Trifluoromethylation Enables Compact 2D Linear Stacking and Improves the Efficiency and Stability of Q-PHJ Organic Solar Cells.

Compared to the bulk heterojunction (BHJ) devices, the quasiplanar heterojunction (Q-PHJ) exhibits a more stable morphology and superior charge transfer performance. To achieve both high efficiency and long-term stability, it is necessary to design new materials for Q-PHJ devices. In this study, QxIC-CF3 and QxIC-CH3 are designed and synthesized for the first time. The trifluoromethylation of the central core exerts a modulatory effect on the molecular stacking pattern, leveraging the strong electrostatic potential and intermolecular interactions. Compared with QxIC-CH3, the single crystal structure reveals that QxIC-CF3 exhibits a more compact 2D linear stacking behavior. These benefits, combined with the separated electron and hole transport channels in Q-PHJ device, lead to increased charge mobility and reduced energy loss. The devices based on D18/QxIC-CF3 exhibit an efficiency of 18.1%, which is the highest power conversion efficiency (PCE) for Q-PHJ to date. Additionally, the thermodynamic stability of the active layer morphology enhances the lifespan of the aforementioned devices under illumination conditions. Specifically, the T80 is 420 h, which is nearly twice that of the renowned Y6-based BHJ device (T80 = 220 h). By combining the advantages of the trifluoromethylation and Q-PHJ device, efficient and stable organic solar cell devices can be constructed.

Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling.

BACKGROUND: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified. METHODS: Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon. RESULTS: Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. CONCLUSIONS: Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.

The relationship between serum sodium concentration and albuminuria: a retrospective cohort study.

BACKGROUND: Lowering dietary salt intake reduces albuminuria, an early marker of renal damage and a sensitive predictor of adverse cardiovascular outcomes. The mechanisms underlying this effect are uncertain but small changes in serum sodium concentration may be important: this retrospective cohort study investigated the hypothesis that higher serum sodium concentration is a risk factor for albuminuria (defined as a urine albumin:creatinine ratio, or UACR, ≥ 3 mg/mmol). METHODS: Primary care data from the Royal College of General Practitioners Research and Surveillance Centre was used to identify 47,294 individuals with a UACR result available between April 2010 and March 2015, and no known albuminuria prior to this. Exclusion criteria were: missing or abnormal serum sodium concentration at baseline (< 135 or > 146 mmol/L); age < 18 years; diabetes mellitus; decompensated liver disease; heart failure; and stage 5 chronic kidney disease. RESULTS: After adjustment for known risk factors, there was a significant 'U-shaped' relationship between serum sodium concentration and albuminuria. The lowest risk was associated with a serum sodium of 138-140 mmol/L. In comparison, the risk of albuminuria was 18% higher with a serum sodium of 135-137 mmol/L and 19% higher with serum sodium of 144-146 mmol/L. There was no association between serum sodium concentration and blood pressure. CONCLUSION: The finding of a positive association between higher serum sodium concentration and albuminuria is in support of the hypothesis, but the inverse relationship between serum sodium concentration and albuminuria at lower concentrations warrants further explanation.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes.

BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

Emergency rescue of a patient with hemorrhagic shock caused by superior mesenteric artery rupture: A case report.

BACKGROUND: Superior mesenteric artery (SMA) injuries rarely occur during blunt abdominal injuries, with an incidence of < 1%. The clinical manifestations mainly include abdominal hemorrhage and peritoneal irritation, which progress rapidly and are easily misdiagnosed. Quick and accurate diagnosis and timely effective treatment are greatly significant in managing emergent cases. This report describes emergency rescue by a multidisciplinary team of a patient with hemorrhagic shock caused by SMA rupture. CASE SUMMARY: A 55-year-old man with hemorrhagic shock presented with SMA rupture. On admission, he showed extremely unstable vital signs and was unconscious with a laceration on his head, heart rate of 143 beats/min, shallow and fast breathing (frequency > 35 beats/min), and blood pressure as low as 20/10 mmHg (1 mmHg = 0.133 kPa). Computed tomography revealed abdominal and pelvic hematocele effusion, suggesting active bleeding. The patient was suspected of partial rupture of the distal SMA branch. The patient underwent emergency mesenteric artery ligation, scalp suture, and liver laceration closure. In view of conditions with acute onset, rapid progression, and high bleeding volume, key points of nursing were conducted, including activating emergency protocol, opening of the green channel, and arranging relevant examinations with various medical staff for quick diagnosis. The seamless collaboration of the multidisciplinary team helped shorten the preoperative preparation time. Emergency laparotomy exploration and mesenteric artery ligation were performed to mitigate hemorrhagic shock while establishing efficient venous accesses and closely monitoring the patient's condition to ensure hemodynamic stability. Strict measures were taken to avoid intraoperative hypothermia and infection. CONCLUSION: After 3.5 h of emergency rescue and medical care, bleeding was successfully controlled, and the patient's condition was stabilized. Subsequently, the patient was transferred to the intensive care unit for continuous monitoring and treatment. On the sixth day, the patient was weaned off the ventilator, extubated, and relocated to a specialized ward. Through diligent medical intervention and attentive nursing, the patient made a full recovery and was discharged on day 22. The follow-up visit confirmed the patient's successful recovery.

The efficacy of postoperative radiotherapy in resected pâ ¢A-N2 EGFR mutant and wild-type lung adenocarcinoma.

The resected pⅢA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild-type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1 months; p = 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p = 0.004). In EGFR wild-type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2 months; p = 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p = 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.

A pair of E3 ubiquitin ligases control immunity and flowering by targeting different ELF3 proteins in rice.

The ubiquitin-proteasome system (UPS) plays crucial roles in cellular processes including plant growth, development, and stress responses. In this study, we report that a pair of E3 ubiquitin ligases, AvrPiz-t-interaction protein 6 (APIP6) and IPA1-interaction protein 1 (IPI1), intricately target early flowering3 (ELF3) paralogous proteins to control rice immunity and flowering. APIP6 forms homo-oligomers or hetero-oligomers with IPI1. Both proteins interact with OsELF3-2, promoting its degradation to positively control resistance against the rice blast fungus (Magnaporthe oryzae). Intriguingly, overexpression of IPI1 in Nipponbare caused significantly late-flowering phenotypes similar to the oself3-1 mutant. Except for late flowering, oself3-1 enhances resistance against M. oryzae. IPI1 also interacts with and promotes the degradation of OsELF3-1, a paralog of OsELF3-2. Notably, IPI1 and APIP6 synergistically modulate OsELF3s degradation, finely tuning blast disease resistance by targeting OsELF3-2, while IPI1 controls both disease resistance and flowering by targeting OsELF3-1. This study unravels multiple functions for a pair of E3 ligases in rice.

Interpretable Machine Learning-Based Risk Score for Predicting Ten-Year Corneal Graft Survival After Penetrating Keratoplasty and Deep Anterior Lamellar Keratoplasty in Asian Eyes.

PURPOSE: To predict 10-year graft survival after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) using a machine learning (ML)-based interpretable risk score. METHODS: Singapore Corneal Transplant Registry patients (n = 1687) who underwent DALK (n = 524) or PK (n = 1163) for optical indications (excluding endothelial diseases) were followed up for 10 years. Variable importance scores from random survival forests were used to identify variables associated with graft survival. Parsimonious analysis using nested Cox models selected the top factors. An ML-based clinical score generator (AutoScore) converted identified variables into an interpretable risk score. Predictive performance was evaluated using Kaplan-Meier (KM) curves and time-integrated AUC (iAUC) on an independent testing set. RESULTS: Mean recipient age was 51.8 years, 54.1% were male, and majority were Chinese (60.0%). Surgical indications included corneal scar (46.5%), keratoconus (18.3%), and regraft (16.2%). Five-year and ten-year KM survival was 93.4% and 92.3% for DALK, compared with 67.6% and 56.6% for PK (log-rank P < 0.001). Five factors were identified by ML algorithm as predictors of 10-year graft survival: recipient sex, preoperative visual acuity, choice of procedure, surgical indication, and active inflammation. AutoScore stratified participants into low-risk and high-risk groups-with KM survival of 73.6% and 39.0%, respectively (log-rank P < 0.001). ML analysis outperformed traditional Cox regression in predicting graft survival beyond 5 years (iAUC 0.75 vs. 0.69). CONCLUSIONS: A combination of ML and traditional techniques identified factors associated with graft failure to derive a clinically interpretable risk score to stratify PK and DALK patients-a technique that may be replicated in other corneal transplant programs.

Additively-Manufactured Broadband Metamaterial-Based Luneburg Lens for Flexible Beam Scanning.

Multi-beam microwave antennas have attracted enormous attention owing to their wide range of applications in communication systems. Here, we propose a broadband metamaterial-based multi-beam Luneburg lens-antenna with low polarization sensitivity. The lens is constructed from additively manufactured spherical layers, where the effective permittivity of the constituting elements is obtained by adjusting the ratio of dielectric material to air. Flexible microstrip patch antennas operating at different frequencies are used as primary feeds illuminating the lens to validate the radiation features of the lens-antenna system. The proposed Luneburg lens-antenna achieves ±72° beam scanning angle over a broad frequency range spanning from 2 GHz to 8 GHz and presents a gain between 15.3 dBi and 22 dBi, suggesting potential applications in microwave- and millimeter-wave mobile communications, radar detection and remote sensing.

Confined Growth of Highly Ordered Metal Atomic Arrays for Seawater Oxidation.

Metal atom catalysts have been among the most important research objects due to their specific physical and chemical properties. However, precise control of the anchoring of metal atoms is still challenging to achieve. Cobalt and iridium atomic arrays formed sequentially ordered stable arrays in graphdiyne (GDY) triangular cavities depending on their intrinsic chemical properties and interactions. The success of this method was attributed to multifunctional integration of GDY, enabling selective growth from one to several atoms and various atomic densities. The bimetallic atom arrays show several advantages resulting from reducibility of acetylene bonds, space limiting effect, incomplete charge transfer between GDY and metal atoms, and sp-C hybridized triple bond skeleton. This well-designed system exhibits unprecedented oxygen evolution reaction (OER) performance with a mass activity of 2.6 A mgcat.-1 at a low overpotential of 300 mV, which is 216.6 times higher than the state-of-the-art IrO2 catalyst, and long-term stability.

A fluid-structure interaction simulation on the impact of transcatheter micro ventricular assist devices on aortic valves.

BACKGROUND AND OBJECTIVE: The implantation of ventricular assist devices (VADs) has become an important treatment option for patients with heart failure. Aortic valve insufficiency is a common complication caused by VADs implantation. Currently, there is very little quantitative research on the effects of transcatheter micro VADs or the intervention pumps on the aortic valves. METHODS: In this study, the multi-component arbitrary Lagrange-Eulerian method is used to perform fluid-structure interaction simulations of the aortic valve model with and without intervention pumps. The effects of intervention pumps implantation on the opening area of the aortic valves, the stress distribution, and the flow characteristics are quantitatively analyzed. Statistical results are consistent with clinical guidelines and experiments. RESULTS: The implantation of intervention pumps leads to the valve insufficiency and causes weak valve regurgitation. In the short-term treatment, the valve regurgitation is within a controllable range. The distribution and variation of stress on the leaflets are also affected by intervention pumps. The whirling flow in the flow direction affects the closing speed of the aortic valves and optimizes the stress distribution of the valves. In the models with whirling flow, the effects of intervention pumps implantation on valve motion and stress distribution differ from those without whirling flow. However, the valve insufficiency and valve regurgitation caused by intervention pumps still exist in the models with whirling flow. Conventional artificial bioprosthetic valves have limited effectiveness in treating the valve diseases caused by intervention pumps implantation. CONCLUSIONS: This study quantitatively investigates the impact of intervention pumps on the aortic valves, and investigates the effect of blood rotation on the valve behavior, which is a gap in previous research. We suggest that in the short-term treatment, the implantation of intervention pumps has limited impact on aortic valves, caution should be exercised against valve regurgitation issues caused by intervention pumps.

Polysaccharides from Artemisia argyi leaves: Environmentally friendly ultrasound-assisted extraction and antifatigue activities.

Artemisia argyi leaf polysaccharide (AALPs) were prepared through ultrasound-assisted extraction (UAE), and their antifatigue activities were evaluated. Extraction was optimized using response surface methodology (RSM), which yielded the following optimal UAE conditions: ultrasonication power of 300 W, extraction temperature of 51 °C, liquid:solid ratio of 20 mL/g, and ultrasonication time of 47 mins. The above optimal conditions resulted in the maximum extraction rate of 10.49 %. Compared with hot water extraction (HWE), UAE supported higher yields and total sugar, uronic acid, and sulfate contents of AALPs. Meanwhile, AALP prepared through UAE (AALP-U) exhibited higher stability due to its smaller particle size and higher absolute value of zeta potential than AALP prepared through HWE (AALP-H). In addition, AALP-U demonstrated stronger antioxidant activity than AALP-H. In forced swimming tests on mice, AALP-U could significantly prolong swimming time with a dose-dependent effect, increase liver and muscle glycogen levels, and improve other biochemical indices, thus showing great potential for application in functional food.

Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

Analysis of rotational grazing management for sheep in mixed grassland.

Sown mixed grassland is rarely used for livestock raising and grazing; however, different forages can provide various nutrients for livestock, which may be beneficial to animal health and welfare. We established a sown mixed grassland and adopted a rotational grazing system, monitored the changes in aboveground biomass and sheep weights during the summer grazing period, measured the nutrients of forage by near-infrared spectroscopy, tested the contents of medium- and long-chain fatty acids by gas chromatography, and explored an efficient sheep fattening system that is suitable for agro-pastoral interlacing areas. The results showed that the maximum forage supply in a single grazing paddock was 4.6 kg DM/d, the highest dry matter intake (DMI) was 1.80 kg DM/ewe/d, the average daily weight gain (ADG) was 193.3 g, the DMI and ADG were significantly correlated (P < 0.05), and the average feed weight gain ratio (F/G) reached 8.02. The average crude protein and metabolizable energy intake by sheep were 286 g/ewe/d and 18.5 MJ/ewe/d respectively, and the n-6/n-3 ratio of polyunsaturated fatty acids in mutton was 2.84. The results indicated that the sheep fattening system had high feed conversion efficiency, could improve the yield and quality of sheep, and could be promoted in suitable regions.

Effects of exposure to multiple metallic elements in the first trimester of pregnancy on the risk of preterm birth.

Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 µg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB.

Chlorinated Oligomers with Regulate Planarity Achieving Superior Photovoltaic Performance.

Chlorine substitution, as an effective and low-cost modification strategy, has been applied in the design of donor and acceptor structures in organic solar cells. We synthesized a series of chlorinated dimerized acceptors to investigate the effect of chlorine numbers and locations on the photovoltaic properties. The results show that the planarity and morphology of DYV-γ-2Cl are greatly improved due to the appropriate numbers and positions of the substituted chlorine atoms. Therefore, the device based on PM6:DYV-γ-2Cl achieves a superior power conversion efficiency (PCE) of 15.54% among the three oligomeric acceptors with optimized molecular planarity and film morphology. This work demonstrated the positive effect of suitable numbers and the substitution positions of chlorines on the molecular arrangement and photovoltaic properties of the corresponding dimerized acceptors.

Ciliary tip actin dynamics regulate photoreceptor outer segment integrity.

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a leading RP gene, regulates actin-binding protein activity central to this process. Actin dynamics, required for disc formation, are perturbed in Rpgr mouse models, leading to aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. Actin manipulation partially rescues this, suggesting the pathway could be targeted therapeutically. These findings help define how actin-mediated dynamics control outer segment turnover.

The rice E3 ubiquitin ligase-transcription factor module targets two trypsin inhibitors to enhance broad-spectrum disease resistance.

Broad-spectrum disease resistance (BSR) is crucial for controlling plant diseases and relies on immune signals that are subject to transcriptional and post-translational regulation. How plants integrate and coordinate these signals remains unclear. We show here that the rice really interesting new gene (RING)-type E3 ubiquitin ligase OsRING113 targets APIP5, a negative regulator of plant immunity and programmed cell death (PCD), for 26S proteasomal degradation. The osring113 mutants in Nipponbare exhibited decreased BSR, while the overexpressing OsRING113 plants showed enhanced BSR against Magnaporthe oryzae (M. oryzae) and Xanthomonas oryzae pv. oryzae (Xoo). Furthermore, APIP5 directly suppressed the transcription of the Bowman-Birk trypsin inhibitor genes OsBBTI5 and AvrPiz-t-interacting protein 4 (APIP4). Overexpression of these two genes, which are partially required for APIP5-mediated PCD and disease resistance, conferred BSR. OsBBTI5 and APIP4 associated with and stabilized the pathogenesis-related protein OsPR1aL, which promotes M. oryzae resistance. Our results identify an immune module with integrated and coordinated hierarchical regulations that confer BSR in plants.

Recently acquired HCV infection in men who have sex with men in Germany in the direct-acting antivirals era and during the COVID-19 pandemic.

INTRODUCTION: Direct-acting antivirals (DAAs) are key to eliminating hepatitis C virus (HCV). In men who have sex with men (MSM) with HIV co-infection, recently acquired HCV infection is common. Sexual practices and reinfection rates may hamper micro-elimination despite high treatment rates. METHODS: The cohort included MSM with recently acquired HCV infection from 2014 to 2021. The patients' demographic, clinical, behavioural, and laboratory data and treatment and reinfection outcomes were documented. RESULTS: A total of 237 men with recently acquired HCV infection were included: 216 (91%) had HIV. The median age was 46 years (interquartile range [IQR] 39-52), and the median CD4 count was 660/mm3 (IQR 527-835). The annual incidence of recently acquired HCV remained between 0.28% and 0.43% but dropped to 0.02% in 2021 during the COVID pandemic, almost reaching micro-elimination. The reinfection incidence was 15.5 per 100 patient-years (95% confidence interval 12.6-18.8), and reinfection was associated with the use of crystal methamphetamine (p = 0.032) and ketamine (p = 0.042). In total, 31.3% had multiple reinfections, and four reinfections occurred in users of pre-exposure prophylaxis. CONCLUSIONS: High treatment and cure rates did not lead to HCV elimination. A change in sexual behaviour, potentially imposed by COVID-19 restrictions, led to micro-elimination in the NoCo cohort. As recently acquired HCV is prevalent in MSM with and without HIV, surveillance is necessary to consolidate elimination goals.