Reduction in the risk of contrast-induced nephropathy using enhanced external counter-pulsation in patients with chronic kidney disease.

OBJECTIVE: To evaluate the efficacy of EECP in the prevention of contrast-induced nephropathy (CIN) in patients with chronic kidney disease (CKD). METHODS: A prospective trial was undertaken in the participants. A total of 280 patients with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m2 who underwent percutaneous coronary artery procedures were enrolled and divided into two groups: the control group (n = 100) and the EECP group (n = 180). All patients received extracellular fluid volume expansion therapy with 0.9% normal saline, and patients in the EECP groups were also treated with EECP. The renal function indexes of the two groups were determined 48-72 h after coronary artery procedures. RESULTS: In the EECP group, the BUN and serum creatinine (Scr) after coronary artery procedures were significantly lower than those before coronary artery procedures (BUN: 8.4 ± 3.5 vs. 6.6 ± 2.7 mmol/L, p < 0.001; Scr: 151.9 ± 44.7 vs. 144.5 ± 48.3 µmol/L, p < 0.001), while the eGFR was significantly increased (43.6 ± 11.4 vs. 47.1 ± 13.9 ml/min/1.73 m2, p < 0.001). The degree of Scr elevation was lower in the EECP group than in the control group (12.4 ± 15.0 vs. 20.9 ± 24.8 µmol/L, p = 0.026). Additionally, the EECP group had a lower incidence of post-procedures Scr elevation than the control group (36.5 vs. 48.0%, p = 0.042), a higher incidence of post-procedures eGFR elevation (62.2 vs. 48.0%, p = 0.021), and a lower risk of CIN (1.1 vs. 6.0%, p = 0.019). CONCLUSION: EECP therapy has a protective effect on renal function and can reduce the risk of CIN in patients with CKD.

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

Hippocampal subfield morphology from first episodes of bipolar disorder type II and major depressive disorder in a drug naïve Chinese cohort.

Introduction: Symptoms during the onset of major depressive disorder [MDD] and bipolar disorder type II [BD-II] are similar. The difference of hippocampus subregion could be a biological marker to distinguish MDD from BD-II. Methods: We recruited 61 drug-naïve patients with a first-episode MDD and BD-II episode and 30 healthy controls (HC) to participate in a magnetic resonance imaging [MRI] study. We built a general linear model (one-way analysis of covariance) with 22 hippocampal subfields and two total hippocampal volumes as dependent variables, and the diagnosis of MDD, BD-II, and HC as independent variables. We performed pair-wise comparisons of hippocampal subfield volumes between MDD and HC, BD-II and MDD, BD-II and HC with post hoc for primary analysis. Results: We identified three regions that differed significantly in size between patients and controls. The left hippocampal fissure, the hippocampal-amygdaloid transition area (HATA), and the right subiculum body were all significantly larger in patients with MDD compared with the HC. In the onset of first-episode of MDD, the hippocampal volume increased significantly, especially on the left side comparing to HC. However, we found differences between MDD and BD-II were not statistically significant. The volume of the left HATA and right subiculum body in BD-II was larger. Conclusions: The sample size of this study is relatively small, as it is a cross-sectional comparative study. In both MDD and BD-II groups, the volume of more left subregions appeared to increase. The left subregions were severely injured in the development of depressive disorder.

Changes in reasons for visits to primary care after the start of the COVID-19 pandemic: An international comparative study by the International Consortium of Primary Care Big Data Researchers (INTRePID).

BACKGROUND: The COVID-19 pandemic has reshaped healthcare delivery worldwide. OBJECTIVE: To explore potential changes in the reasons for visits and modality of care in primary care settings through the International Consortium of Primary Care Big Data Researchers (INTRePID). METHODS: We conducted a cross-sectional, retrospective study from 2018-2021. We examined visit volume, modality, and reasons for visits to primary care in Argentina, Australia, Canada, China, Peru, Norway, Singapore, Sweden, and the USA. The analysis involved a comparison between the pre-pandemic and pandemic periods. RESULTS: There were more than 215 million visits from over 38 million patients during the study period in INTRePID primary care settings. Most INTRePID countries experienced a decline in monthly visit rates during the first year of the pandemic, with rate ratios (RR) and 95% confidence intervals (CI) ranging from RR:0.57 (95%CI:0.49-0.66) to RR:0.90 (95%CI:0.83-0.98), except for in Canada (RR:0.99, 95%CI:0.94-1.05) and Norway (RR:1.00, 95%CI:0.92-1.10), where rates remained stable and in Australia where rates increased (RR:1.19, 95%CI:1.11-1.28). Argentina, China, and Singapore had limited or no adoption of virtual care, whereas the remaining INTRePID countries varied in the extent of virtual care utilization. In Peru, virtual visits accounted for 7.34% (95%CI:7.33%-7.35%) of all interactions in the initial year of the pandemic, dipping to 5.22% (95%CI:5.21%-5.23%) in the subsequent year. However, in Canada 75.30% (95%CI:75.20%-75.40%) of the visits in the first year were virtual, decreasing to 62.77% (95%CI:62.66%-62.88%) in the second year. Diabetes, hypertension and/or hyperlipidemia and general health exams were in the top 10 reasons for visits in 2019 for all countries. Anxiety, depression and/or other mental health related reasons were among the top 10 reasons for virtual visits in all countries that had virtual care. CONCLUSIONS: The pandemic resulted in changes in reasons for visits to primary care, with virtual care mitigating visit volume disruptions in many countries.

A single-dose intranasal live-attenuated codon deoptimized vaccine provides broad protection against SARS-CoV-2 and its variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) continues its significant health and economic impact globally. Despite the success of spike-protein vaccines in preventing severe disease, long-lasting protection against emerging variants and the prevention of breakthrough infections and transmission remain elusive. We generate an intranasal live-attenuated SARS-CoV-2 vaccine, CDO-7N-1, using codon deoptimization. CDO-7N-1 shows highly attenuated replication and minimal or no lung pathology in vivo over multiple passages. It induces robust mucosal and systemic neutralizing antibody and T-cell subset responses, in mice (female K18-hACE2 and male HFH4-hACE2 mice), hamsters, and macaques triggered by a single immunization. Mice and hamsters vaccinated with CDO-7N-1 are protected from challenge with wild-type (WT) SARS-CoV-2 and other variants of concern. Serum from vaccinated animals neutralizes WT SARS-CoV-2, variants of concern (beta and delta), variants of interest (omicron XBB.1.5) and SARS-CoV-1. Antibody responses are sustained and enhanced by repeated immunization or infection with WT SARS-CoV-2. Immunity against all SARS-CoV-2 proteins by CDO-7N-1 should improve efficacy against future SARS-CoV-2 variants.

Dependence of the formation kinetics of carbon dioxide hydrate on clay aging for solid carbon dioxide storage.

Clay-based marine sediments have great potential for safe and effective carbon dioxide (CO2) encapsulation by storing enormous amounts of CO2 in solid gas hydrate form. However, the aging of clay with time changes the surface properties of clay and complicates the CO2 hydrate formation behaviors in sediments. Due to the long clay aging period, it is difficult to identify the role of clay aging in the formation of CO2 hydrate in marine sediments. Here, we used ultrasonication and plasma treatment to simulate the breakage and oxidation of clay nanoflakes in aging and investigated the influence of clay aging on CO2 hydrate formation kinetics. We found that the breakage and oxidation of clay nanoflakes would disrupt the siloxane rings and graft hydroxyl on the clay nanoflakes. This decreased the negative charge density of clay nanoflakes and weakened the interfacial interaction of clay nanoflakes with the surrounding water. Therefore, the small clay nanoflakes enriched in hydroxyl would disrupt the surrounding tetrahedral water structure analogous to the CO2 hydrate, resulting in the prolongation of CO2 hydrate nucleation. These results revealed the influence of the structure-function relationship of clay nanoflakes with CO2 hydrate formation and are favorable for the development of hydrate-based CO2 storage.

Changes in primary care visits for respiratory illness during the COVID-19 pandemic: a multinational study by the International Consortium of Primary Care Big Data Researchers (INTRePID).

Objectives: The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses. Design: Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis. Setting: Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States. Participants: Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021. Main outcome measures: Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases. Results: INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from -10.9% [95% confidence interval (CI): -33.1 to +11.3%] in Norway to -79.9% (95% CI: -86.4% to -73.4%) in China for acute infectious respiratory disease visits and - 2.1% (95% CI: -12.1 to +7.8%) in Peru to -59.9% (95% CI: -68.6% to -51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic. Conclusion: The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

Age-appropriate adaptation of creativity tasks for infants aged 12-24 months.

Creativity is an important skill that relates to innovation, problem-solving and artistic achievement. However, relatively little is known about the early development of creative potential in very young children, in part due to a paucity of tasks suitable for use during infancy. Current measures of creativity in early childhood include the Unusual Box Test, Torrance's Thinking Creatively in Action and Movement (TCAM) task and the Toca Kitchen Monsters task. These tasks are designed for children aged above 12, 36 and 18 months respectively, but very few measures of creativity can be used for infants aged below 2. Accordingly, here we report age-appropriate adaptations of TCAM and Toca Kitchen Monsters tasks for infants as young as 12 to 24 months. Considerations taken into account include (1) infants' cognitive capacities (i.e., attention span, language comprehension skills, motor skills, and approach to play), and (2) practicality of the stimuli, including suitability for use amid the COVID-19 pandemic. The modified creativity battery for infants includes three tasks: Music Play, Object Play and Exploratory Play tasks. The task protocols elaborated in this paper are intended to facilitate studies on the early development of creativity in infants aged between 12 and 24 months. Primary highlights include:•Age-appropriate adaptation of creativity tasks for use with infants aged between 12 and 24 months.•Consideration of infants' cognitive capacities and stimulus practicality.•Innovative use of movement as expression of infants' creative behaviour.

Effect of the COVID-19 pandemic on mental health visits in primary care: an interrupted time series analysis from nine INTRePID countries.

Background: The COVID-19 pandemic impacted mental health disorders, affecting both individuals with pre-existing conditions and those with no prior history. However, there is limited evidence regarding the pandemic's impact on mental health visits to primary care physicians. The International Consortium of Primary Care Big Data Researchers (INTRePID) explored primary care visit trends related to mental health conditions in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden, and the USA. Methods: We conducted an interrupted time series analysis in nine countries to examine changes in rates of monthly mental health visits to primary care settings from January 1st, 2018, to December 31st, 2021. Sub-group analysis considered service type (in-person/virtual) and six categories of mental health conditions (anxiety/depression, bipolar/schizophrenia/other psychotic disorders, sleep disorders, dementia, ADHD/eating disorders, and substance use disorder). Findings: Mental health visit rates increased after the onset of the pandemic in most countries. In Argentina, Canada, China, Norway, Peru, and Singapore, this increase was immediate ranged from an incidence rate ratio of 1·118 [95% CI 1.053-1.187] to 2.240 [95% CI 2.057-2.439] when comparing the first month of pandemic with the pre-pandemic trend. Increases in the following months varied across countries. Anxiety/depression was the leading reason for mental health visits in most countries. Virtual visits were reported in Australia, Canada, Norway, Peru, Sweden, and the USA, accounting for up to 40% of the total mental health visits. Interpretation: Findings suggest an overall increase in mental health visits, driven largely by anxiety/depression. During the COVID-19 pandemic, many of the studied countries adopted virtual care in particular for mental health visits. Primary care plays a crucial role in addressing mental ill-health in times of crisis. Funding: Canadian Institutes of Health Research grant #173094 and the Rathlyn Foundation Primary Care EMR Research and Discovery Fund.

Global impacts of COVID-19 pandemic on sexual and reproductive health services: An international comparative study on primary care from the INTRePID Consortium.

OBJECTIVE: To understand how the COVID-19 pandemic has impacted sexual and reproductive health (SRH) visits. DESIGN: An ecological study comparing SRH services volume in different countries before and after the onset of the COVID-19 pandemic. SETTING: Seven countries from the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID) across four continents. POPULATION: Over 3.8 million SRH visits to primary care physicians in Australia, China, Canada, Norway, Singapore, Sweden and the USA. METHODS: Difference in average SRH monthly visits before and during the pandemic, with negative binomial regression modelling to compare predicted and observed number of visits during the pandemic for SRH visits. MAIN OUTCOME MEASURES: Monthly number of visits to primary care physicians from 2018 to 2021. RESULTS: During the pandemic, the average volume of monthly SRH visits increased in Canada (15.6%, 99% CI 8.1-23.0%) where virtual care was pronounced. China, Singapore, Sweden and the USA experienced a decline (-56.5%, 99% CI -74.5 to -38.5%; -22.7%, 99% CI -38.8 to -6.5%; -19.4%, 99% CI -28.3 to -10.6%; and -22.7%, 99% CI -38.8 to -6.5%, respectively); while Australia and Norway showed insignificant changes (6.5%, 99% CI -0.7 to -13.8% and 1.7%, 99% CI -6.4 to -9.8%). The countries that maintained (Australia, Norway) or surpassed (Canada) pre-pandemic visit rates had the greatest use of virtual care. CONCLUSIONS: In-person SRH visits to primary care decreased during the pandemic. Virtual care seemed to counterbalance that decline. Although cervical cancer screening appeared insensitive to virtual care, strategies such as incorporating self-collected samples for HPV testing may provide a solution in a future pandemic.

Aryl hydrocarbon receptor sulfenylation promotes glycogenolysis and rescues cancer chemoresistance.

Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.

The effects of rate pressure product at admission on cardiopulmonary function during hospitalization in patients with acute myocardial infarction.

OBJECTIVE: This study aimed to analyze the correlation between the rate pressure product (RPP) and cardiopulmonary function during hospitalization in patients with acute myocardial infarction (AMI). METHODS: A total of 362 patients with AMI were selected for the study, and the median admission RPP was used as the cutoff point to divide the patients into a low-RPP group (n = 181) and a high-RPP group (n = 181). The relationship between the RPP at admission and the cardiopulmonary function during hospitalization was analyzed. RESULTS: The patients in the high-RPP group had a higher body mass index (BMI) (p = 0.014), a higher prevalence of combined hypertension and diabetes mellitus (p < 0.001), a lower incidence of smoking (p = 0.044), and a higher incidence of oscillatory ventilation (6.1% vs. 1.7%, p = 0.029). The differences in RPP at rest, during warm-up, and within 1 and 4 minutes of recovery were statistically significant between the two groups (p < 0.01 on each occasion), while the differences in anaerobic threshold (AT) and watt max (Max) were not statistically significant (p > 0.05 for both). The patients in the low-RPP group had higher oxygen uptake (VO2 [AT]: 14.9 ± 3.4 vs. 14.2 ± 3.6, p = 0.048) and (VO2peak [Max]:18.2 ± 3.8 vs. 17.3 ± 3.8, p = 0.020). The RPP at admission was negatively correlated with VO2 (AT) and VO2peak (p < 0.05) using the regression Equation VO2peak = 33.682 + (-0.012 * RPP at admission/100) + (-0.105 * Age) + (-0.350 * BMI), while there was no correlation between the RPP at admission and VO2 (AT) (p = 0.149). CONCLUSION: The RPP at admission was negatively correlated with cardiopulmonary function during hospitalization in patients with AMI. Patients with a high RPP were more likely to have a combination of obesity, hypertension, diabetes mellitus, and reduced oxygen uptake during exercise, while a high RPP at admission appeared to affect their cardiovascular response indicators during exercise.

FHL1 promotes chikungunya and o'nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design.

Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1-/- mice, which when infected with CHIKV or o'nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1-/- and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease.

The Long-Term Effect of Maternal Iron Levels in the Second Trimester on Mild Thinness among Preschoolers: The Modifying Effect of Small for Gestational Age.

The supplementation of multiple micronutrients throughout pregnancy can reduce the risk of adverse birth outcomes and various diseases in children. However, the long-term effect of maternal multiple micronutrient levels in the second trimester on the overall development of preschoolers remains unknown. Therefore, 1017 singleton mother-infant pairs and 6-year-old preschoolers were recruited based on the China-Wuxi Birth Cohort Study. Meanwhile, information on the demographic characteristics of pregnant women and preschoolers, maternal copper, calcium, iron, magnesium, and zinc levels in whole blood during the second trimester, and neonatal outcomes, were collected. We aimed to investigate the long-term impact of maternal copper, calcium, iron, magnesium, and zinc levels in the second trimester on mild thinness among 6-year-old preschoolers, and the modifying effect of small for gestational age (SGA), within the Chinese population. Multiple logistic regression models revealed that high-level maternal iron in the second trimester reduced the risk of mild thinness [adjusted OR: 0.46 (95% CI: 0.26, 0.80)] among 6-year-old preschoolers. However, no significant association was found for the remaining four maternal essential metal elements. Additionally, the restricted cubic spline function showed that the risk of mild thinness decreased when maternal iron concentration exceeded 7.47 mmol/L in whole blood during the second trimester. Furthermore, subgroup analysis indicated that the long-term protective effect of high-level maternal iron on mild thinness was only observed in SGA infants. Summarily, high-level maternal iron in the second trimester distinctly lowers the risk of mild thinness among 6-year-old preschoolers, especially in preschoolers with birth outcomes of SGA. Our findings offer evidence for the implementation of iron supplementation in the second trimester as a preventive measure against mild thinness in children.

A novel low-temperature evaporation wastewater treatment apparatus based on hydrate adsorption.

Heavy metal pollution is an urgent challenge worldwide due to the acceleration of industrialization. While adsorption desalination is regarded as an innovative method for wastewater treatment, the current technologies have been impeded by high costs and intensive energy consumption. In this work, a novel low-temperature evaporation wastewater treatment apparatus based on hydrate adsorption was proposed. The water vapor from wastewater evaporation reacted with CO2 to form hydrate under the pressure of 3.3 MPa, constantly promoting wastewater evaporation due to the consumption of water vapor. The effect of feeding concentration on treatment effect was analyzed in terms of removal efficiency, water yield, and enrichment factor. Remarkably, a maximum removal efficiency of 97.4% can be achieved by treating an artificial solution with a Cu2+ concentration of 500 mg/L. Furthermore, compared with the control group that only depended on evaporation and condensation without forming hydrate, the maximum water yield of purified water in the experimental group increased to 310%. This innovative design concept for a low-temperature wastewater treatment apparatus based on hydrate adsorption presents a promising solution for the green and energy-efficient treatment of heavy metal wastewater.

Loss of Atg5 in Sertoli cells enhances the susceptibility of cadmium-impaired testicular spermatogenesis in mice.

Cadmium (Cd), one of the most common contaminants in diet and drinking water, impairs testicular germ cell development and spermatogenesis. Autophagy is essential for maintaining Sertoli cell function and Sertoli-germ cell communication. However, the role of Sertoli cell autophagy in Cd-caused spermatogenesis disorder remains unclear. Here, the mice of autophagy-related gene 5 (Atg5) knockouts in Sertoli cells were used to investigate the effect of autophagy deficiency on Cd-impaired spermatogenesis and its underlying mechanisms. Results showed that Sertoli cell-specific knockout of Atg5 exacerbated Cd-reduced sperm count and MVH (a specific marker for testicular germ cells) level in mice. Additionally, Sertoli cell Atg5 deficiency reduced the number of spermatocytes and decreased the level of meiosis-related proteins (SYCP3 and STRA8) in Cd-treated mouse testes. Loss of Atg5 in Sertoli cell exacerbated Cd-reduced the level of retinoic acid (RA) and retinal dehydrogenase (ALDH1A1 and ALDH1A) in mouse testes. Meanwhile, we found that the level of transcription factor WT1 was significantly downregulated in Atg5-/- plus Cd-treated testes. Further experiments showed that Wt1 overexpression restored Cd-decreased the levels of ALDH1A1 in Sertoli cells. Collectively, the above data suggest that knockout of Atg5 in Sertoli cell enhances the susceptibility of Cd-impaired testicular spermatogenesis. These findings provide new insights into autophagy of Sertoli cell preventing environmental toxicants-impaired testicular spermatogenesis.

Activation of AMPKα2 attenuated doxorubicin-induced cardiotoxicity via inhibiting lipid peroxidation associated ferroptosis.

Ferroptosis has been suggested to involve in doxorubicin (DOX)-induced cardiotoxicity. However, the underlying mechanisms and regulatory targets of cardiomyocyte ferroptosis remains to be understood. This study demonstrated that the up-regulation of ferroptosis associated proteins genes were accompanied with the down-regulation of AMPKα2 phosphorylation in DOX treated mouse heart or neonatal rat cardiomyocytes (NRCMs). AMPKα2 knockout (AMPKα2-/-) significantly exacerbated mouse cardiac dysfunction, increased mortality, promoting ferroptosis associated mitochondrial injuries, enhanced ferroptosis associated proteins and genes expression, and lead to accumulation of lactate dehydrogenase (LDH) and malondialdehyde (MDA) in mouse serum and hearts respectively. Ferrostatin-1 administration markedly improved cardiac function, decreased mortality, inhibited mitochondrial injuries and ferroptosis associated proteins and genes expression, and depressed accumulation of LDH and MDA in DOX treated AMPKα2-/- mouse. Moreover, Adeno-associated virus serotype 9 AMPKα2 (AAV9-AMPKα2) or AICAR treatment mediated AMPKα2 activation could significantly improve cardiac function and depress ferroptosis in mouse. AMPKα2 activation or silence could also inhibit or promote ferroptosis associated injuries in DOX treated NRCMs respecitively. Mechanistically, AMPKα2/ACC mediated lipid metabolism has been suggested to involve in regulating DOX-treatment induced ferroptosis other than mTORC1 or autophagy dependent pathway. The metabolomics analysis exhibited that AMPKα2-/- significantly enhanced accumulation of polyunsaturated fatty acids (PFAs), oxidized lipid, and phosphatidylethanolamine (PE). Finally, this study also demonstrated that metformin (MET) treatment could inhibit ferroptosis and improve cardiac function via activating AMPKα2 phosphorylation. The metabolomics analysis exhibited that MET treatment significantly depressed PFAs accumulation in DOX treated mouse hearts. Collectively, this study suggested that AMPKα2 activation might protect against anthracycline chemotherapeutic drugs mediated cardiotoxicity via inhibiting ferroptosis.

Enantio- and Diastereoselective Synthesis of Chiral Tetrasubstituted α-Amino Allenoates Bearing a Vicinal All-Carbon Quaternary Stereocenter with Dual-Copper-Catalysis.

The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are of importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions of 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording chiral tetrasubstituted α-amino allenoates bearing a vicinal all-carbon quaternary stereocenter in high yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to >20 : 1 dr). Importantly, the stereodivergent synthesis of the products was realized by the asymmetric γ-addition reaction and the Grignard reagent promoted epimerization. Moreover, the dual-copper-catalyzed γ-addition reactions were smoothly applied to a gram-scale reaction and adopted to introduce chiral tetrasubstituted allenyl moieties into bioactive molecules. Mechanistic experiments and density functional theory (DFT) calculations demonstrated that the asymmetric γ-addition reactions were catalyzed by double chiral copper catalysts.

Monolithic MXene Aerogels Encapsulated Phase Change Composites with Superior Photothermal Conversion and Storage Capability.

The inherently intermittent feature of solar energy requires reliable energy conversion and storage systems for utilizing the most abundant solar energy. Phase change materials are potential solutions to store a large amount of heat produced by solar light. However, few of the phase change materials have the ability to efficiently convert solar energy into heat; additionally, phase change materials need to be encapsulated in porous substrates for enhancing their leaking resistance and photo-to-thermal performance. In this work, monolithic MXene aerogels, fabricated by Al3+ cross-linking and freeze-drying, were used as the encapsulation and photothermal materials. The composites phase change materials of MXene/polyethylene glycol can be made with a large polyethylene glycol loading above 90 wt% with the maximum of 97 wt%, owing to the large porosity of MXene aerogels. The low content of MXene has a limited impact on the phase transition temperature and enthalpy of polyethylene glycol, with an enthalpy retention rate ranging from 89.2 to 96.5% for 90-97 wt% polyethylene glycol loadings. MXene aerogels greatly improve the leaking resistance of polyethylene glycol above its melting point of 60 °C, even at 100 °C. The composites phase change materials also show outstanding cycling stability for 500 cycles of heat storage and release, retaining 97.7% of the heat storage capability. The optimized composite phase change material has a solar energy utilization of 93.5%, being superior to most of the reported results. Our strategy produces promising composite phase change materials for solar energy utilization using the MXene aerogels as the encapsulation and photothermal materials.

Role of MXRA8 in Ross River Virus Disease Pathogenesis.

Arthritogenic alphaviruses such as Ross River virus (RRV) and Chikungunya virus (CHIKV) are responsible for large-scale epidemics that cause debilitating acute and chronic musculoskeletal diseases. MXRA8 was recently discovered as an entry receptor for multiple alphaviruses including CHIKV, RRV, Mayaro virus (MAYV), and O'nyong-nyong virus (ONNV). However, the role of MXRA8 in the development of alphavirus-induced musculoskeletal inflammation has not yet been fully studied. Here, we attempt to fully characterize the contribution of MXRA8 to RRV disease in an established mouse model. MXRA8 knockout (MXRA8-/-) mice generated on a C57BL/6J background, showed abrogated disease signs and reduced viral replication, which correlated with lower viral load, diminished proinflammatory cytokines, and limited cell infiltrates in inflamed tissues. Immunomodulation genes were upregulated to higher levels in RRV-infected wild-type (WT) mice than in MXRA8-/- mice. Intriguingly, Cdkn1a and Ifi44 genes in blood and CD127/IL7RA, CD45, BatF3, IFNGR, Ly6G/Ly6C, CD40, CD127, F4/80, and MHC-II genes in quadriceps were found to be upregulated in RRV-infected MXRA8-/- mice compared to WT mice. Our results showed an essential role of MXRA8 in the immune response of mice infected with RRV and, more importantly, demonstrated novel changes in immunomodulation genes, which shed light on the immunopathogenesis of alphavirus-induced disease. IMPORTANCE Previous studies have shown the importance of the cell surface protein MXRA8 as an entry receptor for several different prominent alphaviruses such as CHIKV, RRV, MAYV, and ONNV. In particular, the role of MXRA8 in the tissue tropism, viral pathogenesis, and immune response of a CHIKV mouse model have already been briefly characterized. However, the role of MXRA8 warrants further characterization in RRV disease background, since there are noticeable differences in the disease profile between CHIKV and RRV. For example, patients infected with CHIKV are usually affected by sudden onset of severe arthritis and fever, whereas RRV-infected patients generally only have minor joint pain and mild fever. Here, we characterized the role of MXRA8 in RRV disease and assessed several key mechanisms of MXRA8 that may contribute to the disease progression.