Miracle-dz/UniFAR-FTUs huggingface dataset:
Nuclear genetic regulation of the human mitochondrial transcriptome

Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (TBRG4, MTPAP and LONP1), implicating genetic mechanisms that act in trans across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.
Cognitive Fitness to Drive in Huntington's Disease: Assessing the Clinical Utility of DriveSafe DriveAware.

BACKGROUND DriveSafe DriveAware (DSDA) has been validated as an off-road screening tool for predicting on-road driving performance in clinical populations, but its utility in people with Huntington's disease (HD) is unknown. OBJECTIVE Our aim was to evaluate the utility of DSDA in people with HD by demonstrating sensitivity of DSDA scores to HD progression and exploring associations between DSDA performance and cognitive functions that are essential to driving and impaired in people with HD. METHODS We administered the iPad application version of DSDA to 26 pre-symptomatic and symptomatic participants with HD. Disease progression was assessed via measures of motor impairment, disease burden and functional capacity. Standardised neuropsychological tests were used to assess cognitive function across several domains including attention, processing speed, planning, and visuoperception. RESULTS Results underscore the sensitivity of DSDA to HD progression and cognitive impairment; that is, poorer DSDA performance was associated with greater HD severity and poorer cognitive ability across the domains of attention, processing speed, and planning. Nevertheless, we identified a proportion of participants with HD who were predicted to pass on-road testing based on DSDA, but scored in the impaired range on multiple cognitive tests. These participants tended to score closer to the cut-off score used by DSDA to categorise pass/fail outcomes. CONCLUSIONS Our findings demonstrate potential for use of DSDA in the HD population, however, significant variability in cognitive performance among those predicted to 'pass' on-road driving assessment suggests the screening tool requires further development for use with HD drivers.
Comparing laboratory and industrial yeast platforms for the direct conversion of cellobiose into ethanol under simulated industrial conditions

ABSTRACT An engineered yeast producing all the cellulases needed for cellulose saccharification could produce ethanol from lignocellulose at a lower cost. This study aimed to express fungal &bgr;‐glucosidases in Saccharomyces cerevisiae to convert cellobiose into ethanol. Furthermore, two engineering platforms (laboratory vs industrial strain) have been considered towards the successful deployment of the engineered yeast under simulated industrial conditions. The industrial S. cerevisiae M2n strain was engineered through the &dgr;‐integration of the &bgr;‐glucosidase Pccbgl1 of Phanerochaete chrysosporium. The most efficient recombinant, M2n[pBKD2‐Pccbgl1]‐C1, was compared to the laboratory S. cerevisiae Y294[Pccbgl1] strain, expressing Pccbgl1 from episomal plasmids, in terms of cellobiose fermentation in a steam exploded sugarcane bagasse pre‐hydrolysate. Saccharomyces cerevisiae Y294[Pccbgl1] was severely hampered by the pre‐hydrolysate. The industrial M2n[pBKD2‐Pccbgl1]‐C1 could tolerate high inhibitors‐loading in pre‐hydrolysate under aerobic conditions. However, in oxygen limited environment, the engineered industrial strain displayed ethanol yield higher than the laboratory Y294[Pccbgl1] only when supplemented with supernatant containing further recombinant &bgr;‐glucosidase. This study showed that the choice of the host strain is crucial to ensure bioethanol production from lignocellulose. A novel cellobiose‐to‐ethanol route has been developed and the recombinant industrial yeast could be a promising platform towards the future consolidated bioprocessing of lignocellulose into ethanol.
Interpretable Dynamic Treatment Regimes

ABSTRACT Precision medicine is currently a topic of great interest in clinical and intervention science. A key component of precision medicine is that it is evidence-based, that is, data-driven, and consequently there has been tremendous interest in estimation of precision medicine strategies using observational or randomized study data. One way to formalize precision medicine is through a treatment regime, which is a sequence of decision rules, one per stage of clinical intervention, that map up-to-date patient information to a recommended treatment. An optimal treatment regime is defined as maximizing the mean of some cumulative clinical outcome if applied to a population of interest. It is well-known that even under simple generative models an optimal treatment regime can be a highly nonlinear function of patient information. Consequently, a focal point of recent methodological research has been the development of flexible models for estimating optimal treatment regimes. However, in many settings, estimation of an optimal treatment regime is an exploratory analysis intended to generate new hypotheses for subsequent research and not to directly dictate treatment to new patients. In such settings, an estimated treatment regime that is interpretable in a domain context may be of greater value than an unintelligible treatment regime built using “black-box” estimation methods. We propose an estimator of an optimal treatment regime composed of a sequence of decision rules, each expressible as a list of “if-then” statements that can be presented as either a paragraph or as a simple flowchart that is immediately interpretable to domain experts. The discreteness of these lists precludes smooth, that is, gradient-based, methods of estimation and leads to nonstandard asymptotics. Nevertheless, we provide a computationally efficient estimation algorithm, prove consistency of the proposed estimator, and derive rates of convergence. We illustrate the proposed methods using a series of simulation examples and application to data from a sequential clinical trial on bipolar disorder. Supplementary materials for this article are available online.
Misidentification Subtype of Alzheimer's Disease Psychosis Predicts a Faster Cognitive Decline

The presence of psychosis is associated with a more rapid decline in Alzheimer's disease (AD), but the impact of paranoid (persecutory delusions) and misidentification (misperceptions and/or hallucinations) subtypes of psychosis on the speed of decline in AD is still unclear. We analyzed data on Alzheimer's Disease Neuroimaging Initiative 2 participants with late mild cognitive impairment or AD, and we described individual trajectories of Alzheimer's Disease Assessment Scale–Cognitive Subscale scores using a semimechanistic logistic model with a mixed effects–based approach, which accounted for dropout and adjusted for baseline Mini Mental State Examination scores. The covariate model included psychosis subtypes, age, gender, education, medications, and Apolipoprotein E epsilon 4 (Apo‐e ε4 genotype). We found that the Alzheimer's Disease Assessment Scale–Cognitive Subscale rate of increase was doubled in misidentification (βr,misid_subtype = 0.63, P = 0.031) and mixed (both subtypes; βr,mixed_subtype = 0.70, P = 0.003) when compared with nonpsychotic (or paranoid) patients, suggesting that the misidentification subtype may represent a distinct AD sub‐phenotype associated with an accelerated pathological process.
Epigallocatechin-3-Gallate Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis via Suppression of Oxidant Stress and Apoptosis by Targeting Hypoxia-Inducible Factor-1α/ Angiopoietin-Like 4 Pathway

Background: Focal and segmental glomerular sclerosis (FSGS) is a common cause of nephrotic syndrome and end-stage renal disease. It has been reported that overproduction of reactive oxygen species (ROS) and cell apoptosis are associated with the development of FSGS. Epigallocatechin-3-gallate (EGCG) is a bioactive constituent accounting for more than 50% of the total catechins in green tea, which have anti-oxidative and anti-apoptotic effects. Based on this, this study was designed to evaluate the renoprotective effect of EGCG treatment on Adriamycin-induced FSGS. Methods: In C57BL/6 mice, Adriamycin nephropathy (AN) was induced by Adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then the mice were given with EGCG (20 mg/kg body weight) or YC-1 (Lificiguat, a specific inhibitor of hypoxia-inducible factor-1α [HIF-1α], 50 mg/kg body weight) or both intraperitoneally. Both the EGCG and YC-1 were given on the day of Adriamycin injection and continued for 6 weeks. The animals were organized into the following 5 groups for the animal experiments: the control group, the AN group, the AN + EGCG group, the AN + YC-1 group and the AN + EGCG + YC-1 group. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. The HIF-1α and the angiopoietin-like 4 (ANGPTL4) expression were detected by Western blot, real-time PCR, immunohistochemistry or immunofluorescence. Dihydroethidium staining and NADPH oxidase 1 (Nox1) measurement were used to detect ROS production. Terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) staining and caspase-3 measurement was used to detect cell apoptosis. Results: When the animals were treated with Adriamycin, both the ROS production and TUNEL positive cells increased. Besides, the expression of HIF-1α, ANGPTL4, and caspase-3 were also up-regulated, while EGCG treatment could attenuate these changes. Interestingly, compared with treatment with YC-1 or EGCG alone, more pronounced inhibition of ANGPTL4, caspase-3 and Nox1 were obtained when YC-1 and EGCG were administered simultaneously. Conclusion: EGCG attenuates FSGS through the suppression of Oxidant Stress and apoptosis by targeting the HIF-1α/ANGPTL4 pathway.
Using Rates of Low Scores to Assess Agreement between Brief Computerized Neuropsychological Assessment Batteries: A Clinically-based Approach for Psychometric Comparisons.

OBJECTIVE To assess agreement between four brief computerized neurocognitive assessment tools (CNTs), ANAM, CogState, CNS Vital Signs, and ImPACT, by comparing rates of low scores. METHODS Four hundred and six US Army service members (SMs) with and without acute mild traumatic brain injury completed two randomly assigned CNTs with order of administration also randomly assigned. We performed a base rate analysis for each CNT to determine the proportions of SMs in the control and mTBI groups who had various numbers of scores that were 1.0+, 1.5+, and 2.0+ standard deviations below the normative mean. We used these results to identify a hierarchy of low score levels ranging from poorest to least poor performance. We then compared the agreement between every low score level from each CNT pair administered to the SMs. RESULTS More SMs in the mTBI group had low scores on all CNTs than SMs in the control group. As performance worsened, the association with mTBI became stronger for all CNTs. Most if not all SMs who performed at the worst level on any given CNT also had low scores on the other CNTs they completed but not necessarily at an equally low level. CONCLUSION These results suggest that all of the CNTs we examined are broadly similar but still retain some psychometric differences that need to be better understood. Furthermore, the base rates of low scores we present could themselves be useful to clinicians and researchers as a guide for interpreting results from the CNTs.
Body Donation after Medically Assisted Death: An Emerging Consideration for Donor Programs

Around the world, the recent introduction of assisted death laws has meant that undertaking medical assistance in dying (MAID) is now an option for some persons wishing to end their life. Some of these people donate their bodies to medical science, and by doing so have created a new route from which donor programs can now receive bodies. Such donations have also illuminated a myriad of novel ethical questions. This article considers the emotive and controversial topic of MAID in relation to body donation, describing the experiences of McMaster University, Canada, where several MAID body donors have been received by the anatomical donor program. It provides background on the development and implementation of MAID in Canada, and describes the experience of staff and students at McMaster to MAID donations. It also explores the relevance of MAID to body donation programs, and discusses several of the ethical challenges facing body donation programs who may encounter MAID body donors. These include the appropriateness of accepting MAID donors, issues with informed consent, the effect of personal engagement with MAID donors, information sharing around MAID donations, governance issues, and negative historical parallels between MAID and euthanasia. Suggestions on how to manage MAID body donation focus on how issues affecting institutions, faculty, and students may be approached utilizing appropriate transparency and communication, some of which may facilitate student professional development around the topic of MAID. It is also suggested that the development of ethically appropriate guidelines on MAID body donations may positively guide the anatomical community.
A SIR-independent role for cohesin in subtelomeric silencing and organization

Significance Cohesin is a conserved chromatin-associated SMC complex crucial for higher-order chromosome architecture. Cohesin mutations in humans are associated with severe developmental defects thought to arise from altered gene expression. We report that cohesin is an important determinant of subtelomeric gene repression in budding yeast. The conserved histone deacetylase Sir2, along with other silencing factors, is required for telomere silencing. However, silencing in extensive subtelomeric regions is SIR-independent, but poorly understood. We found that cohesin deficiency results in preferential derepression of multiple subtelomeric genes and its contribution to silencing is Sir-independent. Interestingly, cohesin mutants are defective in nuclear envelope tethering and compaction of subtelomeric regions. Our findings suggest that cohesin may directly contribute to subtelomeric silencing by altering telomere organization. Cohesin is a key determinant of chromosome architecture due to its DNA binding and tethering ability. Cohesin binds near centromeres and chromosome arms and also close to telomeres, but its role near telomeres remains elusive. In budding yeast, transcription within 20 kb of telomeres is repressed, in part by the histone-modifying silent information regulator (SIR) complex. However, extensive subtelomeric repressed domains lie outside the SIR-binding region, but the mechanism of silencing in these regions remains poorly understood. Here, we report a role for cohesin in subtelomeric silencing that extends even beyond the zone of SIR binding. Clusters of subtelomeric genes were preferentially derepressed in a cohesin mutant, whereas SIR binding was unaltered. Genetic interactions with known telomere silencing factors indicate that cohesin operates independent of the SIR-mediated pathway for telomeric silencing. Mutant cells exhibited Mpk1-dependent Sir3 hyperphosphorylation that contributes to subtelomeric derepression to a limited extent. Compaction of subtelomeric domains and tethering to the nuclear envelope were impaired in mutant cells. Our findings provide evidence for a unique SIR-independent mechanism of subtelomeric repression mediated by cohesin.
The Preoperative Prognostic Nutritional Index Predicts Short-Term and Long-Term Outcomes of Patients with Stage II/III Gastric Cancer: Analysis of a Multi-Institution Dataset

Background/Aims: Identification of nutritional indicators to predict short-term and long-term outcomes is necessary to provide appropriate treatment to patients with gastric cancer. Methods: We designed an analysis of a multicenter dataset of patients with gastric cancer who underwent gastrectomy between 2010 and 2014. We enrolled 842 eligible patients who had stage II/III gastric cancer. The area under the curve (AUC) values were compared among prognostic nutritional index (PNI), calculated as 10 × albumin g/dL + 0.005 × total lymphocyte count/mm3, and its constituents, and the predictive value of preoperative PNI for postoperative short-term and long-term outcomes was evaluated. Results: Preoperative PNI exhibited higher AUC values (0.719) for 1-year survival than its constituents, and the optimal cutoff value was 47. The disease-free and overall survival of patients in the PNI-low group were significantly shorter compared with those in the PNI-high group. The prognostic difference between the PNI-high and PNI-low groups was significantly greater in the subgroup of patients who underwent total gastrectomy. Clinically relevant postoperative complications were more frequently observed in the PNI-low group. Conclusions: The preoperative PNI is a useful predictor reflecting the incidence of complications after gastrectomy and the prognosis of patients with stage II/III gastric cancer.
A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

Bicuspid aortic valve (BAV) is the most common congenital heart defect with a prevalence of 1%–2% in the general population. NOTCH1, SMAD6, and GATA5 are associated with BAV in humans, but few cases have been reported that did not involve NOTCH1. Here, we identified novel in‐frame variants in SMAD6 (c.1168_1173dup; p.Gly390_Ile391dup) in a BAV patient, who presented with dilatation of the ascending aorta and severe calcification of the aortic valve.
Evolution of Drought–Flood Abrupt Alternation and Its Impacts on Surface Water Quality from 2020 to 2050 in the Luanhe River Basin

It has become a hot issue to study extreme climate change and its impacts on water quality. In this context, this study explored the evolution characteristics of drought–flood abrupt alternation (DFAA) and its impacts on total nitrogen (TN) and total phosphorous (TP) pollution, from 2020 to 2050, in the Luanhe river basin (LRB), based on the predicted meteorological data of the representative concentration pathways (RCPs) climate scenarios and simulated surface water quality data of the Soil and Water Assessment Tool (SWAT) model. The results show that DFAA occurred more frequently in summer, with an increasing trend from northwest to southeast of the LRB, basically concentrated in the downstream plain area, and the irrigation area. Meanwhile, most of the DFAA events were in light level. The incidence of TN pollution was much larger than the incidence of TP pollution and simultaneous occurrence of TN and TP pollution. The TN pollution was more serious than TP pollution in the basin. When DFAA occurred, TN pollution almost occurred simultaneously. Also, when TP pollution occurred, the TN pollution occurred simultaneously. These results could provide some references for the effects and adaptation-strategies study of extreme climate change and its influence on surface water quality.
E‐cadherin expression is associated with somatostatin analogue response in acromegaly

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin‐like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E‐cadherin expression by immunohistochemistry in fifty‐five GH‐producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E‐cadherin levels exhibit a worse response to SSAs. E‐cadherin levels are associated with GH‐producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E‐cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.
The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

Seminal amyloids are well known for their role in enhancing HIV infection. Among all the amyloidogenic peptides identified in human semen, PAP248‐286 was found to be the most active and was termed as semen‐derived enhancer of viral infection (SEVI). Although amyloidogenic nature of the peptide is mainly linked with enhancement of the viral infection, the most active physiological conformation of the aggregated peptide remains inconclusive. Lipids are known to modulate aggregation pathway of a variety of proteins and peptides and constitute one of the most abundant biomolecules in human semen. PAP248‐286 significantly differs from the other known amyloidogenic peptides, including Aβ and IAPP, in terms of critical concentration, surface charge, fibril morphology, and structural transition during aggregation. Hence, in the present study, we aimed to assess the effect of a lipid, 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine (DOPC), on PAP248‐286 aggregation and the consequent conformational outcomes. Our initial observation suggested that the presence of the lipid considerably influenced the aggregation of PAP248‐286. Further, ZDOCK and MD simulation studies of peptide multimerization have suggested that the hydrophobic residues at C‐terminus are crucial for PAP248‐286 aggregation and are anticipated to be major DOPC‐interacting partners. Therefore, we further assessed the aggregation behaviour of C‐terminal (PAP273‐286) fragment of PAP248‐286 and observed that DOPC possesses the ability to interfere with the aggregation behaviour of both the peptides used in the current study. Mechanistically, we propose that the presence of DOPC causes considerable inhibition of the peptide aggregation by interfering with the peptide's disordered state to β‐sheet transition.