The intestinal γδ T cells: functions in the gut and in the distant organs

Located in the frontline against the largest population of microbiota, the intestinal mucosa of mammals has evolved to become an effective immune system. γδ T cells, a unique T cell subpopulation, are rare in circulation blood and lymphoid tissues, but rich in the intestinal mucosa, particularly in the epithelium. Via rapid production of cytokines and growth factors, intestinal γδ T cells are key contributors to epithelial homeostasis and immune surveillance of infection. Intriguingly, recent studies have revealed that the intestinal γδ T cells may play novel exciting functions ranging from epithelial plasticity and remodeling in response to carbohydrate diets to the recovery of ischemic stroke. In this review article, we update regulatory molecules newly defined in lymphopoiesis of the intestinal γδ T cells and their novel functions locally in the intestinal mucosa, such as epithelial remodeling, and distantly in pathological setting, e.g., ischemic brain injury repair, psychosocial stress responses, and fracture repair. The challenges and potential revenues in intestinal γδ T cell studies are discussed

Synchronous multi-decadal climate variability of the whole Pacific areas revealed in tree rings since 1567

Oceanic and atmospheric patterns play a crucial role in modulating climate variability from interannual to multi-decadal timescales by causing large-scale co-varying climate changes. The brevity of the existing instrumental records hinders the ability to recognize climate patterns before the industrial era, which can be alleviated using proxies. Unfortunately, proxy based reconstructions of oceanic and atmospheric modes of the past millennia often have modest agreements with each other before the instrumental period, raising questions about the robustness of the reconstructions. To ensure the stability of climate signals in proxy data through time, we first identified tree-ring datasets from distant regions containing coherent variations in Asia and North America, and then interpreted their climate information. We found that the multi-decadal covarying climate patterns of the middle and high latitudinal regions around the northern Pacific Ocean agreed quite well with the climate reconstructions of the tropical and southern Pacific areas. This indicates a synchronous variability at the multi-decadal timescale of the past 430 years for the entire Pacific Ocean. This pattern is closely linked to the dominant mode of the Pacific sea surface temperature (SST) after removing the warming trend. This Pacific multi-decadal SST variability resembles the Interdecadal Pacific Oscillation

Clinical value analysis of simple resection of pancreatic solid pseudopapillary tumor

Objective To explore the clinical application value of simple resection in the treatment of pancreatic solid pseudopapillary tumor(SPT). Methods Retrospective analysis of clinical and follow-up data of pancreatic SPT patients who underwent simple pancreatectomy and conventional pancreatectomy from January 2015 to December 2022 in the pancreatic cystic tumor database of Huashan Hospital, Fudan University. A total of 87 patients with pancreatic SPT, including 14 cases underwent simple resection and 73 cases underwent conventional resection, were included. The average age was (36.2±11.7) years old, and females accounting for 87.4%. Results The accuracy of preoperative imaging diagnosis reached 88.5%. Simple resection had a significant advantage over conventional resection in terms of surgical time [(138.3±56.4) min vs. (241.2±89.2) min, P<0.05]. Simple resection was not inferior to conventional resection in terms of common postoperative complications. Out of 87 cases, only 3 patients in conventional resection group experienced postoperative recurrence and metastasis, and all recurrent patients were still alive. There was no statistically significant difference in postoperative pancreatic endocrine and exocrine dysfunction, and quality of life between simple resection group and conventional resection group. Conclusions Simple resection of pancreatic SPT is reasonable and feasible, but the risks in actual clinical work cannot be ignored. Therefore, selective simple resection of SPT has certain clinical application value

Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations

<p>Abstract</p> <p>Background</p> <p>A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines.</p> <p>Materials and methods</p> <p>The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin were tested against a panel of human melanoma cell lines with defined BRAF and NRAS mutations for effects on viability, cell cycle and apoptosis. Signaling molecules in the MAPK, PI3K-AKT and LKB1-AMPK pathways were studied by Western blot.</p> <p>Results</p> <p>Single agent metformin inhibited proliferation in 12 out of 19 cell lines irrespective of the BRAF mutation status, but in one NRAS^Q61Kmutant cell line it powerfully stimulated cell growth. Synergistic anti-proliferative effects of the combination of metformin with vemurafenib were observed in 6 out of 11 BRAF^V600Emutants, including highly synergistic effects in two BRAF^V600Emutant melanoma cell lines. Antagonistic effects were noted in some cell lines, in particular in BRAF^V600Emutant cell lines resistant to single agent vemurafenib. Seven out of 8 BRAF wild type cell lines showed marginally synergistic anti-proliferative effects with the combination, and one cell line had highly antagonistic effects with the combination. The differential effects were not dependent on the sensitivity to each drug alone, effects on cell cycle or signaling pathways.</p> <p>Conclusions</p> <p>The combination of vemurafenib and metformin tended to have stronger anti-proliferative effects on BRAF^V600Emutant cell lines. However, determinants of vemurafenib and metformin synergism or antagonism need to be understood with greater detail before any potential clinical utility of this combination.</p

Cullin 3SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6

The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines. Furthermore, we demonstrated that Cullin 3-based ubiquitin E3 ligase(s) primarily reduced the stability of HDAC6. Importantly, we identified SPOP, an adaptor protein of Cullin 3 family E3 ligases, specifically interacted with HDAC6, and promoted its poly-ubiquitination and subsequent degradation in cells. Notably, cancer-derived SPOP mutants disrupted their binding with HDAC6 and thereby failed to promote HDAC6 degradation. More importantly, increased cellular proliferation and migration in SPOP-depleted HCT116 colon cancer cells could be partly reversed by additional depletion of HDAC6, suggesting that HDAC6 is a key downstream effector for SPOP tumor suppressor function. Together, our data identify the tumor suppressor SPOP as an upstream negative regulator for HDAC6 stability, and SPOP loss-of-function mutations might lead to elevated levels of the HDAC6 oncoprotein to facilitate tumorigenesis and metastasis in various human cancers

Disentangling the effects of vapor pressure deficit on northern terrestrial vegetation productivity

The impact of atmospheric vapor pressure deficit (VPD) on plant photosynthesis has long been acknowledged, but large interactions with air temperature (T) and soil moisture (SM) still hinder a complete understanding of the influence of VPD on vegetation production across various climate zones. Here, we found a diverging response of productivity to VPD in the Northern Hemisphere by excluding interactive effects of VPD with T and SM. The interactions between VPD and T/SM not only offset the potential positive impact of warming on vegetation productivity but also amplifies the negative effect of soil drying. Notably, for high-latitude ecosystems, there occurs a pronounced shift in vegetation productivity\u27s response to VPD during the growing season when VPD surpasses a threshold of 3.5 to 4.0 hectopascals. These results yield previously unknown insights into the role of VPD in terrestrial ecosystems and enhance our comprehension of the terrestrial carbon cycle\u27s response to global warming

Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells

We describe a microchip designed to quantify the levels of a dozen cytoplasmic and membrane proteins from single cells. We use the platform to assess protein–protein interactions associated with the EGF-receptor-mediated PI3K signaling pathway. Single-cell sensitivity is achieved by isolating a defined number of cells (n = 0–5) in 2 nL volume chambers, each of which is patterned with two copies of a miniature antibody array. The cells are lysed on-chip, and the levels of released proteins are assayed using the antibody arrays. We investigate three isogenic cell lines representing the cancer glioblastoma multiforme, at the basal level, under EGF stimulation, and under erlotinib inhibition plus EGF stimulation. The measured protein abundances are consistent with previous work, and single-cell analysis uniquely reveals single-cell heterogeneity, and different types and strengths of protein–protein interactions. This platform helps provide a comprehensive picture of altered signal transduction networks in tumor cells and provides insight into the effect of targeted therapies on protein signaling networks

Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032

Blocking oncogenic signaling induced by the BRAFV600E mutation is a promising approach for melanoma treatment. We tested the anti-tumor effects of a specific inhibitor of Raf protein kinases, PLX4032/RG7204, in melanoma cell lines. PLX4032 decreased signaling through the MAPK pathway only in cell lines with the BRAFV600E mutation. Seven out of 10 BRAFV600E mutant cell lines displayed sensitivity based on cell viability assays and three were resistant at concentrations up to 10 μM. Among the sensitive cell lines, four were highly sensitive with IC50 values below 1 μM, and three were moderately sensitive with IC50 values between 1 and 10 μM. There was evidence of MAPK pathway inhibition and cell cycle arrest in both sensitive and resistant cell lines. Genomic analysis by sequencing, genotyping of close to 400 oncogeninc mutations by mass spectrometry, and SNP arrays demonstrated no major differences in BRAF locus amplification or in other oncogenic events between sensitive and resistant cell lines. However, metabolic tracer uptake studies demonstrated that sensitive cell lines had a more profound inhibition of FDG uptake upon exposure to PLX4032 than resistant cell lines. In conclusion, BRAFV600E mutant melanoma cell lines displayed a range of sensitivities to PLX4032 and metabolic imaging using PET probes can be used to assess sensitivity

Urbanization and air quality as major drivers of altered spatiotemporal patterns of heavy rainfall in China

Context Land use/land cover change and other human activities contribute to the changing climate on regional and global scales, including the increasing occurrence of extreme precipitation events, but the relative importance of these anthropogenic factors, as compared to climatic factors, remains unclear. Objectives The main goal of this study was to determine the relative contributions of human-induced and climatic factors to the altered spatiotemporal patterns of heavy rainfall in China during the past several decades. Methods We used daily precipitation data from 659 meteorological stations in China from 1951 to 2010, climatic factors, and anthropogenic data to identify possible causes of the observed spatiotemporal patterns of heavy rainfall in China in the past several decades, and quantify the relative contributions between climatic and human-induced factors.This research was supported by the 973 Project ‘‘National Key Research and Development Program– Global Change and Mitigation Project: Global change risk of population and economic system: mechanisms and assessments’’ under Grant No. 201531480029, Ministry of Science and Technology of China, People’s Republic of China, the National Natural Science Foundation of Innovative Research Group Project ‘‘Earth Surface Process Model and Simulation’’ under Grant No. 41621061