GDPF: a data resource for the distribution of prokaryotic protein families across the global biosphere.

Microorganisms encode most of the functions of life on Earth. However, conventional research has primarily focused on specific environments such as humans, soil and oceans, leaving the distribution of functional families throughout the global biosphere poorly comprehended. Here, we present the database of the global distribution of prokaryotic protein families (GDPF, http://bioinfo.qd.sdu.edu.cn/GDPF/), a data resource on the distribution of functional families across the global biosphere. GDPF provides global distribution information for 36 334 protein families, 19 734 superfamilies and 12 089 KEGG (Kyoto Encyclopedia of Genes and Genomes) orthologs from multiple source databases, covering typical environments such as soil, oceans, animals, plants and sediments. Users can browse, search and download the distribution data of each entry in 10 000 global microbial communities, as well as conduct comparative analysis of distribution disparities among multiple entries across various environments. The GDPF data resource contributes to uncovering the geographical distribution patterns, key influencing factors and macroecological principles of microbial functions at a global level, thereby promoting research in Earth ecology and human health.

PAT: a comprehensive database of prokaryotic antimicrobial toxins.

Antimicrobial toxins help prokaryotes win competitive advantages in intraspecific or interspecific conflicts and are also a critical factor affecting the pathogenicity of many pathogens that threaten human health. Although many studies have revealed that antagonism based on antimicrobial toxins plays a central role in prokaryotic life, a database on antimicrobial toxins remains lacking. Here, we present the prokaryotic antimicrobial toxin database (PAT, http://bioinfo.qd.sdu.edu.cn/PAT/), a comprehensive data resource collection on experimentally validated antimicrobial toxins. PAT has organized information, derived from the reported literature, on antimicrobial toxins, as well as the corresponding immunity proteins, delivery mechanisms, toxin activities, structural characteristics, sequences, etc. Moreover, we also predict potential antimicrobial toxins in prokaryotic reference genomes and show the taxonomic information and environmental distribution of typical antimicrobial toxins. These details have been fully incorporated into the PAT database, where users can browse, search, download, analyse and view informative statistics and detailed information. PAT resources have already been used in our prediction and identification of prokaryotic antimicrobial toxins and may contribute to promoting the efficient investigation of antimicrobial toxin functions, the discovery of novel antimicrobial toxins, and an improved understanding of the biological roles and significance of these toxins.

Neoadjuvant camrelizumab plus apatinib for locally advanced microsatellite instability-high or mismatch repair-deficient colorectal cancer (NEOCAP): a single-arm, open-label, phase 2 study.

BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Single-cell transcriptome analysis of the mouse lungs during the injury and recovery periods after lipopolysaccharide administration.

OBJECTIVE: This study sought to investigate the cellular and molecular alterations during the injury and recovery periods of ALI and develop effective treatments for ALI. METHODS: Pulmonary histology at 1, 3, 6, and 9 days after lipopolysaccharide administration mice were assessed. An unbiased single-cell RNA sequencing was performed in alveoli tissues from injury (day 3) and recovery (day 6) mice after lipopolysaccharide administration. The roles of Fpr2 and Dpp4 in ALI were assessed. RESULTS: The most severe lung injury occurred on day 3, followed by recovery entirely on day 9 after lipopolysaccharide administration. The numbers of Il1a+ neutrophils, monocytes/macrophages, and Cd4+ and Cd8+ T cells significantly increased at day 3 after LPS administration; subsequently, the number of Il1a+ neutrophils greatly decreased, the numbers of monocytes/macrophages and Cd4+ and Cd8+ T cells continuously increased, and the number of resident alveolar macrophages significantly increased at day 6. The interactions between monocytes/macrophages and pneumocytes during the injury period were enhanced by the Cxcl10/Dpp4 pair, and inhibiting Dpp4 improved ALI significantly, while inhibiting Fpr2 did not. CONCLUSIONS: Our results offer valuable insights into the cellular and molecular mechanisms underlying its progression and identify Dpp4 as an effective therapeutic target for ALI.

Prognostic analysis of rectal cancer patients after neoadjuvant chemoradiotherapy: different prognostic factors in patients with different TRGs.

PURPOSE: The extent of tumor regression varies widely among locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME). The purpose of this retrospectively study is to assess prognostic factors in LARC patients with NCRT, and further to analyze survival outcomes in patients with different tumor regression grades (TRGs). METHODS: This study includes LARC patients who underwent NCRT and TME at our institution. We retrospectively analyzed the clinicopathological characteristics and survival of all patients, and performed subgroup analysis for patients with different TRGs. Survival differences were compared using the Kaplan-Meier method and the log rank test. Additionally, a multiple Cox proportional hazard model was used to identify independent prognostic factors. RESULTS: The study included 393 patients, with 21.1%, 26.5%, 45.5%, and 6.9% achieving TRG 0, TRG 1, TRG 2, and TRG 3, respectively. The overall survival (OS) rate and disease-free survival (DFS) rate for all patients were 89.4% and 70.7%, respectively. Patients who achieved TRG 0-3 had different 5-year OS rates (96.9%, 91.1%, 85.2%, and 68.8%, P = 0.001) and 5-year DFS rates (80.8%, 72.4%, 67.0%, 55.8%, P = 0.031), respectively. Multivariate analyses showed that the neoadjuvant rectal (NAR) score was an independent prognostic indicator for both overall survival (OS) (HR = 4.040, 95% CI = 1.792-9.111, P = 0.001) and disease-free survival (DFS) (HR = 1.971, 95% CI = 1.478-2.628, P ˂ 0.001). In the subgroup analyses, the NAR score was found to be associated with DFS in patients with TRG 1 and TRG 2. After conducting multivariate analysis, it was found that ypT stage was a significant predictor of DFS for TRG 1 patients (HR = 4.384, 95% CI = 1.721-11.168, P = 0.002). On the other hand, ypN stage was identified as the dominant prognostic indicator of DFS for TRG 2 patients (HR = 2.795, 95% CI = 1.535-5.091, P = 0.001). However, none of these characteristics was found to be correlated with survival in patients with TRG 0 or TRG 3. CONCLUSION: NAR score, in particular, appears to be the most powerful prognostic factor. It is important to consider various prognostic predictors for patients with different TRGs.

Role of small nucleolar RNAs in alternative splicing of the doublesex gene in the silkworm, Bombyx mori.

More and more evidence shows that small noncoding RNAs (ncRNAs) play diverse roles in development, stress response and other cellular processes, but functional study of intermediate-size ncRNAs is still rare. Here, the expression profile of 16 intermediate-size ncRNAs in ovary and testis of silkworm Bombyx mori were analyzed. Twelve ncRNAs, including 5 small nucleolar RNAs (snoRNAs) and 7 unclassified ncRNAs, accumulated more in the testis than in the ovary of silkworm, especially Bm-163, Bm-51 and Bm-68. Four ncRNAs (including three orphan snoRNAs and one unclassified ncRNA) had higher expression level in the ovary than in the testis, especially Bm-86. Overexpression of the testis-enriched snoRNA Bm-68 in the female led to the accumulation of male-specific isoform of doublesex (BmdsxM) and increased the expression ratio of BmdsxM: BmdsxF. While overexpression of ovary-enriched snoRNA Bm-86 in the male decreased the expression ratio of BmdsxM: BmdsxF, indicating the roles of the two snoRNAs played in the alternative splicing of Bmdsx of silkworm, which will provide new clues for the functional study of snoRNAs in insects.

[Effect of Shoutai Pills on expression of key glycolytic proteins and apoptosis related factors at maternal fetal interface in mouse model of threatened abortion with syndrome of kidney deficiency].

This study aims to explore the mechanism of Shoutai Pills in treating threatened abortion. According to the random number table method, ICR female mice were randomized into a normal group, a model group, a dydrogesterone group, and a Shoutai Pills group, with 15 mice in each group. Mice were administrated with normal saline(normal and model groups) or the suspension of Shoutai Pills or dydrogesterone by gavage at 9:00 am every day. At 16:00 every day, mice in the normal group were administrated with an equal volume of distilled water, while those in the model, Shoutai Pills, and dydrogesterone groups were administrated with hydrocortisone solution by gavage for 4 consecutive days. ICR female and male mice were caged in a ratio of 2∶1 during the pre-estrous or estrous period. From the first day of pregnancy, drug administration was continued for 5 consecutive days. On day 6, mice were administrated with mifepristone by gavage to establish the model of kidney deficiency-induced abortion. On day 6 of pregnancy, 10 female ICR mice were randomly selected from each group, and the uterus was collected for observation of the pathological changes of trophoblasts at the maternal-fetal interface by hematoxylin-eosin(HE) staining. The protein levels of key enzymes of glycolysis, hexokinase 2(HK2), enolase 1(ENO1), pyruvate kinase M2(PKM2), and lactate dehydrogenase A(LDHA), were determined by Western blot and immunofluorescence. The expression of apoptosis-related proteins including B cell lymphoma-2(Bcl-2), Bcl-2-associated protein X(Bax), and cysteinyl aspartate-specific proteinase-3(caspase-3) was determined by Western blot and real-time PCR. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling was employed to examine apoptosis. The embryo loss rate of the remaining five female mice was calculated by trypan blue staining method on day 14 of pregnancy. On day 14 of pregnancy, the embryo loss rate of the normal group was 5.00%, which was lower than that(27.78%) in the model group(P<0.05). Dydrogesterone and Shoutai Pills groups showed reduced embryo loss rates(10.26% and 7.50%, respectively) compared with the model group. On day 6 of pregnancy, compared with the normal group, the model group showed down-regulated expression of HK2, ENO1, PKM2, LDHA, and Bcl-2 and up-regulated expression of Bax and caspase-3(P<0.05). Compared with the model group, dydrogesterone and Shoutai Pills up-regulated the expression of HK2, ENO1, PKM2, LDHA, and Bcl-2 and down-regulated the expression of Bax and caspase-3(P<0.05). Compared with that in the normal group, the apoptosis rate in the model group increased(P<0.05). Compared with the model group, dydrogesterone and Shoutai Pills reduced the apoptosis rate(P<0.05). In conclusion, Shoutai Pills can reduce the embryo loss rate and protect embryos by promoting aerobic glycolysis at the maternal-fetal interface and inhibiting the apoptosis of trophoblasts in mice.

Estimate of the degradation potentials of cellulose, xylan, and chitin across global prokaryotic communities.

Complex polysaccharides (e.g. cellulose, xylan, and chitin), the most abundant renewable biomass resources available on Earth, are mainly degraded by microorganisms in nature. However, little is known about the global distribution of the enzymes and microorganisms responsible for the degradation of cellulose, xylan, and chitin in natural environments. Through large-scale alignments between the sequences released by the Earth Microbiome Project and sequenced prokaryotic genomes, we determined that almost all prokaryotic communities have the functional potentials to degrade cellulose, xylan, and chitin. The median abundances of genes encoding putative cellulases, xylanases, and chitinases in global prokaryotic communities are 0.51 (0.17-1.01), 0.24 (0.05-0.57), and 0.33 (0.11-0.71) genes/cell, respectively, and the composition and abundance of these enzyme systems are environmentally varied. The taxonomic sources of the three enzymes are highly diverse within prokaryotic communities, and the main factor influencing the diversity is the community's alpha diversity index rather than gene abundance. Moreover, there are obvious differences in taxonomic sources among different communities, and most genera with degradation potentials are narrowly distributed. In conclusion, our analysis preliminarily depicts a panorama of cellulose-, xylan-, and chitin-degrading enzymatic systems across global prokaryotic communities.

Efficacy of granulocyte colony-stimulating factor for infertility undergoing IVF: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) for infertility and recurrent spontaneous abortion. METHODS: Existing research was searched in PubMed, Embase and Cochrane Library till Dec 2021. Randomized control trials (RCTs) that compared G-CSF administration with the control group in infertility women undergoing IVF were included. The primary outcomes included clinical pregnancy rate; the secondary outcomes included live birth rate, abortion ratebiochemical pregnancy rate, embryo implantation rate, as well as endometrial thickness. RESULT(S): 20 RCTs were included in this study. G-CSF increased the clinical pregnancy rate (RR = 1.85; 95% CI: 1.07, 3.18) and the endometrial thickness (MD = 2.25; 95% CI: 1.58,2.92;) in patients with thin endometrium undergoing IVF. G-CSF increased the biochemical pregnancy rate (RR = 2.12; 95% CI: 1.54, 2.93), the embryo implantation rate (RR = 2.51; 95% CI: 1.82, 3.47) and the clinical pregnancy rate (RR = 1.93; 95% CI: 1.63, 2.29) in patients with a history of repeated implantation failure undergoing IVF. No differences were found in pregnancy outcomes of general IVF patients. CONCLUSIONS: Granulocyte colony-stimulating factor is likely to be a potential option for infertility women undergoing IVF with thin endometrium or recurrent implantation failure . TRIAL REGISTRATION: Retrospectively registered (The PROSPERO registration number: CRD42022360161).

Molecular Insights into Curvature Effects on the Capacitance of Electrical Double Layers in Tricationic Ionic Liquids with Carbon Nanotube Electrodes.

Ionic liquid (IL) electrolytes and carbon nanotube (CNT) electrodes have exhibited promising electrochemical performance in supercapacitors. Nevertheless, the adaptability of tricationic ILs (TILs) in CNT-based supercapacitors remains unknown. Herein, the performance of supercapacitors with (6,6), (8,8), (12,12), and (15,15) CNT electrodes in the TIL [C6(mim)3](Tf2N)3 was assessed via molecular dynamics simulations, paying attention to the electric double-layer (EDL) structures and the relations between the CNT curvature and capacitance. The results disclose that counterion and co-ion number densities near CNT electrodes have a marked reduction, compared with that of the graphene electrode. The capacitance of the EDL in the TIL increases significantly as the CNT curvature increases and the capacitance of the TIL/CNT systems is higher than that of the TIL/graphene system. Moreover, different EDL structures in the TIL and the monocationic IL (MIL) [C6mim][Tf2N] near CNT electrodes were revealed, showing higher-concentration anions [Tf2N]- at the CNT surfaces in the TIL. It is also verified that the TIL has a greater energy-storage ability under high potentials. Furthermore, the almost flat or weakly camel-like capacitance-voltage (C-V) curve of EDLs in the TIL turns into a bell shape in the MIL, because of the ion accumulation at the CNT surfaces and the associations between ions.

Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair-Deficient Colorectal Cancer.

BACKGROUND: Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti-PD-1 treatment for localized mismatch repair-deficient (dMMR) colorectal cancer (CRC). PATIENTS AND METHODS: The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. RESULTS: A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2-3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4-45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3-4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. CONCLUSIONS: Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.

Neoadjuvant Immune Checkpoint Inhibition Improves Organ Preservation in T4bM0 Colorectal Cancer With Mismatch Repair Deficiency: A Retrospective Observational Study.

BACKGROUND: Colorectal cancer with mismatch repair deficiency is usually less aggressive and associated with a lower risk of distant metastasis. Immune checkpoint inhibition, rather than traditional chemoradiotherapy, has shown great advantages in treating such patients. OBJECTIVE: This study aimed to verify the hypothesis that locally very advanced (T4b) colorectal cancer without distant metastases might present with higher probability of mismatch repair deficiency and be more sensitive to neoadjuvant immune checkpoint inhibition. DESIGN: This study was designed as a single-center retrospective observational study. SETTINGS: The study was conducted in a tertiary referral center in China. PATIENTS: The study included patients who were clinically diagnosed with T4bM0 colorectal cancer from 2008 to 2019. MAIN OUTCOME MEASURES: Clinicopathological characteristics, mismatch repair status, and survival outcomes of patients with mismatch repair deficiency were analyzed. RESULTS: A total of 268 patients were included. The incidence of patients with mismatch repair deficiency in the T4bM0 population was 27.6% (75/268), with 84.0% (63/75) in the colon and 16.0% (12/75) in the rectum. For tumors located in the proximal colon, 45.0% (50/111) exhibited mismatch repair deficiency, whereas the incidence of mismatch repair deficiency in sigmoid colon cancer and rectal cancer was only 15.9% (25/157). Neoadjuvant immune checkpoint inhibition significantly reduced the open surgery rate ( p = 0.000) and multivisceral resection rate ( p = 0.025). The pathological complete remission rate in the neoadjuvant immune checkpoint inhibition group was significantly higher than that in neoadjuvant chemoradiotherapy/chemotherapy group (70.0% vs 0%; p = 0.004). No tumor downstaging was observed after neoadjuvant chemotherapy. Neoadjuvant immune checkpoint inhibition provided significantly better disease-free survival ( p = 0.0078) and relatively longer overall survival ( p = 0.15) than other groups. LIMITATIONS: This study is limited by the possible selection bias and small sample size. CONCLUSIONS: Our data depicted the high incidence of mismatch repair deficiency in T4bM0 mismatch repair deficiency and the effectiveness of the neoadjuvant immune checkpoint inhibition group in organ preservation. Precision oncology requires identification of the protein status of mismatch repair at initial diagnosis to make a rational treatment decision for these patients. See Video Abstract at http://links.lww.com/DCR/B952 . LA INHIBICIN DEL PUNTO DE CONTROL INMUNITARIO NEOADYUVANTE MEJORA LA PRESERVACIN DE RGANOS EN EL CNCER COLORRECTAL TBM CON DEFICIENCIA DE REPARACIN DE ERRORES DE COINCIDENCIA UN ESTUDIO OBSERVACIONAL RETROSPECTIVO: ANTECEDENTES:Los pacientes con cáncer colorrectal con deficiencia en la reparación de desajustes suelen (dMMR) ser menos agresivos y se asocian con un menor riesgo de metástasis a distancia. La inhibición del punto de control inmunitario, en lugar de la quimiorradioterapia tradicional, ha mostrado grandes ventajas en el tratamiento de estos pacientes.OBJETIVO:Este estudio tuvo como objetivo verificar nuestra hipótesis de que el CCR localmente muy avanzado (T4b) sin metástasis a distancia podría presentarse con una mayor probabilidad de dMMR y ser más sensible a la inhibición del punto de control inmunitario neoadyuvante.DISEÑO:Este estudio fue diseñado como un estudio observacional retrospectivo de un solo centro.CONFIGURACIÓN:El estudio se realizó en un centro de referencia terciario en China.PACIENTES:Se incluyeron pacientes con diagnóstico clínico de CCR T4bM0 desde 2008 hasta 2019.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron las características clinicopatológicas, el estado de MMR y los resultados de supervivencia de los pacientes con dMMR.RESULTADOS:Se incluyeron un total de 268 pacientes. La incidencia de dMMR en la población T4bM0 fue del 27,6% (75/268), con un 84,0% (63/75) en colon y un 16,0% (12/75) en recto. Para los tumores ubicados en el colon proximal, el 45,0% (50/111) exhibió dMMR, mientras que la incidencia de dMMR en el cáncer de colon sigmoideo y el cáncer de recto fue solo del 15,9% (25/157). La inhibición del punto de control inmunitario neoadyuvante redujo significativamente la cirugía abierta y la tasa de resección multivisceral ( p = 0,000 y p = 0,025, respectivamente). La tasa de PCR en el grupo de inhibición del punto de control inmunitario neoadyuvante fue significativamente mayor que en el grupo de quimiorradioterapia/quimioterapia neoadyuvante (70,0% frente a 0%, p = 0,004). No se observó reducción del estadio del tumor después de la quimioterapia neoadyuvante. La inhibición del punto de control inmunitario neoadyuvante proporcionó una supervivencia sin enfermedad significativamente mejor ( p = 0,0078) y una supervivencia general relativamente más larga ( p = 0,15) que otros grupos.LIMITACIONES:Este estudio está limitado por el posible sesgo de selección y el pequeño tamaño de la muestra.CONCLUSIONES:Nuestros datos representan la alta incidencia de dMMR en T4bM0 CRC y la eficacia del grupo de inhibición del punto de control inmunitario neoadyuvante en la preservación de órganos. La oncología de precisión requiere la identificación del estado de la proteína MMR en el diagnóstico inicial para tomar una decisión de tratamiento racional para estos pacientes especiales. Consulte el Video Resumen en http://links.lww.com/DCR/B952 . (Traducción-Dr. Yesenia Rojas-Khalil ).

Effect of environmental level of methomyl on hatching, morphology, immunity and development related genes expression in zebrafish (Danio rerio) embryo.

The extensive use of carbamate pesticides has led to a range of environmental and health problems, such as surface and groundwater contamination, and endocrine disorders in organisms. In this study, we focused on examining the effects of toxic exposure to the carbamate pesticide methomyl on the hatching, morphology, immunity and developmental gene expression levels in zebrafish embryos. Four concentrations of methomyl (0, 2, 20, and 200 µg/L) were administered to zebrafish embryos for a period of 96 h. The study found that exposure to methomyl accelerated the hatching process of zebrafish embryos, with the strongest effect recorded at the concentration of 2 µg/L. Methomyl exposure also trigged significantly reductions in heart rate and caused abnormalities in larvae morphology, and it also stimulated the synthesis and release of several inflammatory factors such as IL-1ß, IL-6, TNF-α and INF-α, lowered the IgM contents, ultimately enhancing inflammatory response and interfering with immune function. All of these showed the significant effects on exposure time, concentration and their interaction (Time × Concentration). Furthermore, the body length of zebrafish exposed to methomyl for 96 h was significantly shorter, particularly at higher concentrations (200 µg/L). Methomyl also affected the expression levels of genes associated with development (down-regulated igf1, bmp2b, vasa, dazl and piwi genes), demonstrating strong developmental toxicity and disruption of the endocrine system, with the most observed at the concentration of 200 µg/L and 96 h exposure to methomyl. The results of this study provide valuable reference information on the potential damage of methomyl concentrations in the environment on fish embryo development, while also supplementing present research on the immunotoxicity of methomyl.

Peroxisome Proliferator Activated Receptor-γ Agonistic Compounds from the Jellyfish-Derived Fungus Cladosporium oxysporum.

In our search for peroxisome proliferator-activated receptor (PPAR) agonists, five undescribed compounds, namely two acyclic diterpenes (1 and 2; cladopsol A and cladopsol B), two sesquiterpenes (3 and 4; cladopsol C and cladopsol D), and one C21-ecdysteroid (5; cladopsol E), and 15 known compounds were isolated from the jellyfish-derived fungus - Cladosporium oxysporum. The structures of the undescribed compounds were defined using UV, NMR, HR-ESI-MS, and electronic circular dichroism (ECD) spectroscopy and a modified Mosher's method. Luciferase reporter assay and docking analysis suggested that cladopsol B may function as a PPAR-γ partial agonist with a potential antidiabetic lead which may evade the side effects of full agonists. Moreover, cladopsol B stimulated glucose uptake in HepG2 cells with an efficacy comparable to that of rosiglitazone, but with less side effect induced by lipid accumulation in 3T3-L1 cells. Therefore, cladopsol B could serve as a molecular skeleton in a study of advanced antidiabetic lead with less side effect.

Cytochrome P450 26A1 regulates the clusters and killing activity of NK cells during the peri-implantation period.

Cytochrome P450 26A1 (CYP26A1) plays a vital role in early pregnancy in mice. Our previous studies have found that CYP26A1 affects embryo implantation by modulating natural killer (NK) cells, and that there is a novel population of CYP26A1+ NK cells in the uteri of pregnant mice. The aim of this study was to investigate the effects of CYP26A1 on the subsets and killing activity of NK cells. Through single-cell RNA sequencing (scRNA-seq), we identified four NK cell subsets in the uterus, namely, conventional NK (cNK), tissue-resident NK (trNK) 1 and 2, and proliferating trNK (trNKp). The two most variable subpopulations after uterine knockdown of CYP26A1 were trNKp and trNK2 cells. CYP26A1 knockdown significantly downregulated the expression of the NK cell function-related genes Cd44, Cd160, Vegfc, and Slamf6 in trNK2 cells, and Klra17 and Ogn in trNKp cells. Both RNA-seq and cytotoxicity assays confirmed that CYP26A1+ NK cells had low cytotoxicity. These results indicate that CYP26A1 may affect the immune microenvironment at the maternal-foetal interface by regulating the activity of NK cells.

Mutation of glucose-methanol-choline oxidoreductase leads to thermosensitive genic male sterility in rice and Arabidopsis.

Thermosensitive genic male sterility (TGMS) lines serve as the major genetic resource for two-line hybrid breeding in rice. However, their unstable sterility under occasional low temperatures in summer highly limits their application. In this study, we identified a novel rice TGMS line, ostms18, of cultivar ZH11 (Oryza sativa ssp. japonica). ostms18 sterility is more stable in summer than the TGMS line carrying the widely used locus tms5 in the ZH11 genetic background, suggesting its potential application for rice breeding. The ostms18 TGMS trait is caused by the point mutation from Gly to Ser in a glucose-methanol-choline (GMC) oxidoreductase; knockout of the oxidoreductase was previously reported to cause complete male sterility. Cellular analysis revealed the pollen wall of ostms18 to be defective, leading to aborted pollen under high temperature. Further analysis showed that the tapetal transcription factor OsMS188 directly regulates OsTMS18 for pollen wall formation. Under low temperature, the flawed pollen wall in ostms18 is sufficient to protect its microspore, allowing for development of functional pollen and restoring fertility. We identified the orthologous gene in Arabidopsis. Although mutants for the gene were fertile under normal conditions (24°C), fertility was significantly reduced under high temperature (28°C), exhibiting a TGMS trait. A cellular mechanism integrated with genetic mutations and different plant species for fertility restoration of TGMS lines is proposed.

Activating BK channels ameliorates vascular smooth muscle calcification through Akt signaling.

Vascular calcification (VC) is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process, in which vascular smooth muscle cells (VSMCs) transform into osteoblast/chondrocyte-like cells as in bone formation. VC is associated with significant morbidity and mortality in chronic kidney disease (CKD) and cardiovascular disease, but the underlying mechanisms remain unclear. In this study we investigated the role of large-conductance calcium-activated potassium (BK) channels in 3 experimental VC models. VC was induced in vascular smooth muscle cells (VSMCs) by ß-glycerophosphate (ß-GP), or in rats by subtotal nephrectomy, or in mice by high-dosage vitamin D3. We showed that the expression of BK channels in the artery of CKD rats with VC and in ß-GP-treated VSMCs was significantly decreased, which was functionally confirmed by patch-clamp recording. In ß-GP-treated VSMCs, BK channel opener NS1619 (20 µM) significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity. Furthermore, NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN, as well as Runx2 (a key transcription factor involved in preosteoblast to osteoblast differentiation), and increased the expression of α-SMA protein, whereas BK channel inhibitor paxilline (10 µM) caused the opposite effects. In primary cultured VSMCs from BK-/- mice, BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs. Moreover, calcification was more severe in thoracic aorta rings of BK-/- mice than in those of wild-type littermates. Administration of BK channel activator BMS191011 (10 mg· kg-1 ·d-1) in high-dosage vitamin D3-treated mice significantly ameliorated calcification. Finally, co-treatment with Akt inhibitor MK2206 (1 µM) or FoxO1 inhibitor AS1842856 (3 µM) in calcified VSMCs abrogated the effects of BK channel opener NS1619. Taken together, activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways. Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.

A New Fungal Triterpene from the Fungus Aspergillus flavus Stimulates Glucose Uptake without Fat Accumulation.

Through activity-guided fractionation, a new triterpene (asperflagin, 1) was isolated as a PPAR-γ agonist from the jellyfish-derived fungus Aspergillus flavus. Asperflagin displayed selective and moderate transactivation effects on PPAR-γ in Ac2F rat liver cells. Based on further biological evaluation and molecular docking analysis, we postulated that asperflagin might function as a PPAR-γ partial agonist. This compound was calculated to display a typical PPAR-γ ligand-receptor interaction that is distinct from that of full agonistic antidiabetics such as rosiglitazone, and may retain the antidiabetic effect without accompanying weight gain. Weight gain and obesity are typical side effects of the PPAR-γ full agonist rosiglitazone, and lead to suboptimal outcomes in diabetic patients. Compared to rosiglitazone, asperflagin showed higher glucose uptake in HepG2 human liver cells at concentrations of 20 and 40 µM but induced markedly lower adipogenesis and lipid accumulation in 3T3-L1 preadipocytes. These results suggest that asperflagin may be utilized for further study on advanced antidiabetic leads.

Anticoagulant activity analysis and origin identification of Panax notoginseng using HPLC and ATR-FTIR spectroscopy.

INTRODUCTION: Panax notoginseng is one of the traditional precious and bulk-traded medicinal materials in China. Its anticoagulant activity is related to its saponin composition. However, the correlation between saponins and anticoagulant activities in P. notoginseng from different origins and identification of the origins have been rarely reported. OBJECTIVES: We aimed to analyze the correlation of components and activities of P. notoginseng from different origins and develop a rapid P. notoginseng origin identification method. MATERIALS AND METHODS: Pharmacological experiments, HPLC, and ATR-FTIR spectroscopy (variable selection) combined with chemometrics methods of P. notoginseng main roots from four different origins (359 individuals) in Yunnan Province were conducted. RESULTS: The pharmacological experiments and HPLC showed that the saponin content of P. notoginseng main roots was not significantly different. It was the highest in main roots from Wenshan Prefecture (9.86%). The coagulation time was prolonged to observe the strongest effect (4.99 s), and the anticoagulant activity was positively correlated with the contents of the three saponins. The content of ginsenoside Rg1 had the greatest influence on the anticoagulant effect. The results of spectroscopy combined with chemometrics show that the variable selection method could extract a small number of variables containing valid information and improve the performance of the model. The variable importance in projection has the best ability to identify the origins of P. notoginseng; the accuracy of the training set and the test set was 0.975 and 0.984, respectively. CONCLUSION: This method is a powerful analytical tool for the activity analysis and identification of Chinese medicinal materials from different origins.