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Single cell suppression profiling of human regulatory T cells
Deep learning powered single-cell clustering framework with enhanced accuracy and stability
Breaking linear scaling relationships in oxygen evolution via dynamic structural regulation of active sites
The relationship between involutional ectropion and inflammatory disorders of the eyelids and ocular surface: insights from a large-scale national study
Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates
Abstract In the realm of biology, peptide bonds are formed via reactive phosphate-containing intermediates, facilitated by compartmentalized environments that ensure precise coupling and folding. Herein, we use aminoacyl phosphate esters, synthetic counterparts of biological aminoacyl adenylates, that drive selective peptide bond formation through side chain-controlled reactivity and self-assembly. This strategy results in the preferential incorporation of positively charged amino acids from mixtures containing natural and non-natural amino acids during the spontaneous formation of amide bonds in water. Conversely, aminoacyl phosphate esters that lack assembly and exhibit fast reactivity result in random peptide coupling. By introducing structural modifications to the phosphate esters (ethyl vs. phenyl) while retaining aggregation, we are able to tune the selectivity by incorporating aromatic amino acid residues. This approach enables the synthesis of sequences tailored to the specific phosphate esters, overcoming limitations posed by certain amino acid combinations. Furthermore, we demonstrate that a balance between electrostatic and aromatic stacking interactions facilitates covalent self-sorting or co-assembly during oligomerization reactions using unprotected N-terminus aminoacyl phosphate esters. These findings suggest that self-assembly of abiotic aminoacyl phosphate esters can activate a selection mechanism enabling the departure from randomness during the autonomous formation of amide bonds in water.
A mild and scalable one-pot synthesis of N-substituted 2-aminobenzimidazoles via visible light mediated cyclodesulfurization
Abstract A visible light mediated photocatalyst-free synthesis of N-substituted 2-aminobenzimidazoles directly from o-phenylenediamines and isothiocyanates is developed in a one-pot fashion. This one-pot reaction proceeds through three steps: N-substitution of o-phenylenediamines, thiourea formation and visible light mediated cyclodesulfurization. This method enables the rapid and efficient synthesis of structurally diverse N-substituted 2-aminobenzimidazoles, achieving yields up to 92% across 69 examples. The practicality of the reaction is demonstrated by gram-scale synthesis. The key advantages of this method include the use of less toxic solvent in aqueous media, the elimination of photocatalyst, and a simple, practical setup (one-pot, open-flask, and ambient temperature). Mechanistic insights are gathered through control experiments, including light on/off cycles and radical inhibition studies. The results indicate that the reaction involves with radical pathway mediated by visible light.
Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane
Abstract Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP 1,2 ) are the standard of care for Ebola virus disease (EVD). Anti-GP 1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP 1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk–MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP 1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.
Assessing climate sensitivity of the Upper Indus Basin using fully distributed, physically-based hydrologic modeling and multi-model climate ensemble approach
Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis
Abstract Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in their niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here we demonstrate intrinsic deletion of transcription factor Yin Yang 1 (YY1) in MuSCs exacerbates dystrophic pathologies by altering composition and heterogeneity of MPs and FAPs. Further analysis reveals YY1 loss induces expression of immune genes in MuSCs, including C-C motif chemokine ligand 5 ( Ccl5 ). Augmented CCL5 secretion promotes MP recruitment via CCL5/C-C chemokine receptor 5 (CCR5) crosstalk, which subsequently hinders FAP clearance through elevated Transforming growth factor-β1 (TGFβ1). Maraviroc-mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we demonstrate YY1 represses Ccl5 transcription by binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study demonstrates the critical role of MuSCs in actively shaping their niche and provides novel insight into the therapeutic intervention of muscle dystrophy.
Polypharmacy and self-medication among older adults in Indian urban communities—a cross-sectional study
Abstract Older adults are vulnerable to unsafe medication practices. This cross-sectional study estimated the prevalence and factors of polypharmacy and self-medication among 600 older adults from six Indian cities. The updated Screening Tool of Older Persons’ Prescriptions and Screening Tool to Alert to Right Treatment criteria (version 3) were used. Knowledge, attitudes, and reported practices regarding self-medication were assessed. Descriptive statistics, binary logistic regression, and multivariable analysis were used. The prevalence of polypharmacy was 33.7% (95% CI 29.9–37.6%), with significant associations to multiple comorbidities [adjusted odds ratio (aOR) 2.5 (95% CI 1.1–4.1)], recent transition of care [aOR 3.3 (95% CI 1.4–5.7)], and recent hospitalization [aOR 4.6 (95% CI 2–7.7)]. The proportions of prescriptions with potentially inappropriate medications and potential prescribing omissions were 28.8% (95% CI 25.2–32.6%) and 20.3% (95% CI 17.2–23.8%), respectively. The prevalence of self-medication was 19.7% (95% CI 16.6–23.1%), associated with factors, such as staying alone [aOR 4.5 (95% CI 2.4–6.6)], multiple comorbidities [aOR 3 (95% CI 1.4–6.7)], and recent hospitalization [aOR 4.8 (95% CI 1.5–8)]. Among those who self-medicated, 65.3% lacked knowledge of self-medication, 50% did not comprehend the risks, and 40.7% reported unsafe self-medication practices. The findings emphasize interventions’ necessity for promoting safe medication use in older adults.
Duchenne muscular dystrophy: recent insights in brain related comorbidities
Potato starch quality in relation to the treatments and long-term storage of tubers
Abstract Starch is the most important component of potato tubers, the structure and composition of which play a key role in their utilization as well as processing and storage. Potato seed treatment may play the biggest role in ensuring proper plant growth and development. Isolated starch from tubers of different potato varieties for food processing was evaluated immediately after harvesting and after long-term storage with consideration of different products for potato seed treatment. The quality of starch was evaluated in terms of starch grain size, total starch content, pH, starch stability after freezing, gelatinization temperature as well as phosphorus and amylose content. The varieties differed significantly in starch content and quality. The Beo variety had the highest starch content in dry tuber weight (77.8%) and the best starch quality characteristics (the lowest starch stability after freezing − 18.0% and highest gelatinization temperature − 64.0 ℃ onset and 68.4 ℃ end). Simultaneous treatment of tubers with Supporter and Moncut 460 SC contributed to the highest starch content in tubers (77.6% d. m.) as well as increasing its stability after freezing (20.8%) and decreasing its gelatinization temperatures (61.7 ℃ onset and 66.0 ℃ end). This may be due to the increased proportion of large starch grains and higher amylose and phosphorus content. A slight decrease in starch quality traits was shown after long-term storage of tubers. Maintaining constant conditions during storage along with the applied treatments contributed to this. It is recommended to use products for potato seed treatment in the production technology of potato for consumption and for starch production.
In-situ electrochemical activation accelerates the magnesium-ion storage
A prospective cohort study of the association between mode of delivery and postpartum posttraumatic stress disorder
Recent centennial drought on the Tibetan Plateau is outstanding within the past 3500 years
Abstract Given growing concerns about global climate change, it is critical to understand both historical and current shifts in the hydroclimate, particularly in regions critically entwined with global circulation. The Tibetan Plateau, the Earth’s largest and highest plateau, is a nexus for global atmospheric processes, significantly influencing East Asian hydroclimate dynamics through the synergy of the Asian Monsoon and the Westerlies. Yet, understanding historical and recent hydroclimate fluctuations and their wide-ranging ecological and societal consequences remains challenging due to short instrumental observations and partly ambiguous proxy reconstructions. Here, we present a precisely-dated 3476-year precipitation reconstruction derived from tree-ring δ18O data on the Tibetan Plateau, representing one of the few multi-millennia-long annually-resolved terrestrial δ18O records to date. Our findings reveal that the 20th century drought extremes are severe within the past three millennia, and likely linked to the weakening of both the Asian Monsoon and Westerlies due to anthropogenic aerosol emissions. Additionally, our analyses identified three distinct stages (110 BC–AD 280, AD 330–770 and AD 950–1300) characterized by shifts toward arid hydroclimate conditions, corresponding to significant social unrest and dynasty collapses, which underscores the potential societal impacts of severe hydroclimatic shifts.
Corrosion and degradation behavior of MCSTE-Processed AZ31 magnesium alloy
Abstract This study aims to investigate the impact of multi-channel spiral twist extrusion (MCSTE) on the corrosion and degradation properties of biodegradable AZ31 (Mg-3Al-1Zn, wt.%) magnesium alloy. Square AZ31 billets were processed using route C-MCSTE (with a 180° rotation between passes) at 250°C and with a ram speed of 10 mm/min for up to 8 passes. The extrusion process was conducted via dies with twist angles of 30° and 40°. The microstructural changes and grain size distribution in the alloy were determined with a Scanning Electron Microscopy equipped with Electron Backscatter Diffraction. Electrochemical tests were conducted in a simulated body fluid to model the environment in which medical implants operate. The mechanical properties of the alloy were tested before and after processing using compression tests. The billets processed with a 30° twist angle demonstrated superior mechanical and corrosion resistance compared to those processed with a 40° die. A 66% reduction in grain size was found in billets processed for 4 passes using the 30°-die as compared to the as-annealed condition. Billets processed for 4 and 8 passes showed ultimate compressive strength improvements of 23% and 31%, respectively compared to the as-annealed condition. The 8-pass processed sample using the 30° twist ring die showed 76% improvement in the corrosion rate compared to the as-annealed state. Furthermore, billets processed for 4 passes showed corrosion resistance and ultimate compressive strength improvements of 108% and 23%; respectively compared to the as-annealed condition. These findings imply that the developed MCSTE process can be adopted for industrial use, especially in the manufacturing of biodegradable magnesium alloys for medical implants.