Miracle-dz/UniFAR-FTUs huggingface dataset:
Sublethal and transgenerational effects of lambda-cyhalothrin and abamectin on the development and reproduction of Cydia pomonella

The codling moth Cydia pomonella (Lepidoptera: Tortricidae) is a major invasive pest of pome fruits and walnuts worldwide. Lambda-cyhalothrin (LCT) and abamectin (AM) have been frequently used in C. pomonella control, but control of this pest is very difficult because shortly after hatching, larvae of this insect bore tunnels and hide inside host plant fruit. In this study, a simulated field spray bioassay method was developed against neonate larvae of C. pomonella and concentration-response bioassays were conducted to evaluate the susceptibility of the neonate larvae to LCT and AM. Exposure of neonate larvae to sublethal concentrations (LC30) of LCT or AM significantly reduced the survival rate of larvae (4th and 5th instars), lowered the mean weight of larvae and pupae, and decreased the daily maximal number of eggs laid and the total number of eggs laid (fecundity) per female. The sublethal effects, including reduced body mass, mean fecundity and net reproductive rate, extended mean generation time, and shortened oviposition period, were also found in transgenerational offspring. Furthermore, the transgenerational maternal effects were more obvious for AM than LCT, in comparison to the control. Additionally, the estimated population size was decreased by exposure to LC30 of LCT and AM, and the observed reduction of fecundity and population size within and across generations was likely the result of the downregulation of the reproduction-related vitellogenin gene (CpVg) after exposure to LC30 of LCT and AM. These results provide a better understanding of the overall effects of LCT and AM on C. pomonella and the transgenerational effects which should be taken into consideration when using insecticides in order to control C. pomonella.
The thermodynamic state of aerobic glycolytic flux plays a critical role in stabilizing aerobic glycolytic flux of cancer cells

Inhibition of aerobic glycolysis (AG) is a strategy for cancer treatment, but its clinical translation has not been successful, suggesting that the mechanism underlying the inhibition of AG is not completely understood. We introduce thermodynamic state of AG (TSAG) into AG flux control, which refers the actual change of Gibbs free energy (ΔG) of reactions along the pathway. By using PKM2 knockdown and knockout models, we found that TSAG is resistant to PKM2 perturbation and it can effectively counteract the inhibitory effect of PKM2 perturbation on AG flux. Moreover, we deciphered the interrelationship between TSAG, AG rate, intermediate concentrations, and PK activity, revealed that TSAG is a system property of AG independent of cancer cells’ pathophysiological features and it plays important roles in stabilizing AG flux responding to perturbation. We propose that both inhibition of glycolytic enzyme and disruption of TSAG are required for effective AG inhibition.
Posterodorsal Medial Amygdala Urocortin-3, GABA, and Glutamate Mediate Suppression of LH Pulsatility in Female Mice

The posterodorsal subnucleus of the medial amygdala (MePD) is an upstream modulator of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes. Inhibition of MePD urocortin-3 (Ucn3) neurons prevents psychological stress-induced suppression of LH pulsatility while blocking the stress-induced elevations in corticosterone (CORT) secretion in female mice. We explore the neurotransmission and neural circuitry suppressing the GnRH pulse generator by MePD Ucn3 neurons and we further investigate whether MePD Ucn3 efferent projections to the PVN control CORT secretion and LH pulsatility. Ucn3-cre-tdTomato female ovariectomised (OVX) mice were unilaterally injected with AAV-ChR2 and implanted with optofluid cannulae targeting the MePD. We optically activated Ucn3 neurons in the MePD with blue light at 10Hz and monitored the effect on LH pulses. Next, we combined optogenetic stimulation of MePD Ucn3 neurons with pharmacological antagonism of GABAA or GABAB receptors with bicuculline or CGP, respectively, as well as a combination of NMDA and AMPA receptor antagonists, AP5 and CNQX respectively, and observed the effect on pulsatile LH secretion. A separate group of Ucn3-cre-tdTomato OVX mice with oestradiol replacement were unilaterally injected with AAV-ChR2 in the MePD and implanted with fibreoptic cannulae targeting the PVN. We optically stimulated MePD Ucn3 neuron terminals with blue light at 20Hz and monitored the effect on CORT secretion and LH pulses. We reveal for the first time that activation of Ucn3 neurons in the MePD inhibits GnRH pulse generator frequency via GABA and glutamate signalling within the MePD, while MePD Ucn3 projections to the PVN modulate the HPG and HPA axes.
Large library docking for novel SARS‐CoV‐2 main protease non‐covalent and covalent inhibitors

Antiviral therapeutics to treat SARS‐CoV‐2 are needed to diminish the morbidity of the ongoing COVID‐19 pandemic. A well‐precedented drug target is the main viral protease (MPro), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure‐based approach, we docked 1.2 billion non‐covalent lead‐like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non‐covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS‐CoV‐2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure‐based techniques against MPro itself.
Evaluation of ERIC-PCR and MALDI-TOF as typing tools for multidrug resistant Klebsiella pneumoniae clinical isolates from a tertiary care center in India

Background and Aim Multidrug resistant Klebsiella pneumoniae is associated with nosocomial infections in both outbreak and non-outbreak situations. The study intends to evaluate the potential of enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR), a genomic based typing and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) proteomic-based typing techniques for clonal relatedness among multidrug resistant Klebsiella pneumoniae isolates. Methodology Multidrug resistant clinical isolates of Klebsiella pneumoniae (n =137) were collected from March 2019 to February 2020. Identification and protein-based phylogenetic analysis were performed by MALDI-TOF MS. Genomic typing was done by ERIC-PCR and analyzed by an online data analysis service (PyElph). Dice method with unweighted pair group method with arithmetic mean (UPGMA) program was used to compare the ERIC profiles. The samples were also evaluated by PCR for the presence of genes encoding carbapenemases, extended spectrum beta lactamases (ESBLs) and mobile colistin resistance-1 (mcr1). Result and Conclusion Isolates were typed into 40 ERIC types, and six groups by MALDI-TOF-MS. PCR-based analysis revealed that all the strains harbored two or more ESBL and carbapenemase genes. None of the isolates revealed the presence of the plasmid mediated mcr-1 gene for colistin resistance. The study presents ERIC based typing as more robust in comparison to MALDI-TOF for finding the clonal relatedness in epidemiological studies.
Dynamics of immune memory and learning in bacterial communities

From bacteria to humans, adaptive immune systems provide learned memories of past infections. Despite their vast biological differences, adaptive immunity shares features from microbes to vertebrates such as emergent immune diversity, long-term coexistence of hosts and pathogens, and fitness pressures from evolving pathogens and adapting hosts, yet there is no conceptual model that addresses all of these together. To address these questions, we propose and solve a simple phenomenological model of CRISPR-based adaptive immunity in microbes. We show that in coexisting phage and bacteria populations, immune diversity in both populations emerges spontaneously and in tandem, that bacteria track phage evolution with a context-dependent lag, and that high levels of diversity are paradoxically linked to low overall CRISPR immunity. We define average immunity, an important summary parameter predicted by our model, and use it to perform synthetic time-shift analyses on available experimental data to reveal different modalities of coevolution. Finally, immune cross-reactivity in our model leads to qualitatively different states of evolutionary dynamics, including an influenza-like traveling wave regime that resembles a similar state in models of vertebrate adaptive immunity. Our results show that CRISPR immunity provides a tractable model, both theoretically and experimentally, to understand general features of adaptive immunity.
Learning alters neural activity to simultaneously support memory and action

How are we able to learn new behaviors without disrupting previously learned ones? To understand how the brain achieves this, we used a brain-computer interface (BCI) learning paradigm, which enables us to detect the presence of a memory of one behavior while performing another. We found that learning to use a new BCI map altered the neural activity that monkeys produced when they returned to using a familiar BCI map, in a way that was specific to the learning experience. That is, learning left a “memory trace. ” This memory trace co-existed with proficient performance under the familiar map, primarily by altering dimensions of neural activity that did not impact behavior. Such a memory trace could provide the neural underpinning for the joint learning of multiple motor behaviors without interference.
Baseline Testosterone Predicts Body Composition and Metabolic Response to Testosterone Therapy

Context Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy. Objective The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl. Methods This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40–74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA). Results Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (−3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (−4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (−6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (−40.2 ± 35.1 vs. −27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed. Conclusion T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.
The Spectrum of Parenchymal Changes in Kidneys Affected by Intrarenal Reflux, Diagnosed by Contrast-Enhanced Voiding Urosonography and DMSA Scan

Purpose To describe the parenchymal defects in kidneys with intrarenal reflux (IRR) diagnosed using contrast-enhanced voiding urosonography (ceVUS) and 99mTc-DMSA scintigraphy (DMSA scan). Materials and Methods A group of 186 uretero-renal units (URUs) was analyzed using ceVUS and DMSA scans: 47 without vesicoureteral reflux (VUR) (group A) and 139 with VURs, comprising 73 VURs without (group B), and 66 with IRR (group C). VURs included non-dilating (grades I–II), mildly non-dilating (grade III), and non-dilating (grades IV–V) grades. The parenchymal changes were analyzed using a DMSA scan. Results The median age for VUR diagnosis was 16.5 months in girls, and 8.5 months in boys (Z = 3.9; p = 0.001). IRR occurred in 51.4% of boys and in 25.9% of girls (χ2 = 12.4; p < 0.001). The non-dilating VUR occurred in 44% of boys and 24.1% of girls (χ2 = 7.7; p = 0.005). IRRs characterized upper and lower renal segments (81.8 and 63.6%) and middle segments (33.3%). Both incidence and increase in IRR correlated with the grade of VUR (p < 0.001). The incidence of reduced DMSA signal was statistically different among groups A + B and C, but not between groups A and B (χ2 = 32.2; p < 0.001). No statistically significant relationship existed between the reduced DMSA signal and the grade of VUR in group C. The reduced DMSA signal appeared in 9.9% positions in kidneys from group A, 14% from group B, and 32% from group C. Out of all 118 IRRs, 38.1% had reduced and 61.9% had normal DMSA signal. Among 11 parenchymal scars found in all three groups, 2 belonged to group B, 9 to group C, while group A had no scars. Conclusion The parenchymal changes are the most prominent in the group with IRR, but they do not significantly differ among kidneys with different grades of VUR. VURs of higher grades are associated with a higher incidence of IRR and early clinical presentation. Scars can also appear in lower-grade VURs accompanied by IRR. Boys with VUR have earlier clinical presentation than girls, as they have significantly higher grades of VUR with a higher proportion of IRRs. Therefore, we suggest a subdivision of VURs into those with IRR and abundant parenchymal damage, and those without IRR and less parenchymal damage.
Dao-Chi Powder Ameliorates Pancreatitis-Induced Intestinal and Cardiac Injuries via Regulating the Nrf2-HO-1-HMGB1 Signaling Pathway in Rats

Dao-Chi powder (DCP) has been widely used in the treatment of inflammatory diseases in the clinical practice of traditional Chinese medicine, but has not been used in acute pancreatitis (AP). This study aimed to evaluate the effect of DCP on severe AP (SAP) and SAP-associated intestinal and cardiac injuries. To this end, an SAP animal model was established by retrograde injection of 3.5% taurocholic acid sodium salt into the biliopancreatic ducts of rats. Intragastric DCP (9.6 g/kg.BW) was administered 12 h after modeling. The pancreas, duodenum, colon, heart and blood samples were collected 36 h after the operation for histological and biochemical detection. The tissue distributions of the DCP components were determined and compared between the sham and the SAP groups. Moreover, molecular docking analysis was employed to investigate the interactions between the potential active components of DCP and its targets (Nrf2, HO-1, and HMGB1). Consequently, DCP treatment decreased the serum levels of amylase and the markers of gastrointestinal and cardiac injury, further alleviating the pathological damage in the pancreas, duodenum, colon, and heart of rats with SAP. Mechanistically, DCP rebalanced the pro-/anti-inflammatory cytokines and inhibited MPO activity and MDA levels in these tissues. Furthermore, Western blot and RT-PCR results showed that DCP intervention enhanced the expression of Nrf2 and HO-1 in the duodenum and colon of rats with SAP, while inhibiting the expression of HMGB1 in the duodenum and heart. HPLC-MS/MS analysis revealed that SAP promoted the distribution of ajugol and oleanolic acid to the duodenum, whereas it inhibited the distribution of liquiritigenin to the heart and ajugol to the colon. Molecular docking analysis confirmed that the six screened components of DCP had relatively good binding affinity with Nrf2, HO-1, and HMGB1. Among these, oleanolic acid had the highest affinity for HO-1. Altogether, DCP could alleviated SAP-induced intestinal and cardiac injuries via inhibiting the inflammatory responses and oxidative stress partially through regulating the Nrf2/HO-1/HMGB1 signaling pathway, thereby providing additional supportive evidence for the clinical treatment of SAP.
Susceptibility Genes and HLA for Cold Medicine-Related SJS/TEN with SOC

We investigated the genetic predisposition for the pathogenesis of Stevens–Johnson syndrome/epidermal necrolysis with severe ocular complications (SJS/TEN with SOC). Cold medicines (CMs) including multi-ingredient cold-medications and non-steroidal anti-inflammatory drugs (NSAIDs) were implicated in the development of SJS/TEN with SOC. Studies on the association between HLA genotypes and CM-related SJS/TEN with SOC (CM-SJS/TEN with SOC) revealed an association with HLA-A*02:06 in the Japanese; it may be a marker in Koreans. HLA-B*44:03 was associated with the Japanese, Thais, and Indians; in Brazilians of European ancestry, it may be a positive marker. PTGER3 is a susceptibility gene; HLA-A*02:06 and PTGER3 polymorphisms exerted additive effects in Japanese and Korean patients. A genome-wide association study showed that IKZF1 was associated with the Japanese. A meta-analysis including Japanese, Koreans, Indians, and Brazilians also revealed an association between CM-SJS/TEN with SOC and IKZF1. The upregulation of hsa-miR-628-3p in the plasma of SJS/TEN with SOC patients may suppress the expression of TLR3 and innate immune-related genes. Not only CMs but also the interaction of TLR3, PTGER3, IKZF1, and HLA and maybe some microbial infections are necessary for the onset of SJS/TEN with SOC.
Dairy Cows Experimentally Infected With Bovine Leukemia Virus Showed an Increased Milk Production in Lactation Numbers 3–4: A 4-Year Longitudinal Study

Bovine leukemia virus (BLV) is widespread in global cattle populations, but the effects of its infection on milk quantity and quality have not been clearly elucidated in animal models. In this study, 30 healthy first-lactation cows were selected from ≈2,988 cows in a BLV-free farm with the same criteria of parity, age, lactation number, as well as milk yield, SCS, and composition (fat, protein, and lactose). Subsequently, these cows were randomly assigned to the intervention (n = 15) or control (n = 15) group, and reared in different cowsheds. Cows in the intervention group were inoculated with 1 × phosphate-buffered solution (PBS) resuspended in peripheral blood mononuclear cells (PBMC) from a BLV-positive cow, while the controls were inoculated with the inactivated PBMC from the same individual. From June 2016 to July 2021, milk weight (kg) was automatically recorded by milk sensors, and milk SCS and composition were originated from monthly performed dairy herd improvement (DHI) testing. Fluorescence resonance energy transfer (FRET)–qPCR and ELISA showed that cows in the intervention group were successfully infected with BLV, while cows in the control group were free of BLV for the entire period. At 45 days post-inoculation (DPI), the numbers of whole blood cells (WBCs) (P = 0.010), lymphocytes (LYMs) (P = 0.002), and monocytes (MNCs) (P = 0.001) and the expression levels of IFN-γ (P = 0.013), IL-10 (P = 0.031), and IL-12p70 (P = 0.008) increased significantly in the BLV infected cows compared to the non-infected. In lactation numbers 2–4, the intervention group had significantly higher overall milk yield (P < 0.001), fat (P = 0.031), and protein (P = 0.050) than the control group, while milk SCS (P = 0.038) and lactose (P = 0.036) decreased significantly. Further analysis indicated that BLV infection was associated with increased milk yield at each lactation stage in lactation numbers 3–4 (P = 0.021 or P < 0.001), but not with SCS and milk composition. Together, this 4-year longitudinal study revealed that artificial inoculation of BLV increased the milk yield in cows in this BLV challenge model.
Mixed Comparison of Different Exercise Interventions for Function, Respiratory, Fatigue, and Quality of Life in Adults With Amyotrophic Lateral Sclerosis: Systematic Review and Network Meta-Analysis

Background Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease whose primary hallmark is the progressive degeneration of motor neurons in the brainstem, spinal cord, and cerebral cortex that leads to weakness, spasticity, fatigue, skeletal muscle atrophy, paralysis, and even death. Exercise, as a non-pharmacological tool, may generally improve muscle strength, cardiovascular function, and quality of life. However, there are conflicting reports about the effect of exercise training in adults with ALS. Aims This systematic review and network meta-analysis aim to conduct a mixed comparison of different exercise interventions for function, respiratory, fatigue, and quality of life in adults with ALS. Methods Randomized controlled trials with ALS participants were screened and included from the databases of PubMed, Medline, and Web of Science. Physical exercise interventions were reclassified into aerobic exercise, resistance training, passive exercise, expiratory muscle exercise, and standard rehabilitation. Patient-reported outcome measures would be reclassified from perspectives of function, respiratory, fatigue, and quality of life. The effect size would be transferred into the percentage change of the total score. Result There were 10 studies included, with the agreement between authors reaching a kappa-value of 0.73. The network meta-analysis, which was conducted under the consistency model, identified that a combined program of aerobic exercise, resistance exercise, and standard rehabilitation showed the highest potential to improve quality of life (0.64 to be the best) and reduce the fatigue (0.39 to be the best) for ALS patients, while exercise program of aerobic and resistance training showed the highest potential (0.51 to be the best) to improve ALS patients' physical function. The effect of exercise on the respiratory was still unclear. Conclusion A multi-modal exercise and rehabilitation program would be more beneficial to ALS patients. However, the safety and guide for practice remain unclear, and further high-quality randomized controlled trials (RCTs) with a larger sample are still needed. Systematic Review Registration https://www.crd. york.ac. uk/prospero/display_record. php? ID=CRD42021253442, CRD42021253442.