BHLHE40 drives protective polyfunctional CD4 T cell differentiation in the female reproductive tract against Chlamydia.

The protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor recently emerged as a key regulator of host immunity to infections, autoimmune diseases and cancer. In this study, we investigated the role of Bhlhe40 in protective T cell responses to the intracellular bacterium Chlamydia in the female reproductive tract (FRT). Mice deficient in Bhlhe40 exhibited severe defects in their ability to control Chlamydia muridarum shedding from the FRT. The heightened bacterial burdens in Bhlhe40-/- mice correlated with a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased polyfunctional CD4 T cells co-producing IFN-γ, IL-17A and GM-CSF. Genetic ablation of IL-10 or functional blockade of IL-10R increased CD4 T cell polyfunctionality and partially rescued the defects in bacterial control in Bhlhe40-/- mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures in Bhlhe40-deficient CD4 T cells, whereas WT CD4 T cells were further down on the differentiation trajectory with distinct effector functions beyond IFN-γ production by Th1 cells. Altogether, we identified Bhlhe40 as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT against Chlamydia.

Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies.

ABSTRACT: We report a first-in-human clinical trial using chimeric antigen receptor (CAR) T cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies. Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T cells. CAR-37 T cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4 of 5 patients. Tumor responses were observed in 4 of 5 patients with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in 2 of these patients, efforts to ablate CAR-37 T cells, which were engineered to coexpress truncated epidermal growth factor receptor, with cetuximab were unsuccessful. Hematopoiesis was restored in these 2 patients after allogeneic hematopoietic stem cell transplantation. No other severe, nonhematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of interleukin-18 (IL-18) with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients than in both cytopenic and noncytopenic cohorts of CAR-19-treated patients. In conclusion, CAR-37 T cells exhibited antitumor activity, with significant CAR expansion and cytokine production. CAR-37 T cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant. This trial was registered at www.ClinicalTrials.gov as #NCT04136275.

Bright light treatment counteracts stress-induced sleep alterations in mice, via a visual circuit related to the rostromedial tegmental nucleus.

Light in the environment greatly impacts a variety of brain functions, including sleep. Clinical evidence suggests that bright light treatment has a beneficial effect on stress-related diseases. Although stress can alter sleep patterns, the effect of bright light treatment on stress-induced sleep alterations and the underlying mechanism are poorly understood. Here, we show that bright light treatment reduces the increase in nonrapid eye movement (NREM) sleep induced by chronic stress through a di-synaptic visual circuit consisting of the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), lateral habenula (LHb), and rostromedial tegmental nucleus (RMTg). Specifically, chronic stress causes a marked increase in NREM sleep duration and a complementary decrease in wakefulness time in mice. Specific activation of RMTg-projecting LHb neurons or activation of RMTg neurons receiving direct LHb inputs mimics the effects of chronic stress on sleep patterns, while inhibition of RMTg-projecting LHb neurons or RMTg neurons receiving direct LHb inputs reduces the NREM sleep-promoting effects of chronic stress. Importantly, we demonstrate that bright light treatment reduces the NREM sleep-promoting effects of chronic stress through the vLGN/IGL-LHb-RMTg pathway. Together, our results provide a circuit mechanism underlying the effects of bright light treatment on sleep alterations induced by chronic stress.

Three-Dimensional DNA Hydrogel Mediated Dual-Mode Sensing Method for Quantification of Epithelial Cell Adhesion Molecule in Biological Fluid Samples.

Monitoring changes in the expression of marker proteins in biological fluids is essential for biomarker-based disease diagnosis. Epithelial cell adhesion molecule (EpCAM) has been identified as a broad-spectrum biomarker for various chronic diseases and as a therapeutic target. However, the development of simple and reliable methods for quantifying EpCAM changes in biological fluids faces challenges due to the variability of its expression across different diseases, the presence of soluble forms, and matrix effects. In this paper, a surface-enhanced Raman scattering (SERS)-fluorescence (FL) dual-mode sensing method was established for quantification of trace EpCAM in biological fluids based on bimetallic Au@Ag nanoparticles and nitrogen-doped quantum dots encapsulated DNA hydrogel hybrid with graphene oxide (Au@Ag-NQDs/GO). The DNA hydrogel was constructed based on three-dimensional (3D) structure DNA-mediated strategy using an aptamer DNA (AptDNA) linker. The interaction of the AptDNA with EpCAM triggered the disassembly of the DNA hydrogel. Consequently, the release of Au@Ag nanoparticles induced an "on-off" switch in the SERS signal while the weakened FL quenching effect in Au@Ag-NQDs/GO system achieved "off-on" switch of FL signal, enabling the simultaneous SERS-FL quantification of EpCAM. The established dual-mode method exhibited outstanding sensitivity and stability in quantifying EpCAM in the range of 0.5-60.0 pg/mL, with the limits of detection (LODs) of SERS and FL as 0.17 and 0.35 pg/mL, respectively. When applied for real sample analysis, the method showed satisfactory specificity and recoveries in cancer cells lysate, serum, and urine samples with RSDs of 2.8-6.3%, 4.0-6.3%, and 2.8-5.7%, respectively. The developed SERS-FL sensing method offered a sensitive, reliable, and practical quantification strategy for trace EpCAM in diverse biological fluid samples, which would benefit the early diagnosis of disease and further health management.

Identification and functional analysis of GmPasL regulating pod color in vegetable soybean.

BACKGROUND: Vegetable soybean is rich in nutrients and has a unique flavor. It is highly preferred by people because of its pharmacological activities, including those that regulate the intestines and lower blood pressure. The pod color of vegetable soybeans is an important quality that indicates their freshness and has a significant impact on their commercialization. RESULTS: In this study, pod color was evaluated in 301 vegetable soybean accessions collected from various regions. Genome-wide association analysis was carried out using the Mixed linear model (MLM), a total of 18 quantitative trait loci including 117 SNPs were detected. Two significant QTLs located on chromosomes 6 (qGPCL4 /qGPCa1/qGPCb2) and 18 (qGPCL10/qGPCb3) were consistently detected across different variables. Based on gene functional annotation, 30 candidate genes were identified in these two candidate intervals. Combined with transcriptome analysis, Glyma.18g241700 has been identified as a candidate gene for regulating pod color in vegetable soybeans. Glyma.18g241700 encodes a chlorophyll photosystem I subunit XI. which localizes to the chloroplast named GmPsaL, qRT-PCR analysis showed that GmPsaL was specifically highly expressed in developing pods. Furthermore, overexpression of GmPsaL in transgenetic Arabidopsis plants produced dark green pods. CONCLUSIONS: These findings may be useful for clarifying the genetic basis of the pod color of vegetable soybeans. The identified candidate genes may be useful for the genetic improvement of the appearance quality of vegetable soybeans.

Designing Heterodiatomic Carbon Hydrangea Superstructures via Machine Learning-Regulated Solvent-Precursor Interactions for Superior Zinc Storage.

Carbon superstructures with exquisite morphologies and functionalities show appealing prospects in energy realms, but the systematic tailoring of their microstructures remains a perplexing topic. Here, hydrangea-shaped heterodiatomic carbon superstructures (CHS) are designed using a solution phase manufacturing route, wherein machine learning workflow is applied to screen precursor-matched solvent for optimizing solvent-precursor interaction. Based on the established solubility parameter model and molecular growth kinetics simulation, ethanol as the optimal solvent stimulates thermodynamic solubilization and growth of polymeric intermediates to evoke CHS. Featured with surface-active motifs and consecutive charge transfer paths, CHS allows high accessibility of zincophilic sites and fast ion migration with low energy barriers. A anion-cation hybrid charge storage mechanism of CHS cathode is disclosed, which entails physical alternate uptake of Zn2+/CF3SO3 - ions at electroactive sites and chemical bipedal redox of Zn2+ ions with carbonyl/pyridine motifs. Such a beneficial electrochemistry contributes to all-round improvement in Zn-ion storage, involving excellent capacities (231 mAh g-1 at 0.5 A g-1; 132 mAh g-1 at 50 A g-1), high energy density (152 Wh kg-1), and long-lasting cyclability (100 000 cycles). This work expands the design versatilities of superstructure materials and will accelerate experimental procedures during carbon manufacturing through machine learning in the future.

ScRNA-seq reveals dark- and light-induced differentially expressed gene atlases of seedling leaves in Arachis hypogaea L.

Although the regulatory mechanisms of dark and light-induced plant morphogenesis have been broadly investigated, the biological process in peanuts has not been systematically explored on single-cell resolution. Herein, 10 cell clusters were characterized using scRNA-seq-identified marker genes, based on 13 409 and 11 296 single cells from 1-week-old peanut seedling leaves grown under dark and light conditions. 6104 genes and 50 transcription factors (TFs) displayed significant expression patterns in distinct cell clusters, which provided gene resources for profiling dark/light-induced candidate genes. Further pseudo-time trajectory and cell cycle evidence supported that dark repressed the cell division and perturbed normal cell cycle, especially the PORA abundances correlated with 11 TFs highly enriched in mesophyll to restrict the chlorophyllide synthesis. Additionally, light repressed the epidermis cell developmental trajectory extending by inhibiting the growth hormone pathway, and 21 TFs probably contributed to the different genes transcriptional dynamic. Eventually, peanut AHL17 was identified from the profile of differentially expressed TFs, which encoded protein located in the nucleus promoted leaf epidermal cell enlargement when ectopically overexpressed in Arabidopsis through the regulatory phytohormone pathway. Overall, our study presents the different gene atlases in peanut etiolated and green seedlings, providing novel biological insights to elucidate light-induced leaf cell development at the single-cell level.

TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

BACKGROUND: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. METHODS: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. CONCLUSIONS: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3', 5'-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.

Resting cell formation in the marine diatom Thalassiosira pseudonana.

Resting cells represent a survival strategy employed by diatoms to endure prolonged periods of unfavourable conditions. In the oceans, many diatoms sink at the end of their blooming season and therefore need to endure cold and dark conditions in the deeper layers of the water column. How they survive these conditions is largely unknown. We conducted an integrative analysis encompassing methods from histology, physiology, biochemistry, and genetics to reveal the biological mechanism of resting-cell formation in the model diatom Thalassiosira pseudonana. Resting-cell formation was triggered by a decrease in light and temperature with subsequent catabolism of storage compounds. Resting cells were characterised by an acidic and viscous cytoplasm and altered morphology of the chloroplast ultrastructure. The formation of resting cells in T. pseudonana is an energy demanding process required for a biophysical alteration of the cytosol and chloroplasts to endure the unfavourable conditions of the deeper ocean as photosynthetic organisms. However, most resting cells (> 90%) germinate upon return to favorable growth conditions.

Calculation and measurement of trapping stiffness in femtosecond optical tweezers.

Due to the characteristics of ultra-short pulse width and ultra-high peak power, femtosecond pulse laser can effectively induce nonlinear optical effects in trapped objects. As a result, it holds great value in the fields of micro and nano manipulation, microfluidics, and cell biology. However, the nonlinear optical effects on the stiffness of femtosecond optical traps remain unclear. Calibration of trap stiffness is crucial for accurately measuring forces and manipulating small particles. In this paper, we compare the stiffness between femtosecond optical traps and continuous wave optical traps. Experimental results demonstrate that the stiffness of the femtosecond optical trap in the splitting direction is greater than that in other directions and the stiffness of the continuous wave optical trap under the same laser power condition. Additionally, as the laser power increases, the stiffnesses of both the femtosecond optical trap and the continuous wave optical trap gradually increases. In contrast to a linear increase of the continuous wave optical trap, the stiffness of the femtosecond optical trap exhibits an exponential rise with increasing laser power. This research provides guidance and reference for improving the force measurement accuracy of femtosecond optical tweezer system.

High-efficiency single-frequency DBR fiber laser at 1091 nm utilizing a Yb:YAG crystal-derived silica fiber.

A single-frequency distributed Bragg Reflector (DBR) fiber laser operating at 1091 nm was demonstrated by using a Yb:YAG crystal-derived silica fiber (YDSF). The YDSF was prepared via the molten core (MC) method, with a Yb2O3 doping concentration of 5.60 wt.% in the core, resulting in a gain coefficient of 1.45 dB/cm at 1091 nm. Employing 0.8 cm of the YDSF, we attained a single-frequency laser with a maximum output power of 145 mW and a slope efficiency of 31.8%. The laser exhibited an optical signal-to-noise ratio (OSNR) exceeding 71 dB, a linewidth of ∼34 kHz, and a stabilized relative intensity noise (RIN) at -132 dB/Hz for frequencies over 4.5 MHz. The fiber laser could serve as an outstanding seed source for high-power, narrow-linewidth fiber amplifiers operating at 1091 nm.

A double-tuned 1 H/31 P coil for rabbit heart metabolism detection at 3 T.

Magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) employing proton nuclear resonance has emerged as a pivotal modality in clinical diagnostics and fundamental research. Nonetheless, the scope of MRI/MRS extends beyond protons, encompassing nonproton nuclei that offer enhanced metabolic insights. A notable example is phosphorus-31 (31 P) MRS, which provides valuable information on energy metabolites within the skeletal muscle and cardiac tissues of individuals affected by diabetes. This study introduces a novel double-tuned coil tailored for 1 H and 31 P frequencies, specifically designed for investigating cardiac metabolism in rabbits. The proposed coil design incorporates a butterfly-like coil for 31 P transmission, a four-channel array for 31 P reception, and an eight-channel array for 1 H reception, all strategically arranged on a body-conformal elliptic cylinder. To assess the performance of the double-tuned coil, a comprehensive evaluation encompassing simulations and experimental investigations was conducted. The simulation results demonstrated that the proposed 31 P transmit design achieved acceptable homogeneity and exhibited comparable transmit efficiency on par with a band-pass birdcage coil. In vivo experiments further substantiated the coil's efficacy, revealing that the rabbit with experimentally induced diabetes exhibited a lower phosphocreatine/adenosine triphosphate ratio compared with its normal counterpart. These findings emphasize the potential of the proposed coil design as a promising tool for investigating the therapeutic effects of novel diabetes drugs within the context of animal experimentation. Its capability to provide detailed metabolic information establishes it as an indispensable asset within this realm of research.

1283-1460 nm continuously tunable, watt-level bismuth-doped phosphosilicate fiber laser and its frequency doubling to a visible laser.

We report, to the best of our knowledge, the first demonstration of an O + E-band tunable watt-level bismuth-doped phosphosilicate fiber laser and its frequency doubling to tunable red laser. Benefiting from the two types of bismuth active centers associated with silicon and phosphorus introduced in one fiber, an ultrabroad gain is available in the designed low-water-peak bismuth-doped phosphosilicate fiber (Bi-PSF) pumped by a self-made 1239 nm Raman fiber laser. The high-efficiency tunable lasing is achieved with a maximum output power of 1.705 W around 1320 nm and a slope efficiency of 33.0%. The wavelength can be continuously tuned from 1283 to 1460 nm over a 177 nm spectral range, almost covering the whole O+E-bands. We further employ a polarization beam splitter in the cavity to output an O + E-band linear-polarization laser for second-harmonic generation by a designed multi-period MgO2:PPLN crystal, and a 650-690-nm tunable visible laser is correspondingly obtained. Such an O+E-wideband tunable high-power laser and the SHG red laser may have great potential in the all-band optical communications, biophotonics, and spectroscopy.

From Compressed-Sensing to Deep Learning MR: Comparative Biventricular Cardiac Function Analysis in a Patient Cohort.

BACKGROUND: Conventional segmented, retrospectively gated cine (Conv-cine) is challenged in patients with breath-hold difficulties. Compressed sensing (CS) has shown values in cine imaging but generally requires long reconstruction time. Recent artificial intelligence (AI) has demonstrated potential in fast cine imaging. PURPOSE: To compare CS-cine and AI-cine with Conv-cine in quantitative biventricular functions, image quality, and reconstruction time. STUDY TYPE: Prospective human studies. SUBJECTS: 70 patients (age, 39 ± 15 years, 54.3% male). FIELD STRENGTH/SEQUENCE: 3T; balanced steady state free precession gradient echo sequences. ASSESSMENT: Biventricular functional parameters of CS-, AI-, and Conv-cine were measured by two radiologists independently and compared. The scan and reconstruction time were recorded. Subjective scores of image quality were compared by three radiologists. STATISTICAL TESTS: Paired t-test and two related-samples Wilcoxon sign test were used to compare biventricular functional parameters between CS-, AI-, and Conv-cine. Intraclass correlation coefficient (ICC), Bland-Altman analysis, and Kendall's W method were applied to evaluate agreement of biventricular functional parameters and image quality of these three sequences. A P-value <0.05 was considered statistically significant, and standardized mean difference (SMD) < 0. 100 was considered no significant difference. RESULTS: Compared to Conv-cine, no statistically significant differences were identified in CS- and AI-cine function results (all P > 0.05), except for very small differences in left ventricle end-diastole volumes of 2.5 mL (SMD = 0.082) and 4.1 mL (SMD = 0.096), respectively. Bland-Altman scatter plots revealed that biventricular function results were mostly distributed within the 95% confidence interval. All parameters had acceptable to excellent interobserver agreements (ICC: 0.748-0.989). Compared with Conv-cine (84 ± 13 sec), both CS (14 ± 2 sec) and AI (15 ± 2 sec) techniques reduced scan time. Compared with CS-cine (304 ± 17 sec), AI-cine (24 ± 4 sec) reduced reconstruction time. CS-cine demonstrated significantly lower quality scores than Conv-cine, while AI-cine demonstrated similar scores (P = 0.634). CONCLUSION: CS- and AI-cine can achieve whole-heart cardiac cine imaging in a single breath-hold. Both CS- and AI-cine have the potential to supplement the gold standard Conv-cine in studying biventricular functions and benefit patients having difficulties with breath-holds. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.

BACKGROUND: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. METHODS: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8+ T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. RESULTS: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. CONCLUSIONS: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Genome-wide association study reveals the genetic basis of amino acids contents variations in Peanut (Arachis hypogaea L.).

Peanut is a significant source of protein for human consumption. One of the primary objectives in peanut breeding is the development of new cultivars with enhanced nutritional values. To further this goal, a genome-wide association study (GWAS) was conducted to analyze seed amino acids contents in 390 diverse peanut accessions collected worldwide, mainly from China, India, and the United States, in 2017 and 2018. These accessions were assessed for their content of 10 different amino acids. Variations in amino acids contents were observed, and arginine (Arg) was found to have the highest average value among all the amino acids quantified. The geographical distribution of the accessions also revealed variations in amino acids contents. High and positive correlation coefficients were observed among the amino acids, suggesting linked metabolic pathways or genetic regulation. A total of 88 single nucleotide polymorphisms (SNPs) spanning various chromosomes were identified, each associated with different amino acids. By using a combination of GWAS, expression anlaysis, and genomic polymorphisim comparisions, the Ahy_A09g041582 (LAC15) gene located on chromrosome A09 was identified as the key candidate which might be involved in plant growth and regulation and may alter amino acids levels. Expression analysis indicated that Ahy_A09g041582 has higher expressions in the shells and seeds than other genes located in the candidate region. This study may help with marker-based breeding of peanuts with higher nutritional value and offers fresh insights into the genetic basis of the amino acids contents of peanuts.

Metagenomics and Stable Isotopes Uncover the Augmented Sulfide-Driven Autotrophic Denitrification in a Seasonally Hypoxic, Sulfate-Abundant Reservoir.

The mechanism governing sulfur cycling in nitrate reduction within sulfate-rich reservoirs during seasonal hypoxic conditions remains poorly understood. This study employs nitrogen and oxygen isotope fractionation in nitrate, along with metagenomic sequencing to elucidate the intricacies of the coupled sulfur oxidation and nitrate reduction process in the water column. In the Aha reservoir, a typical seasonally stratified water body, we observed the coexistence of denitrification, bacterial sulfide oxidation, and bacterial sulfate reduction in hypoxic conditions. This is substantiated by the presence of abundant N/S-related genes (nosZ and aprAB/dsrAB) and fluctuations in N/S species. The lower 15εNO3/18εNO3 ratio (0.60) observed in this study, compared to heterotrophic denitrification, strongly supports the occurrence of sulfur-driven denitrification. Furthermore, we found a robust positive correlation between the metabolic potential of bacterial sulfide oxidation and denitrification (p < 0.05), emphasizing the role of sulfide produced via sulfate reduction in enhancing denitrification. Sulfide-driven denitrification relied on ∑S2- as the primary electron donor preferentially oxidized by denitrification. The pivotal genus, Sulfuritalea, emerged as a central player in both denitrification and sulfide oxidation processes in hypoxic water bodies. Our study provides compelling evidence that sulfides assume a critical role in regulating denitrification in hypoxic water within an ecosystem where their contribution to the overall nitrogen cycle was previously underestimated.

Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Study of the Enantioselectivity and Recognition Mechanism of Allyl-ß-CD Modified Organic Polymer Monolithic Capillary Column.

Allyl-ß-CD was synthesized and used as the chiral functional monomer to prepare chiral organic polymer monolithic columns in capillary HPLC. First, the enantioselectivity of the prepared allyl-ß-CD modified organic polymer monolithic capillary columns was investigated. Then, the influences of enantioseparation conditions of chiral drugs were further explored. Finally, the recognition mechanism was studied by molecular docking with AutoDock. Complete enantioseparations of four chiral drugs as well as partial enantioseparations of eight chiral drugs have been achieved. Results showed that the RSD values for run-to-run, day-to-day, and column-to-column variations ranged from 1.2% to 4.6%, 1.4% to 4.7%, and 2.0% to 6.1%, respectively. The enantioselectivity factor rather than resolution is correlated with the binding free energy difference between enantiomers with allyl-ß-CD. Furthermore, the abundant ether bonds, hydroxyl groups, and hydrophobic cavities in cyclodextrin are responsible for the enantioseparation ability of the chiral monolithic capillary columns.