Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovering Genetic Modulators of the Protein Homeostasis System through Multilevel Analysis

Every protein progresses through a natural lifecycle from birth to maturation to death; this process is coordinated by the protein homeostasis system. Environmental or physiological conditions trigger pathways that maintain the homeostasis of the proteome. An open question is how these pathways are modulated to respond to the many stresses that an organism encounters during its lifetime. To address this question, we tested how the fitness landscape changes in response to environmental and genetic perturbations using directed and massively parallel transposon mutagenesis in Caulobacter crescentus. We developed a general computational pipeline for the analysis of gene-by-environment interactions in transposon mutagenesis experiments. This pipeline uses a combination of general linear models (GLMs), statistical knockoffs, and a nonparametric Bayesian statistical model to identify essential genetic network components that are shared across environmental perturbations. This analysis allows us to quantify the similarity of proteotoxic environmental perturbations from the perspective of the fitness landscape. We find that essential genes vary more by genetic background than by environmental conditions, with limited overlap among mutant strains targeting different facets of the protein homeostasis system. We also identified 146 unique fitness determinants across different strains, with 19 genes common to at least two strains, showing varying resilience to proteotoxic stresses. Experiments exposing cells to a combination of genetic perturbations and dual environmental stressors show that perturbations that are quantitatively dissimilar from the perspective of the fitness landscape are likely to have a synergistic effect on the growth defect. Significance Statement This study provides critical insights into how cells adapt to environmental and genetic challenges affecting protein homeostasis. Using multilevel statistical analysis and transposon mutagenesis, we find that a model organism, Caulobacter crescentus, lacks a universal redundancy mechanism for coping with stress, as evidenced by the limited overlap in essential genes across different environmental and genetic perturbations. Our methods also pinpoint key fitness determinants and enable the prediction of perturbation combinations that synergistically affect cell growth.
Domain coupling in activation of a family C GPCR

The G protein–coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological function. The molecular basis for this diversity remains poorly delineated. We employ molecular dynamics, single-molecule spectroscopy, and hydrogen–deuterium exchange to dissect the pathway of activation triggered by glutamate. We find that activation entails multiple loosely coupled steps and identify a novel pre-active intermediate whose transition to the active state forms dimer interactions that set signaling efficacy. Such subunit interactions generate functional diversity that differs across homodimers and heterodimers. The agonist-bound receptor is remarkably dynamic, with low occupancy of G protein–coupling conformations, providing considerable headroom for modulation of the landscape by allosteric ligands. Sites of sequence diversity within the dimerization interface and diverse coupling between activation rearrangements may contribute to precise decoding of glutamate signals and transients over broad spatial and temporal scales.
E. coli leverages growth arrest to remodel its proteome upon entry into starvation

It is widely believed that, owing to the limitation of nutrients in natural environments, bacteria spend most of their life in a non-growing state. However, despite its major clinical and ecological implications, very little is known about what determines the phenotype of starved bacteria, in particular what controls the concentration of different gene products inside the cells. Using microfluidics and quantitative fluorescence microscopy, we monitored growth and gene expression in many independent E. coli lineages as we switched them from exponential growth to starvation. We observed that all cells stopped growing immediately and that no cell death occurred for more than two days. At the same time, gene expression undergoes a dramatic remodeling upon entry into starvation in a promoter-dependent manner. Some promoters, including ribosomal protein promoters, arrest gene expression immediately, others show a slow exponential decay of expression on a 10 h time scale, while a third category exhibits a transient burst of activity before decaying exponentially. Remarkably, the time dynamics of these changes are highly homogeneous across single cells. In addition, we demonstrated that the gene expression response does not qualitatively depend on the dynamics of starvation entry. Combining the observed time-dependent protein production and decay rates, we showed with mathematical modeling that a delay between growth arrest and shutdown of gene expression allows a massive increase in the concentration of certain proteins without requiring an upregulation of their expression. Moreover, protein concentrations deep in starvation appeared to be mainly determined by the expression dynamics during the first 10 h of starvation. Finally, we established that this expression program at the onset of starvation is critical for cell viability. In particular, by inhibiting gene expression during different periods of starvation, we were able to show that the tolerance to stress after 2 days is determined by gene expression occurring during the first 10 h, which thus constitutes a preventive response. These results provide a starting point for quantitative studies of cell maintenance and the emergence of specific phenotypes when nutrients become scarce.
Oolonghomobisflavans from Camellia sinensis disaggregate tau fibrils across Alzheimer’s disease models

Alzheimer’s disease (AD) is a common debilitating neurodegenerative disease with limited treatment options. Amyloid-β (Aβ) and tau fibrils are well-established hallmarks of AD, which can induce oxidative stress, neuronal cell death, and are linked to disease pathology. Here, we describe the effects of Oolonghomobisflavan A (OFA) and Oolonghomobisflavan B (OFB) on tau fibril disaggregation and prionogenic seeding. Transcriptomic analysis of OF-treated animals reveals the induction of a proteostasis-enhancing and health-promoting signature. OFA treatment reduced the burden of Tau protein aggregation in a C. elegans model expressing pathogenic human tau (“hTau-expressing”) and promoted Tau disaggregation and inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer’s disease brain donors. Correspondingly, treatment with OF improved multiple fitness and aging-related health parameters in the hTau-expressing C. elegans model, including reproductive output, muscle function, and importantly, reversed the shortened lifespan stemming from pathogenic Tau expression. Collectively, this study provides new evidence supporting the neuroprotective effects of OFs and reveal a new therapeutic strategy for targeting AD and other neurodegenerative diseases characterized by tauopathy.
The eﬀect of global and regional solar shading on 1 climate: A simulation study

9 The potential climate impact of solar geoengineering is examined using climate model 10 simulations by artiﬁcially reducing the incoming solar radiation at the top of the atmo-11 sphere. Climate scenario simulations indicate that a doubling of atmospheric carbon diox-12 ide (2xCO 2 ) induces a surface temperature rise which is ampliﬁed over the poles primar-13 ily during the respective winter. The warming also causes intensiﬁcation and poleward 14 shift of the global precipitation pattern. In our model, a 2.1% globally uniform solar re-15 duction can largely compensate the global mean warming caused by a doubling of CO 2 . 16 We ﬁnd that solar shading is eﬃcient to restore the temperature at the region where the 17 background sunshine is strong, regionally at low-latitudes, seasonally during summer. 18 Solar shading would lead to an overall weakening of the global hydrological cycle, result-19 ing in a large-scale drought. A 3.6% solar reduction in the tropics can largely reduce the 20 tropical and global warming as well. However, it reduces the precipitation at the cen-21 tral tropics, while increase the precipitation over the monsoon region. Comparatively, 22 a 14% solar reduction over the poles can eﬀectively prevent the polar summer temper-23 ature increase and sea-ice retreat. However, caused by the increased temperature gra-24 dient, polar solar shading increases the storm activity at high-latitudes, especially dur-25 ing summer when the solar reduction reaches its maximum amplitude. Our simulations 26 show that solar shading could be an eﬀective way to stabilize the polar cryosphere. Nev-27 ertheless, it has a strong impact on the hydrological cycle and provides a heterogenous 28 regional climate signal. 29
Aeromagnetic signature of an exhumed double dome system in the SW Grenville Province (Canada)

Analysis of aeromagnetic data in the Grenville Province reveals the presence of two regional‐scale unmapped structural domes (the Morin and Mékinac‐Taureau domes) with an oval‐shaped magnetic pattern bounded by regional‐scale shear zones and a geometry that is similar to that produced in crustal flow models under extension, which predict two upright domes of foliation (double dome) separated by a steep shear zone. The Mékinac‐Taureau dome, a metamorphic core complex, and the Morin dome may have been exhumed by channel flow. Exhumation occurred by a combination of thrust, normal‐sense and wrench shear zones. The preservation of paragneisses in the Morin dome suggests that it underwent a lesser degree of exhumation than did the Mékinac‐Taureau dome. This study shows how the integration of local field information with magnetic data in a regional tectonic setting can reveal and delineate concealed gneiss domes and highlights a role for strike‐slip tectonics in the creation of regional structures involving the exhumation of deep crust.
MULTIDISCIPLINARY: APPLIED BUSINESS AND EDUCATION

The research aimed to assess the implementation of various components of disaster management programs including Vulnerability Assessment, Planning and Preparedness, Institutional Framework and Coordination , Resource Management and Allocation, Early Warning Systems , Response Mechanisms and Emergency Operations , Public Education and Training Disaster Drills and Exercises. Additionally, the study aimed to determine the level of disaster preparedness among school personnel and students, identify any significant differences in program implementation among schools, and explore the relationship between program implementation and disaster preparedness. The data collection involved surveys, questionnaires, and interviews with school principals, teachers, and learners during the third quarter of the 2016-2017 school year. The sample consisted of six schools, and the gathered data were analyzed using appropriate statistical tools.The findings indicated that most of the disaster management activities were implemented in the schools within Zone IV, contributing to an effective implementation of the programs. Teachers were moderately prepared in planning and warning system activities but showed preparedness in other areas such as vulnerability assessment, planning and preparedness, institutional framework and coordination , resource management and allocation, early warning systems , response mechanisms and emergency operations , public education and training disaster drills and exercises. Similarly, students displayed moderate pre-paredness in warning system activities and preparedness in other aspects. Overall, the students in Zone IV were considered prepared for potential disasters in their community and school.
VARIOUS TYPES OF CYBER THREATS *** 3

Resume Security of the Internet and online communication has become an essential challenge in contemporary world. Paper discusses different types of cyber threats: cyber-attack, cyber terrorism and cybercrime. Individuals, companies and the states rely their communication and daily functioning on information and communication technologies (ICT). The purpose of the study is to highlight importance of the ICT safety use by pointing to seriousness of the cyber threats. The main methods applied in paper to examine published scientific materials are: inductive and deductive method, analytical and synthesis method, hypothet-ical-deductive method and method of content analysis. Results of the study indicate need for actively dealing with cyber threats. The intent of this study is both to inform and raise awareness of cyber threats within the communities. Findings of the study contribute to the broader knowledge in research area.
2001-2022 global gross primary productivity dataset using an 1 ensemble model based on random forest 2

The continuous advancement of remote sensing technology has been instrumental in improving models for 15 estimating terrestrial gross primary productivity (GPP). However, challenges arise from inconsistent spatial distributions and 16 interannual variations in GPP datasets, impeding our comprehensive understanding of the entire terrestrial carbon cycle. In 17 contrast to previous models relying on remote sensing and environmental variables, we developed a an ensemble model 18 based on random forest named GPP ERF . This model utilized the GPP outputs from established remote sensing-based models 19 (EC-LUE, GPP-kNDVI, GPP-NIRv, Revised-EC-LUE) as inputs for GPP estimations. GPP ERF demonstrated significant 20 effectiveness by explaining 83.7% of the monthly variation in GPP across 171 sites. This performance surpassed the selected 21 remote sensing models (72.4%-77.1%) and an independent random forest model using remote sensing and environmental 22 variables (77.7%). Over the period from 2001 to 2022, the global estimated GPP value using the ensemble model based on 23 random forest was 131.2 PgC yr -1 , exhibiting a trend
Developing Mathematical Resilience Among Diverse Learners: Preliminary Progress and Problematics

Research shows that developing students’ resilience can rapidly raise student achievement in mathematics. Despite recognising its importance, teachers often do not have access to a repertoire of practices to develop resilient mathematics learners. The present study explores aspects of resilience among a cohort of students from three low socio-economic, high poverty, urban schools in New Zealand. Our exploration uncovers some aspects of the students’ perceptions (about learning mathematics) that were favourable and/or problematic with respect to the development of resilience. Implications for furthering the development of resilient learners are discussed.
Projections of Future Precipitation Extremes Over Europe: A Multimodel Assessment of Climate Simulations

Projections of precipitation and its extremes over the European continent are analyzed in an extensive multimodel ensemble of 12 and 50 km resolution EURO‐CORDEX Regional Climate Models (RCMs) forced by RCP2.6, RCP4.5, and RCP8.5 (Representative Concentration Pathway) aerosol and greenhouse gas emission scenarios. A systematic intercomparison with ENSEMBLES RCMs is carried out, such that in total information is provided for an unprecedentedly large data set of 100 RCM simulations. An evaluation finds very reasonable skill for the EURO‐CORDEX models in simulating temporal and geographical variations of (mean and heavy) precipitation at both horizontal resolutions. Heavy and extreme precipitation events are projected to intensify across most of Europe throughout the whole year. All considered models agree on a distinct intensification of extremes by often more than +20% in winter and fall and over central and northern Europe. A reduction of rainy days and mean precipitation in summer is simulated by a large majority of models in the Mediterranean area, but intermodel spread between the simulations is large. In central Europe and France during summer, models project decreases in precipitation but more intense heavy and extreme rainfalls. Comparison to previous RCM projections from ENSEMBLES reveals consistency but slight differences in summer, where reductions in southern European precipitation are not as pronounced as previously projected. The projected changes of the European hydrological cycle may have substantial impact on environmental and anthropogenic systems. In particular, the simulations indicate a rising probability of summertime drought in southern Europe and more frequent and intense heavy rainfall across all of Europe.
ЕВАЛУАЦИЈА НА КВАЛИТЕТОТ НА ЕЈАКУЛАТ КАЈ МЛАДИТЕ МАЖИ ВО РЕПУБЛИКА СЕВЕРНА МАКЕДОНИЈА

Research data show that in the last 50 years (1938-1991) there has been a trend of decreasing sperm concentration in the male population in Europe by 2.3% and in the USA by 0.8%. The reasons for such negative trend are not known, but it is assumed that lifestyle and environmental factors have an influence on genetic factors. Aim of this study was to evaluate sperm quality in young, healthy men in our country, and to compare sperm quality in our population with others in the world. Material and methods: Ejaculates from 203 healthy male subjects, aged 18-32, were stored in a thermostat at 36 0 C and analyzed manually on a native slide and hematoxylin-eosin-stained slides, under a phase contrast microscope. Sperm motility was assessed at two-time intervals, group A, 60 minutes after ejaculation and group B, 120 minutes after ejaculation, while sperm concentration and sperm morphology were assessed at one time interval. Results:Semen analysis showed an average volume of ejaculate3.45 ± 1.5 ml, sperm concentration in 1 milliliter62.4 ± 39.2 x10(6) /ml, while total sperm concentration was 211.2 ± 173.2 x10(6). In group A, values for progressive spermatozoa were 48.6 ± 18.1 x10(6) /ml and in group B, values for progressive spermatozoa were 47.9 ± 17.3 x10(6) /ml. There was no statistically significant difference between the two time intervals (group A and group B) when interpreting sperm motility, p>0.005. Analysis of morphology of spermatozoa showed a mean value of 6.9% for morphologically normal spermatozoa. Conclusion: The quality of ejaculate in young men in North Macedonia is in the range of reference values according to WHO, and also our results are similar to those from Germany, Turkey, Bulgaria, Faroe Islands. Abstract
METHODS OF TEACHING LANGUAGE AND LITERATURE

This study examines reading and writing skills in English as a foreign language (EFL) of 12-year-old students in the middle schools in Pavlodar (North part of Kazakhstan). The participants were six graders, Kazakh (N=115) and Russian (N=145) native speakers from seven randomly chosen middle secondary schools in Pavlodar. Kazakh and Russian students performed the tests in English assessing reading and writing skills, and responded several questions regarding socio-economic status (SES) in order to explore the interaction of SES and skills in EFL. The results showed that Kazakh students performed better in writing, whereas Russians were better in reading. Moreover, weak correlation between reading and writing skills in English may emerge the effect of non-transparent orthography of English and the deep transparency in Kazakh and Russian languages. The instruments proved to be appropriate for Kazakhstani context although writing tests need further improvements. Apparent independence of reading and writing performances may be due to the compound nature of score in writing, limited number of classes, fewer opportunities for everyday interaction in EFL.
Assessing the Utility of Shellﬁsh Sanitation Monitoring Data for Long-Term Estuarine Water Quality Analysis

Regular testing of coastal waters for fecal coliform bacteria by shellﬁsh sanitation programs could provide data to ﬁll large gaps in existing coastal water quality monitoring, but research is needed to understand the opportunities and limitations of using these data for inference of long-term trends. In this study, we analyzed spatiotemporal trends from multidecadal fecal coliform concentration observations collected by a shellﬁsh sanitation program, and assessed the feasibility of using these monitoring data to infer long-term water quality dynamics. We evaluated trends in fecal coliform concentrations for a 20-year period (1999-2021) using data collected from spatially ﬁxed sampling sites (n = 466) in North Carolina (USA). Findings indicated that shellﬁsh sanitation data can be used for long-term water quality inference under relatively stationary management conditions, and that salinity trends can be used to measure the extent of management-driven bias in fecal coliform observations collected in a particular area
World Journal of Gastroenterology

Severe gallstone pancreatitis (GSP) refractory to maximum conservative therapy has wide clinical variations, and its pathophysiology remains controversial. This Editorial aimed to investigate the pathophysiology of severe disease based on Opie’s theories of obstruction, the common channel, and duodenal reflux and describe its types. Severe GSP might be a hybrid disease with pathology polarized between acute cholangitis with mild pancreatitis (biliary type) and necrotizing pancreatitis uncomplicated with biliary tract disease (pancreatic type), in which hepatobiliary and pancreatic lesion severity is inversely related to the presence or absence of impacted ampullary stones. Severe GSP is caused by stones that are persistently impacted at the ampulla with biliopancreatic obstruction (biliary type), and probably, stones that are either temporarily lodged at the duodenal orifice or passed into the duodenum, thereby permitting reflux of bile or possible duodenal contents into the pancreas (pancreas type). When the status of the stones and the presence or absence of impacted ampullary stones with biliopan-creatic obstruction are determined, the clinical course and outcome can be predicted. Gallstones represent the main cause of acute pancreatitis globally, and clinicians are expected to encounter GSP more often. Awareness of the etiology and pathogenesis of severe disease is mandatory.
Universal Cash Transfer Impacts on Maternal and Infant Health

In this paper, I examine how the receipt of an unconditional cash transfer during pregnancy impacts maternal and infant health outcomes. Using linked birth certiﬁcate data, I apply a within-mother estimator to analyze how receipt of the Alaska permanent fund dividend (PFD), an annual cash transfer for all Alaska residents, a ↵ ects the likelihood of being born preterm or low birth weight and the likelihood of experiencing complications at the time of labor and delivery. I ﬁnd that receiving an additional $ 1,000 in PFD payment during the 12 months prior to birth decreases the likelihood of having a labor/delivery complication by approximately 12% and reduces the likelihood of being born very preterm by approximately 22%. The results are strongest for mothers with less than a high school education.
Getting It Right Matters: Temperature Goal Interpretations in Geoscience Research

The adoption of the 1.5°C long‐term warming limit in the Paris Agreement made 1.5°C a “hot topic” in the scientific community, with researchers eager to address this issue. Long‐term warming limits have a decade‐long history in international policy. To effectively inform the climate policy debate, geoscience research hence needs a core understanding of their legal and policy context. Here we describe this context in detail and illustrate its importance by showing the impact it can have on global carbon budget estimates. We show that definitional clarity is essential on this important matter.