Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery.

JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

Efficient synthesis of α-amino-vinylphosphine oxides from alkyl nitriles via manganese-catalyzed phosphinoenamination.

A protocol for the synthesis of α-amino-vinylphosphine oxides by phosphinoenamination reaction between alkyl nitriles and phosphine oxides was developed. The combination of Mn(OAc)2 as a Lewis acid and guanidine as a Lewis base was found to be an efficient catalytic system for this reaction. A series of alkyl nitriles and phosphine oxides are compatible with this conversion, furnishing the desired products in up to 95% yield under mild conditions. Furthermore, this method demonstrates the capability of gram-scale synthesis.

Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein.

The nucleocapsid protein (NP) plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life. Despite its vital role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assembly and host inflammatory response, it remains an unexplored target for drug development. In this study, we identified a small-molecule compound (ciclopirox) that promotes NP degradation using an FDA-approved library and a drug-screening cell model. Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation. Ciclopirox induced abnormal NP aggregation through indirect interaction, leading to the formation of condensates with higher viscosity and lower mobility. These condensates were subsequently degraded via the autophagy-lysosomal pathway, ultimately resulting in a shortened NP half-life and reduced NP expression. Our results suggest that NP is a potential drug target, and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer: A Single-Institution Study.

Objective: This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2 (HER2)-low early breast cancer (BC) and HER2-IHC0 BC. Methods: Patients diagnosed with HER2-negative BC ( N = 999) at our institution between January 2011 and December 2015 formed our study population. Clinicopathological characteristics, association between estrogen receptor (ER) expression and HER2-low, and evolution of HER2 immunohistochemical (IHC) score were assessed. Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes (5-year follow-up) between the HER2-IHC0 and HER2-low groups. Results: HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor (PgR) positivity than HER2-IHC0 BC group ( P < 0.001). The rate of HER2-low status increased with increasing ER expression levels (Mantel-Haenszel χ 2 test, P < 0.001, Pearson's R = 0.159, P < 0.001). Survival analysis revealed a significantly longer overall survival (OS) in HER2-low BC group than in HER2-IHC0 group ( P = 0.007) in the whole cohort and the hormone receptor (HR)-negative group. There were no significant differences between the two groups in terms of disease-free survival (DFS). The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. Conclusion: HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

OsNLP3 enhances grain weight and reduces grain chalkiness in rice.

Grain weight, a key determinant of yield in rice (Oryza sativa L.), is governed primarily by genetic factors, whereas grain chalkiness, a detriment to grain quality, is intertwined with environmental factors such as mineral nutrients. Nitrogen (N) is recognized for its impact on grain chalkiness, yet the underlying molecular mechanisms remain elusive. This study revealed the pivotal role of rice NODULE INCEPTION-LIKE PROTEIN 3 (OsNLP3) in simultaneously regulating grain weight and grain chalkiness. Our investigation showed that the loss of OsNLP3 leads to a reduction in both grain weight and dimension, in contrast to the enhancement observed with OsNLP3 overexpression. OsNLP3 directly suppresses the expression of OsCEP6.1 and OsNF-YA8, which were identified as negative regulators associated with grain weight. Consequently, two novel regulatory modules, OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8, were identified as key players in grain weight regulation. Notably, the OsNLP3-OsNF-YA8 module not only augments grain weight but also mitigates grain chalkiness in response to N. This research clarifies the molecular mechanisms orchestrating grain weight through the OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8 modules, underscoring the pivotal role of the OsNLP3-OsNF-YA8 module in alleviating grain chalkiness. These findings offer potential targets for concurrently enhancing rice yield and quality.

Positive Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Hypertension May Be Attenuated by Endogenous Sex Hormones: A Nationally Representative Cross-Sectional Study.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substance (PFAS) has endocrine-disrupting properties and may affect blood pressure. Endogenous hormones also play a crucial role in the progression of hypertension. However, their interaction with hypertension remains to be explored. METHODS: This study included 10 794 adults aged ≥18 years from the China National Human Biomonitoring program. Weighted multiple logistic regression and linear regression were used to examine the associations of serum PFAS with hypertension, diastolic blood pressure, and systolic blood pressure. Joint effects of PFAS mixtures on hypertension, diastolic blood pressure, and systolic blood pressure were evaluated using quantile-based g-computation. Additive and multiplicative interactions were used to assess the role of PFAS with testosterone and estradiol on hypertension. RESULTS: The prevalence of hypertension in Chinese adults was 35.50%. Comparing the fourth quartile with the first quartile, odds ratio (95% CI) of hypertension were 1.53 (1.13-2.09) for perfluorononanoic acid, 1.40 (1.03-1.91) for perfluorodecanoic acid, 1.34 (1.02-1.78) for perfluoroheptane sulfonic acid, and 1.46 (1.07-1.99) for perfluorooctane sulfonic acid. Moreover, PFAS mixtures, with perfluorononanoic acid contributing the most, were positively associated with hypertension, diastolic blood pressure, and systolic blood pressure. PFAS and endogenous hormones had an antagonistic interaction in hypertension. For example, the relative excess risk ratio, attributable proportion, and synergy index for perfluorononanoic acid and estradiol were -3.61 (-4.68 to -2.53), -1.65 (-2.59 to -0.71), and 0.25 (0.13-0.47), respectively. CONCLUSIONS: Perfluorononanoic acid, perfluorodecanoic acid, perfluoroheptane sulfonic acid, perfluorooctane sulfonic acid, and PFAS mixtures showed positive associations with hypertension, systolic blood pressure, and diastolic blood pressure. Positive associations of PFAS with hypertension might be attenuated by increased levels of endogenous sex hormones.

Understanding the Impact of Group 14 Elements on the Reactivity of [1 + 2] Cycloaddition Reaction between a Cyclic (Alkyl)(amino)carbene Analogue with a Group 14 Element and a Heavy Acetylene Molecule.

Computational exploration using the density functional theory framework (M06-2X-D3/def2-TZVP) was undertaken to investigate the [1 + 2] cycloaddition reaction between a five-membered-ring heterocyclic carbene analogue (G14-Rea; G14 = group 14 element) and a heavy acetylene molecule (G14G14-Rea). It was theoretically observed that exclusively Si-Rea, Ge-Rea, and Sn-Rea demonstrate the capacity to participate in the [1 + 2] cycloaddition reaction with the triply bonded SiSi-Rea. In addition, only three heavy acetylenes (SiSi-Rea, GeGe-Rea, and SnSn-Rea) can catalyze the [1 + 2] cycloaddition reaction with Si-Rea. Our theoretical findings elucidated that the reactivity trend observed in these [1 + 2] cycloaddition reactions primarily arise from the deformation energies of the distorted G14G14-Rea. Also, our study reveals that the bonding characteristics of their respective transition states are controlled by the singlet-singlet interaction (donor-acceptor interaction), rather than the triplet-triplet interaction (electron-sharing interaction). Additionally, our work demonstrates that the bonding behavior between G14-Rea and G14G14-Rea is predominantly determined by the filled p-π orbital of G14G14-Rea (HOMO) → the empty perpendicular p-π orbital of G14-Rea (LUMO), rather than the vacant p-π* orbital of G14G14-Rea (LUMO) ← the filled sp2 orbital of G14-Rea (HOMO).

Identification and validation of biomarkers in membranous nephropathy and pan-cancer analysis.

Background: Membranous nephropathy (MN) is an autoimmune disease and represents the most prevalent type of renal pathology in adult patients afflicted with nephrotic syndrome. Despite substantial evidence suggesting a possible link between MN and cancer, the precise underlying mechanisms remain elusive. Methods: In this study, we acquired and integrated two MN datasets (comprising a single-cell dataset and a bulk RNA-seq dataset) from the Gene Expression Omnibus database for differential expression gene (DEG) analysis, hub genes were obtained by LASSO and random forest algorithms, the diagnostic ability of hub genes was assessed using ROC curves, and the degree of immune cell infiltration was evaluated using the ssGSEA function. Concurrently, we gathered pan-cancer-related genes from the TCGA and GTEx databases, to analyze the expression, mutation status, drug sensitivity and prognosis of hub genes in pan-cancer. Results: We conducted intersections between the set of 318 senescence-related genes and the 366 DEGs, resulting in the identification of 13 senescence-related DEGs. Afterwards, we meticulously analyzed these genes using the LASSO and random forest algorithms, which ultimately led to the discovery of six hub genes through intersection (PIK3R1, CCND1, TERF2IP, SLC25A4, CAPN2, and TXN). ROC curves suggest that these hub genes have good recognition of MN. After performing correlation analysis, examining immune infiltration, and conducting a comprehensive pan-cancer investigation, we validated these six hub genes through immunohistochemical analysis using human renal biopsy tissues. The pan-cancer analysis notably accentuates the robust association between these hub genes and the prognoses of individuals afflicted by diverse cancer types, further underscoring the importance of mutations within these hub genes across various cancers. Conclusion: This evidence indicates that these genes could potentially play a pivotal role as a critical link connecting MN and cancer. As a result, they may hold promise as valuable targets for intervention in cases of both MN and cancer.

The relationship between unpredictability in childhood and depression among college students: the mediating roles of coping style and resilience.

BACKGROUND: According to previous studies, unpredictability in childhood could significantly increase the risk of depression in adulthood. Only a few studies have explored the relationship between these two variables in China. This paper aims to explore the relationship between unpredictability in childhood and depression and examine the mediating roles of coping styles and resilience. METHODS: We investigated 601 college students, who had an average age of 19.09 (SD = 2.78) years. Participants completed questionnaires regarding unpredictability in childhood, coping style, resilience, and depression. We analyzed survey data using the bias-corrected bootstrap method. RESULTS: The findings revealed a significant positive association between unpredictability in childhood and depression among college students. Mature coping style, immature coping style, and resilience were found to mediate this relationship independently. Furthermore, the study unveiled a serial mediation process, wherein both mature and immature coping styles, followed by resilience, sequentially mediate the relationship between unpredictability in childhood and depression, underscoring the complex interplay between these variables. CONCLUSIONS: The results indicated that the risk of depression among college students who have experienced unpredictable childhood should be valued. Attention to coping styles and resilience should be paid to decrease depression among college students who have experienced unpredictable childhood.

Rhizosphere microbial markers (micro-markers): A new physical examination indicator for traditional Chinese medicines.

Rhizosphere microorganisms, as one of the most important components of the soil microbiota and plant holobiont, play a key role in the medicinal plant-soil ecosystem, which are closely related to the growth, adaptability, nutrient absorption, stress tolerance and pathogen resistance of host plants. In recent years, with the wide application of molecular biology and omics technologies, the outcomes of rhizosphere microorganisms on the health, biomass production and secondary metabolite biosynthesis of medicinal plants have received extensive attention. However, whether or to what extent rhizosphere microorganisms can contribute to the construction of the quality evaluation system of Chinese medicinal materials is still elusive. Based on the significant role of rhizosphere microbes in the survival and quality formation of medicinal plants, this paper proposed a new concept of rhizosphere microbial markers (micro-markers), expounded the relevant research methods and ideas of applying the new concept, highlighted the importance of micro-markers in the quality evaluation and control system of traditional Chinese medicines (TCMs), and introduced the potential value in soil environmental assessment, plant pest control and quality assessment of TCMs. It provides reference for developing ecological planting of TCMs and ensuring the production of high quality TCMs by regulating rhizosphere microbial communities.

Characteristics and immune functions of the endogenous CRISPR-Cas systems in myxobacteria.

The clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR-Cas) system widely occurs in prokaryotic organisms to recognize and destruct genetic invaders. Systematic collation and characterization of endogenous CRISPR-Cas systems are conducive to our understanding and potential utilization of this natural genetic machinery. In this study, we screened 39 complete and 692 incomplete genomes of myxobacteria using a combined strategy to dispose of the abridged genome information and revealed at least 19 CRISPR-Cas subtypes, which were distributed with a taxonomic difference and often lost stochastically in intraspecies strains. The cas genes in each subtype were evolutionarily clustered but deeply separated, while most of the CRISPRs were divided into four types based on the motif characteristics of repeat sequences. The spacers recorded in myxobacterial CRISPRs were in high G+C content, matching lots of phages, tiny amounts of plasmids, and, surprisingly, massive organismic genomes. We experimentally demonstrated the immune and self-target immune activities of three endogenous systems in Myxococcus xanthus DK1622 against artificial genetic invaders and revealed the microhomology-mediated end-joining mechanism for the immunity-induced DNA repair but not homology-directed repair. The panoramic view and immune activities imply potential omnipotent immune functions and applications of the endogenous CRISPR-Cas machinery. IMPORTANCE: Serving as an adaptive immune system, clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR-Cas) empower prokaryotes to fend off the intrusion of external genetic materials. Myxobacteria are a collective of swarming Gram-stain-negative predatory bacteria distinguished by intricate multicellular social behavior. An in-depth analysis of their intrinsic CRISPR-Cas systems is beneficial for our understanding of the survival strategies employed by host cells within their environmental niches. Moreover, the experimental findings presented in this study not only suggest the robust immune functions of CRISPR-Cas in myxobacteria but also their potential applications.

Analysis of the 1-year efficacy of four different surgical methods for treating Chinese super obese (BMI ≥ 50 kg/m2) patients.

This study aimed to retrospectively analyze the perioperative and postoperative follow-up data of patients with super obesity who had undergone RYGB, SG, BPD/DS, and SADI-S. A retrospective observational study was conducted to analyze the perioperative and postoperative follow-up data of 60 patients with super obesity who had undergone bariatric surgery. A total of 34 men and 26 women were included in this study. The participants had an average preoperative BMI of 53.81 ± 3.25 kg/m2. The body weight and BMI of all four patient groups decreased significantly at 3, 6, and 12 months postoperatively compared with the preoperative values. Additionally, the TWL (%) and EWL (%) of all four groups increased gradually over the same period. Compared with the preoperative values, the systolic and diastolic blood pressure, glycosylated hemoglobin, uric acid, triglycerides, and total cholesterol decreased to varying degrees in the four groups 1 year postoperatively. RYGB, SG, BPD/DS, and SADI-S are all safe and effective in treating super obese patients and improving their metabolic diseases to a certain extent.

The mechanism of biofilm detachment in porous medium under flow field.

Biofilms are communities formed by bacteria adhering to surfaces, widely present in porous medium, and their growth can lead to clogging. Our experiment finds that under certain flow conditions, biofilms detach in pores and form a dynamically changing flow path. We define detachment that occurs far from the boundary of the flow path (with a distance greater than 200 µm) as internal detachment and detachment that occurs at the boundary of the flow path as external detachment. To understand the mechanism of biofilm detachment, we study the detachment behaviors of the Bacillus subtilis biofilm in a porous medium in a microfluidic device, where Bacillus subtilis strain is triple fluorescent labeled, which can represent three main phenotypes during the biofilm formation: motile cells, matrix-producing cells, and spores. We find that slow small-scale internal detachment occurs in regions with very few motile cells and matrix-producing cells, and bacterial movement in these areas is disordered. The increase in the number of matrix-producing cells induces clogging, and after clogging, the rapid detachment of the bulk internal biofilm occurs due to the increased pressure difference at the inlet and outlet. When both internal and external detachments occur simultaneously, the number of matrix-producing cells in the internal detachment area is 2.5 times that in the external detachment area. The results indicate that biofilm detachment occurs in areas with fewer matrix-producing cells, as matrix-producing cells can help resist detachment by secreting extracellular polymeric substances (EPSs).

Apparent Diffusion Coefficient on Diffusion-Weighted Magnetic Resonance Imaging to Predict the Prognosis of Patients with Endometrial Cancer: A Meta-Analysis.

Apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DWI) may help diagnose endometrial cancer (EC). However, the association between ADC and the recurrence and survival of EC remains unknown. We performed a systematic review and meta-analysis to investigate whether pretreatment ADC on DWI could predict the prognosis of women with EC. PubMed, Embase, and Cochrane's Library were searched for relevant cohort studies comparing the clinical outcomes between women with EC having low versus high ADC on pretreatment DWI. Two authors independently conducted data collection, literature searching, and statistical analysis. Using a heterogeneity-incorporating random-effects model, we analyzed the results. In the meta-analysis, 1358 women with EC were included from eight cohort studies and followed for a median duration of 40 months. Pooled results showed that a low pretreatment ADC on DWI was associated with poor disease-free survival (DFS, hazard ratio [HR]: 3.29, 95% CI: 2.04 to 5.31, p < 0.001; I2 = 41%). Subgroup analysis according to study design, tumor stage, MRI Tesla strength, ADC cutoff, follow-up duration, and study quality score showed consistent results (p for subgroup analysis all > 0.05). The predictive value of low ADC for poor DFS in women with EC decreased in multivariate studies compared to univariate studies (HR: 2.59 versus 32.57, p = 0.002). Further studies showed that a low ADC was also associated with poor overall survival (HR: 3.36, 95% CI: 1.33 to 8.50, p = 0.01, I2 = 0). In conclusion, a low ADC on pretreatment DWI examination may predict disease recurrence and survival in women with EC.

Polarization feature fusion and calculation of birefringence dynamics in complex anisotropic media.

As a complex anisotropic medium, variation in birefringence within biological tissues is closely associated with numerous physiological behaviors and phenomena. In this Letter, we propose a polarization feature fusion method and corresponding polarimetric parameters, which exhibit excellent performance of capturing the birefringence dynamic variation process in complex anisotropic media. By employing the feature fusion method, we combine and transform polarization basis parameters (PBPs) to derive fused polarization feature parameters (FPPs) with explicit expressions. Subsequently, we conduct Monte Carlo (MC) simulation to demonstrate the effectiveness of the proposed FPPs from two variation dimensions of birefringence direction θ and modulus Δn. Leveraging mathematical modeling and linear transformations, we investigate and abstract their response patterns concerning θ and Δn. Finally, the experiments confirm that the FPPs show superior adaptability and interpretability in characterizing the birefringence dynamic process of turbid media. The findings presented in this study provide new, to the best of our knowledge, methodological insights of information extraction for computational polarimetry in biomedical research.

Corporate social responsibility, political connections, and barrier industry diversification: Evidence from China.

In this paper, using the data of private sector enterprises listed in China from 2009 to 2014, we study the relationships between corporate social responsibility, political connections, and barrier industry diversification among Chinese public-listed private-sector enterprises. The empirical test results reveal that establishing political connections can contribute to diversification of these firms, while engaging in corporate social responsibility helps to promote their barrier industry diversification. More engagement in corporate social responsibility makes it easier for them to establish political connections and strengthen the association between political connections and barrier industry diversification. This study provides new empirical evidence for not only understanding the relationship between political connections of these firms and access to economic resources but also a new perspective regarding their conduct related to corporate social responsibility (CSR).

Comparison of the two histological subtypes of ampullary adenocarcinoma: a retrospective study.

OBJECTIVES: This study aimed to compare the intestinal and pancreatobiliary subtypes of ampullary adenocarcinoma in a large patient group due to limited data on survival and risk factors. METHODS: A retrospective analysis of the clinical and pathological findings and the survival of 184 patients with ampullary adenocarcinoma who underwent curative operation between 2007 and 2018 was performed. RESULTS: Pancreatobiliary subtype had a higher prevalence of jaundice before operation than the intestinal subtype (p < 0.05). Pancreatobiliary subtype had a larger tumor size (> 2 mm) (p < 0.01) and poorer differentiation (p < 0.05) than the intestinal subtype. Perineural invasion more frequently occurred in pancreatobiliary subtype than the intestinal subtype (p < 0.01) and pancreatobiliary subtype had a higher prevalence of positive dissected lymph nodes (p < 0.05) with an advanced disease stage (p < 0.01) than the intestinal subtype. Patients of the pancreatobiliary subtype had poorer disease-free and overall survival than patients of the intestinal subtype. No survival benefit of adjuvant chemotherapy was found in either patients of the intestinal subtype or pancreatobiliary subtype. No significant difference was found in any subtypes regarding the recurrent regions. CONCLUSIONS: Pancreatobiliary subtype exhibited a higher recurrence rate and a poorer overall survival rate with more unfavorable pathological characteristics than the intestinal subtype.

OBJETIVOS: Los datos sobre la supervivencia y los factores de riesgo del adenocarcinoma ampular son limitados debido a su rareza. Este estudio buscó comparar el subtipo intestinal y el subtipo pancreático-biliar en pacientes con adenocarcinoma ampular. MÉTODOS: Análisis retrospectivo de hallazgos clínicos y patológicos y la supervivencia de 184 pacientes con adenocarcinoma ampular tratados entre 2007 y 2018. RESULTADOS: El subtipo pancreático-biliar tuvo una mayor prevalencia de ictericia antes de la operación y un tamaño de tumor mayor, y una peor diferenciación, que el subtipo intestinal. La invasión perineural fue más frecuente en el subtipo pancreático-biliar, con una mayor prevalencia de linfonodos disecados positivos y un estadio avanzado de la enfermedad. Los pacientes del subtipo pancreático-biliar tuvieron una supervivencia libre de enfermedad y una supervivencia general peores que los pacientes del subtipo intestinal. No se encontró ningún beneficio de la quimioterapia adyuvante en pacientes del subtipo intestinal o pancreático-biliar. No hubo diferencia significativa en las regiones recurrentes. CONCLUSIÓN: El subtipo pancreático-biliar mostró una tasa de recurrencia y una tasa de supervivencia general peores, con características patológicas más desfavorables que el subtipo intestinal.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

Silylation and (Hetero)aryl/alkenylation of Unactivated Alkenes via Radical-Mediated Distal 1,4-Migration with Hydrosilanes under Organophotocatalysis.

We report a novel organic photoredox catalysis to achieve unprecedented γ-(hetero)aryl/alkenyl-δ-silyl aliphatic amines via silyl-mediated distal (hetero)aryl/alkenyl migration of aromatic/alkenyl amines bearing unactivated alkenes with hydrosilanes. This protocol features mild and metal-free reaction conditions, high atom economy, excellent selectivity, and functional group compatibility. Mechanistic studies suggest that silylation and (hetero)aryl/alkenylation involve photoredox hydrogen atom transfer catalysis and subsequent 1,4-migration of a remote (hetero)aryl/alkenyl group from nitrogen to carbon.

Stereoselective amino acid synthesis by photobiocatalytic oxidative coupling.

Photobiocatalysis-where light is used to expand the reactivity of an enzyme-has recently emerged as a powerful strategy to develop chemistries that are new to nature. These systems have shown potential in asymmetric radical reactions that have long eluded small-molecule catalysts1. So far, unnatural photobiocatalytic reactions are limited to overall reductive and redox-neutral processes2-9. Here we report photobiocatalytic asymmetric sp3-sp3 oxidative cross-coupling between organoboron reagents and amino acids. This reaction requires the cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts and an oxidizing agent. We repurpose a family of pyridoxal-5'-phosphate-dependent enzymes, threonine aldolases10-12, for the α-C-H functionalization of glycine and α-branched amino acid substrates by a radical mechanism, giving rise to a range of α-tri- and tetrasubstituted non-canonical amino acids 13-15 possessing up to two contiguous stereocentres. Directed evolution of pyridoxal radical enzymes allowed primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, to be coupled in an enantio- and diastereocontrolled fashion. Cooperative photoredox-pyridoxal biocatalysis provides a platform for sp3-sp3 oxidative coupling16, permitting the stereoselective, intermolecular free-radical transformations that are unknown to chemistry or biology.