to false memory. Given the broader scope of general memory compared to false memory, the prediction is put forth that general memory recollection will not be distinguishable from deception due to broader regions of activation in the brain. Appropriate meta-analyses for deception and general memory recollection were selected and used to determine z-scores and voxel coordinates of activity in different regions of the brain. The brain structures with the highest z-scores during general memory analysis were the caudate, the medial frontal gyrus, and the insula. The brain structures with the highest z-scores during deception analysis were the inferior frontal gyrus, the supramarginal gyrus, and the insula. After further analysis, it was determined that activation for general memory vs deception can be distinguished by looking at the activation of the cingulate gyrus and the precuneus.