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Fire is a principal disturbance agent in Northeastern Asia forests with the highest fire radiative power globally. The limitation of the wide network of sites with long reconstructed fire histories restricts our understanding of factors forcing regional fire dynamics. We aggregated 30 fire scars-based fire chronologies in Northeastern Asia to create a composite region chronology from 1701 to 2010. We assessed the correlation between solar activity, drought (as represented by the Self-Calibrated Palmer Drought Severity Index, scPDSI), Arctic Oscillation (AO), and forest fire. Large fires were associated with drought, positive AO, and lower sunspot numbers, as revealed by Superposed epoch analysis. The pathways of solar activity force drought and AO, hence, driving fire activity indicated by structural equation modeling. As Solar Cycle 25 (starting in December 2019 and lasting until about 2030) is projected to be as weak as the Dalton minimum (1795–1820 AD), we expect fire activity to remain high over this period. Our findings provide insights into the extraterrestrial forcing of forest fire activity and its prediction in Northeastern Asia.

Abstract Escherichia coli, one of the most efficient expression hosts for recombinant proteins (RPs), is widely used in chemical, medical, food and other industries. However, conventional expression strains are unable to effectively express proteins with complex structures or toxicity. The key to solving this problem is to alleviate the host burden associated with protein overproduction and to enhance the ability to accurately fold and modify RPs at high expression levels. Here, we summarize the recently developed optimization strategies for the high-level production of RPs from the two aspects of host burden and protein activity. The aim is to maximize the ability of researchers to quickly select an appropriate optimization strategy for improving the production of RPs.

Abstract Ivermectin is a widely used antiparasitic drug and shows promising anticancer activity in various cancer types. Although multiple signaling pathways modulated by ivermectin have been identified in tumor cells, few studies have focused on the exact target of ivermectin. Herein, we report the pharmacological effects and targets of ivermectin in prostate cancer. Ivermectin caused G0/G1 cell cycle arrest, induced cell apoptosis and DNA damage, and decreased androgen receptor (AR) signaling in prostate cancer cells. Further in vivo analysis showed ivermectin could suppress 22RV1 xenograft progression. Using integrated omics profiling, including RNA-seq and thermal proteome profiling, the forkhead box protein A1 (FOXA1) and non-homologous end joining (NHEJ) repair executer Ku70/Ku80 were strongly suggested as direct targets of ivermectin in prostate cancer. The interaction of ivermectin and FOXA1 reduced the chromatin accessibility of AR signaling and the G0/G1 cell cycle regulator E2F1, leading to cell proliferation inhibition. The interaction of ivermectin and Ku70/Ku80 impaired the NHEJ repair ability. Cooperating with the downregulation of homologous recombination repair ability after AR signaling inhibition, ivermectin increased intracellular DNA double-strand breaks and finally triggered cell death. Our findings demonstrate the anticancer effect of ivermectin in prostate cancer, indicating that its use may be a new therapeutic approach for prostate cancer.

Objective To evaluate the safety and efficacy of transurethral retrograde en-bloc excavation of bladder tumor （EEBT） after basal injection with sterile water for non-muscular invasive bladder cancer （NMIBC）. Methods Clinical data of 60 patients with NMIBC were analyzed retrospectively. All patients were divided into two groups according to the surgical procedure. In the EEBT group, 30 patients received transurethral EEBT after basal injection with sterile water, and 30 patients underwent conventional transurethral resection of bladder tumor （TURBT） in the TURBT group. The baseline data, perioperative parameters, postoperative tumor pathological stage and the pathologists’ degree of satisfaction with the specimen were compared between two groups. All patients received follow-up. The tumor recurrence rate was statistically compared between two groups. Results There was no significant difference in gender, age, tumor size, tumor location, proportion of single and multiple tumors and preoperative complications between two groups （all P > 0.05）. No statistical significance was also observed in the bladder perforation rate, postoperative tumor pathological stage and pathological T stage between EEBT group and TURBT group（all P > 0.05）. Compared with the TURBT group, the operation time was longer, whereas intraoperative blood loss was less, the incidence of obturator reflex was lower, postoperative indwelling catheter time and the length of hospital stay were shorter, the pathologists’ degree of satisfaction with the specimen was higher, and the one-year tumor recurrence rate was lower in the EEBT group （all P < 0.05）. Conclusion Compared with TURBT, transurethral retrograde EEBT after basal injection with sterile water has multiple advantages of less intraoperative blood loss, faster postoperative recovery, intact tumor specimen and lower one-year tumor recurrence rate in the treatment of NMIBC.

Abstract Background Drug-induced hypersensitivity syndrome (DIHS) is a rare, potentially life-threatening systemic drug reaction. Antithyroid drugs (ATDs) causing DIHS have seldom been reported before. Case presentation We present a case of propylthiouracil (PTU)-induced DIHS, which included fever, skin rash, lymphadenopathy, hepatosplenomegaly, serious liver and kidney dysfunction, peripheral blood eosinophilia, and atypical lymphocytosis. Following supportive therapy, intravenous immunoglobulin (IVIG), and systemic corticosteroid, the patient experienced a resolution of fever and rash combined with progressive normalization of hematological index and organ function. These clinical features, and the skin lesion biopsy confirmed DIHS diagnosis. Conclusions To our knowledge, this is the second reported case of PTU-induced DIHS worldwide and the first human leukocyte antigen (HLA) typing of PTU-induced DIHS. Clinicians should cautiously distinguish hyperthyroidism etiology and identify the indication of ATDs. Timely recognition and formal DIHS treatment are required in patients with ATDs.

Abstract Background Napsin B Aspartic Peptidase, Pseudogene (NAPSB) was associated with CD4 + T cell infiltration in pancreatic ductal adenocarcinoma. However, the biological role of NAPSB in hepatocellular carcinoma (HCC) remains to be determined. Methods The expression of NAPSB in HCC as well as its clinicopathological association were analyzed using data from several public datasets. qRT-PCR was used to verify the relative expression of NAPSB in patients with HCC using the Zhongnan cohort. Kaplan–Meier analyses, and univariate and multivariate Cox regression were conducted to determine the prognosis value of NAPSB on patients with HCC. Then enrichment analyses were performed to identify the possible biological functions of NAPSB. Subsequently, the immunological characteristics of NAPSB in the HCC tumor microenvironment (TME) were demonstrated comprehensively. The role of NAPSB in predicting hot tumors and its impact on immunotherapy and chemotherapy responses was also analyzed by bioinformatics methods. Results NAPSB was downregulated in patients with HCC and high NAPSB expression showed an improved survival outcome. Enrichment analyses showed that NAPSB was related to immune activation. NAPSB was positively correlated with immunomodulators, tumor-infiltrating immune cells, T cell inflamed score and cancer-immunity cycle, and highly expressed in immuno-hot tumors. High expression of NAPSB was sensitive to immunotherapy and chemotherapy, possibly due to its association with pyroptosis, apoptosis and necrosis. Conclusions NAPSB was correlated with an immuno-hot and inflamed TME, and tumor cell death. It can be utilized as a promising predictive marker for prognosis and therapy in HCC.

Highlights Fabrication, characterizations and photothermal properties of MXenes are systematically described. Photothermal-derived antibacterial performances and mechanisms of MXenes-based materials are summarized and reviewed. Recent advances in the derivative applications relying on antibacterial properties of MXenes-based materials, including in vitro and in vivo sterilization, solar water evaporation and purification, and flexible antibacterial fabrics, are investigated. Abstract The pernicious bacterial proliferation and emergence of super-resistant bacteria have already posed a great threat to public health, which drives researchers to develop antibiotic-free strategies to eradicate these fierce microbes. Although enormous achievements have already been achieved, it remains an arduous challenge to realize efficient sterilization to cut off the drug resistance generation. Recently, photothermal therapy (PTT) has emerged as a promising solution to efficiently damage the integrity of pathogenic bacteria based on hyperthermia beyond their tolerance. Until now, numerous photothermal agents have been studied for antimicrobial PTT. Among them, MXenes (a type of two-dimensional transition metal carbides or nitrides) are extensively investigated as one of the most promising candidates due to their high aspect ratio, atomic-thin thickness, excellent photothermal performance, low cytotoxicity, and ultrahigh dispersibility in aqueous systems. Besides, the enormous application scenarios using their antibacterial properties can be tailored via elaborated designs of MXenes-based materials. In this review, the synthetic approaches and textural properties of MXenes have been systematically presented first, and then the photothermal properties and sterilization mechanisms using MXenes-based materials are documented. Subsequently, recent progress in diverse fields making use of the photothermal and antibacterial performances of MXenes-based materials are well summarized to reveal the potential applications of these materials for various purposes, including in vitro and in vivo sterilization, solar water evaporation and purification, and flexible antibacterial fabrics. Last but not least, the current challenges and future perspectives are discussed to provide theoretical guidance for the fabrication of efficient antimicrobial systems using MXenes.

BackgroundLynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs.MethodsImmunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations.ResultsIn the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis.ConclusionLS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Abstract Submarine methane seepage can potentially be promoted by the dissociation of the marine hydrates surrounding the continental margins due to oceanic warming since the Last Glacial Maximum. This seepage could be archived by authigenic carbonates at seeping sites, but the time lag caused by heat transmission through the sediment column leads to an inconsistency between the ages of the carbonate and the period of bottom water warming. Here we present the records of the authigenic carbonate crust from drilling site D1 in the Mid‐Okinawa Trough. Uranium–thorium dating results show that the carbonate crust mainly grew downwards during 14–6 ka. Gas hydrates hosted in the relatively thin stability zone dissociated in a rapid response to bottom water warming and intensified the methane seepage. Our study better supports the hypothesis that a considerable amount of methane can be released from marine hydrates due to global climatic changes.

N-nitrosodimethylamine (NDMA) is an environmental and food contaminant, but limited data to concern whether NDMA has adverse effects on the brain. This study first determined the concentration of NDMA in foods from aquaculture markets in Shenzhen, then analyzed the effects on C57BL/6 mice and further evaluated on the urine samples of elderly Chinese residents with normal cognition (NC, n = 144), cognitive decline (CD, n = 116) and mild cognitive impairment (MCI, n = 123). The excessive rate of NDMA in foods was 3.32% (27/813), with a exceeding range of 4.78–131.00 μg/kg. Behavioral tests showed that 60 days treatment of mice with 3 mg/kg NDMA reduced cognitive performance. Cognitive impairment in human was significantly associated with sex, educational levels, length of residence in Shenzhen, household registration, passive smoking, rice, fresh vegetables, bacon products. NDMA was detected in 55.4% (212/383) of urine samples, with a median concentration of 0.23 μg/L (1.20 × 10 –7–157.39 μg/L). The median concentration for NC, CD and MCI were 0.32, 0.27, and 0 μg/L, respectively. The urinary NDMA concentration had a strong negative correlation with cognitive impairment (Kendall’s Tau-b = −0.89, P = 0.024). The median estimated daily intake (EDI) of NDMA was determined to be 6.63 ng/kg-bw/day. Taken together, there appears to be an association between NDMA and human and murine cognition, which provides a new clue to Alzheimer’s disease (AD).

Mangrove-derived actinomycetes represent a rich source of novel bioactive natural products in drug discovery. In this study, four new polyene macrolide antibiotics antifungalmycin B-E (1–4), along with seven known analogs (5–11), were isolated from the fermentation broth of the mangrove strain Streptomyces hiroshimensis GXIMD 06359. All compounds from this strain were purified using semi-preparative HPLC and Sephadex LH-20 gel filtration while following an antifungal activity-guided fractionation. Their structures were elucidated through spectroscopic techniques including UV, HR-ESI-MS, and NMR. These compounds exhibited broad-spectrum antifungal activity against Talaromyces marneffei with minimum inhibitory concentration (MIC) values being in the range of 2–128 μg/mL except compound 2. This is the first report of polyene derivatives produced by S. hiroshimensis as bioactive compounds against T. marneffei. In vitro studies showed that compound 1 exerted a significantly stronger antifungal activity against T. marneffei than other new compounds, and the antifungal mechanism of compound 1 may be related to the disrupted cell membrane, which causes mitochondrial dysfunction, resulting in leakage of intracellular biological components, and subsequently, cell death. Taken together, this study provides a basis for compound 1 preventing and controlling talaromycosis.

Surface engineering has been proved efficient and universally applicable in improving the performance of CeO2 in various fields. However, previous approaches have typically required high-temperature calcination or tedious procedures, which makes discovery of a moderate and facile modification approach for CeO2 an attractive subject. In this paper, porous CeO2 nanosheets with effective nitrogen-doping were synthesized via a low-temperature NH3/Ar plasma treatment and exhibited boosted hydrogen evolution reaction performance with low overpotential (65 mV) and long-term stability. The mechanism of the elevated performance was investigated by introducing Ar-plasma-treated CeO2 with no nitrogen-doping as the control group, which revealed the dominant role of nitrogen-doping by providing abundant active sites and improving charge transfer characteristics. This work illuminates further investigations into the surface engineering methodologies boosted by plasma and the relative mechanism of the structure–activity relationship.

The montmorillonite-sodium alginate (MMT-SA) colon-targeting microcapsules have been designed as a WGX-50 encapsulation and controlled release vehicle used in oral administration. The MMT-SA microcapsule was formed from a cross-linking reaction, and the stable micropore in the microcapsule changed with a different MMT-SA mixed mass ratio. The MMT-SA microcapsule has a reinforced micropore structure and an enhanced swell–dissolution in SIF and SCF with alkaline environment, which is attributed to the incorporated MMT. The MMT-SA microcapsule exhibited a high WGX-50 encapsulation rate up to 98.81 ± 0.31% and an obvious WGX-50 controlled release in the simulated digestive fluid in vitro. The WGX-50 loaded with MMT-SA microcapsule showed a weak minimizing drug loss in SGF (Simulated Gastric Fluid) with an acidic environment, while it showed a strong maximizing drug release in SIF (Simulated Intestinal Fluid) and SCF (Simulated Colonic Fluid) with an alkaline environment. These features make the MMT-SA microcapsule a nominated vehicle for colon disease treatment used in oral administration.

Climate change is already significantly affecting the frequency of wildfires in most regions of the world, and the risk of wildfires is expected to amplify further with global warming. Accordingly, there is growing concern about the mechanisms and impacts of extreme fires. In this study, a coupling of the Weather Research and Forecasting model and the Rothermel Fire model (WRF-Fire) is employed to reproduce the spread of fire within the national boundary of inner Mongolia from 21 to 27 May 2009. Simulations were run with or without feedback from fire-to-atmosphere models, and the study focused on how the energy flux of simulated fires changes the local meteorological environment. The coupled simulation could reproduce the burned area well, and the wind speed was the dominant factor in the fire spread, with a maximum value no more than 6.4 m/s, when the terrain height changes little and the proportion of grassland is low. After the feedback, the propagation speed of the fire accelerated, accompanying the release of latent and sensible heat, and local circulation formed near the front of the fire, leading to a convergence and divergence zone in the downwind area. It is worth noting that during a period of more than 140 h of simulation, the area of the fire field increased by 17% from ignition time. Therefore, considering the fire–atmosphere interaction is necessary for accurately predicting fire behavior.

SnO2 nanospheres with diameters of 30∼50 nm and PtxCu1-x bimetallic nanoparticles with sizes of approximately 10 nm were synthesized via hydrothermal and solvothermal methods, respectively. The PtxCu1-x bimetallic nanoparticles were impregnated on the surface of the SnO2 spheres to form PtxCu1-x-SnO2 nanocomposites. By varying the atomic ratios between platinum (Pt) and copper (Cu), we found that Pt0.75Cu0.25-SnO2, with a large specific surface area of 89.21 m2/g, enabled the selective and accurate detection of low-concentration formaldehyde compared to other metal-deposited samples and pure SnO2. The response value of Pt0.75Cu0.25-SnO2 to 500 × 10−9 formaldehyde was approximately 20 at an operating temperature of 160 ℃ with an extremely high-speed response (15 s). The porous structures with large specific surface areas, as well as the improved catalytic effects of Pt0.75Cu0.25, comprehensively contributed to the enhanced sensing performance towards formaldehyde.

Abstract PandaX-4T is a ton-scale dark matter direct detection experiment using a dual-phase TPC technique at the China Jinping Underground Laboratory. Various ultra-low background technologies have been developed and applied to material screening for PandaX-4T, including HPGe gamma spectroscopy, ICP-MS, NAA, radon emanation measurement system, krypton assay station, and alpha detection system. Low background materials were selected to assemble the detector. Surface treatment procedures were investigated to further suppress radioactive background. Combining measured results and Monte Carlo simulation, the total material background rates of PandaX-4T in the energy region of 1–25 keVee are estimated to be (9.9 ± 1.9) × 10 −3 mDRU for electron recoil and (2.8 ± 0.6) × 10 −4 mDRU for nuclear recoil. In addition, natKr in the detector is estimated to be < 8 ppt.

Objective To compare hepatic artery infusion chemotherapy (HAIC) with transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma combined with both anti-angiogenesis and immunotherapy for effectiveness and safety. Methods Ninety-three patients with hepatocellular carcinoma including stage B 18 cases and stage C 75 cases, and 74 males, 19 females with a median age of 57 (27-78) in Tianjin Medical University Cancer Hospital from January 2019 to December 2020 were studied retrospectively. In the treatment combined with anti-angiogenesis and immunotherapy, 50 cases received TACE and 43 cases received HAIC. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 was used to evaluate the efficacy of treatment. The primary endpoints were both objective response rate (ORR) and disease control rate (DCR), and the secondary endpoints both median progression free survival (mPFS) and median overall survival (mOS). Results Both ORR (72.09% vs. 44.00%, P=0.006) and DCR (88.37% vs. 60.00%, P=0.002) were significantly more in HAIC group than in TACE group. The median follow-up duration was 12.13 months in HAIC group and 11.95 months in TACE group. mPFS in TACE group was 11.83 months (95%CI: 4.36-19.31 months) with mOS 17.93 months (95%CI: 11.80-24.06 months). Both mPFS and mOS did not reach in HAIC group. There were significant differences in PFS and OS between two groups (P=0.017; P=0.007). Conclusions The patients with advanced hepatocellular carcinoma would benefit from HAIC combined with both anti-angiogenesis and immunotherapy in disease control and survival with less side effects and better safety when compared with TACE combination treatment.

Objective: PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade. The factors that drive inducible PD-L1 expression have been extensively studied, but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown. Methods: DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout. Protein function was inhibited by chemical inhibitors. Protein levels were examined by Western blot, mRNA levels were examined by real-time RT-PCR, and surface protein expression was determined by cellular immunofluorescence and flow cytometry. Immune evasion was examined by in vitro T cell-mediated killing. Results: We determined the core regions (chr9: 5, 496, 378–5, 499, 663) of a previously identified PD-L1L2-super-enhancer (SE). Through systematic analysis, we found that the E26 transformation-specific (ETS) variant transcription factor (ETV4) bound to this core DNA region but not to DNA surrounding PD-L1L2SE. Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2. ETV4 transcription was dependent on ERK activation, and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling from αvβ3 integrin, which profoundly affected ETV4 transcription and PD-L1/L2 expression. Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing. Conclusions: We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion. These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.

Objective: Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition, not only aiding seeding and colonization, but also rendering the tumor cells generally chemoresistant. We previously found that upregulated E-cadherin in the epithelial micrometastases activated canonical survival pathways, including PI3K-Akt, that protected the tumor cells from death; however, the extent of protection from blocking the pathway in its entirety was modest, because different isoforms may have alternately affected cell functioning. Here, we characterized Akt isoform expressions in primary and metastatic prostate cancers, as well as their individual contributions to chemoresistance. Methods: Akt isoforms and E-cadherin were manipulated with drugs, knocked down, and over expressed. Tumor cell killing was determined in vitro and in vivo. Overall survival was calculated from patient records and specimens. Results: Pan-Akt inhibition sensitized tumor cells to chemotherapy, and specific blockade of Akt1 or/and Akt2 caused cells to be more chemoresponsive. Overexpression of Akt3 induced apoptosis. A low dose of Akt1 or Akt2 inhibitor enabled standard chemotherapies to significantly eradicate metastatic prostate tumors in a mouse model, acting as chemosensitizers. In human specimens, we found Akt1 and Akt2 positively correlated, whereas Akt3 inversely correlated, with the overall survival of prostate cancer patients. Akt1high/Akt2high/Akt3low tumors had the worst outcomes. Conclusions: E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance, whereas Akt3 made cells more fragile. These findings emphasized the need to target Akt1/2, rather than pan-Akt, as a rational therapeutic approach.

Four Si3N4 crystal structures were predicted using an ab initio evolutionary methodology. The mechanical and dynamic stabilities were confirmed by the density functional theory assuming zero-pressure conditions. Energetic stability calculations indicated that the structures are metastable phases at ambient pressure, but their formation is more favorable at high pressures. At zero pressure, the densities of the hp-Si3N4, cp-Si3N4, oc-Si3N4, and ti-Si3N4 phases were 3.21, 3.28, 3.70, and 3.24 g/cm3, respectively. The calculated band structures and densities of states indicated that they have semiconductive properties, with gaps ranging from 0.754 to 3.968 eV. Mechanical property calculations revealed that the hardness of the Si3N4 compounds ranged between 11.2 and 23.3 GPa, which were higher than the corresponding values for the synthesized Si3N4 phases. These four Si3N4 structures are potentially valuable candidates for the synthesis of Si3N4 compounds.

Upward diffusing methane in gas hydrate geological systems is consumed in the sediment and water column by a series of biogeochemical reactions, which not only affect living foraminifera but also lead to early diagenetic alteration of buried foraminiferal tests. Previous studies of the impact of methane release events on fossil foraminifera focused mainly on carbon and oxygen isotopes, with little attention given to other geochemical proxies to date. Here, we examine the test wall microstructure and analyze the elemental and stable carbon-oxygen isotopic compositions of buried foraminifera from gas hydrate-bearing sediments at Site GMGS2-16 in the northern South China Sea. Our results show that diagenetic alteration of foraminiferal tests at Site GMGS2-16 is mainly linked to high-Mg calcite overgrowths. Test δ13C covaries negatively with the degree of diagenetic alteration (based on petrographic characteristics) but positively with Mg/Ca ratios. With increasing diagenetic alteration, Ba/Ca, Mn/Ca, Fe/Ca, Mo/Ca, U/Ca, V/Ca, Ni/Ca and Co/Ca also generally increase, but Sr/Ca and Cu/Ca exhibit variable changes. We infer that foraminiferal tests are highly susceptible to alteration by methane-bearing fluids, and that the elemental ratios of diagenetically altered tests are potentially reliable proxies for paleo-methane release events. At Site GMGS2-16, the overall pattern of diagenetic alteration of foraminiferal tests records frequent vertical fluctuations of the sulfate-methane transition zone (SMTZ) caused by variable fluid flux and methane release rates, with two discrete large-scale methane release events having maximum ages of ~0.47 ka and ~170 ka.

Sensations, especially nociception, are tightly controlled and regulated by the central and peripheral nervous systems. Osmotic sensation and related physiological and behavioral reactions are essential for animal well-being and survival. In this study, we find that interaction between secondary nociceptive ADL and primary nociceptive ASH neurons upregulates Caenorhabditis elegans avoidance of the mild and medium hyperosmolality of 0.41 and 0.88 Osm but does not affect avoidance of high osmolality of 1.37 and 2.29 Osm. The interaction between ASH and ADL is actualized through a negative feedback circuit consisting of ASH, ADL, and RIM interneurons. In this circuit, hyperosmolality-sensitive ADL augments the ASH hyperosmotic response and animal hyperosmotic avoidance; RIM inhibits ADL and is excited by ASH; thus, ASH exciting RIM reduces ADL augmenting ASH. The neuronal signal integration modality in the circuit is disexcitation. In addition, ASH promotes hyperosmotic avoidance through ASH/RIC/AIY feedforward circuit. Finally, we find that in addition to ASH and ADL, multiple sensory neurons are involved in hyperosmotic sensation and avoidance behavior.