Miracle-dz/UniFAR-FTUs huggingface dataset:
Abnormal Left-Hemispheric Sulcal Patterns Correlate with Neurodevelopmental Outcomes in Subjects with Single Ventricular Congenital Heart Disease.

Neurodevelopmental abnormalities are the most common noncardiac complications in patients with congenital heart disease (CHD). Prenatal brain abnormalities may be due to reduced oxygenation, genetic factors, or less commonly, teratogens. Understanding the contribution of these factors is essential to improve outcomes. Because primary sulcal patterns are prenatally determined and under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD. In this study, we reveal significant alterations in sulcal patterns among subjects with single ventricle CHD (n = 115, 14.7 ± 2.9 years [mean ± standard deviation]) compared with controls (n = 45, 15.5 ± 2.4 years) using a graph-based pattern-analysis technique. Among patients with CHD, the left hemisphere demonstrated decreased sulcal pattern similarity to controls in the left temporal and parietal lobes, as well as the bilateral frontal lobes. Temporal and parietal lobes demonstrated an abnormally asymmetric left-right pattern of sulcal basin area in CHD subjects. Sulcal pattern similarity to control was positively correlated with working memory, processing speed, and executive function. Exome analysis identified damaging de novo variants only in CHD subjects with more atypical sulcal patterns. Together, these findings suggest that sulcal pattern analysis may be useful in characterizing genetically influenced, atypical early brain development and neurodevelopmental risk in subjects with CHD.
Impressive neurological recovery following C-spine dislocation in a patient on long term immunosuppression

Abstract We report excellent neurological improvement in a patient with C6/C7 dislocation following a high speed road traffic accident. This case in particular is unusual because the patient was the recipient of an organ transplant during childhood and was therefore on long term immunosuppressant medication at the time of injury. In this report we reflect on the role of steroid use in traumatic spinal cord injury and put our case within the context of current evidence and this unusual clinical scenario.
A controlled clinical trial of preoperative pain neuroscience education for patients about to undergo total knee arthroplasty

Objective: The aim of this study was to determine if a preoperative pain neuroscience education program would result in superior outcomes compared to usual preoperative education for total knee arthroplasty. Design: Controlled clinical trial with alternating allocation. Setting: Community-based hospital. Subjects: Consecutive sample of 120 patients scheduled for total knee arthroplasty. Intervention: Traditional hospital preoperative total knee arthroplasty education program on its own, or with an additional 30-minute group pain neuroscience education session. Main measures: Primary outcomes were measurements at one, three, and six months for pain, function, fear of movement, and pain catastrophization. We also compared opioid usage, healthcare expenses, and patient satisfaction between groups. Results: There were no statistically significant differences in any outcome measures between the two groups over time, except for patient satisfaction. Those in the experimental group had more agreement with statements about “preparation for surgery” (P = .038), “would do again” (P = .032), and “met expectations” (P = .033) compared to those in the control group averaged over the three measurement times. Patients improved in several outcome measures over time regardless of group assignment, with a 34% improvement in pain, 36% improvement in function, 16% improvement in fear of movement, and 23% improvement in pain catastrophization scores. Conclusion: Adding a brief 30-minute pain neuroscience education session to a traditional preoperative total knee arthroplasty education program did not result in any significant improvements, except patient satisfaction.
Disruption of the network between Onuf’s nucleus and myenteric ganglia, and developing Hirschsprung-like disease following spinal subarachnoid haemorrhage: an experimental study

Abstract Purpose/Aim of the study: Auerbach/Meissner network of lower abdominopelvic organs managed by parasympathetic nerve fibres of lumbosacral roots arising from Onuf’s nucleus located in conus medullaris. Aim of this study is to evaluate if there is any relationship between Onuf’s nucleus ischemia and Auerbach/Meissner network degeneration following spinal subarachnoid haemorrhage (SAH). Materials and Methods: Study was conducted on 24 male rabbits included control (Group I, n = 5), serum saline-SHAM (Group II, n = 5), and spinal SAH (Group III, n = 14) groups. Spinal SAH performed by injecting homologous blood into subarachnoid space at Th12–L4 level and followed three weeks. Live and degenerated neuron densities of Onuf’s nucleus, Auerbach and Meissner ganglia (n/mm3) were determined by Stereological methods. Results: The mean degenerated neuron density of Onuf’s nucleus was significantly higher in Group III than in Groups I–II (152 ± 26, 2 ± 1 and 5 ± 2/mm3 respectively, p < 0.005). The degenerated neuron density of Auerbach’s ganglia was significantly higher in Group III than in Groups I–II (365 ± 112, 3 ± 1 and 9 ± 3/mm3 respectively, p < 0.005). The degenerated neuron density of Meissner’s ganglia was significantly higher in Group III than in Groups I–II (413 ± 132, 2 ± 1 and 11 ± 4/mm3 respectively, p < 0.005). Conclusions: Onuf’s nucleus pathologies should be considered as Auerbach/Meissner ganglia degeneration and also related Hirschsprung-like diseases in the future.
Influence of Interleukin-6 (IL-6) Promoter Gene Polymorphisms (−174G>C, −572G>C, and −597G>A) on IL-6 Plasma Levels and Their Impact in the Development of Acute Ischemic Stroke in Young Indians

This study aimed to determine whether there is an influence of interleukin 6 (IL-6) gene promoter polymorphisms on IL-6 plasma levels and its role in the development of ischemic stroke in young Indians. One hundred young patients with ischemic stroke (age ≥ 45 years) and equal number of age- and sex-matched controls were genotyped for 174G>C, −572G>C, and −597G>A promoter polymorphisms by polymerase chain reaction–restriction fragment length polymorphism. Plasma IL-6 levels were measured by enzyme-linked immunosorbent assay. Plasma IL-6 levels were significantly higher in patients as compared to controls (patients: 28.61 ± 8.61 pg/mL, controls: 7.60 ± 4.10 pg/mL, P = .001). Both −174G>C (allelic χ2/P value: 4.79/.028, genotypic χ2/P value: 5.3/.021) and −572G>C (allelic χ2/P value: 9.63/.00113 Genotypic χ2/P value: 74/.0002) polymorphisms exhibited genotypic as well as allelic significant association with the disease phenotype. Comparison was made between patients and controls for all 3 polymorphisms using a recessive model with respect to plasma IL-6 levels; no polymorphism showed any significant correlative association with the increased IL-6 levels (P = .31, .51, .32). Interleukin 6 is an inflammatory marker that is considerably influenced by nongenetic factors and is not a good candidate gene for studying genetic components associated with ischemic stroke. It seems that the variability in IL-6 levels is an integrated effect of nongenetic influences and the inflammatory events that follow ischemic stroke instead of being its cause. It is suggested that there is no direct association between −174G>C, −572G>C, and −597G>A polymorphisms and elevated IL-6 levels in the development of ischemic stroke.
Functional importance of an inverted formin C‐terminal tail at morphologically dynamic epithelial junctions

Epithelial cell–cell junctions have dual roles of accommodating morphological changes in an epithelium, while maintaining cohesion during those changes. An abundance of junction proteins has been identified, but many details on how intercellular junctions respond to morphological changes remain unclear. In Caenorhabditis elegans, the spermatheca is an epithelial sac that repeatedly dilates and constricts to allow ovulation. It is thought that the junctions between spermatheca epithelial cells undergo reversible partial unzipping to allow rapid dilation. Previously, we found that EXC‐6, a C. elegans protein homolog of the human disease‐associated formin INF2, is expressed in the spermatheca and promotes oocyte entry. We show here that EXC‐6 localizes toward the apical aspect of the spermatheca epithelial junctions, and that the EXC‐6‐labeled junction domains “unzip” and dramatically flatten with oocyte entry into the spermatheca. We demonstrate that the C‐terminal tail of EXC‐6 is necessary and sufficient for junction localization. Moreover, expression of the tail alone worsens ovulation defects, suggesting this region not only mediates EXC‐6 localization, but also interacts with other components important for junction remodeling.
Integrative Analysis of Genomic and Clinical Data Reveals Intrinsic Characteristics of Bladder Urothelial Carcinoma Progression

The progression of bladder cancer is generally a complex and dynamic process, involving a variety of biological factors. Here, we aimed to identify a set of survival-related genes that play an important role in the progression of bladder cancer and uncover their synergistic patterns. Based on the large-scale genomic profiling data and clinical information of 404 bladder cancer patients derived from The Cancer Genome Atlas (TCGA) database, we first discovered 1078 survival-related genes related to their survival states using univariate and multivariate Cox proportional hazardous regression. We then investigated the dynamic changes of the cooperative behaviors of these 1078 genes by analyzing their respective genomic features, including copy number variations, DNA methylations, somatic mutations, and microRNA regulatory networks. Our analyses showed that during the progression of bladder cancer, the biological disorder involving the identified survival-related genes can be reflected by multiple levels of abnormal gene regulation, ranging from genomic alteration to post-transcriptional dysregulation. In particular, the stage-specific co-expression networks of these genes undergo a series of structural variations. Our findings provide useful hints on understanding the underlying complex molecular mechanisms related to the evolution of bladder cancer and offer a new perspective on clinical diagnosis and treatment of bladder cancer.
The Effect of Electrolytes on Blood Pressure: A Brief Summary of Meta-Analyses

Nutrition is known to exert an undeniable impact on blood pressure with especially salt (sodium chloride), but also potassium, playing a prominent role. The aim of this review was to summarize meta-analyses studying the effect of different electrolytes on blood pressure or risk for hypertension, respectively. Overall, 32 meta-analyses evaluating the effect of sodium, potassium, calcium and magnesium on human blood pressure or hypertension risk were included after literature search. Most of the meta-analyses showed beneficial blood pressure lowering effects with the extent of systolic blood pressure reduction ranging between −0.7 (95% confidence interval: −2.6 to 1.2) to −8.9 (−14.1 to −3.7) mmHg for sodium/salt reduction, −3.5 (−5.2 to −1.8) to −9.5 (−10.8 to −8.1) mmHg for potassium, and −0.2 (−0.4 to −0.03) to −18.7 (−22.5 to −15.0) mmHg for magnesium. The range for diastolic blood pressure reduction was 0.03 (−0.4 to 0.4) to −5.9 (−9.7 to −2.1) mmHg for sodium/salt reduction, −2 (−3.1 to −0.9) to −6.4 (−7.3 to −5.6) mmHg for potassium, and −0.3 (−0.5 to −0.03) to −10.9 (−13.1 to −8.7) mmHg for magnesium. Moreover, sufficient calcium intake was found to reduce the risk of gestational hypertension.
SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation

Significance BRUCE/Apollon is an unusual inhibitor of apoptosis protein containing a ubiquitin-conjugating domain. Here we show that BRUCE is also an inhibitor of autophagy by promoting the proteasomal degradation of LC3-I, the precursor of LC3-II, which is critical in autophagosome biogenesis and substrate recruitment. SIP/CacyBP, which is highly expressed in neurons and various tumors, promotes autophagy by enhancing autophagic degradation of BRUCE and promoting autophagosome formation. DNA damage by the anticancer agents camptathecin and etoposide caused monoubiquitination of SIP by the ubiquitin ligase Nrdp1 and stimulated apoptosis. Deletion of SIP reduced the autophagic degradation of BRUCE and damaged mitochondria. This study identifies unanticipated mechanisms that regulate both autophagy and apoptosis, whose roles in physiology and disease will be important to investigate. BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28γ causes proteasomal degradation of LC3-I and thus inhibits autophagy. LC3-I on the phagophore membrane is conjugated to phosphatidylethanolamine to form LC3-II, which is required for the formation of autophagosomes and selective recruitment of substrates. SIP/CacyBP is a ubiquitination-related protein that is highly expressed in neurons and various tumors. Under normal conditions, SIP inhibits the ubiquitination and degradation of BRUCE, probably by blocking the binding of Nrdp1 to BRUCE. On DNA damage by topoisomerase inhibitors, Nrdp1 causes monoubiquitination of SIP and thus promotes apoptosis. However, on starvation, SIP together with Rab8 enhances the translocation of BRUCE into the recycling endosome, formation of autophagosomes, and degradation of BRUCE by optineurin-mediated autophagy. Accordingly, deletion of SIP in cultured cells reduces the autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Thus, by stimulating proteasomal degradation of LC3-I, BRUCE also inhibits autophagy. Conversely, SIP promotes autophagy by blocking BRUCE-dependent degradation of LC3-I and by enhancing autophagosome formation and autophagic destruction of BRUCE. These actions of BRUCE and SIP represent mechanisms that link the regulation of autophagy and apoptosis under different conditions.
l-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy

Dietary l-serine supplements correct NMDAR deficiency and neurodevelopmental defects in a pediatric patient. Treating NMDA receptor deficiency with a dietary supplement Patients with Rett-like syndrome show impaired neuronal, motor, cognitive, and social development. Soto et al. studied the etiology and treatment of the disorder in a 5-year-old patient who had a mutation in GRIN2B, the gene encoding the NMDA receptor subunit GluN2B. Expressing this mutant in cultured neurons impaired both electrophysiological activity and dendritic morphology, but these features were improved with the application of the known NMDA receptor agonist, d-serine. d-Serine administration has some toxicity in rodents, but its stereoisomer l-serine is a natural, nonessential amino acid found in various foods. Adding l-serine powder to the patient’s food or drink over the course of more than a year increased the amount of d-serine in the plasma and cerebrospinal fluid and markedly improved all neurodevelopment assessments, suggesting that this rather simple treatment might be extended to various patients with disorders associated with NMDA receptor deficiency. Autosomal dominant mutations in GRIN2B are associated with severe encephalopathy, but little is known about the pathophysiological outcomes and any potential therapeutic interventions. Genetic studies have described the association between de novo mutations of genes encoding the subunits of the N-methyl-d-aspartate receptor (NMDAR) and severe neurological conditions. Here, we evaluated a missense mutation in GRIN2B, causing a proline-to-threonine switch (P553T) in the GluN2B subunit of NMDAR, which was found in a 5-year-old patient with Rett-like syndrome with severe encephalopathy. Structural molecular modeling predicted a reduced pore size of the mutant GluN2B-containing NMDARs. Electrophysiological recordings in a HEK-293T cell line expressing the mutated subunit confirmed this prediction and showed an associated reduced glutamate affinity. Moreover, GluN2B(P553T)-expressing primary murine hippocampal neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR-dependent insertion of the AMPA receptor subunit GluA1 at stimulated synapses. Furthermore, the naturally occurring coagonist d-serine restored function to GluN2B(P553T)-containing NMDARs. l-Serine dietary supplementation of the patient was hence initiated, resulting in the increased abundance of d-serine in the plasma and brain. The patient has shown notable improvements in motor and cognitive performance and communication after 11 and 17 months of l-serine dietary supplementation. Our data suggest that l-serine supplementation might ameliorate GRIN2B-related severe encephalopathy and other neurological conditions caused by glutamatergic signaling deficiency.
Detecting Brachypodium distachyon Chromosomes Bd4 and Bd5 in MH- and X-Ray-Induced Micronuclei Using mcFISH

Micronuclei are biomarkers of genotoxic effects and chromosomal instability. They are formed when chromosome fragments or whole chromosomes fail to disjoin into daughter nuclei. We present qualitative and quantitative analyses of the involvement of specific chromosome regions of chromosomes Bd4 and Bd5 in the formation of micronuclei of Brachypodium distachyon root tip cells following maleic hydrazide (MH) treatment and X-radiation. This is visualised by cytomolecular approaches using bacterial artificial chromosome (BAC)-based multicolour fluorescence in situ hybridisation (mcFISH) in combination with 5S and 25S rDNA probes. The results showed that the long arm of submetacentric chromosome Bd4 forms micronuclei at twice the frequency of its short arm, suggesting that the former is more prone to double-strand breaks (DSBs). In contrast, no difference was observed in the frequency of micronuclei derived from the long and short arms of submetacentric chromosome Bd5. Interestingly, the proximal region of the short arm of Bd5 is more prone to DSBs than its distal part. This demonstrates that 5S rDNA and 35S rDNA loci are not “hot spots” for DNA breaks after the application of these mutagens.
Transcriptome Changes during Major Developmental Transitions Accompanied with Little Alteration of DNA Methylome in Two Pleurotus Species

Pleurotus tuoliensis (Pt) and P. eryngii var. eryngii (Pe) are important edible mushrooms. The epigenetic and gene expression signatures characterizing major developmental transitions in these two mushrooms remain largely unknown. Here, we report global analyses of DNA methylation and gene expression in both mushrooms across three major developmental transitions, from mycelium to primordium and to fruit body, by whole-genome bisulfite sequencing (WGBS) and RNA-seq-based transcriptome profiling. Our results revealed that in both Pt and Pe the landscapes of methylome are largely stable irrespective of genomic features, e.g., in both protein-coding genes and transposable elements (TEs), across the developmental transitions. The repressive impact of DNA methylation on expression of a small subset of genes is likely due to TE-associated effects rather than their own developmental dynamics. Global expression of gene orthologs was also broadly conserved between Pt and Pe, but discernible interspecific differences exist especially at the fruit body formation stage, and which are primarily due to differences in trans-acting factors. The methylome and transcriptome repertories we established for the two mushroom species may facilitate further studies of the epigenetic and transcriptional regulatory mechanisms underpinning gene expression during development in Pleurotus and related genera.
The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor

ABSTRACT The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis. We previously reported that MMTV-Wnt1 mice, an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-EarlyEx and Wnt1-LateEx. Here, we extend this initial observation and show that Wnt1-EarlyEx tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-EarlyEx tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-EarlyEx tumors had primarily Cd49fpos/Epcamneg FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-LateEx tumors had a bloody gross pathology, which was highlighted by the presence of ‘blood lakes’ identified by H&E staining. These tumors had primarily Cd49fpos/Epcampos FACS profiles, but also contained a secondary Cd49fpos/Epcamneg subpopulation. Wnt1-LateEx tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitively shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors that differ in multiple biological aspects including sensitivity to an EGFR inhibitor. Summary: The MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors. Importantly, these subtypes differ in their therapeutic response to erlotinib, an EGFR inhibitor.
Time-Series Chlorophyll Fluorescence Imaging Reveals Dynamic Photosynthetic Fingerprints of sos Mutants to Drought Stress

Resistance to drought stress is one of the most favorable traits in breeding programs yet drought stress is one of the most poorly addressed biological processes for both phenomics and genetics. In this study, we investigated the potential of using a time-series chlorophyll fluorescence (ChlF) analysis to dissect the ChlF fingerprints of salt overly sensitive (SOS) mutants under drought stress. Principle component analysis (PCA) was used to identify a shifting pattern of different genotypes including sos mutants and wild type (WT) Col-0. A time-series deep-learning algorithm, sparse auto encoders (SAEs) neural network, was applied to extract time-series ChlF features which were used in four classification models including linear discriminant analysis (LDA), k-nearest neighbor classifier (KNN), Gaussian naive Bayes (NB) and support vector machine (SVM). The results showed that the discrimination accuracy of sos mutants SOS1-1, SOS2-3, and wild type Col-0 reached 95% with LDA classification model. Sequential forward selection (SFS) algorithm was used to obtain ChlF fingerprints of the shifting pattern, which could address the response of sos mutants and Col-0 to drought stress over time. Parameters including QY, NPQ and Fm, etc. were significantly different between sos mutants and WT. This research proved the potential of ChlF imaging for gene function analysis and the study of drought stress using ChlF in a time-series manner.