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Branched PFOA and PFOS have shorter half-lives, lower toxicity, and weaker serum protein binding than linear ones, offering better environmental and health safety. Yet methods to access such branched motifs remain under developed. We now introduce a one-step dehydroxy-perfluoro- tert -butylation of alcohols, in which perfluoro- tert -butyl phenyl sulfone serves both to activate the C–O bond and to deliver the perfluoro- tert -butyl group. Mechanistic studies—including DFT calculations—reveal that perfluoro- tert -butyl phenyl sulfone first generates perfluoroisobutylene in situ to effect C–O bond cleavage, after which a catalytic iodide engages in the C–C bond-forming event. Remarkably, the isolated perfluoro- tert -butyl anion salt, characterized by single-crystal X-ray diffraction, displays significant negative hyperconjugation, as evidenced by the elongated C–F bonds. This operationally simple protocol tolerates a wide array of functional groups and complex substrates, providing rapid access to branched perfluoroalkyl scaffolds with broad implications for drug discovery and advanced materials. Branched perfluorooctanoic acid and perfluorooctanesulfonic acid have shorter half-lives, lower toxicity, and weaker serum protein binding than linear ones, offering better environmental and health safety, but methods to access such branched motifs remain underdeveloped. Here, the authors introduce a one-step dehydroxy-perfluoro-tert-butylation of alcohols, in which perfluoro-tertbutyl phenyl sulfone serves both to activate the C–O bond and to deliver the perfluoro-tert-butyl group.

Bacterial lung infections cause severe host responses. Here, we showed that global deficiency of caspase-1 can protect against lethal pulmonary Escherichia coli infection by reducing the necroptosis of infiltrated neutrophils, which are key players in immune responses in the lung. Mechanistically, neutrophil necroptosis was not directly triggered in a cell-intrinsic manner by invading bacteria but was triggered by bacteria-stimulated pyroptotic epithelial cell supernatants in vitro . In validation experiments, chimeric mice with nonhematopoietic caspase-1 or GSDMD knockout were protected from lung E. coli infection and exhibited decreased neutrophil death. Nonhematopoietic pyroptosis facilitates the release of dsRNAs and contributes to neutrophil ZBP1-related necroptosis. Moreover, blocking dsRNA or depleting ZBP1 ameliorated the pathophysiological process of pulmonary E. coli infection. Overall, our results demonstrate a paradigm of communication between necroptosis and pyroptosis in different cell types in cooperation with microbes and hosts and suggest that therapeutic targeting of the pyroptosis or necroptosis pathway may prevent pulmonary bacterial infection.

Bloodstream bacterial infections cause one-third of deaths from bacterial infections, and eradication of circulating bacteria is essential to prevent disseminated infections. Here, we found that hepcidin, the master regulator of systemic iron homeostasis, affected Kupffer cell (KC) immune defense against bloodstream bacterial infections by modulating the gut commensal bacteria–derived tryptophan derivative indole-3-propionic acid (IPA). Hepcidin deficiency impaired bacterial capture by KCs and exacerbated systemic bacterial dissemination through morphological changes in KCs. Gut microbiota depletion and fecal microbiota transplantation revealed that the gut microbiota mediated the alteration of KCs volume. Mechanistically, hepcidin deficiency led to a decreased abundance of the IPA-producing commensal Lactobacillus intestinalis and a concomitant reduction in the gut-to-liver shuttling of its metabolite IPA. IPA supplementation or L . intestinalis colonization restored the KC volume and hepatic immune defense against bloodstream bacterial infection in hepcidin-deficient mice. Moreover, hepcidin levels in patients with bacteremia were associated with days of antibiotic usage and hospitalization. Collectively, our findings highlight a previously unappreciated role of hepcidin in sustaining KC-mediated hepatic defense against bloodstream bacterial infections through the gut commensal L . intestinalis and its tryptophan derivative IPA. More importantly, we show that restoring the crosstalk between the gut microbiota and liver through IPA-inspired therapies may offer a promising strategy for enhancing the host defense against bloodstream bacterial infections in those with low hepcidin levels and a high risk for bacterial infections.

Background and Objectives: Previous studies have reported there were associations between ovarian function and dietary factors, metabolic factors and gut microbiota. However, it is unclear whether causal associations exist. We aimed to explore the causal relationship of these factors with risk of primary ovarian failure (POF). Methods and Study Design: Two-sample Mendelian randomization (MR) analysis was performed to genetically predict the causal effects of dietary and metabolic factors and gut microbiota on POF. The inverse variance weighted (IVW) method was used as the primary statistical method. A series of sensitivity analyses, including weighted median, MR-Egger, simple mode, weighted mode methods, and leave-one-out analysis, were conducted to assess the robustness of the MR analysis results. Results: IVW analysis revealed that cigarettes smoked per day, coffee intake and cooked vegetable intake were not causally correlated with POF at the genetic level. However, POF were associated with fresh fruit intake, BMI, Eubacterium (hallii group), Eubacterium (ventriosum group), Adlercreutzia, Intestinibacter, Lachnospiraceae (UCG008), and Terrisporobacter. These findings were robust according to extensive sensitivity analyses. Conclusions: This study identified several dietary factors, metabolic factors and gut microbiota taxa that May be causally implicated in POF, potentially offering new therapeutic targets.

The system of inherent defect insurance is an important measure to serve the real economy through financial means and improve the quality of construction projects, which is the future development direction of China’s construction industry. However, the related research is not perfect due to the short implementation of the insurance. This could bring risks to the promotion of insurance for companies. Insurance ruin theory is an important method in risk management theory, so adopting it to manage the risk inherent defect insurance from the perspective of insurance companies is vital. The research starts with the classic insurance ruin theory and determines the coefficient of premium collection from the perspective of claim settlement distribution expectations. Furthermore, the approximate distribution of claim settlement is deduced, and a comprehensive risk assessment model is constructed. Finally, based on the data of insurance actuarial practice in Shanghai, both the ruin probability of inherent defect insurance in each insuring term and its average required initial reserve are calculated, which provides the analyses on the risks and main subitems of inherent defect insurance as well as relevant suggestions. Finally, the sensitivity analysis is used to further analyse the risk of different insurance stages of IDI, and the relevant measures are proposed. The research can provide theoretical assistances for insurance companies to carry out effective risk management and provide model tools to make scientific decisions.

China is striving to reach a peak in its carbon dioxide emissions by 2030 and achieve carbon neutrality by 2060. The accurate accounting of carbon emissions is important for achieving these dual carbon goals. An extensive literature review and field measurements were conducted to investigate the specific impact of population density on carbon emissions in large integrated healthcare organizations. This research uses VOSviewer to visualize the literature analysis. We determined that the flow of people is a key factor affecting carbon emissions during the operational phase of large-scale comprehensive medical institutions. Through field measurements, the relationship between the density of pedestrian flow and indoor environment measurements was derived, and the incremental equipment operating loads caused by changes in the indoor environment were analyzed. Using the carbon emission factor method advocated by the IPCC, a carbon emission accounting model based on different flow intervals was constructed, and the energy consumption of different equipment was fully considered according to its proportion. The validation results showed that the error between the calculated value and the actual values of the model was 3.07% (less than 5%), which has good validity. The model calculates the direct and indirect carbon emissions in the operational phase based on the population flow perspective, which can provide a reference for the energy-saving design and green operation of large-scale comprehensive medical institutions. The research will continue to focus on the population flow, and the accounting model will be further optimized through machine learning algorithms.

To assess the relationship of genetically predicted sexual behavior (age at first sex (AFS) and the number of sexual partners (NSP)) on cardiovascular diseases (CVDs). We performed two-sample Mendelian randomization (MR) with publicly available datasets from the UK Biobank and FinnGen Study, and analyzed genome-wide association results for sexual behaviors and twelve types of CVDs. The univariable MR method provided a total effect of AFS and NSP on CVDs, and showed evidence that early AFS rather than NSP was associated with CVDs, including angina pectoris (AP), atrial fibrillation and flutter (AFF), coronary atherosclerosis (CAS), deep vein thrombosis of the lower extremity (DVT-LE), heart failure (HF), hypertension (HTN), ischaemic stroke (IS), and myocardial infarction (MI). Given sex as a social determinant of CVD risk, we used gender-stratified SNPs to investigate gender differences in the development of CVDs. These results showed a stronger causal relationship of AFS on CVDs in females than in males. Further multivariable MR analyses indicated a direct effect after accounting for insomnia, number of days of vigorous physical activity 10 + minutes (VPA 10 + min), and time spent watching television (TV). Two-step MR demonstrated these three risk factors act as a mediator in AFS associated AP/HTN/HF. We provide evidence that early AFS increased the risk of CVDs. These associations may be partly caused by VPA 10 + min, insomnia, and the time spent on TV. The causality of AFS on CVDs in females was stronger than in males. Conversely, genetically predicted NSP was not associated with CVDs.

Since the world’s first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.

Branched PFOA and PFOS have shorter half-lives, lower toxicity, and weaker serum protein binding than linear ones, offering better environmental and health safety. Yet methods to access such branched motifs remain under developed. We now introduce a one-step dehydroxy-perfluoro-tert-butylation of alcohols, in which perfluoro-tert-butyl phenyl sulfone serves both to activate the C-O bond and to deliver the perfluoro-tert-butyl group. Mechanistic studies-including DFT calculations-reveal that perfluoro-tert-butyl phenyl sulfone first generates perfluoroisobutylene in situ to effect C-O bond cleavage, after which a catalytic iodide engages in the C-C bond-forming event. Remarkably, the isolated perfluoro-tert-butyl anion salt, characterized by single-crystal X-ray diffraction, displays significant negative hyperconjugation, as evidenced by the elongated C-F bonds. This operationally simple protocol tolerates a wide array of functional groups and complex substrates, providing rapid access to branched perfluoroalkyl scaffolds with broad implications for drug discovery and advanced materials.Branched PFOA and PFOS have shorter half-lives, lower toxicity, and weaker serum protein binding than linear ones, offering better environmental and health safety. Yet methods to access such branched motifs remain under developed. We now introduce a one-step dehydroxy-perfluoro-tert-butylation of alcohols, in which perfluoro-tert-butyl phenyl sulfone serves both to activate the C-O bond and to deliver the perfluoro-tert-butyl group. Mechanistic studies-including DFT calculations-reveal that perfluoro-tert-butyl phenyl sulfone first generates perfluoroisobutylene in situ to effect C-O bond cleavage, after which a catalytic iodide engages in the C-C bond-forming event. Remarkably, the isolated perfluoro-tert-butyl anion salt, characterized by single-crystal X-ray diffraction, displays significant negative hyperconjugation, as evidenced by the elongated C-F bonds. This operationally simple protocol tolerates a wide array of functional groups and complex substrates, providing rapid access to branched perfluoroalkyl scaffolds with broad implications for drug discovery and advanced materials.

The divergent reductive cross-coupling with an ambident electrophile is rare. Previously, we demonstrated a nickel-catalyzed reductive 2-pyridination of aryl iodides with difluoromethyl 2-pyridyl sulfone (2-PySO 2 CF 2 H) via selective C(sp 2 )–S bond cleavage of the sulfone by using a phosphine ligand. In this communication, we report a novel nickel-catalyzed reductive coupling of aryl iodides and 2-PySO 2 CF 2 H reagent, which constitutes a new method for aromatic difluoromethylation. The use of a tridentate terpyridine ligand is pivotal for the selective C(sp 3 )–S bond cleavage of the sulfone. This method employs readily available nickel catalyst and 2-PySO 2 CF 2 H as the difluoromethylation reagent, providing a facile access to difluoromethylarenes under mild reaction conditions without pre-generation of arylmetal reagents.