Characterization and Transcriptomic Analysis of Sorghum EIN/EIL Family and Identification of Their Roles in Internode Maturation.

Ethylene-insensitive 3/Ethylene-insensitive3-like proteins (EIN3/EIL) represent a group of transcription factors critical for the ethylene signaling transduction that manipulate downstream ethylene-responsive genes, thereby regulating plant growth, development, and stress responses. However, the identification, evolution, and divergence of the EIL family remain to be studied in Sorghum bicolor. Here, we identified eight SbEILs, which were expanded due to whole-genome-duplication (WGD) events. Characterization of the protein sequences and expression atlas demonstrates that the WGD-duplicated SbEILs could become divergent due to the differential expression patterns, rather than domain and motif architectures. Comparative expression analysis was performed between the RNA-seq data sets of internodes from several sorghum cultivars to understand the potential roles of SbEIL members in internode elongation and maturation. Our results identified SbEIL3 and 7 (the latter as a homolog of OsEIL7/OsEIL1) to be the highly expressed SbEIL genes in sorghum internodes and revealed a potential functional link between SbEIL7 and internode maturation. The co-expression analysis and comparative expression analysis with ethylene-regulated gene sets found that SbEIL7 was co-regulated with a set of ubiquitin-related protein degradation genes, suggesting possible involvement of SbEIL7 in protein degradation and processing during the post-anthesis stages. Altogether, our findings lay a foundation for future functional studies of ethylene signaling-mediated gene regulation and improvement of sorghum internode development.

Structural basis for the concerted antiphage activity in the SIR2-HerA system.

Recently, a novel two-gene bacterial defense system against phages, encoding a SIR2 NADase and a HerA ATPase/helicase, has been identified. However, the molecular mechanism of the bacterial SIR2-HerA immune system remains unclear. Here, we determine the cryo-EM structures of SIR2, HerA and their complex from Paenibacillus sp. 453MF in different functional states. The SIR2 proteins oligomerize into a dodecameric ring-shaped structure consisting of two layers of interlocked hexamers, in which each subunit exhibits an auto-inhibited conformation. Distinct from the canonical AAA+ proteins, HerA hexamer alone in this antiphage system adopts a split spiral arrangement, which is stabilized by a unique C-terminal extension. SIR2 and HerA proteins assemble into a ∼1.1 MDa torch-shaped complex to fight against phage infection. Importantly, disruption of the interactions between SIR2 and HerA largely abolishes the antiphage activity. Interestingly, binding alters the oligomer state of SIR2, switching from a dodecamer to a tetradecamer state. The formation of the SIR2-HerA binary complex activates NADase and nuclease activities in SIR2 and ATPase and helicase activities in HerA. Together, our study not only provides a structural basis for the functional communications between SIR2 and HerA proteins, but also unravels a novel concerted antiviral mechanism through NAD+ degradation, ATP hydrolysis, and DNA cleavage.

An L-type calcium channel blocker nimodipine exerts anti-fibrotic effects by attenuating TGF-ß1 induced calcium response in an in vitro model of thyroid eye disease.

BACKGROUND: Thyroid eye disease (TED) is a vision-threatening autoimmune disorder. Orbital tissue fibrosis leading to intractable complications remains a troublesome issue in TED management. Exploration of novel therapeutic targets and agents to ameliorate tissue fibrosis is crucial for TED. Recent work suggests that Ca2+ signaling participates in tissue fibrosis. However, whether an alteration of Ca2+ signaling has a role in fibrogenesis during TED remains unclear. In this study, we aimed to investigate the role of Ca2+ signaling in the fibrogenesis process during TED and the potential therapeutic effects of a highly selective inhibitor of the L-type calcium channel (LTCC), nimodipine, through a TGF-ß1 induced in vitro TED model. METHODS: Primary culture of orbital fibroblasts (OFs) were established from orbital adipose connective tissues of patients with TED and healthy control donors. Real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing were used to assess the genes expression associated with LTCC in OFs. Flow cytometry, RT-qPCR, 5-ethynyl-2'-deoxyuridine (EdU) proliferation assay, wound healing assay and Western blot (WB) were used to assess the intracellular Ca2+ response on TGF-ß1 stimulation, and to evaluate the potential therapeutic effects of nimodipine in the TGF-ß1 induced in vitro TED model. The roles of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 1 (STAT1) in fibrogenesis during TED were determined by immunohistochemistry, WB, flow cytometry and co-immunoprecipitation assay. Selective inhibitors were used to explore the downstream signaling pathways. RESULTS: LTCC inhibitor nimodipine blocked the TGF-ß1 induced intracellular Ca2+ response and further reduced the expression of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (Col1A1) and collagen type I alpha 2 (Col1A2) in OFs. Besides, nimodipine inhibited cell proliferation and migration of OFs. Moreover, our results provided evidence that activation of the CaMKII/STAT1 signaling pathway was involved in fibrogenesis during TED, and nimodipine inhibited the pro-fibrotic functions of OFs by down-regulating the CaMKII/STAT1 signaling pathway. CONCLUSIONS: TGF-ß1 induces an LTCC-mediated Ca2+ response, followed by activation of CaMKII/STAT1 signaling pathway, which promotes the pro-fibrotic functions of OFs and participates in fibrogenesis during TED. Nimodipine exerts potent anti-fibrotic benefits in vitro by suppressing the CaMKII/STAT1 signaling pathway. Our work deepens our understanding of the fibrogenesis process during TED and provides potential therapeutic targets and alternative candidate for TED.

Dietary-timing-induced gut microbiota diurnal oscillations modulate inflammatory rhythms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by inflammatory activity with distinct rhythmic fluctuations. However, the precise mechanisms governing these inflammatory rhythms remain elusive. Here, we explore the interaction between dietary patterns, gut microbiota diurnal oscillations, and the rhythmicity of RA in both collagen-induced arthritis (CIA) mice and patients with RA and highlight the significance of dietary timing in modulating RA inflammatory rhythms linked to gut microbiota. Specifically, we discovered that Parabacteroides distasonis (P. distasonis) uses ß-glucosidase (ß-GC) to release glycitein (GLY) from the diet in response to daily nutritional cues, influencing RA inflammatory rhythms dependent on the sirtuin 5-nuclear factor-κB (SIRT5-NF-κB) axis. Notably, we validated the daily fluctuations of P. distasonis-ß-GC-GLY in patients with RA through continuous sampling across day-night cycles. These findings underscore the crucial role of dietary timing in RA rhythmicity and propose potential clinical implications for novel therapeutic strategies to alleviate arthritis.

Potential Roles of the GRF Transcription Factors in Sorghum Internodes during Post-Reproductive Stages.

Growth-regulating factor (GRF) is a plant-specific family of transcription factors crucial for meristem development and plant growth. Sorghum (Sorghum bicolor L. Moench) is a cereal species widely used for food, feed and fuel. While sorghum stems are important biomass components, the regulation of stem development and the carbohydrate composition of the stem tissues remain largely unknown. Here, we identified 11 SbGRF-encoding genes and found the SbGRF expansion driven by whole-genome duplication events. By comparative analyses of GRFs between rice and sorghum, we demonstrated the divergence of whole-genome duplication (WGD)-derived OsGRFs and SbGRFs. A comparison of SbGRFs' expression profiles supports that the WGD-duplicated OsGRFs and SbGRFs experienced distinct evolutionary trajectories, possibly leading to diverged functions. RNA-seq analysis of the internode tissues identified several SbGRFs involved in internode elongation, maturation and cell wall metabolism. We constructed co-expression networks with the RNA-seq data of sorghum internodes. Network analysis discovered that SbGRF1, 5 and 7 could be involved in the down-regulation of the biosynthesis of cell wall components, while SbGRF4, 6, 8 and 9 could be associated with the regulation of cell wall loosening, reassembly and/or starch biosynthesis. In summary, our genome-wide analysis of SbGRFs reveals the distinct evolutionary trajectories of WGD-derived SbGRF pairs. Importantly, expression analyses highlight previously unknown functions of several SbGRFs in internode elongation, maturation and the potential involvement in the metabolism of the cell wall and starch during post-anthesis stages.

Sub-picometer level all-solid-state narrow linewidth single-frequency Pr3+:LiYF4 laser in the near-infrared spectral region.

We report an all-solid-state near-infrared single-frequency (single longitudinal mode, SLM) Pr3+:LiYF4 (Pr:YLF) laser with the spectral linewidth at the sub-picometer level. The SLM lasers with center wavelengths of 868 and 907 nm are realized in Pr:YLF crystal for the first time to the best of our knowledge. The maximum output powers of SLM lasers at 868 and 907 nm are 102  and 213mW, corresponding to the narrowest spectral linewidths of 82 MHz (0.21 pm) and 94 MHz (0.26 pm), respectively. At the maximum output power, the beam quality factors in the x and y directions are measured as 1.25 and 1.16 at 868 nm and 1.21 and 1.13 at 907 nm, respectively. The output power stabilities of the 868 and 907 nm SLM lasers are calculated as 1.39% and 0.87%, respectively. The successful realization of 868 and 907 nm all-solid-state SLM lasers makes up for the gap that the Pr:YLF SLM lasers developed in the past are focused on the visible region, enriches the types of near-infrared (NIR) SLM lasers, and can provide practical applications in biomedicine, cold atom physics, and optical atom manipulation.

Antiviral Chlorinated Drimane Meroterpenoids from the Fungus Talaromyces pinophilus LD-7 and Their Biosynthetic Pathway.

Ten new drimane meroterpenoids talarines A-J (1-10), along with six known analogues (11-16), were isolated from desert soil-derived fungus Talaromyces pinophilus LD-7. Their 2D structures were elucidated by comprehensive interpretation of NMR and HRESIMS data. Electronic circular dichroism calculation was used to establish their absolute configurations. Compounds 2, 10, and 11 showed antiviral activities toward vesicular stomatitis virus with IC50 values of 18, 15, and 23 nM, respectively. The structure-bioactivity relationship indicated that chlorine substitution at C-5 contributed greatly to their antiviral activities. Finally, we identified a new halogenase outside the biosynthetic gene cluster, which was responsible for C-5 halogenation of the precursor isocoumarin 17 as a tailoring step in chlorinated meroterpenoids assembly.

Capsaicin exerts synergistic pro-apoptotic effects with cisplatin in TSCC through the calpain pathway via TRPV1.

Capsaicin (CAP) exerts significant anti-tumor effects on a variety of tumors, with low intrinsic toxicity. Cisplatin (DDP) is currently the first-line drug for the treatment of oral cancer; however, its clinical efficacy is impeded by chemoresistance and negligible side effects. Whether the combined use of CAP and DDP has a synergistic antitumor effect on tongue squamous cell carcinoma (TSCC) cells and its underlying mechanisms remains unclear. The present study revealed that CAP reduced the activity of TSCC cells in a dose- and time-dependent manner. We also observed changes in the mitochondrial functional structure of TSCC cells, along with the induction of mitochondrial apoptosis. Moreover, when CAP was combined with DDP, a synergistic cytotoxic effect on TSCC cells was observed, which had a significant impact on inducing apoptosis, inhibiting proliferation, and disrupting the mitochondrial membrane potential in TSCC cells compared to the single-drug treatment and control groups. These effects are associated with TRPV1, a high-affinity CAP receptor. The combined use of CAP and DDP can activate the TRPV1 receptor, resulting in intracellular Ca2+ overload and activation of the calpain pathway, ultimately leading to mitochondrial apoptosis. This potential mechanism was validated in TSCC xenograft models. In conclusion, our findings clearly demonstrate that CAP exerts synergistic pro-apoptotic effects with DDP in TSCC through the calpain pathway mediated by TRPV1. Thus, CAP can be considered an effective adjuvant drug for DDP in the treatment of TSCC.

Working Memory Guides Action Valuation in Model-based Decision-making Strategy.

Humans use both model-free (or habitual) and model-based (or goal-directed) strategies in sequential decision-making. Working memory (WM) is essential for the model-based strategy; however, its exact role in these processes remains elusive. This study investigates the influence of WM processes on decision-making and the underlying cognitive computing mechanisms. Specifically, we used experimental data from two-stage decision tasks and found that delay and load, two WM-specific variables, impact goal-revisiting behaviors. Then, we proposed possible computational mechanisms by which WM participates in information processing and integrated them into the model-based system. The proposed Hybrid-WM model reproduced the observed experimental effects and fit human behavior better than the classic hybrid reinforcement learning model. These results were verified with independent data sets. Furthermore, differences in model parameters explain the age-related difference in sequential decision-making. Overall, this study suggests that WM guides action valuation in model-based strategies, highlighting the contribution of higher cognitive functions to sequential decision-making.

The impact of metabolic syndrome on clinical outcomes following total knee arthroplasty in osteoarthritis patients.

Background: Metabolic syndrome (MetS) is a combination of interconnected conditions, including insulin resistance, abdominal obesity, high blood pressure, and abnormal blood lipid levels. The objective of this research was to investigate the impact of MetS on the quality of life and clinical outcomes following total knee arthroplasty (TKA) in patients with osteoarthritis (OA). Methods: A retrospective descriptive study was conducted to enroll OA patients who underwent primary TKA at Zhongda Hospital, Southeast University from January 2015 to August 2019. A total of 83 OA patients who did and 144 (MetS group) who did not have MetS (non-MetS group) were included. An analysis was conducted on the patient's clinical data. Results: The two groups had similar results in terms of lengths of stay (P=0.93), hospital costs (P=0.24), and overall complication rates (P=0.99). There was no significant difference in the average erythrocyte sedimentation rate and C-reactive protein levels between the groups. However, the MetS group exhibited notably lower Hospital for Special Surgery knee scores and Short Form [36] health survey (SF-36) scores compared to the non-MetS group (both P>0.05) during the one-year follow-up period. Conclusions: OA patients who have MetS had significantly worse knee joint function and quality of life after TKA. There are certain constraints in the current research. First, it belongs to a single-center retrospective study. Further study will be necessary to determine the generality of this conclusion. Second, this study is retrospective, and the number of patients included is not large. Third, due to the diverse clinical groups in our hospital, it is challenging to comprehensively document all the clinical data of the patients involved in this study. Forth, this study did not compare the preoperative differences between the two groups, as well as analyze the postoperative improvement changes in depth. We will compare the preoperative and postoperative differences between the two groups in more depth in future large sample studies.