Miracle-dz/UniFAR-FTUs huggingface dataset:
Multi-Objective Drug Design Based on Graph-Fragment Molecular Representation and Deep Evolutionary Learning

Drug discovery is a challenging process with a huge molecular space to be explored and numerous pharmacological properties to be appropriately considered. Among various drug design protocols, fragment-based drug design is an effective way of constraining the search space and better utilizing biologically active compounds. Motivated by fragment-based drug search for a given protein target and the emergence of artificial intelligence (AI) approaches in this field, this work advances the field of in silico drug design by (1) integrating a graph fragmentation-based deep generative model with a deep evolutionary learning process for large-scale multi-objective molecular optimization, and (2) applying protein-ligand binding affinity scores together with other desired physicochemical properties as objectives. Our experiments show that the proposed method can generate novel molecules with improved property values and binding affinities.
Effect of Maternal Antidepressant Use During the Pre-pregnancy/Early Pregnancy Period on Congenital Heart Disease: A Prospective Cohort Study in Central China

Background With the increase in maternal antidepressant prescribing before/during pregnancy, concerns about the safety of antidepressants have come into focus. The purpose of this study was to explore the association between maternal antidepressant use before pregnancy/in early pregnancy and the risk of congenital heart disease (CHD) in children, and to provide a scientific basis for clinical safety of antidepressant use. Methods The prospective cohort study ultimately included 34,104 singleton pregnancies. Modified Poisson regression model with robust error variances was used to evaluate RRs and 95% confidence intervals (CIs) for the risk of CHD in offspring exposed to maternal antidepressant in the 3 months before pregnancy and early pregnancy. In addition, sensitivity analysis was further performed to explore the robustness of the results. Results In this study, the maternal antidepressant exposure rate was 2.83% in the 3 months before pregnancy, 2.42% in early pregnancy, and the incidence of CHD was 8.973 per 1,000 live births. We found that maternal antidepressant use in the 3 months before pregnancy and early pregnancy were all associated with an increased risk of CHD, ~2.54 times and 2.87 times, respectively, of non-use of antidepressants after adjusting for potential confounders. This association was also found in CHD specific phenotypic analysis. Of these, offspring whose mothers were exposed to antidepressants in the 3 months before pregnancy had the highest risk of transposition of the great arteries (aOR = 5.50, 95% CI: 1.91–15.88). The offspring of mothers exposed to antidepressants in early pregnancy had the highest risk of developing ventricular septal defect (aOR = 4.80, 95% CI: 2.50–9.24). Sensitivity analysis verified the stability of the results. Conclusions Maternal antidepressant use in the 3 months before pregnancy and early pregnancy were all associated with an increased risk of CHD in their offspring. In order to reduce the risk of teratogenesis, we recommend that pregnant women prepare for pregnancy after their condition improves or receive the minimum effective dose of medication.
Research on the Mechanism of Cognitive Decline in Patients With Acoustic Neuroma

Little is known about neuropsychological research on patients with acoustic neuroma (AN), especially cognitive neuropsychology. We aim to compare the cognitive function of patients with AN and healthy controls (HCs) and explore possible underlying mechanisms. Various neuropsychological assessments were performed on all participants. Tract-based spatial statistics (TBSS) was used to compare DTI metrics such as fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Correlation analysis was analyzed between DTI metrics and cognitive scales. Compared with the HC group, the AN group performed worse in the neuropsychological evaluations, and TBSS analysis showed widespread alteration of the FA, AD, RD, and MD, which correlated with the cognitive function. These white matter tracts include minor forceps, major forceps, anterior thalamic radiation, superior longitudinal fasciculus, corticospinal tract, and right inferior fronto-occipital fasciculus. Meanwhile, we found for the first time that cognitive decline was related to the decrease of FA in minor forceps, which can be used as a neurobiological marker of cognitive impairment in patients with AN. The occurrence of cognition impairment is common in patients with AN. Including neuropsychological evaluation in the routine clinical assessment and appropriate treatment may strengthen clinical management and improve the quality of life of patients.
Plant Foraging Strategies Driven by Distinct Genetic Modules: Cross-Ecosystem Transcriptomics Approach

Plants have evolved diverse strategies for foraging, e.g., mycorrhizae, modification of root system architecture, and secretion of phosphatase. Despite extensive molecular/physiological studies on individual strategies under laboratory/greenhouse conditions, there is little information about how plants orchestrate these strategies in the field. We hypothesized that individual strategies are independently driven by corresponding genetic modules in response to deficiency/unbalance in nutrients. Roots colonized by mycorrhizal fungi, leaves, and root-zone soils were collected from 251 maize plants grown across the United States Corn Belt and Japan, which provided a large gradient of soil characteristics/agricultural practice and thus gene expression for foraging. RNA was extracted from the roots, sequenced, and subjected to gene coexpression network analysis. Nineteen genetic modules were defined and functionally characterized, from which three genetic modules, mycorrhiza formation, phosphate starvation response (PSR), and root development, were selected as those directly involved in foraging. The mycorrhizal module consists of genes responsible for mycorrhiza formation and was upregulated by both phosphorus and nitrogen deficiencies. The PSR module that consists of genes encoding phosphate transporter, secreted acid phosphatase, and enzymes involved in internal-phosphate recycling was regulated independent of the mycorrhizal module and strongly upregulated by phosphorus deficiency relative to nitrogen. The root development module that consists of regulatory genes for root development and cellulose biogenesis was upregulated by phosphorus and nitrogen enrichment. The expression of this module was negatively correlated with that of the mycorrhizal module, suggesting that root development is intrinsically an opposite strategy of mycorrhizae. Our approach provides new insights into understanding plant foraging strategies in complex environments at the molecular level.
Computational Framework for Radionuclide Migration Assessment in Clay Rocks

In the context of nuclear waste disposal, a pre-requisite to assure their long term safety is the need for safety assessment studies aided by computational simulations, in particular, radionuclide migration from the waste to the geosphere. It is established that underground repositories for nuclear waste will provide retardation barriers for radionuclides. However, the understanding of the sorption mechanisms of radionuclides onto mineral surfaces (i.e., illite, montmorillonite) is essential for modelling their migration. On the other hand, mechanistic-based radionuclide migration simulations, typically for 1 million years, poses a computational challenge. Surrogate-based simulations can be useful to enable sensitivity/uncertainty analysis that would be prohibitive otherwise. Considering the current challenges in modelling radionuclide migration and the importance of the results and implications of these simulations (i.e., for the public and nuclear waste management agencies), it is necessary to provide appropriate computational tools in a transparent and easy-to-use way. In this work, we aim to provide such tools in a framework that combines the simulation capabilities of OpenGeoSys6 for radionuclide migration and the approachable nature of Project Jupyter (i.e., JupyterLab), which provides a modular web-based environment for development, simulation and data. In this way, we aim to promote the collaborative research of radionuclide migration assessment and, at the same time, to guarantee the availability and reproducibility of the scientific outcome through the OpenGeoSys initiative.
Interdecadal Variability of Spring Eurasian Snowmelt and Its Impact on Eastern China Summer Precipitation

In this study, the interdecadal variability of Eurasian spring snowmelt and its relationship with Eastern China summer precipitation (ECSP) are investigated based on observations and reanalysis data. Results show that the second mode of the empirical orthogonal function (EOF) analysis of the spring snowmelt, featured as a west-east dipole pattern, displays two interdecadal changes near the late-1970s and in the mid-2000s. The increased spring snowmelt over the Western Siberia (WSI) and the opposite situation over the Eastern Europe (EEU) are significantly linked to a meridional quadrupole summertime rainfall pattern on interdecadal time scales, with excessive rainfall over the regions of southern China (SC) and the Huang-Huai River (HHR) and deficient rainfall over the middle and lower reaches of Yangtze River Valley (YRV) and Inner Mongolia-northeastern China (IMNC). Besides, the possible mechanisms are discussed from the perspective of the hydrological effect related to snowmelt-induced soil moisture. Increased spring snowmelt can produce more water inflowing into the soil, leading to anomalous soil moisture, which can persist into summer. Excessive (deficient) snowmelt-related soil moisture anomalies over the WSI (EEU) in summer will change local land thermal conditions and thus generate cyclonic (anticyclonic) circulations with a quasi-barotropic structure. Therefore, the eastward-propagating wave-activity flux (WAF) could be strengthened over the WSI and EEU in the mid- and upper-troposphere and further propagate downstream. Combining the local response of atmospheric circulations to summer surface heating induced by local snowmelt-related SM anomalies over Mongolia, an anomalous anticyclonic (cyclonic) circulation near the Lake Baikal (SC) and the related strong descending (ascending) motion over the IMNC (SC) are founded. Besides, strong positive (negative) upper-level divergence appears over the YRV (HHR), which is the right (left) side of the exit region of upper-level jet. The upper-level divergence could be attributed to the convergence (divergence) of meridional winds on the right side of the anticyclonic circulation, thus the uniform descending (ascending) motion also appears over the YRV (HHR) through the collocation of upper-level convergence (divergence) and the compensatory lower-level circulations. Consequently, a quadrupole pattern of secondary circulation over Eastern China is founded, thereby causing the anomalously distributed ECSP under favorable water vapor conditions.
Analysis of Factors Associated With Recurrence of Early-Stage Endometrial Carcinoma and Atypical Endometrial Hyperplasia in Infertile Women After In Vitro Fertilization Treatment

Purpose To explore the relationship between different artificial reproductive treatment (ART) strategies and tumor outcomes, by analyzing clinical data of patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH). Methods This retrospective study was performed in a tertiary hospital. Patients (n=131) with EC or AEH, who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment between June 2010 and June 2021, were divided into a recurrence group and a non-recurrence group. Clinical characteristics and tumor outcomes were assessed. Results 131 patients were followed up for 4-132 months; 33 patients had recurrence, the recurrence rate was 25.2%, 3-year recurrence-free survival (RFS) rate was 83.2 ± 3.4%, and the 5-year RFS rate was 72.9 ± 4.4%. Factors including the frequency of controlled ovarian stimulation (COS) and the total days of ovarian stimulation had no significant effect on the recurrence of tumor lesions (p=0.368 and 0.969, respectively). Histology type (HR: 4.94, 95%CI: 2.41-10.15, p <0.001) and successful/un successful live birth (HR: 0.30, 95%CI: 0.14-0.65, p=0.003) were independent factors of recurrence. Twenty-two of the 82 patients who received a single COS had recurrence. Different COS protocols, the total dose of gonadotropin (Gn), and the serum E2 level on the trigger day had no significant effect on recurrence (p=0.326, 0.889 and 0.468, respectively). Conclusions The degree at which an endometrial lesion progresses into carcinoma is a key factor affecting the recurrence of EC/AEH in patients after IVF/ICSI treatment, and successful live birth is a protective factor for the recurrence of endometrial lesions. Different COS protocols and COS frequencies, as well as the dosage and duration of Gn used during IVF did not affect the recurrence of endometrial lesions.
Historical Perspectives, State of Art and Research Trends of SPAD Arrays and Their Applications (Part II: SPAD Arrays)

The ability to detect single photons is becoming an enabling key capability in an increasing number of fields. Indeed, its scope is not limited to applications that specifically rely on single photons, such as quantum imaging, but extends to applications where a low signal is overwhelmed by background light, such as laser ranging, or in which faint excitation light is required not to damage the sample or harm the patient. In the last decades, SPADs gained popularity with respect to other single-photon detectors thanks to their small size, possibility to be integrated in complementary metal-oxide semiconductor processes, room temperature operability, low power supply and, above all, the possibility to be fast gated (to time filter the incoming signal) and to precisely timestamp the detected photons. The development of large digital arrays that integrates the detectors and circuits has allowed the implementation of complex functionality on-chip, tailoring the detectors to suit the need of specific applications. This review proposes a complete overview of silicon SPADs characteristics and applications. In the previous Part I, starting with the working principle, simulation models and required frontend, the paper moves to the most common parameters adopted in literature for characterizing SPAD performance and describes single pixels applications and their performance. In this Part II, the focus is posed on the development of SPAD arrays, presenting some of the most notable examples found in literature. The actual exploitation of these designs in real applications (e.g., automotive, bioimaging and radiation detectors) is then discussed.
PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

Background Chronic inflammation contributes to approximately 20% of cancers; the underlying mechanisms are still elusive. Here, using an animal model of colitis to colon-cancerous transformation, we demonstrated that endoplasmic reticulum (ER) stress couples with metabolic reprogramming to promote a malignant transformation of chronic inflammation. Methods The animal model for chronic colitis to colon-cancerous transformation was established in C57BL/6N mice by azoxymethane (AOM) and dextran sodium sulfate (DSS) treatments. The differential proteins in control and AOM/DSS-treated colon mucosa were determined using proteomic analysis; the kinetics of metabolic modifications were monitored by mitochondrial oxygen flux, extracellular acidification, and targeted metabolomics; the molecule linker between ER stress and metabolic modifications were identified by coimmunoprecipitation, KEGG pathway analysis, and the subcutaneous tumor model using gene-specific knockdown colon cancer cells. Tissue array analysis were used to evaluate the differential protein in cancer and cancer-adjacent tissues. Results AOM/DSS treatment induced 38 tumors in 10 mice at the 14th week with the mean tumor size 9.35 ± 3.87 mm2, which was significantly decreased to 5.85 ± 0.95 mm2 by the ER stress inhibitor 4-phenylbutyric acid (4PBA). Seven differential proteins were determined from control (1,067 ± 48) and AOM/DSS-treated mucosa (1,077 ± 59); the level of ER protein PDIA2 (protein disulfide isomerase-associated 2) was increased over 7-fold in response to AOM/DSS treatment. PDIA2 interacted with 420 proteins that were involved in 8 signaling pathways, in particular with 53 proteins in metabolic pathways. PDIA2 translocated from ER to mitochondria and interacted with the components of complexes I and II to inhibit oxophosphorylation but increase glycolysis. Knockdown PDIA2 in colon cancer cells restored the metabolic imbalance and significantly repressed tumor growth in the xenograft animal model. 4PBA therapy inhibited the AOM/DSS-mediated overexpression of PDIA2 and metabolic modifications and suppressed colon cancer growth. In clinic, PDIA2 was overexpressed in colon cancer tissues rather than cancer-adjacent tissues and was related with the late stages and lymph node metastasis of colon cancer. Conclusions Persistent ER stress reprograms the metabolism to promote the malignant transformation of chronic colitis; PDIA2 serves as a molecule linker between ER stress and metabolic reprogramming. The inhibition of ER stress restores metabolic homeostasis and attenuates the cancerous transformation of chronic inflammation.
The Natural History of Spinocerebellar Ataxia Type 3 in Mainland China: A 2-Year Cohort Study

Objective The natural history of spinocerebellar ataxia type 3 (SCA3) has been reported in several populations and shows heterogeneity in progression rate and affecting factors. However, it remains unexplored in the population of Mainland China. This study aimed to identify the disease progression rate and its potential affecting factors in patients with SCA3 in Mainland China. Participants and Methods We enrolled patients with genetically confirmed SCA3 in Mainland China. Patients were seen at three visits, i.e., baseline, 1 year, and 2 years. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA), and the secondary outcomes were the Inventory of Non-Ataxia Signs (INAS) as well as the SCA Functional Index (SCAFI). Results Between 1 October 2015, and 30 September 2016, we enrolled 263 patients with SCA3. We analyzed 247 patients with at least one follow-up visit. The annual progression rate of SARA was 1.49 points per year (SE 0.08, 95% confidence interval [CI] 1.33–1.65, p < 0.0001). The annual progression rates of INAS and SCAFI were 0.56 points per year (SE 0.05, 95% CI 0.47–0.66, p < 0.001) and −0.30 points per year (SE 0.01, 95% CI −0.33∼-0.28, p < 0.001), respectively. Faster progression in SARA was associated with longer length of the expanded allele of ATXN3 (p < 0.0001); faster progression in INAS was associated with lower INAS at baseline (p < 0.0001); faster decline in SCAFI was associated with shorter length of the normal allele of ATXN3 (p = 0.036) and higher SCAFI at baseline (p < 0.0001). Conclusion Our results provide quantitative data on the disease progression of patients with SCA3 in Mainland China and its corresponding affecting factors, which could facilitate the sample size calculation and patient stratification in future clinical trials. Trial Registration This study was registered with Chictr.org on 15 September 2015, number ChiCTR-OOC-15007124.
Ribosomal Protein S6 Gene Haploinsufﬁciency Is Associated with Activation of a p53-Dependent Checkpoint during Gastrulation (cid:1)

Nascent ribosome biogenesis is required during cell growth. To gain insight into the importance of this process during mouse oogenesis and embryonic development, we deleted one allele of the ribosomal protein S6 gene in growing oocytes and generated S6 -heterozygous embryos. Oogenesis and embryonic development until embryonic day 5.5 (E5.5) were normal. However, inhibition of entry into M phase of the cell cycle and apoptosis became evident post-E5.5 and led to perigastrulation lethality. Genetic inactivation of p53 bypassed this checkpoint and prolonged development until E12.5, when the embryos died, showing decreased expression of D-type cyclins, diminished fetal liver erythropoiesis, and placental defects. Thus, a p53-dependent checkpoint is activated during gastrulation in response to ribosome insufﬁciency to prevent improper execution of the developmental program. Cell
Digital hybrid current mode control for DC–DC converters

A digital hybrid current mode (HCM) control technique which combines peak current and average current mode (ACM) control methods is studied. The proposed controller consists of three control loops, an analogue fast current loop, a digital slow current loop and an outer voltage loop. For the control method, both continuous and discrete-time models are built. Similarly, a continuous-time model for ACM control is provided for comparison. For both control techniques, a compensator design method is proposed. The control methods are implemented on a 6 W synchronous buck converter with a mixed-signal ARM-based microcontroller. Controller models are verified with the frequency response measurements of the inner and outer loops. In digital HCM control, higher DC gain and phase margin is achieved with the same gain margin compared to digital ACM control. Furthermore, the transient responses of the systems are analysed. When the outer voltage loop is open, 30% faster dynamic response is measured by the digital HCM method. With voltage compensation, comparable dynamic response on the output voltage is achieved without inductor current overshooting by the digital HCM control.
EOS3nn: An iTOUGH2 Module for Non-Newtonian Liquid and Gas Flow Documentation and User’s Guide

This report documents the iTOUGH2 module EOS3nn, developed for modeling two-phase isothermal flow of a non-Newtonian liquid and a non-condensible gas in multidimensional, porous and fractured geologic media. This document supplements the TOUGH2 and iTOUGH2 user’s guides and is therefore not a self-contained manual. It presents information on the physical processes modeled and the mathematical and numerical methods used. Also included are two sample problems for code testing and benchmarking. Modeling scenarios and approaches are discussed to illustrate problem setup and usage of the EOS3nn module.
Offense and Defense in Granulomatous Inflammation Disease

Granulomatous inflammation (GI) diseases are a group of chronic inflammation disorders characterized by focal collections of multinucleated giant cells, epithelioid cells and macrophages, with or without necrosis. GI diseases are closely related to microbes, especially virulent intracellular bacterial infections are important factors in the progression of these diseases. They employ a range of strategies to survive the stresses imposed upon them and persist in host cells, becoming the initiator of the fighting. Microbe-host communication is essential to maintain functions of a healthy host, so defense capacity of hosts is another influence factor, which is thought to combine to determine the result of the fighting. With the development of gene research technology, many human genetic loci were identified to be involved in GI diseases susceptibility, providing more insights into and knowledge about GI diseases. The current review aims to provide an update on the most recent progress in the identification and characterization of bacteria in GI diseases in a variety of organ systems and clinical conditions, and examine the invasion and escape mechanisms of pathogens that have been demonstrated in previous studies, we also review the existing data on the predictive factors of the host, mainly on genetic findings. These strategies may improve our understanding of the mechanisms underlying GI diseases, and open new avenues for the study of the associated conditions in the future.