Heavy metal induced shifts in microbial community composition and interactions with dissolved organic matter in coastal sediments.

Heavy metals can impact the structure and function of coastal sediment. The dissolved organic matter (DOM) pool plays an important role in determining both the heavy metal toxicity and microbial community composition in coastal sediments. However, how heavy metals affect the interactions between microbial communities and DOM remains unclear. Here, we investigated the influence of heavy metals on the microbial community structure (including bacteria and archaea) and DOM composition in surface sediments of Beibu Gulf, China. Our results revealed firstly that chromium, zinc, cadmium, and lead were the heavy metals contributing to pollution in our studied area. Furthermore, the DOM chemical composition was distinctly different in the contaminated area from the uncontaminated area, characterized by a higher average O/C ratio and increased prevalence of carboxyl-rich alicyclic molecules (CRAM) and highly unsaturated compounds (HUC). This indicates that DOM in the contaminated area was more recalcitrant compared to the uncontaminated area. Except for differences in archaeal diversity between the two areas, there were no significant variations observed in the structure of archaea and bacteria, as well as the diversity of bacteria, across the two areas. Nevertheless, our co-occurrence network analysis revealed that the B2M28 and Euryarchaeota, dominating bacterial and archaeal groups in the contaminated area were strongly related to CRAM. The network analysis also unveiled correlations between active bacteria and elevated proportions of nitrogen-containing DOM molecules. In contrast, the archaea-DOM network exhibited strong associations with nitrogen- and sulfur-containing molecules. Collectively, these findings suggest that heavy metals indeed influence the interaction between microbial communities and DOM, potentially affecting the accumulation of recalcitrant compounds in coastal sediments.

Prognostic value of inflammatory nutritional scores in locally advanced esophageal squamous cell carcinoma patients undergoing neoadjuvant chemoimmunotherapy: a multicenter study in China.

Objective: This study investigates the prognostic significance of inflammatory nutritional scores in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) undergoing neoadjuvant chemoimmunotherapy. Methods: A total of 190 LA-ESCC patients were recruited from three medical centers across China. Pre-treatment laboratory tests were utilized to calculate inflammatory nutritional scores. LASSO regression and multivariate logistic regression analyses were conducted to pinpoint predictors of pathological response. Kaplan-Meier and Cox regression analyses were employed to assess disease-free survival (DFS) prognostic factors. Results: The cohort comprised 154 males (81.05%) and 36 females (18.95%), with a median age of 61.4 years. Pathological complete response (pCR) was achieved in 17.38% of patients, while 44.78% attained major pathological response (MPR). LASSO and multivariate logistic regression analyses identified that hemoglobin, albumin, lymphocyte, and platelet (HALP) (P=0.02) as an independent predictors of MPR in LA-ESCC patients receiving neoadjuvant chemoimmunotherapy. Kaplan-Meier and log-rank tests indicated that patients with low HALP, MPR, ypT1-2, ypN0 and, ypTNM I stages had prolonged DFS (P < 0.05). Furthermore, univariate and multivariate Cox regression analyses underscored HALP (P = 0.019) and ypT (P = 0.029) as independent predictive factors for DFS in ESCC. Conclusion: Our study suggests that LA-ESCC patients with lower pre-treatment HALP scores exhibit improved pathological response and reduced recurrence rate. As a comprehensive index of inflammatory nutritional status, pre-treatment HALP may be a reliable prognostic marker in ESCC patients undergoing neoadjuvant chemoimmunotherapy.

Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from Mpro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 Mpro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named 'leritrelvir' for COVID-19 treatment in China.

Association between per- and polyfluoroalkyl substances exposure and prevalence of chronic obstructive pulmonary disease: The mediating role of serum albumin.

BACKGROUND: No study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims to explore this relationship. METHODS: This study enrolled 4541 individuals who had available data on PFAS, COPD, and covariates from NHANES 2007-2018. Serum PFAS including perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) were analyzed, because of high detective rates. Considering the skew distribution of PFAS levels, the natural logarithm-transformed PFAS (Ln-PFAS) was used. Logistic regression analysis, restricted cubic spline (RCS), and weighted quantile sum (WQS) regression were performed to explore the single, nonlinear, and mixed effects. A mediating analysis was used to evaluate the mediated effects of albumin. RESULTS: Individuals with COPD had higher levels of PFHxS, PFNA, PFOA, and PFOS compared to those without COPD. Ln-PFNA (OR males: 1.92, 95 % CI:1.31 to 2.80, P: <0.001; OR females: 1.07, 95 % CI: 0.81 to 1.40, P: 0.636) and ln-PFOA (OR males: 2.17, 95 % CI:1.38 to 3.41, P: <0.001; OR females: 1.49, 95 % CI: 1.08 to 2.05, P: 0.016) were associated with COPD risk especially in males. The interaction between PFNA exposure and sex on COPD risk was significant (P interaction: <0.001). The RCS curve demonstrated the nonlinear relationship between the ln-PFOA (P nonlinear:0.001), ln-PFNA (P nonlinear:0.045), and COPD risk in males. WQS analysis showed mixed PFAS exposure was correlated with COPD risk in males (OR: 1.44, 95 % CI:1.18 to 1.75, P: <0.001). Albumin mediated the relationship between PFOA and COPD (mediated proportion: -17.94 %). CONCLUSION: This study concludes PFOA and PFNA are linked to a higher COPD risk in males, and serum albumin plays a mediating role in the relationship between PFOA and COPD. Thess findings are beneficial for the prevention of COPD. Further studies are required to explore potential mechanisms.

Comparison of efficacy and safety between neoadjuvant chemotherapy and neoadjuvant immune checkpoint inhibitors combined with chemotherapy for locally advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: The application of neoadjuvant immune checkpoint inhibitors combined with chemotherapy (NICT) in treating locally advanced oesophageal squamous cell carcinoma (ESCC) is a subject of considerable research interest. In light of this, we undertook a comprehensive meta-analysis aiming to compare the efficacy and safety of this novel approach with conventional neoadjuvant chemotherapy (NCT) in the management of ESCC. METHODS: A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science to gather relevant literature on the efficacy and safety of NICT compared to conventional NCT in locally advanced ESCC published before June 2023. Effect indicators, including odds ratios (ORs) with associated 95% CIs, were employed to evaluate the safety and efficacy outcomes. The risk of bias was assessed using the Cochrane bias risk assessment tool, and s ubgroup analysis and sensitivity analysis were conducted to investigate the findings further. RESULTS: A total of nine studies qualified for the meta-analysis, all of which investigated the efficacy and safety of NICT compared to conventional NCT. The pooled rates of pathologic complete response and major pathologic response in the NICT group were significantly higher compared to the NCT group, with values of 26.9% versus 8.3% ( P <0.00001) and 48.1% versus 24.6% ( P <0.00001), respectively. The ORs for achieving pathologic complete response and major pathologic response were 4.24 (95% CI, 2.84-6.32, I 2 =14%) and 3.30 (95% CI, 2.31-4.71, I 2 =0%), respectively, indicating a significant advantage for the NICT group. Regarding safety outcomes, the pooled incidences of treatment-related adverse events and serious adverse events in the NICT group were 64.4% and 11.5%, respectively, compared to 73.8% and 9.3% in the NCT group. However, there were no significant differences observed between the two groups in terms of treatment-related adverse events (OR=0.67, 95% CI, 0.29-1.54, P =0.35, I 2 =58%) or serious adverse events (OR=1.28, 95% CI, 0.69-2.36, P =0.43, I 2 =0%). Furthermore, no significant differences were found between the NICT and NCT groups regarding R0 resection rates, anastomotic leakage, pulmonary infection, and postoperative hoarseness. CONCLUSIONS: Neoadjuvant immune checkpoint inhibitors combined with chemotherapy demonstrate efficacy and safety in treating resectable oesophageal squamous cell carcinoma. Nevertheless, additional randomized trials are required to confirm the optimal treatment regimen.

Cellulose nanofiber hydrogel with high conductivity electrolytes for high voltage flexible supercapacitors.

Although flexible double layer capacitors based on hydrogels overcome the drawbacks of commercial double layer capacitors such as low safety and non-deformability, it is still considered as attractive challenges to achieve high conductivity for hydrogel electrolytes as well as high operating voltages for hydrogel flexible supercapacitors. In this paper, ion migration channels were engineered by immobilizing positive and negative charges on polymer skeleton and dispersing cellulose nanofibers in the polymerized polyelectrolyte network, providing ultra-high ionic conductivity (103 mS cm-1). In addition, K3[Fe(CN)6] was introduced through a soaking method, leading to redox reactions on the surface of carbon electrode during charging and discharging, supporting a relatively wide voltage window (1.8 V). Moreover, the specific capacitance at high current remained 55 % of the specific capacitance at low current, indicating excellent rate performance. In addition, the device displayed high cycling stability (80.05 % after 10,000 cycles). Notably, we successfully light up the red LED with only one device. Accordingly, this work provides a feasible design concept for the development of cellulose nanofibers (CNF) hydrogel-based solid-state electrolyte with high conductivity for flexible supercapacitors with wide potential window and high energy density.

Genomic insights into the adaptation of Synechococcus to the coastal environment on Xiamen.

Synechococcus are widely distributed in the global ocean, from the pelagic zone to coastal waters. However, little is known about Synechococcus in coastal seawater due to limitations in isolation and culture conditions. In this study, a combination of metagenomic sequencing technology, flow cytometry sorting, and multiple displacement amplification was used to investigate Synechococcus in the coastal seawater of Xiamen Island. The results revealed 18 clades of Synechococcus and diverse metabolic genes that appear to contribute to their adaptation to the coastal environment. Intriguingly, some metabolic genes related to the metabolism of carbohydrates, energy, nucleotides, and amino acids were found in 89 prophage regions that were detected in 16,258 Synechococcus sequences. The detected metabolic genes can enable prophages to contribute to the adaptation of Synechococcus hosts to the coastal marine environment. The detection of prophages also suggests that the cyanophages have infected Synechococcus. On the other hand, the identification of 773 genes associated with antiviral defense systems indicates that Synechococcus in Xiamen have evolved genetic traits in response to cyanophage infection. Studying the community diversity and functional genes of Synechococcus provides insights into their role in environmental adaptation and marine ecosystems.

Highly Sensitive and Quantitative Magnetic Nanoparticle-Based Lateral Flow Immunoassay with an Atomic Magnetometer.

Lateral flow immunoassay (LFIA) is a simple point-of-care method for detecting various analytes. However, the lack of test result precision and poor quantification are the main bottlenecks of LFIA. Although magnetic nanoparticles (MNPs) have gained prominence as potent labels in LIFA, the quantitative detection method for trace biomarkers remains to be improved. Here, we propose a promising real-time biosensing platform based on a highly sensitive atomic magnetometer to fulfill the quantitative detection of MNP-based lateral flow immunochromatographic assays. The strategy entails obtaining the residual flux density component spectrum by continuously and linearly scanning the trace MNP label and then resolving the magnetization and quantity from the spectrum. Moreover, we exploit the theoretical model of the magnetic dipole to verify the method's reliability. Regarding carcinoembryonic antigen detection, the atomic magnetometer exhibits a low detection limit of ∼0.01 ng mL-1 with a 100-fold enhancement factor compared to optical detection methods and a more straightforward mechanism than other magnetic detection approaches. Together, these results provide valuable insight for the potential application of atomic magnetometer quantum measurement techniques in intelligent diagnosis and treatment.

Nomogram-based prediction model for survival of COVID-19 patients: A clinical study.

The study aim to construct an effective model for predicting the survival period of COVID-19 patients. METHODS: Clinical data of 386 COVID-19 patients were collected from December 2022 to January 2023. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. LASSO regression and multivariate Cox regression analyses were used to identify prognostic factors, and a nomogram was constructed. Nomogram was evaluated using decision curve analysis, receiver operating characteristic curve, consistency index (c-index), and calibration curve. RESULTS: 86 patients (22.3%) died. A new nomogram for predicting the survival was established based on age, resting oxygen saturation, Blood urea nitrogen (BUN), c-reactive protein-to-albumin ratio (CAR), and pneumonia visual score. The decision curve indicated high clinical applicability. The nomogram c-indexes in the training and validation cohorts were 0.846 and 0.81, respectively. The area under the curves (AUCs) for the 15-day and 30-day survival probabilities were 0.906 and 0.869 in the training cohort, and 0.851 and 0.843 in the validation cohort. The calibration curves demonstrated consistency between predicted and actual survival probabilities. CONCLUSIONS: Our nomogram has the capacity to assist clinical practitioners in estimating the survival rate of COVID-19 patients, thereby facilitating more optimal management strategies and therapeutic interventions with substantial clinical applicability.

Combination of Chest Computed Tomography Value and Clinical Laboratory Data for the Prognostic Risk Evaluation of Patients with COVID-19.

Objective: This study aims to investigate the independent prognostic factors of patients with coronavirus disease 2019 (COVID-19) and thereafter construct a related prognostic model. Methods: The subjects were screened following the COVID-19 diagnostic criteria. The independent prognostic factors were selected based on the indicators, including medical history, clinical manifestation, laboratory tests, imaging examination and clinical prognosis. Subsequently, we constructed a nomogram model to predict short-term prognosis. Results: Clinical information was obtained from 393 COVID-19 patients admitted to Zhongshan Hospital at Xiamen University between December 2022 and January 2023. The independent risk factors determined by Cox multivariate regression analysis included gender (OR: 0.355, 95% CI: 0.16~0.745), age (OR: 3.938, 95% CI: 1.221~15.9), pectoral muscle index (PMI, OR: 4.985, 95% CI: 2.336~11.443), pneumonia severity score (PSS, OR: 6.486, 95% CI: 2.082~21.416) and lactate dehydrogenase (LDH, OR: 3.857, 95% CI: 1.571~10.266). A short-term prognostic nomogram was developed based on the five independent risk factors above. The area under the receiver operating characteristic (ROC) curve (AUC) of the nomogram model was 0.857. The calibration curve confirmed the outcomes of the prognostic model, which exhibited excellent consistency with the actual results. Conclusion: In summary, gender, age, pectoral muscle index, pneumonia severity score, and lactate dehydrogenase are all independent risk factors for COVID-19 mortality. Thus, the nomogram based on the above indicators can predict the risk of mortality in COVID-19 patients. This may have the potential of being clinical application in prognostic evaluation of COVID-19.

Co-crystal structure provides insights on transaminase CrmG recognition amino donor L-Arg.

ω-transaminase has attracted growing attention for chiral amine synthesis, although it commonly suffers from severe by-product inhibition. ω-transaminase CrmG is critical for the biosynthesis of Caerulomycin A, a natural product that possesses broad bioactivity, including immunosuppressive and anti-cancer. Compared to L-Arg, amino donor L-Glu, L-Gln or L-Ala is more preferred by CrmG. In this study, we determined the crystal structure of CrmG in complex with amino donor L-Arg, unveiling the detailed binding mode. Specifically, L-Arg exhibits an extensive contact with aromatic residues F207 and W223 on the roof of CrmG active site via cation-π network. This interaction may render the deamination by-product of L-Arg to be an inhibitor against PMP-bound CrmG by stabilizing its flexible roof, thus reducing the reactivity of L-Arg as an amino donor for CrmG. These data provide further evidence to support our previous proposal that CrmG can overcome inhibition from those by-products that are not able to stabilize the flexible roof of active site in PMP-bound CrmG. Thus, our result can not only facilitate the biosynthesis of CRM A but also be beneficial for the rational design of ω-transaminase to bypass by-product inhibition.

Additional neoadjuvant immunotherapy does not increase the risk of anastomotic leakage after esophagectomy for esophageal squamous cell carcinoma: a multicenter retrospective cohort study.

PURPOSE: Neoadjuvant chemoimmunotherapy (nICT) is a novel and promising therapy model for locally advanced esophageal squamous cell carcinoma.The objective of this study aimed to assessed the impact of additional neoadjuvant immunotherapy on patients' short-term outcomes, particularly the incidence of anastomotic leakage (AL) and pathological response. METHODS: Patients with locally advanced esophageal squamous cell carcinoma who received neoadjuvant chemotherapy (nCT)/ nICT combination with radical esophagectomy were enrolled from three medical centers in China. The authors used propensity score matching (PSM, ration:1:1, caliper=0.01) and inverse probability processing weighting (IPTW) to balance the baseline characteristics and compare the outcomes. Conditional logistic regression and weighted logistic regression analysis were used to further evaluate whether additional neoadjuvant immunotherapy would increase the risk of postoperative AL. RESULTS: A total of 331 patients getting partially advanced ESCC receiving nCT or nICT were enrolled from three medical centers in China. After PSM/IPTW, the baseline characteristics reached an equilibrium between the two groups. After matching, there were no significant difference in the AL incidence between the two groups ( P =0.68, after PSM; P =0.97 after IPTW), and the incidence of AL in the two groups was 15.85 versus 18.29%, and 14.79 versus 15.01%, respectively. After PSM/IPTW, both groups were similar in pleural effusion and pneumonia. After IPTW, the nICT group had a higher incidence of bleeding (3.36 vs. 0.30%, P =0.01), chylothorax (5.79 0.30%, P =0.001), and cardiac events (19.53 vs. 9.20%, P =0.04). recurrent laryngeal nerve palsy (7.85 vs. 0.54%, P =0.003). After PSM, both groups were similar in palsy of the recurrent laryngeal nerve (1.22 vs. 3.66%, P =0.31) and cardiac events (19.51 vs. 14.63%, P =0.41). Weighted logistic regression analysis showed that additional neoadjuvant immunotherapy was not responsible for AL (OR=0.56, 95% CI: [0.17, 1.71], after PSM; 0.74, 95% CI: [0.34,1.56], after IPTW). The nICT group had dramatically higher pCR in primary tumor than the nCT group ( P =0.003, PSM; P =0.005, IPTW), 9.76 versus 28.05% and 7.72 versus 21.17%, respectively. CONCLUSIONS: Additional neoadjuvant immunotherapy could benefit pathological reactions without increasing the risk of AL and pulmonary complications. The authors require further randomized controlled research to validate whether additional neoadjuvant immunotherapy would make a difference in other complications, and determine whether pathologic benefits could translate into prognostic benefits, which would require longer follow-up.

A millikelvin precision temperature control system designed for a low cost, portable and variable temperature blackbody from 298.15 to 693.15 K.

Millikelvin precision portable variable temperature blackbody from 298.15 to 693.15 K is very important in the on-site calibration of infrared measuring instruments. The stability of the blackbody temperature directly affects the calibration quality. However, the temperature measurement and control system is the key component to guarantee the stability of the blackbody temperature. In this article, a measurement and control system of the low-cost and portable blackbody was designed and verified. A Pt100 platinum resistance thermometer was employed to measure the temperature of the blackbody radiation source. Based on the round-robin structure and current reversing technology, the precision of the temperature measurement achieved a sub-millikelvin level. To overcome the drawbacks that traditional proportional integral derivative (PID) controller would lead to large overshoot and long adjustment time during the temperature control of the large thermal inertia blackbody, a feedforward and segmented PID controller was introduced to improve the dynamic performance of the blackbody radiation source. The experimental results showed that the precision of the temperature measurement at 0.5 Hz was better than 0.5 mK and the temperature stability within 10 min was better than 3 mK in the temperature range from 298.15 to 693.15 K. Hence, the millikelvin precision measurement and control system has a strong prospect for practical application in high-performance blackbody development.

Crystallization of Slag Films of CaO-Al2O3-BaO-CaF2-Li2O-Based Mold Fluxes for High-Aluminum Steels' Continuous Casting.

In this study, solidified films of CaO-Al2O3-BaO-CaF2-Li2O-based mold fluxes with different contents of Al2O3 addition were acquired by immersing an improved water-cooled copper probe in bulk molten slags. This probe can obtain films with representative structures. Different slag temperatures and probe immersion times were employed to investigate the crystallization process. The crystals in the solidified films were identified using X-ray diffraction, the morphologies of the crystals were observed using optical microscopy and scanning electron microscopy, and the kinetic conditions, especially the activation energy of devitrified crystallization in glassy slags, were calculated and discussed based on the differential scanning calorimetry. The results indicated that after adding extra Al2O3, the growing speed and thickness of the solidified films increased, and more time was required for the film thickness to reach a steady state. In addition, fine spinel (MgAl2O4) precipitated in the films at the early stage of solidification after adding 10 wt% of extra Al2O3. Together with LiAlO2, spinel (MgAl2O4) acted as nuclei for the precipitation of BaAl2O4. The apparent activation energy of initial devitrified crystallization decreased from 314.16 KJ/mol (original slag) to 297.32 KJ/mol (5 wt% Al2O3 added) and 269.46 KJ/mol (10 wt% Al2O3 added). The crystallization ratio of the films also increased after adding extra Al2O3.

Efficacy and Safety of Neoadjuvant Chemoimmunotherapy in Resectable Esophageal Squamous Cell Carcinoma: A Meta-analysis.

PURPOSE: This study aimed to summarize the efficacy and safety of neoadjuvant chemoimmunotherapy in resectable esophageal squamous cell carcinoma (ESCC). METHODS: Literature focusing on the efficacy and safety of neoadjuvant immunotherapy or chemoimmunotherapy in resectable ESCC published before June 2022 was retrieved from PubMed, Embase, Cochrane Library, and Web of Science. The risk of bias was assessed using the Cochrane risk-of-bias assessment tool. Subgroup and sensitivity analyses were further performed. RESULTS: A total of 452 patients from 15 studies were included in this meta-analysis. All of the studies explored the efficacy and safety of neoadjuvant chemoimmunotherapy. The pooled major pathological response (MPR) rate and pathological complete response (PCR) rate were 58.3% and 32.9%, respectively. The pooled incidence of treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were 91.6% and 19.4%, respectively. The pooled R0 resection rate was 92.8%, and the resection rate was 81.1%. Incidence of anastomotic leakage, pulmonary infection, and postoperative hoarseness were 10.7%, 21.3%, and 13.0%, respectively. Compared with 2 cycles of neoadjuvant therapy, patients who received > 2 cycles of neoadjuvant therapy showed higher MPR rate (57.3% vs. 61.1%) and PCR rate (30.6% vs. 37.9%), and the incidence of TRAEs (89.2% vs. 98.9%) tended to be higher. However, no significant difference was found (P > 0.05). Two cycles of neoadjuvant therapy showed higher R0 resection rate and resection rate (R0 resection rate: 96.0% vs. 87.8%, P = 0.02; resection rate: 85.6% vs. 74.7%, P = 0.01). Pembrolizumab- and tislelizumab-based neoadjuvant therapy showed higher MPR rate (72.4% and 72.2%) and PCR rate (41.5 % and 50.0%). Compared with other ICIs, tislelizumab-based neoadjuvant therapy showed lower R0 resection rate (80.5%). The pooled incidence of SAEs for pembrolizumab-based neoadjuvant therapy (2.0%) was lower. Camrelizumab-based neoadjuvant therapy showed lower incidence of pulmonary infection (11.5%). CONCLUSIONS: Neoadjuvant chemoimmunotherapy is effective and safe for resectable ESCC.

You Exude What You Eat: How Carbon-, Nitrogen-, and Sulfur-Rich Organic Substrates Shape Microbial Community Composition and the Dissolved Organic Matter Pool.

Phytoplankton is the major source of labile organic matter in the sunlit ocean, and they are therefore key players in most biogeochemical cycles. However, studies examining the heterotrophic bacterial cycling of specific phytoplankton-derived nitrogen (N)- and sulfur (S)-containing organic compounds are currently lacking at the molecular level. Therefore, the present study investigated how the addition of N-containing (glycine betaine [GBT]) and S-containing (dimethylsulfoniopropionate [DMSP]) organic compounds, as well as glucose, influenced the microbial production of new organic molecules and the microbial community composition. The chemical composition of microbial-produced dissolved organic matter (DOM) was analyzed by ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) demonstrating that CHO-, CHON-, and CHOS-containing molecules were enriched in the glucose, GBT, and DMSP experiments, respectively. High-throughput sequencing showed that Alteromonadales was the dominant group in the glucose, while Rhodobacterales was the most abundant group in both the GBT and DMSP experiments. Cooccurrence network analysis furthermore indicated more complex linkages between the microbial community and organic molecules in the GBT compared with the other two experiments. Our results shed light on how different microbial communities respond to distinct organic compounds and mediate the cycling of ecologically relevant compounds. IMPORTANCE Nitrogen (N)- and sulfur (S)-containing compounds are normally considered part of the labile organic matter pool that fuels heterotrophic bacterial activity in the ocean. Both glycine betaine (GBT) and dimethylsulfoniopropionate (DMSP) are representative N- and S-containing organic compounds, respectively, that are important phytoplankton cellular compounds. The present study therefore examined how the microbial community and the organic matter they produce are influenced by the addition of carbohydrate-containing (glucose), N-containing (GBT), and S-containing (DMSP) organic compounds. The results demonstrate that when these carbon-, N-, and S-rich compounds are added separately, the organic molecules produced by the bacteria growing on them are enriched in the same elements. Similarly, the microbial community composition was also distinct when different compounds were added as the substrate. Overall, this study demonstrates how the microbial communities metabolize and transform different substrates thereby, expanding our understanding of the complexity of links between microbes and substrates in the ocean.

Multiscale characterization reveals oligomerization dependent phase separation of primer-independent RNA polymerase nsp8 from SARS-CoV-2.

RNA replication and transcription machinery is an important drug target for fighting against coronavirus. Non-structure protein nsp8 was proposed harboring primase activity. However, the RNA primer synthesis mechanism of nsp8 is still largely unknown. Here, we purified dimer and tetramer forms of SARS-CoV-2 nsp8. Combined with dynamic light scattering, small-angle neutron scattering and thermo-stability analysis, we found that both dimer and tetramer become loosened and destabilized with decreasing salt concentration, and the dimer form is more stable than the tetramer form. Further investigation showed that nsp8 dimer and tetramer can undergo phase separation but exhibit different phase separation behaviors. Nsp8 dimer can form liquid-like droplets in the buffer with a low concentration of NaCl; phase separation of nsp8 tetramer depends on the assistance of RNA. Our findings on different phase separation behaviors of nsp8 dimer and tetramer may provide insight into the functional studies of nsp8 in coronavirus.

Structural Studies Reveal Unique Non-canonical Regulators of G Protein Signaling Homology (RH) Domains in Sorting Nexins.

As a subgroup of sorting nexins (SNXs) that contain regulator of G protein signaling homology (RH) domain, SNX-RH proteins, including SNX13, SNX14 and SNX25, were proposed to play bifunctional roles in protein sorting and GPCR signaling regulation. However, mechanistic details of SNX-RH proteins functioning via RH domain remain to be illustrated. Here, we delineate crystal structures of the RH domains of SNX13 and SNX25, revealing a homodimer of SNX13 RH domain mediated by unique extended α4 and α5 helices, and a thiol modulated homodimer of SNX25-RH triggered by a unique cysteine on α6 helix. Further studies showed that RH domains of SNX-RH do not possess binding capacity toward Gα subunits, owing to the lack of critical residues for interaction. Thus, this study identifies a group of novel non-canonical RH domains that can act as a dimerization module in sorting nexins, which provides structural basis for mechanism studies on SNX-RH protein functions.

Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors.

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 µM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.

Low-Frequency Bandgaps of the Lightweight Single-Phase Acoustic Metamaterials with Locally Resonant Archimedean Spirals.

In order to achieve the dual needs of single-phase vibration reduction and lightweight, a square honeycomb acoustic metamaterials with local resonant Archimedean spirals (SHAMLRAS) is proposed. The independent geometry parameters of SHAMLRAS structures are acquired by changing the spiral control equation. The mechanism of low-frequency bandgap generation and the directional attenuation mechanism of in-plane elastic waves are both explored through mode shapes, dispersion surfaces, and group velocities. Meanwhile, the effect of the spiral arrangement and the adjustment of the equation parameters on the width and position of the low-frequency bandgap are discussed separately. In addition, a rational period design of the SHAMLRAS plate structure is used to analyze the filtering performance with transmission loss experiments and numerical simulations. The results show that the design of acoustic metamaterials with multiple Archimedean spirals has good local resonance properties, and forms multiple low-frequency bandgaps below 500 Hz by reasonable parameter control. The spectrograms calculated from the excitation and response data of acceleration sensors are found to be in good agreement with the band structure. The work provides effective design ideas and a low-cost solution for low-frequency noise and vibration control in the aeronautic and astronautic industries.