Transfer of disulfide bond formation modules via yeast artificial chromosomes promotes the expression of heterologous proteins in Kluyveromyces marxianus.

Kluyveromyces marxianus is a food-safe yeast with great potential for producing heterologous proteins. Improving the yield in K. marxianus remains a challenge and incorporating large-scale functional modules poses a technical obstacle in engineering. To address these issues, linear and circular yeast artificial chromosomes of K. marxianus (KmYACs) were constructed and loaded with disulfide bond formation modules from Pichia pastoris or K. marxianus. These modules contained up to seven genes with a maximum size of 15 kb. KmYACs carried telomeres either from K. marxianus or Tetrahymena. KmYACs were transferred successfully into K. marxianus and stably propagated without affecting the normal growth of the host, regardless of the type of telomeres and configurations of KmYACs. KmYACs increased the overall expression levels of disulfide bond formation genes and significantly enhanced the yield of various heterologous proteins. In high-density fermentation, the use of KmYACs resulted in a glucoamylase yield of 16.8 g/l, the highest reported level to date in K. marxianus. Transcriptomic and metabolomic analysis of cells containing KmYACs suggested increased flavin adenine dinucleotide biosynthesis, enhanced flux entering the tricarboxylic acid cycle, and a preferred demand for lysine and arginine as features of cells overexpressing heterologous proteins. Consistently, supplementing lysine or arginine further improved the yield. Therefore, KmYAC provides a powerful platform for manipulating large modules with enormous potential for industrial applications and fundamental research. Transferring the disulfide bond formation module via YACs proves to be an efficient strategy for improving the yield of heterologous proteins, and this strategy may be applied to optimize other microbial cell factories.

A comprehensive analysis of imaging features and clinical characteristics to differentiate malignant from non-malignant mammographic architectural distortion.

Background: Mammographic architectural distortion (AD) is usually subtle and has variable presentations and causes, which poses a diagnostic challenge for breast radiologists and consequently a complex decision-making challenge for clinicians and patients. Presently, there is no reliable imaging standard to differentiate between malignant and benign ADs preoperatively. This study aimed to perform a comprehensive analysis of detailed mammographic and ultrasonographic features and clinical characteristics to enhance the diagnostic and differential efficacy for AD lesions. The findings have the potential to boost the diagnostic confidence of breast radiologists when encountering with AD lesions and could be instrumental in refining clinical management strategies for ADs. Methods: This retrospective study included consecutive female patients with ADs on screening or diagnostic mammography from January 6, 2015, to December 28, 2018. The patient's clinical data, mammographic and ultrasonographic or "second look" ultrasonographic findings, and pathological results were reviewed. The continuous variables were analyzed using the t-test. The categorical variables were assessed using the Chi-square test or two-tailed Fisher's exact test. Logistic regression analyses were conducted to evaluate potential risk factors for pathologically proven malignant ADs. Machine learning model based on multimodal clinical and imaging features was constructed using R software. Results: Ultimately, 344 patients with 346 AD lesions were enrolled in the study (mean age: 47.40±10.07 years; range, 19-84 years). Of the ADs, 228 were malignant and 118 were non-malignant. Palpable AD on mammography was more likely to indicate malignancy than non-palpable AD (83.43% vs. 49.15%, P<0.001). AD associated with other mammographic findings was more likely to be malignant than pure AD (73.58% vs. 59.36%, P=0.005). Ultrasonography (US) correlates were observed in 345 of these 346 AD lesions. Among these US correlates, 63 (18.26%, 63/345) were detected by "second look" ultrasound. For the US correlates, the mammographic ADs that appeared as non-mass-like hypoechoic areas and masses on US were more likely to be malignant than those that appeared as other abnormalities (P<0.001). The sensitivity, specificity and diagnostic accuracy of the eXtreme Gradient Boosting (XGBoost) model based on clinical and comprehensive imaging features in differentiation of AD lesions in the validation set were 66.46%, 94.23% and 78.9%, respectively, and the AUC was 0.886 (95% confidence interval: 0.825-0.947). Conclusions: The application of mammograms-guided "second-look" ultrasound could enhance the detection of US correlates, particularly non-mass-like features. The comprehensive analysis based on clinical and multimodal imaging features could be beneficial in improving the diagnostic and differential efficacy for AD lesions detected on mammography and instrumental in refining clinical management strategies for ADs.

Preoperative magnetic resonance imaging identify feasibility of breast-conserving surgery for breast cancer patients.

Background: Breast-conserving surgery (BCS) stands as the favored modality for treating early-stage breast cancer. Accurately forecasting the feasibility of BCS preoperatively can aid in surgical planning and reduce the rate of switching of surgical methods and reoperation. The objective of this study is to identify the radiomics features and preoperative breast magnetic resonance imaging (MRI) characteristics that are linked with positive margins following BCS in patients with breast cancer, with the ultimate aim of creating a predictive model for the feasibility of BCS. Methods: This study included a cohort of 221 pretreatment MRI images obtained from patients with breast cancer. A total of seven MRI semantic features and 1,561 radiomics features of lesions were extracted. The feature subset was determined by eliminating redundancy and correlation based on the features of the training set. The least absolute shrinkage and selection operator (LASSO) logistic regression was then trained with this subset to classify the final BCS positive and negative margins and subsequently validated using the test set. Results: Seven features were significant in the discrimination of cases achieving positive and negative margins. The radiomics signature achieved area under the curve (AUC), accuracy, sensitivity, and specificity of 0.760 [95% confidence interval (CI): 0.630, 0.891], 0.712 (95% CI: 0.569, 0.829), 0.882 (95% CI: 0.623, 0.979) and 0.629 (95% CI: 0.449, 0.780) in the test set, respectively. The combined model of radiomics signature and background parenchymal enhancement (BPE) demonstrated an AUC, accuracy, sensitivity, and specificity of 0.759 (95% CI: 0.628, 0.890), 0.654 (95% CI: 0.509, 0.780), 0.679 (95% CI: 0.476, 0.834) and 0.625 (95% CI: 0.408, 0.804). Conclusions: The combination of preoperative MRI radiomics features can well predict the success of breast conserving surgery.

Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4/MyD88-mediated NF-κB p65 and JNK/FoxO1 activation.

BACKGROUND: Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an isoflavone derivative isolated from Pueraria lobata, has been proven to possess exceptional effectiveness in reducing inflammation. However, the effects and underlying mechanisms of puerarin on AKI remain uncertain. PURPOSE: This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism. STUDY DESIGN AND METHODS: The effects of puerarin on AKI and macrophage polarization were investigated in lipopolysaccharide (LPS)-induced or unilateral ureteral obstruction (UUO)-induced mouse models in vivo and LPS-treated macrophages (Raw264.7) in vitro. Additionally, the effects of puerarin on inflammation-related signaling pathways were analyzed. RESULTS: Administration of puerarin effectively alleviated kidney dysfunction and reduced inflammatory response in LPS-induced and UUO-induced AKI. In vitro, puerarin treatment inhibited the polarization of M1 macrophages and the release of inflammatory factors in Raw264.7 cells stimulated by LPS. Mechanistically, puerarin downregulated the activities of NF-κB p65 and JNK/FoxO1 signaling pathways. The application of SRT1460 to activate FoxO1 or anisomycin to activate JNK eliminated puerarin-mediated inhibition of JNK/FoxO1 signaling, leading to suppression of macrophage M1 polarization and reduction of inflammatory factors. Further studies showed that puerarin bound to Toll/interleukin-1 receptor (TIR) domain of MyD88 protein, hindering its binding with TLR4, ultimately resulting in downstream NF-κB p65 and JNK/FoxO1 signaling inactivation. CONCLUSIONS: Puerarin antagonizes NF-κB p65 and JNK/FoxO1 activation via TLR4/MyD88 pathway, thereby suppressing macrophage polarization towards M1 phenotype and alleviating renal inflammatory damage.

Functional transformation of macrophage mitochondria in cardiovascular diseases.

Mitochondria are pivotal in the modulation of macrophage activation, differentiation, and survival. Furthermore, macrophages are instrumental in the onset and progression of cardiovascular diseases. Hence, it is imperative to investigate the role of mitochondria within macrophages in the context of cardiovascular disease. In this review, we provide an updated description of the origin and classification of cardiac macrophages and also focused on the relationship between macrophages and mitochondria in cardiovascular diseases with respect to (1) proinflammatory or anti-inflammatory macrophages, (2) macrophage apoptosis, (3) macrophage pyroptosis, and (4) macrophage efferocytosis. Clarifying the relationship between mitochondria and macrophages can aid the exploration of novel therapeutic strategies for cardiovascular disease.

Reduced human fecundity attributable to ambient fine particles in low- and middle-income countries.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) has been associated with reduced human fecundity. However, the attributable burden has not been estimated for low- and middle-income countries (LMICs), where the exposure-response function between PM2.5 and the infertility rate has been insufficiently studied. OBJECTIVE: This study examined the associations between long-term exposure to PM2.5 and human fecundity indicators, namely the expected time to pregnancy (TTP) and 12-month infertility rate (IR), and then estimated PM2.5-attributable burden of infertility in LMICs. METHODS: We analyzed 164,593 eligible women from 100 Demographic and Health Surveys conducted in 49 LMICs between 1999 and 2021. We assessed PM2.5 exposures during the 12 months before a pregnancy attempt using the global satellite-derived PM2.5 estimates produced by Atmospheric Composition Analysis Group (ACAG). First, we created a series of pseudo-populations with balanced covariates, given different levels of PM2.5 exposure, using a matching approach based on the generalized propensity score. For each pseudo-population, we used 2-stage generalized Gamma models to derive TTP or IR from the probability distribution of the questionnaire-based duration time for the pregnancy attempt before the interview. Second, we used spline regressions to generate nonlinear PM2.5 exposure-response functions for each of the two fecundity indicators. Finally, we applied the exposure-response functions to estimate number of infertile couples attributable to PM2.5 exposure in 118 LMICs. RESULTS: Based on the Gamma models, each 10 µg/m3 increment in PM2.5 exposure was associated with a TTP increase by 1.7 % (95 % confidence interval [CI]: -2.3 %-6.0 %) and an IR increase by 2.3 % (95 %CI: 0.6 %-3.9 %). The nonlinear exposure-response function suggested a robust effect of an increased IR for high-concentration PM2.5 exposure (>75 µg/m3). Based on the PM2.5-IR function, across the 118 LMICs, the number of infertile couples attributable to PM2.5 exposure exceeding 35 µg/m3 (the first-stage interim target recommended by the World Health Organization global air quality guidelines) was 0.66 million (95 %CI: 0.061-1.43), accounting for 2.25 % (95 %CI: 0.20 %-4.84 %) of all couples affected by infertility. Among the 0.66 million, 66.5 % were within the top 10 % high-exposure infertile couples, mainly from South Asia, East Asia, and West Africa. CONCLUSION: PM2.5 contributes significantly to human infertility in places with high levels of air pollution. PM2.5-pollution control is imperative to protect human fecundity in LMICs.

Family-based Helicobacter pylori infection control and management strategy and screen-and-treat strategy are highly cost-effective in preventing multiple upper gastrointestinal diseases in Chinese population at national level.

BACKGROUND: The overall benefits of the newly introduced family-based Helicobacter pylori (H. pylori) infection control and management (FBCM) and screen-and-treat strategies in preventing multiple upper gastrointestinal diseases at national level in China have not been explored. We investigate the cost-effectiveness of these strategies in the whole Chinese population. MATERIALS AND METHODS: Decision trees and Markov models of H. pylori infection-related non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC) were developed to simulate the cost-effectiveness of these strategies in the whole 494 million households in China. The main outcomes include cost-effectiveness, life years (LY), quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). RESULTS: When compared with no-screen strategy, both FBCM and screen-and-treat strategies reduced the number of new cases of NUD, PUD, PUD-related deaths, and the prevalence of GC, and cancer-related deaths. The costs saved by these two strategies were $1467 million and $879 million, quality-adjusted life years gained were 227 million and 267 million, and life years gained were 59 million and 69 million, respectively. Cost-effectiveness analysis showed that FBCM strategy costs -$6.46/QALY and -$24.75/LY, and screen-and-treat strategy costs -$3.3/QALY and -$12.71/LY when compared with no-screen strategy. Compared to the FBCM strategy, the screen-and-treat strategy reduced the incidence of H. pylori-related diseases, added 40 million QALYs, and saved 10 million LYs, but at the increased cost of $588 million. Cost-effectiveness analysis showed that screen-and-treat strategy costs $14.88/QALY and $59.5/LY when compared with FBCM strategy. The robustness of the results was also verified. CONCLUSIONS: Both FBCM and screen-and-treat strategies are highly cost-effective in preventing NUD, PUD, and GC than the no-screen strategy in Chinese families at national level. As FBCM strategy is more practical and efficient, it is expected to play a more important role in preventing familial H. pylori infection and also serves as an excellent reference for other highly infected societies.

Chinese herbal medicine Shufeng Jiedu capsule for mild to moderate COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase II trial.

Background: The COVID-19 pandemic has had a profound global impact, although the majority of recently infected cases have presented with mild to moderate symptoms. Previous clinical studies have demonstrated that Shufeng Jiedu (SFJD) capsule, a Chinese herbal patent medicine, effectively alleviates symptoms associated with the common cold, H1N1 influenza, and COVID-19. This study aimed to assess the efficacy and safety of SFJD capsules in managing symptoms of mild to moderate COVID-19 infection. Methods: A randomized, double-blind, placebo-controlled trial was conducted from May to December 2022 at two hospitals in China. Mild and moderate COVID-19-infected patients presenting respiratory symptoms within 3 days from onset were randomly assigned to either the SFJD or placebo groups in a 1:1 ratio. Individuals received SFJD capsules or a placebo three times daily for five consecutive days. Participants were followed up for more than 14 days after their RT-PCR nucleoid acid test for SARS-CoV-2 turned negative. The primary outcome measure was time to alleviate COVID-19 symptoms from baseline until the end of follow-up. Results: A total of 478 participants were screened; ultimately, 407 completed the trial after randomization (SFJD, n = 203; placebo, n = 204). No statistically significant difference in baseline parameters was observed between the two groups. The median time to alleviate all symptoms was 7 days in the SFJD group compared to 8 days in the placebo group (p = 0.037). Notably, the SFJD group significantly attenuated fever/chills (p = 0.04) and headache (p = 0.016) compared to the placebo group. Furthermore, the median time taken to reach normal body temperature within 24 h was reduced by 7 hours in the SFJD group compared to the placebo group (p = 0.033). No deaths or instances of serious or critical conditions occurred during this trial period; moreover, no serious adverse events were reported. Conclusion: The trial was conducted in a unique controlled hospital setting, and the 5-day treatment with SFJD capsules resulted in a 1-day reduction in overall symptoms, particularly headache and fever/chills, among COVID-19-infected participants with mild or moderate symptoms. Compared to placebo, SFJD capsules were found to be safe with fewer side effects. SFJD capsules could potentially serve as an effective treatment for alleviating mild to moderate symptoms of COVID-19. Clinical Trial Registration: https://www.isrctn.com/, identifier ISRCTN14236594.

Streamlined whole-genome genotyping through NGS-enhanced thermal asymmetric interlaced (TAIL)-PCR.

Whole-genome genotyping (WGG) stands as a pivotal element in genomic-assisted plant breeding. Nevertheless, sequencing-based approaches for WGG continue to be costly, primarily attributed to the high expenses associated with library preparation and the laborious protocol. During the prior development of Foreground and Background Integrated genotyping by sequencing (FBI-seq), we discovered that any sequence specific primer (SP) inherently possessed the capability to amplify a massive array of stable and reproducible non-specific PCR product across the genome. Here we further improved the FBI-seq by replacing the adapter ligated by Tn5 transposase with arbitrary degenerate (AD) primer. The protocol for the enhanced FBI-seq unexpectedly mirrors a simplified Thermal Asymmetric Interlaced (TAIL)-PCR, a technique widely employed for isolating flanking sequences. However, the improved TAIL-PCR maximizes the PTMA capabilities of both SP and AD primers. Additionally, leveraging next-generation sequencing enhances its ability to assay tens of thousands of genome-wide loci for any species. This cost-effective, user-friendly, and powerful WGG tool, TAIL-PCR by sequencing (TAIL-peq), holds great potential for widespread application in breeding programs, thereby facilitating genome-assisted crop improvement.

Studies on invariant measures of fractional stochastic delay Ginzburg-Landau equations on Rn.

This paper is concerned with invariant measures of fractional stochastic delay Ginzburg-Landau equations on the entire space $ \mathbb{R}^n $. We first derive the uniform estimates and the mean-square uniform smallness of the tails of solutions in corresponding space. Then we deduce the weak compactness of a set of probability distributions of the solutions applying the Ascoli-Arzel$ \grave{a} $. We finally prove the existence of invariant measures by applying Krylov-Bogolyubov's method.

Translatome and transcriptome profiling of neonatal mice hippocampus exposed to sevoflurane anesthesia.

Exposure to anesthesia in early life may cause severe damage to the brain and lead to cognitive impairment. The underlying mechanisms, which have only been investigated in a limited scale, remains largely elusive. We performed translatome and transcriptome sequencing together for the first time in hippocampus of neonatal mice that were exposed to sevoflurane. We treated a group of neonatal mice with 2.5 % sevoflurane for 2 h on day 6, 7, 8, 9 and treated another group on day 6, 7. We performed behavioral study after day 30 for both groups and the control to evaluate the cognitive impairment. On day 36, we collected translatome and transcriptome from the hippocampus in the two groups, compared the gene expression levels between the groups and the control, and validated the results with RT-qPCR. We identified 1750 differentially expressed genes (DEGs) from translatome comparison and 1109 DEGs from transcriptome comparison. As expected, translatome-based DEGs significantly overlapped with transcriptome-based DEGs, and functional enrichment analysis generated similar enriched cognition-related GO terms and KEGG pathways. However, for many genes like Hspa5, their alterations in translatome differed remarkably from those in transcriptome, and Western blot results were largely concordant with the former, suggesting that translational regulation plays a significant role in cellular response to sevoflurane. Our study revealed global alterations in translatome and transcriptome of mice hippocampus after neonatal exposure to sevoflurane anesthesia and highlighted the importance of translatome analysis in understanding the mechanisms responsible for anesthesia-induced cognitive impairment.

A Novel Dual-Band Circularly Polarized Wearable Antenna.

A circularly polarized wearable antenna operating in the 2.45/5.8 GHz ISM dual bands is proposed, which consists of a coplanar waveguide-fed rectangular monopole antenna and two parasitic branches. The monopole rectangular radiation patch can generate 2.45 and 7 GHz frequency bands and has linear polarization characteristics. By adding L-shaped parasitic branches and L-like grounded branches on both sides of the monopole, the 7 GHz operating frequency band can be moved to the 5.8 GHz frequency band, and circular polarization characteristics can be achieved in both the 2.45 and 5.8 GHz frequency bands. The size of the antenna is 48.7 mm × 42.1 mm × 1.016 mm. The simulated -10 dB impedance bandwidths of the antenna are 1.8-2.66 GHz and 5.48-6.98 GHz, respectively. The 3 dB axial ratio bandwidths are 2.34-2.67 GHz and 5.58-6.39 GHz, respectively, and it has dual-band circular polarization characteristics. In addition, the radiation characteristics of the antenna and its safety performance near the human body were analyzed. The antenna prototype has been constructed, and the measurement and simulation results have good consistency. The proposed antenna is suitable for application in wearable devices.

Recombinant Beauveria bassiana expressing Bacillus thuringiensis toxin Cyt1Aa: a promising approach for enhancing Aedes mosquito control.

The entomopathogenic fungus Beauveria bassiana provides an eco-friendly substitute to chemical insecticides for mosquito control. Nevertheless, its widespread application has been hindered by its comparatively slow efficacy in eliminating mosquitoes. To augment the potency of B. bassiana against Aedes mosquitoes, a novel recombinant strain, Bb-Cyt1Aa, was developed by incorporating the Bacillus thuringiensis toxin gene Cyt1Aa into B. bassiana. The virulence of Bb-Cyt1Aa was evaluated against Aedes aegypti and Aedes albopictus using insect bioassays. Compared to the wild-type (WT) strain, the median lethal time (LT50) for A. aegypti larvae infected with Bb-Cyt1Aa decreased by 33.3% at a concentration of 1 × 108 conidia/mL and by 22.2% at 1 × 107 conidia/mL. The LT50 for A. aegypti adults infected with Bb-Cyt1Aa through conidia ingestion was reduced by 37.5% at 1 × 108 conidia/mL and by 33.3% at 1 × 107 conidia/mL. Likewise, the LT50 for A. aegypti adults infected with Bb-Cyt1Aa through cuticle contact decreased by 33.3% and 30.8% at the same concentrations, respectively. Furthermore, the Bb-Cyt1Aa strain also demonstrated increased toxicity against both larval and adult A. albopictus, when compared to the WT strain. In conclusion, our study demonstrated that the expression of B. thuringiensis toxin Cyt1Aa in B. bassiana enhanced its virulence against Aedes mosquitoes. This suggests that B. bassiana expressing Cyt1Aa has potential value for use in mosquito control. IMPORTANCE: Beauveria bassiana is a naturally occurring fungus that can be utilized as a bioinsecticide against mosquitoes. Cyt1Aa is a delta-endotoxin protein produced by Bacillus thuringiensis that exhibits specific and potent insecticidal activity against mosquitoes. In our study, the expression of this toxin Cyt1Aa in B. bassiana enhances the virulence of B. bassiana against Aedes aegypti and Aedes albopictus, thereby increasing their effectiveness in killing mosquitoes. This novel strain can be used alongside chemical insecticides to reduce dependence on harmful chemicals, thereby minimizing negative impacts on the environment and human health. Additionally, the potential resistance of B. bassiana against mosquitoes in the future could be overcome by acquiring novel combinations of exogenous toxin genes. The presence of B. bassiana that expresses Cyt1Aa is of significant importance in mosquito control as it enhances genetic diversity, creates novel virulent strains, and contributes to the development of safer and more sustainable methods of mosquito control.

Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health.

BACKGROUND: Osteoporosis (OP) has become a major public health problem worldwide. Most OP treatments are based on the inhibition of bone resorption, and it is necessary to identify additional treatments aimed at enhancing osteogenesis. In the bone marrow (BM) niche, bone mesenchymal stem cells (BMSCs) are exposed to a hypoxic environment. Recently, a few studies have demonstrated that hypoxia-inducible factor 2alpha (HIF-2α) is involved in BMSC osteogenic differentiation, but the molecular mechanism involved has not been determined. AIM: To investigate the effect of HIF-2α on the osteogenic and adipogenic differentiation of BMSCs and the hematopoietic function of hematopoietic stem cells (HSCs) in the BM niche on the progression of OP. METHODS: Mice with BMSC-specific HIF-2α knockout (Prx1-Cre;Hif-2αfl/fl mice) were used for in vivo experiments. Bone quantification was performed on mice of two genotypes with three interventions: Bilateral ovariectomy, semilethal irradiation, and dexamethasone treatment. Moreover, the hematopoietic function of HSCs in the BM niche was compared between the two mouse genotypes. In vitro, the HIF-2α agonist roxadustat and the HIF-2α inhibitor PT2399 were used to investigate the function of HIF-2α in BMSC osteogenic and adipogenic differentiation. Finally, we investigated the effect of HIF-2α on BMSCs via treatment with the mechanistic target of rapamycin (mTOR) agonist MHY1485 and the mTOR inhibitor rapamycin. RESULTS: The quantitative index determined by microcomputed tomography indicated that the femoral bone density of Prx1-Cre;Hif-2αfl/fl mice was lower than that of Hif-2αfl/fl mice under the three intervention conditions. In vitro, Hif-2αfl/fl mouse BMSCs were cultured and treated with the HIF-2α agonist roxadustat, and after 7 d of BMSC adipogenic differentiation, the oil red O staining intensity and mRNA expression levels of adipogenesis-related genes in BMSCs treated with roxadustat were decreased; in addition, after 14 d of osteogenic differentiation, BMSCs treated with roxadustat exhibited increased expression of osteogenesis-related genes. The opposite effects were shown for mouse BMSCs treated with the HIF-2α inhibitor PT2399. The mTOR inhibitor rapamycin was used to confirm that HIF-2α regulated BMSC osteogenic and adipogenic differentiation by inhibiting the mTOR pathway. Consequently, there was no significant difference in the hematopoietic function of HSCs between Prx1-Cre;Hif-2αfl/fl and Hif-2αfl/fl mice. CONCLUSION: Our study showed that inhibition of HIF-2α decreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche.

COVID-19 hospitalization, mortality and pre-mature mortality by a history of immigration in Ontario, Canada: a population-based cohort study.

Background: Immigrants in high-income countries experienced inequities in COVID-19 severe outcomes. We examined hospitalization and death throughout the pandemic, and change during the vaccine era, in Ontario, Canada. Methods: We conducted a population-based study using linked immigration and health data, following two cohorts for 20 months from January 1, 2020 (pre-vaccine) and September 1, 2021 (vaccine era). We used multivariable Poisson generalized estimating equation regression to estimate adjusted rate ratios (aRR) with 95% confidence intervals (CI), accounting for age, sex and co-morbidities. We calculated age-standardized years of life lost (ASYRs) rates by immigrant category. Findings: Of 11,692,387 community-dwelling adults in the pre-vaccine era cohort and 11,878,304 community-dwelling adults in the vaccine era cohort, 21.6% and 21.4% of adults in each era respectively were immigrants. Females accounted for 57.9% and 57.8% of sponsored family, and 68.4% and 67.6% of economic caregivers, in each era respectively. Compared to other Ontarians in the pre-vaccine era cohort, hospitalization rates were highest for refugees (aRR [95% CI] 3.41 [3.39-3.44]) and caregivers (3.13 [3.07-3.18]), followed by sponsored family and other economic immigrants. Compared to other Ontarians, aRRs were highest for immigrants from Central America (5.00 [4.92-5.09]), parts of South Asia (3.95 [3.89-4.01]) and Jamaica (3.56 [3.51-3.61]) with East Asians having lower aRRs. Mortality aRRs were similar to hospitalization aRRs. In the vaccine era, all aRRs were attenuated and most were similar to or lower than other Ontarians, with refugees and a few regions maintaining higher rates. In the pre-vaccine era ASYRs were higher for all immigrant groups. ASYRs dropped in the vaccine era with only refugees continuing to have higher rates. Interpretation: Immigrants, particularly refugees, experienced greater premature mortality. aRRs for most immigrant groups dropped substantially after high vaccine coverage was achieved. Vaccine outreach and improvements in the social determinants of health are needed. Funding: Canadian Institutes of Health Research, Canada Research Chairs Program.

Carbon-nitrogen transmutation in polycyclic arenol skeletons to access N-heteroarenes.

Developing skeletal editing tools is not a trivial task, and realizing the corresponding single-atom transmutation in a ring system without altering the ring size is even more challenging. Here, we introduce a skeletal editing strategy that enables polycyclic arenols, a highly prevalent motif in bioactive molecules, to be readily converted into N-heteroarenes through carbon-nitrogen transmutation. The reaction features selective nitrogen insertion into the C-C bond of the arenol frameworks by azidative dearomatization and aryl migration, followed by ring-opening, and ring-closing (ANRORC) to achieve carbon-to-nitrogen transmutation in the aromatic framework of the arenol. Using widely available arenols as N-heteroarene precursors, this alternative approach allows the streamlined assembly of complex polycyclic heteroaromatics with broad functional group tolerance. Finally, pertinent transformations of the products, including synthesis complex biheteroarene skeletons, were conducted and exhibited significant potential in materials chemistry.

Synapse Neurotransmitter Channel-Inspired AlOx Memristor with "V" Type Oxygen Vacancy Distribution.

Memristor possesses great potential and advantages in neuromorphic computing, while consistency and power consumption issues have been hindering its commercialization. Low cost and accuracy are the advantages of human brain, so memristors can be used to construct brain-like synaptic devices to solve these problems. In this work, a five-layer AlOx device with a V-shaped oxygen distribution is used to simulate biological synapses. The device simulates synapse structurally. Further, under electrical stimulation, O2- moves to the Ti electrode and oxygen vacancy (Vo) moves to the Pt electrode, thus forming a conductive filament (CF), which simulates the Ca2+ flow and releases neurotransmitters to the postsynaptic membrane, thus realizing the transmission of information. By controlling applied voltage, the regulation of Ca2+ gated pathway is realized to control the Ca2+ internal flow and achieve different degrees of information transmission. Long-term Potentiation (LTP)/Long-term Depression (LTD), Spike Timing Dependent Plasticity (STDP), these basic synaptic performances can be simulated. The AlOx device realizes low power consumption (56.7 pJ/392 fJ), high switching speed (25 ns/60 ns), and by adjusting the window value, the nonlinearity is improved (0.133/0.084), a high recognition accuracy (98.18%) is obtained in neuromorphic simulation. It shows a great prospect in multi-value storage and neuromorphic computing.

Human neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head.

Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a ß14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an adjacent protomer, thereby blocking viral entry. Sequence analysis indicates the lateral patch targeted by H7.HK1 and H7.HK2 to be conserved among influenza subtypes. Both H7.HK1 and H7.HK2 retain HA1 binding and neutralization capacity to later H7N9 isolates from 2016-2017, consistent with structural data showing that the antigenic mutations during this timeframe occur at their epitope peripheries. The HA2-directed mAb H7.HK4 lacks neutralizing activity but when used in combination with H7.HK2 moderately augments female mouse protection. Overall, our data reveal antibodies to a conserved lateral HA1 supersite that confer neutralization, and when combined with a HA2-directed non-neutralizing mAb, augment protection.

Characterizing the loss and acquisition of Tn2-like transposon in Klebsiella pneumoniae: Implications for carbapenemase gene dissemination.

Over 1 year, two KPC-producing and two non-KPC-producing Klebsiella pneumoniae strains were isolated from a patient. Genome and DNA hybridization analyses revealed the first three strains as a clonal lineage, with carbapenem resistance changes due to a Tn2-like transposon on an IncR/IncFII plasmid. The fourth strain, carrying three plasmids, caused a lethal infection and represented a different lineage. All strains belonged to the ST11-SL47-OL101 type. This study highlights the Tn2-like transposon's role in carbapenemase gene spread and the importance of distinguishing between bacterial colonization and infection.