Heavy monsoon rainfall ravaged a large swath of East Asia in summer 2020. Severe flooding of the Yangtze River displaced millions of residents in the midst of a historic public health crisis. This extreme rainy season was not anticipated from El Niño conditions. Using observations and model experiments, we show that the record strong Indian Ocean Dipole event in 2019 is an important contributor to the extreme Yangtze flooding of 2020. This Indian Ocean mode and a weak El Niño in the Pacific excite downwelling oceanic Rossby waves that propagate slowly westward south of the equator. At a mooring in the Southwest Indian Ocean, the thermocline deepens by a record 70 m in late 2019. The deepened thermocline helps sustain the Indian Ocean warming through the 2020 summer. The Indian Ocean warming forces an anomalous anticyclone in the lower troposphere over the Indo-Northwest Pacific region and intensifies the upper-level westerly jet over East Asia, leading to heavy summer rainfall in the Yangtze Basin. These coupled ocean-atmosphere processes beyond the equatorial Pacific provide predictability. Indeed, dynamic models initialized with observed ocean state predicted the heavy summer rainfall in the Yangtze Basin as early as April 2020.

Antibiotic resistance genes (ARGs) in urban rivers are a serious public health concern in regions with poorly planned, rapid development. To gain insights into the predominant factors affecting the fate of ARGs in a highly polluted urban river in eastern China, a total of 285 ARGs, microbial communities, and 20 physicochemical parameters were analyzed for 17 sites. A total of 258 unique ARGs were detected using high-throughput qPCR, and the absolute abundance of total ARGs was positively correlated with total organic carbon and total dissolved nitrogen concentrations (P < 0.01). ARG abundance and diversity were greatly altered by microbial community structure. Variation partitioning analysis showed that the combined effects of multiple factors contributed to the profile and dissemination of ARGs, and variation of microbial communities was the major factor affecting the distribution of ARGs. The disparate distribution of some bacteria, including Bacteroides from mammalian gastrointestinal flora, Burkholderia from zoonotic infectious diseases, and Zoogloea from wastewater treatment, indicates that the urban river was strongly influenced by point-source pollution. Results imply that microbial community shifts caused by changes in water quality may lead to the spread of ARGs, and point-source pollution in urban rivers requires greater attention to control the transfer of ARGs between environmental bacteria and pathogens.

Synthetic biology enables the design of gene networks to confer specific biological functions, yet it remains a challenge to rationally engineer a biological trait as complex as longevity. A naturally occurring toggle switch underlies fate decisions toward either nucleolar or mitochondrial decline during the aging of yeast cells. We rewired this endogenous toggle to engineer an autonomous genetic clock that generates sustained oscillations between the nucleolar and mitochondrial aging processes in individual cells. These oscillations increased cellular life span through the delay of the commitment to aging that resulted from either the loss of chromatin silencing or the depletion of heme. Our results establish a connection between gene network architecture and cellular longevity that could lead to rationally designed gene circuits that slow aging.

Transcription-coupled nucleotide excision repair (TC-NER) is a highly conserved DNA repair pathway that removes bulky lesions in the transcribed genome. Cockayne syndrome B protein (CSB), or its yeast ortholog Rad26, has been known for decades to play important roles in the lesion-recognition steps of TC-NER. Another conserved protein ELOF1, or its yeast ortholog Elf1, was recently identified as a core transcription-coupled repair factor. How Rad26 distinguishes between RNA polymerase II (Pol II) stalled at a DNA lesion or other obstacles and what role Elf1 plays in this process remains unknown. Here, we present cryo-EM structures of Pol II-Rad26 complexes stalled at different obstacles that show that Rad26 uses a common mechanism to recognize a stalled Pol II, with additional interactions when Pol II is arrested at a lesion. A cryo-EM structure of lesion-arrested Pol II-Rad26 bound to Elf1 revealed that Elf1 induces further interactions between Rad26 and a lesion-arrested Pol II. Biochemical and genetic data support the importance of the interplay between Elf1 and Rad26 in TC-NER initiation. Together, our results provide important mechanistic insights into how two conserved transcription-coupled repair factors, Rad26/CSB and Elf1/ELOF1, work together at the initial lesion recognition steps of transcription-coupled repair.

Purpose

The novel coronavirus pneumonia (COVID-19) has continually spread and mutated, requiring a patient risk stratification system to optimize medical resources and improve pandemic response. We aimed to develop a conformal prediction-based tri-light warning system for stratifying COVID-19 patients, applicable to both original and emerging variants.

Methods

We retrospectively collected data from 3646 patients across multiple centers in China. The dataset was divided into a training set (n = 1451), a validation set (n = 662), an external test set from Huoshenshan Field Hospital (n = 1263), and a specific test set for Delta and Omicron variants (n = 544). The tri-light warning system extracts radiomic features from CT (computed tomography) and integrates clinical records to classify patients into high-risk (red), uncertain-risk (yellow), and low-risk (green) categories. Models were built to predict ICU (intensive care unit) admissions (adverse cases in training/validation/Huoshenshan/variant test sets: n = 39/21/262/11) and were evaluated using AUROC ((area under the receiver operating characteristic curve)) and AUPRC ((area under the precision-recall curve)) metrics.

Results

The dataset included 1830 men (50.2 %) and 1816 women (50.8 %), with a median age of 53.7 years (IQR [interquartile range]: 42-65 years). The system demonstrated strong performance under data distribution shifts, with AUROC of 0.89 and AUPRC of 0.42 for original strains, and AUROC of 0.77-0.85 and AUPRC of 0.51-0.60 for variants.

Conclusion

The tri-light warning system can enhance pandemic responses by effectively stratifying COVID-19 patients under varying conditions and data shifts.

Understanding the mechanisms of the cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short cell cycle, and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. By analyzing experimental data, this study shows that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional multiscale chemical-mechanical model was developed and used to suggest and test hypothesized impacts of aging on bud morphogenesis. Experimentally calibrated model simulations showed that during the early stage of budding, tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip, a process guided by the polarized Cdc42 signal. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage as observed in experiments in this work. The model simulation results suggest that the localization of new cell surface material insertion, regulated by chemical signal polarization, could be weakened due to cellular aging in yeast and other cell types, leading to the change and stabilization of the bud aspect ratio.

Objectives

We hypothesized that three-dimensional pseudocontinuous arterial spin labelling (pCASL) may have similar efficacy in astrocytic tumour grading as dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI), and the grading accuracy may be further improved when combined with apparent diffusion coefficient (ADC) values.

Methods

Forty-three patients with astrocytic tumours were studied using diffusion weighted imaging (DWI), pCASL, and DSC-PWI. Histograms of ADC and normalized tumour cerebral blood flow values (nCBF on pCASL and nrCBF on DSC-PWI) were measured and analyzed.

Results

The mean 10 % ADC value was the DWI parameter that provided the best differentiation between low-grade astrocytoma (LGA) and high-grade astrocytoma (HGA). The nCBF and nrCBF (1.810 ± 0.979 and 2.070 ± 1.048) in LGA were significantly lower than those (4.505 ± 2.270 and 5.922 ± 2.630) in HGA. For differentiation between LGA and HGA, the cutoff values of 0.764 × 10(-3) mm(2)/s for mean 10 % ADC, 2.374 for nCBF, and 3.464 for nrCBF provided the optimal accuracy (74.4 %, 86.1 %, and 88.6 %, respectively). Combining the ADC values with nCBF or nrCBF could further improve the grading accuracy to 97.7 % or 95.3 %, respectively.

Conclusions

pCASL is an alternative to DSC-PWI for astrocytic tumour grading. The combination of DWI and contrast-free pCASL offers a valuable choice in patients with risk factors.

Key points

• pCASL shows positive correlation with DSC-PWI in astrocytic tumour grading. • ADC values based on ADC histograms can be an objective method. • Combination of DWI and pCASL or DSC-PWI can improve grading accuracy.

Chromatin instability and protein homeostasis (proteostasis) stress are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of Saccharomyces cerevisiae, a challenge to proteostasis occurs specifically in the fraction of cells with decreased stability within the ribosomal DNA (rDNA). A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)-binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability induced by inhibition of a conserved lysine deacetylase Sir2. Further, loss of rDNA stability induces age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates contribute to age-induced proteostasis decline and limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis stress and highlight the importance of cell-to-cell variability in aging processes.