Miracle-dz/UniFAR-FTUs huggingface dataset:
Using Machine Learning to Identify Metabolomic Signatures of Pediatric Chronic Kidney Disease Etiology

Significance Statement Machine learning used with biostatistics identified metabolomic signatures in the plasma of pediatric patients with CKD, providing clues to cause. Dysmetabolism in the sphingomyelin-ceramide axis is associated with both FSGS and the aplasia/dysplasia/hypoplasia spectrum. Pediatric FSGS is associated with elevated plasmalogen levels, in contrast to reports of associations with plasmalogen deficiencies. Our strategy also revealed associations of obstructive uropathy with gut-derived histidines and of reflux nephropathy with indole-tryptophans. Visual Abstract Background Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN). Methods Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants (n: FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause. Results ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome–derived histidine metabolites. Conclusion ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome–derived histidine metabolites are associated with OU.
Planning Catching Movements: Advantages of Expertise, Visibility and Self-Throwing

Abstract In a ball catching task, the catcher guides their hand to the ball’s future trajectory. The hand may start to move even before the exact position is known, and the interceptive movement may be corrected online. Using a recent method for detecting the phases of catching movements we investigate how juggling experience, self-throwing, and delayed visibility of the ball, influence the timing of the hand’s trajectory. Specifically, we analyze the time from which the goal position of the movement is known, i.e., the time from which the movement becomes smooth. Seventeen jugglers and twenty controls caught ten balls per each of eight conditions. The results indicate that experts’ catching movements acquire the smooth nature of goal-directed movements earlier than novices catching movements do.
Comparison of the Responses of Soil Fungal Community to Straw, Inorganic Fertilizer, and Compost in a Farmland in the Loess Plateau

Determining the response of soil fungi in sensitive ecosystems to external environmental disturbances is an important, yet little-known, topic in microbial ecology. In this study, we evaluated the impact of traditional fertilization management practices on the composition, co-occurrence pattern, and functional groups of fungal communities in loessial soil. ABSTRACT The Loess Plateau is located in the arid and semi-arid regions in northern China. The ecosystem is particularly sensitive to natural and anthropogenic disturbances. Fungi can produce extracellular enzymes, decompose a variety of organic matter, and regulate carbon and nutrient balance. We studied the changes of soil fungal community compositions in response to straw, inorganic fertilizer, and compost in a typical farmland in the Loess Plateau. Our results demonstrated that the addition of straw significantly reduces the Shannon index of the fungal community, in addition, the participation of straw significantly affects the composition of the fungal community. Functional prediction based on FUNGuild showed that straw significantly reduced the relative abundance of saprotrophs, pathotrophs, symbiotrophs, lichenized, ectomycorrhizal, and plant pathogens. Although fertilization practices destroyed the co-occurrence pattern among the fungal species, the addition of straw alleviated this affect. No significant effect of straw, compost, and inorganic fertilizers on the co-occurrence pattern among species in the soil fungal community was observed. Compared with compost and inorganic fertilizer, the addition of straw shaped the community composition by changing the relative abundance of fungal functional taxa. Thus, in the fragile Loess Plateau environment, over-fertilizing or non-order-fertilizing may destroy the co-occurrence pattern of the fungal communities and Loess Plateau ecosystem. IMPORTANCE Determining the response of soil fungi in sensitive ecosystems to external environmental disturbances is an important, yet little-known, topic in microbial ecology. In this study, we evaluated the impact of traditional fertilization management practices on the composition, co-occurrence pattern, and functional groups of fungal communities in loessial soil. Our results show that in the fragile Loess Plateau environment, fertilizer management changed the composition of the fungal community and disrupted the co-occurrence pattern between fungi. The application of straw alleviates the destroying of the co-occurrence pattern. The current research emphasizes the necessity of rational fertilization of farmland in loessial soil.
Secular Improvements in Cognitive Aging: Contribution of Education, Health, and Routine Activities

Objectives Limited evidence exists regarding the reasons for secular changes in cognitive functioning over historical time. Thus, we examined potential explanatory factors for changes in cognitive speed, a central dimension of cognitive functioning. Methods Population-based data of middle-aged and older adults from Germany (N = 5443) was used with baseline participants from 2002 to 2014, comparing the time periods 2002–2014. Results Cognitive speed improved in middle-aged adults (40–65) and older adults (66+). In both age groups, increases were partly explained by education, employment status, volunteering status, routine activities, and physical functioning. Changes in education were more important in explaining increases in older than in middle-aged adults, whereas changes in health were more important for explaining increases in middle-aged adults. Conclusions Cognitive speed increased in both age groups over historical time. Education, employment, volunteering, routine activities, and health were all important in explaining these changes, but their importance differed between age groups.
Efficient Gene Knockout and Knockdown Systems in Neospora caninum Enable Rapid Discovery and Functional Assessment of Novel Proteins

Neospora caninum is a parasite with veterinary relevance, inducing severe disease in dogs and reproductive disorders in ruminants, especially cattle, leading to major losses. The close phylogenetic relationship to Toxoplasma gondii and the lack of pathogenicity in humans drives an interest of the scientific community toward using N. caninum as a model to study the pathogenicity of T. gondii. ABSTRACT The development of molecular genetics has greatly enhanced the study of the biology and pathology associated with parasites of the phylum Apicomplexa. While the molecular tools are highly developed for the apicomplexan Toxoplasma gondii, the closely related parasite Neospora caninum lacks efficient tools for genetic manipulation. To enable efficient homologous recombination in N. caninum, we targeted the Ku heterodimer DNA repair mechanism in the genomic reference strain, Nc-Liverpool (NcLiv), and show that deletion of Ku80 results in a destabilization and loss of its partner Ku70. Disruption of Ku80 generated parasites in which genes are efficiently epitope tagged and only short homology regions are required for gene knockouts. We used this improved strain to target novel nonessential genes encoding dense granule proteins that are unique to N. caninum or conserved in T. gondii. To expand the utility of this strain for essential genes, we developed the auxin-inducible degron system for N. caninum using parasite-specific promoters. As a proof of concept, we knocked down a novel nuclear factor in both N. caninum and T. gondii and showed that it is essential for survival of both parasites. Together, these efficient knockout and knockdown technologies will enable the field to unravel specific gene functions in N. caninum, which is likely to aid in the identification of targets responsible for the phenotypic differences observed between these two closely related apicomplexan parasites. IMPORTANCE Neospora caninum is a parasite with veterinary relevance, inducing severe disease in dogs and reproductive disorders in ruminants, especially cattle, leading to major losses. The close phylogenetic relationship to Toxoplasma gondii and the lack of pathogenicity in humans drives an interest of the scientific community toward using N. caninum as a model to study the pathogenicity of T. gondii. To enable this comparison, it is important to develop efficient molecular tools for N. caninum, to gain accuracy and save time in genetic manipulation protocols. Here, we have developed base strains and protocols using the genomic reference strain of N. caninum to enable efficient knockout and knockdown assays in this model. We demonstrate that these tools are effective in targeting known and previously unexplored genes. Thus, these tools will greatly improve the study of this protozoan, as well as enhance its ability to serve as a model to understand other apicomplexan parasites.
Validation of DE50-MD dogs as a model for the brain phenotype of Duchenne muscular dystrophy

ABSTRACT Duchenne muscular dystrophy (DMD), a fatal musculoskeletal disease, is associated with neurodevelopmental disorders and cognitive impairment caused by brain dystrophin deficiency. Dog models of DMD represent key translational tools to study dystrophin biology and to develop novel therapeutics. However, characterisation of dystrophin expression and function in the canine brain is lacking. We studied the DE50-MD canine model of DMD that has a missense mutation in the donor splice site of exon 50. Using a battery of cognitive tests, we detected a neurocognitive phenotype in DE50-MD dogs, including reduced attention, problem solving and exploration of novel objects. Through a combination of capillary immunoelectrophoresis, immunolabelling, quantitative PCR and RNAScope in situ hybridisation, we show that regional dystrophin expression in the adult canine brain reflects that of humans, and that the DE50-MD dog lacks full-length dystrophin (Dp427) protein expression but retains expression of the two shorter brain-expressed isoforms, Dp140 and Dp71. Thus, the DE50-MD dog is a translationally relevant pre-clinical model to study the consequences of Dp427 deficiency in the brain and to develop therapeutic strategies for the neurological sequelae of DMD.
Risk-Adjusted Mortality Rates as a Quality Proxy Outperform Volume in Surgical Oncology—A New Perspective on Hospital Centralization Using National Population-Based Data

PURPOSE Despite a long-known association between annual hospital volume and outcome, little progress has been made in shifting high-risk surgery to safer hospitals. This study investigates whether the risk-standardized mortality rate (RSMR) could serve as a stronger proxy for surgical quality than volume. METHODS We included all patients who underwent complex oncologic surgeries in Germany between 2010 and 2018 for any of five major cancer types, splitting the data into training (2010-2015) and validation sets (2016-2018). For each surgical group, we calculated annual volume and RSMR quintiles in the training set and applied these thresholds to the validation set. We studied the overlap between the two systems, modeled a market exit of low-performing hospitals, and compared effectiveness and efficiency of volume- and RSMR-based rankings. We compared travel distance or time that would be required to reallocate patients to the nearest hospital with low-mortality ranking for the specific procedure. RESULTS Between 2016 and 2018, 158,079 patients were treated in 974 hospitals. At least 50% of high-volume hospitals were not ranked in the low-mortality group according to RSMR grouping. In an RSMR centralization model, an average of 32 patients undergoing complex oncologic surgery would need to relocate to a low-mortality hospital to save one life, whereas 47 would need to relocate to a high-volume hospital. Mean difference in travel times between the nearest hospital to the hospital that performed surgery ranged from 10 minutes for colorectal cancer to 24 minutes for pancreatic cancer. Centralization on the basis of RSMR compared with volume would ensure lower median travel times for all cancer types, and these times would be lower than those observed. CONCLUSION RSMR is a promising proxy for measuring surgical quality. It outperforms volume in effectiveness, efficiency, and hospital availability for patients. The association between annual hospital volume and outcome is a well-known argument for hospital regionalization. This work studies whether risk-standardized mortality rates (RSMRs) are a stronger proxy for surgical quality in oncologic surgery. In a volume centralization model with a market exit of low-performing hospitals, significantly more patients would need to relocate to a low-mortality hospital to save one life compared with an RSMR model. Regionalization based on RSMR compared with volume would ensure lower travel times for all studied cancer types. Our analysis suggests that an RSMR-based quality management approach may be outperforming quantity-based thresholds.
Elevation Matters More than Season in Shaping the Heterogeneity of Soil and Root Associated Ectomycorrhizal Fungal Community

Altitude and season represent two important environmental gradients that shape the structure of biome, including the heterogeneity of EcM fungi. Previous studies have separately considered the influences of altitude and season on EcM fungal communities, but the relative importance of altitude and season is still unknown. ABSTRACT Ectomycorrhizal (EcM) fungi play important roles in forest ecosystems, and their richness and composition can change along with elevation and season changes. However, no study has estimated the relative importance of altitudinal and seasonal heterogeneity in predicting the distribution of EcM fungal communities by simultaneously considering different sample types (root versus soil). In this study, we collected root and soil samples along a > 1,500-m elevation gradient during wet and dry seasons from Baima Snow Mountain, located in “the Mountains of Southwest China,” one of the 34 biodiversity hot spots, and we analyzed them using next-generation sequencing. Regardless of the sample type, similar EcM fungal richness pattern with increasing elevation (decline in the forest zone, and an increase at the alpine meadow zone) and strong community turnovers among different elevational zones and between two seasons were detected, and changes of EcM fungal community similarity on 400-m altitude gradient were equivalent to the community turnover between dry and wet seasons. Elevation and edaphic factors were shown to have the largest effects on EcM fungal community. The heterogeneity of richness and community composition was stronger among different elevational zones than across different seasons, mainly because the elevation variations in the EcM fungal community were shaped by the combined effects of different environmental factors, while seasonal changes were mainly controlled by temperature and fast-changing soil nutrients. IMPORTANCE Altitude and season represent two important environmental gradients that shape the structure of biome, including the heterogeneity of EcM fungi. Previous studies have separately considered the influences of altitude and season on EcM fungal communities, but the relative importance of altitude and season is still unknown. The present study revealed that elevation influences the heterogeneity of EcM fungal community more than season; this may be because the variability of environmental factors is higher across different elevations than that across seasons.
Stability Indicating New RP-UPLC Method for Simultaneous Determination of a Quaternary Mixture of Paracetamol, Pseudoephedrine, Chlorpheniramine, and Sodium Benzoate in (Cold-Flu) Syrup Dosage Form.

BACKGROUND Combination of paracetamol, pseudoephedrine, chlorpheniramine, and sodium benzoate in (Cold - Flu) 1,2,3 Syrup dosage form are specified for the treatment of common cold and flu symptoms. OBJECTIVE The functional role of this study is to develop a novel, reliable, and selective stability-indicating RP-UPLC method for simultaneous identification of a quaternary mixture of paracetamol, pseudoephedrine, chlorpheniramine, and sodium benzoate in (Cold - Flu) 1,2,3 Syrup dosage form. Method: The specific method is accomplished on a stationary phase Acquity UPLC HSS T3 C18 column (2.1 mm × 100 mm) 1.8 µm with pore size 100Å and column void volume is 1.15 min, utilizing a mixture of purified water -methanol -trifluoroacetic acid (72.5:27.5:1.5, v/v) as the mobile phase at a flow rate of 0.3 mL/min and UPLC detection is adjusted at 205 nm using photodiode array detector (DAD). RESULTS Calibration curves are obtained in the linearity range (25-500 µg/mL) of paracetamol, (10-50 µg/mL) of pseudoephedrine, (0.5-5 µg/mL) of chlorpheniramine, and (3-30 µg/mL) of sodium benzoate with a correlation coefficient > 0.9992, the mean recovery of the developed method is tested and showed good recovery results between (99- 101%), selectivity and forced degradation studies are investigated as per ICH guidelines and no interference is detected due to degradation peaks. CONCLUSIONS The proposed stability-indicating UPLC method for simultaneous determination of three drugs of paracetamol, pseudoephedrine, chlorpheniramine with a preservative sodium benzoate in (Cold - Flu) 1,2,3 Syrup dosage form is successfully accomplished, developed, and validated, and can be easily used in the analysis of drugs in pure or dosage form. HIGHLIGHTS The novelty of the current research work lies in the development of the UPLC method for simultaneous determination of a quaternary mixture of paracetamol, pseudoephedrine, chlorpheniramine, and sodium benzoate in (Cold - Flu) 1,2,3 Syrup dosage form.
“The Internal Police Officer Has Not Retired but Has Slowed Down”: Israeli Women Reframe Their Aging Experiences in the Second Half of Life

Compared with gains, losses have received a substantial amount of research and public attention. The present study aims to shed light on the positive gains associated with older age from the perspective of older women. Five focus groups with 19 Israeli women over the age of 54 were conducted. Trailers of three different films were used to stimulate discussion about old age and aging and allow for reflections on societal norms in light of personal experiences. Focus group interviews were analyzed thematically. Respondents identified four contexts, characterized by reframing their experiences against societal norms. These included gender stereotypes, physical appearance, interpersonal relations, and employment. This study represents an opening to a different discourse around old age, which is characterized by gains and possibilities brought about by changes in reframing one’s experiences, while distancing oneself and exerting free will vis à vis social norms.
Diagnostic performance and prognostic impact of coronary angiography‐based Index of Microcirculatory Resistance assessment: A systematic review and meta‐analysis

The Index of Microcirculatory Resistance (IMR), measured with a pressure‐thermistor tipped coronary guidewire has been established as a gold standard for coronary microvascular assessment. Angiography‐based IMR (angio‐IMR) is a novel method to derive IMR without intracoronary instrumentation or the need for adenosine.
Identification, functional characterization, assembly and structure of ToxIN type III toxin–antitoxin complex from E. coli

Abstract Toxin–antitoxin (TA) systems are proposed to play crucial roles in bacterial growth under stress conditions such as phage infection. The type III TA systems consist of a protein toxin whose activity is inhibited by a noncoding RNA antitoxin. The toxin is an endoribonuclease, while the antitoxin consists of multiple repeats of RNA. The toxin assembles with the individual antitoxin repeats into a cyclic complex in which the antitoxin forms a pseudoknot structure. While structure and functions of some type III TA systems are characterized, the complex assembly process is not well understood. Using bioinformatics analysis, we have identified type III TA systems belonging to the ToxIN family across different Escherichia coli strains and found them to be clustered into at least five distinct clusters. Furthermore, we report a 2.097 Å resolution crystal structure of the first E. coli ToxIN complex that revealed the overall assembly of the protein-RNA complex. Isothermal titration calorimetry experiments showed that toxin forms a high-affinity complex with antitoxin RNA resulting from two independent (5′ and 3′ sides of RNA) RNA binding sites on the protein. These results further our understanding of the assembly of type III TA complexes in bacteria.
The prognostic value of surgical delay in patients undergoing major emergency abdominal surgery: a systematic review and meta-analysis

Abstract Background Mortality following major emergency abdominal surgery is high. Surgical delay is regarded as an important modifiable prognostic factor. Current care-bundles aim at reducing surgical delay, most often using a six-hour cut-off. We aimed to investigate the evidence supporting the in-hospital delay cutoffs currently used. Methods MEDLINE, EMBASE and the Cochrane Library were searched. We included studies assessing in-hospital surgical delay in major emergency abdominal surgery patients. Studies were only included if they performed adjusted analysis. Surgical delay beyond six hours was the primary cutfrom interest. The primary outcome was mortality at longest follow-up. Meta-analyses were conducted if possible. Results Eleven observational studies were included with 16,772 participants. Two studies evaluated delay in unselected major emergency abdominal surgery patients. Three studies applied a six-hour cutoff, but only a study on acute mesenteric ischemia showed an association between delay and mortality. Meta-analysis showed no association with mortality at this cutoff. An association was seen between hourly delay and mortality risk estimate, 1.02 (95% confidence interval [CI], 1.00 − 1.03), and on subgroup analysis of hourly delay in perforated peptic ulcer patients, risk estimate, 1.02 (95% CI, 1.0 − 1.03). All risk estimates had a very low Grading of Recommendations Assessment, Development, and Evaluation score. Conclusion Little evidence supports a six-hour cutoff in unselected major emergency abdominal surgical patients. We found an association between hourly delay and increased mortality; however, evidence supporting this was primarily in patients undergoing surgery for perforated peptic ulcer. This review is limited by the quality of the individual studies.