Protein lipoylation: mitochondria, cuproptosis, and beyond.

Protein lipoylation, a crucial post-translational modification (PTM), plays a pivotal role in mitochondrial function and emerges as a key player in cell death through cuproptosis. This novel copper-driven cell death pathway is activated by excessive copper ions binding to lipoylated mitochondrial proteins, disrupting energy production and causing lethal protein aggregation and cell death. The intricate relationship among protein lipoylation, cellular energy metabolism, and cuproptosis offers a promising avenue for regulating essential cellular functions. This review focuses on the mechanisms of lipoylation and its significant impact on cell metabolism and cuproptosis, emphasizing the key genes involved and their implications for human diseases. It offers valuable insights into targeting dysregulated cellular metabolism for therapeutic purposes.

iGWAS: Image-based genome-wide association of self-supervised deep phenotyping of retina fundus images.

Existing imaging genetics studies have been mostly limited in scope by using imaging-derived phenotypes defined by human experts. Here, leveraging new breakthroughs in self-supervised deep representation learning, we propose a new approach, image-based genome-wide association study (iGWAS), for identifying genetic factors associated with phenotypes discovered from medical images using contrastive learning. Using retinal fundus photos, our model extracts a 128-dimensional vector representing features of the retina as phenotypes. After training the model on 40,000 images from the EyePACS dataset, we generated phenotypes from 130,329 images of 65,629 British White participants in the UK Biobank. We conducted GWAS on these phenotypes and identified 14 loci with genome-wide significance (p<5×10-8 and intersection of hits from left and right eyes). We also did GWAS on the retina color, the average color of the center region of the retinal fundus photos. The GWAS of retina colors identified 34 loci, 7 are overlapping with GWAS of raw image phenotype. Our results establish the feasibility of this new framework of genomic study based on self-supervised phenotyping of medical images.

Poly(U)-specific endoribonuclease ENDOU promotes translation of human CHOP mRNA by releasing uORF element-mediated inhibition.

Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2α phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced. We analyzed a 105-nt inhibitory uORF in the transcript of human CHOP (huORFchop ) and found that overexpression of the zebrafish or human ENDOU poly(U)-endoribonuclease (Endouc or ENDOU-1, respectively) increases CHOP mRNA translation also in the absence of stress. We also found that Endouc/ENDOU-1 binds and cleaves the huORFchop transcript at position 80G-81U, which induces CHOP translation independently of phosphorylated eIF2α. However, both ENDOU and phospho-eIF2α are nonetheless required for maximal translation of CHOP mRNA. Increased levels of ENDOU shift a huORFchop reporter as well as endogenous CHOP transcripts from the monosome to polysome fraction, indicating an increase in translation. Furthermore, we found that the uncapped truncated huORFchop -69-105-nt transcript contains an internal ribosome entry site (IRES), facilitating translation of the cleaved transcript. Therefore, we propose a model where ENDOU-mediated transcript cleavage positively regulates CHOP translation resulting in increased CHOP protein levels upon stress. Specifically, CHOP transcript cleavage changes the configuration of huORFchop thereby releasing its inhibition and allowing the stalled ribosomes to resume translation of the downstream ORF.

Translation initiation landscape profiling reveals hidden open-reading frames required for the pathogenesis of tomato yellow leaf curl Thailand virus.

Plant viruses with densely packed genomes employ noncanonical translational strategies to increase the coding capacity for viral function. However, the diverse translational strategies used make it challenging to define the full set of viral genes. Here, using tomato yellow leaf curl Thailand virus (TYLCTHV, genus Begomovirus) as a model system, we identified genes beyond the annotated gene sets by experimentally profiling in vivo translation initiation sites (TISs). We found that unanticipated AUG TISs were prevalent and determined that their usage involves alternative transcriptional and/or translational start sites and is associated with flanking mRNA sequences. Specifically, two downstream in-frame TISs were identified in the viral gene AV2. These TISs were conserved in the begomovirus lineage and led to the translation of different protein isoforms localized to cytoplasmic puncta and at the cell periphery, respectively. In addition, we found translational evidence of an unexplored gene, BV2. BV2 is conserved among TYLCTHV isolates and localizes to the endoplasmic reticulum and plasmodesmata. Mutations of AV2 isoforms and BV2 significantly attenuated disease symptoms in tomato (Solanum lycopersicum). In conclusion, our study pinpointing in vivo TISs untangles the coding complexity of a plant viral genome and, more importantly, illustrates the biological significance of the hidden open-reading frames encoding viral factors for pathogenicity.

The benefits of contributing to the citizen science platform iNaturalist as an identifier.

As the number of observations submitted to the citizen science platform iNaturalist continues to grow, it is increasingly important that these observations can be identified to the finest taxonomic level, maximizing their value for biodiversity research. Here, we explore the benefits of acting as an identifier on iNaturalist.

Nanoconfinement Enables Photoelectrochemical Selective Oxidation of Glycerol via the Microscale Fluid Effect.

The glycerol oxidation reaction (GOR) run with photoelectrochemical cells (PECs) is one of the most promising ways to upgrade biomass because it is thermodynamically favorable, while irreversible overoxidation leads to unsatisfactory product selectivities. Herein, a tunable one-dimensional nanoconfined environment was introduced into the GOR process, which accelerated mass transfer of glycerol via the microscale fluid effect and changed the main oxidation product from formic acid (FA) to glyceraldehyde (GLD), which led to retention of the heavier multicarbon products. The rate of glycerol diffusion in the nanochannels increased by a factor of 4.92 with decreasing inner diameters. The main product from the PEC-selective oxidation of glycerol changed from the C1 product FA to the C3 product GLD with a great selectivity of 60.7%. This work provides a favorable approach for inhibiting further oxidation of multicarbon products and illustrates the importance of microenvironmental regulation in biomass oxidation.

Picometer-Scale Atomic Shifts Governing Subdisordered Structures in Diamond.

Diamond is considered the most promising next-generation semiconductor material due to its excellent physical characteristics. It has been more than three decades since the discovery of a special structure named n-diamond. However, despite extensive efforts, its crystallographic structure and properties are still unclear. Here, we show that subdisordered structures in diamond provide an explanation for the structural feature of n-diamond. Monocrystalline diamond with subdisordered structures is synthesized via the chemical vapor deposition method. Atomic-resolution scanning transmission electron microscopy characterizations combined with the picometer-precision peak finder technology and diffraction simulations reveal that picometer-scale shifts of atoms within cells of diamond govern the subdisordered structures. First-principles calculations indicate that the bandgap of diamond decreases rapidly with increasing shifting distance, in accordance with experimental results. These findings clarify the crystallographic structure and electronic properties of n-diamond and provide new insights into the bandgap adjustment in diamond.

Comprehensively analysis of IL33 in hepatocellular carcinoma prognosis, immune microenvironment and biological role.

IL33 plays an important role in cancer. However, the role of liver cancer remains unclear. Open-accessed data was obtained from the Cancer Genome Atlas, Xena, and TISCH databases. Different algorithms and R packages are used to perform various analyses. Here, in our comprehensive study on IL33 in HCC, we observed its differential expression across cancers, implicating its role in cancer development. The single-cell analysis highlighted its primary expression in endothelial cells, unveiling correlations within the HCC microenvironment. Also, the expression level of IL33 was correlated with patients survival, emphasizing its potential prognostic value. Biological enrichment analyses revealed associations with stem cell division, angiogenesis, and inflammatory response. IL33's impact on the immune microenvironment showcased correlations with diverse immune cells. Genomic features and drug sensitivity analyses provided insights into IL33's broader implications. In a pan-cancer context, IL33 emerged as a potential tumour-inhibitor, influencing immune-related molecules. This study significantly advances our understanding of IL33 in cancer biology. IL33 exhibited differential expression across cancers, particularly in endothelial cells within the HCC microenvironment. IL33 is correlated with the survival of HCC patients, indicating potential prognostic value and highlighting its broader implications in cancer biology.

Unveiling the role of the KLF4/Lnc18q22.2/ULBP3 axis in the tumorigenesis and immune escape of hepatocellular carcinoma under hypoxic condition.

Hepatocellular carcinoma (HCC) represents a significant global health burden, necessitating an in-depth exploration of its molecular underpinnings to facilitate the development of effective therapeutic strategies. This investigation delves into the complex role of long non-coding RNAs (lncRNAs) in the modulation of hypoxia-induced HCC progression, with a specific emphasis on delineating and functionally characterizing the novel KLF4/Lnc18q22.2/ULBP3 axis. To elucidate the effects of hypoxic conditions on HCC cells, we established in vitro models under both normoxic and hypoxic environments, followed by lncRNA microarray analyses. Among the lncRNAs identified, Lnc18q22.2 was found to be significantly upregulated in HCC cells subjected to hypoxia. Subsequent investigations affirmed the oncogenic role of Lnc18q22.2, highlighting its critical function in augmenting HCC cell proliferation and migration. Further examination disclosed that Kruppel-like factor 4 (KLF4) transcriptionally governs Lnc18q22.2 expression in HCC cells, particularly under hypoxic stress. KLF4 subsequently enhances the tumorigenic capabilities of HCC cells through the modulation of Lnc18q22.2 expression. Advancing downstream in the molecular cascade, our study elucidates a novel interaction between Lnc18q22.2 and UL16-binding protein 3 (ULBP3), culminating in the stabilization of ULBP3 protein expression. Notably, ULBP3 was identified as a pivotal element, exerting dual functions by facilitating HCC tumorigenesis and mitigating immune evasion in hypoxia-exposed HCC cells. The comprehensive insights gained from our research delineate a hitherto unidentified KLF4/Lnc18q22.2/ULBP3 axis integral to the understanding of HCC tumorigenesis and immune escape under hypoxic conditions. This newly unveiled molecular pathway not only enriches our understanding of hypoxia-induced HCC progression but also presents novel avenues for therapeutic intervention.

Macrophage-like rapid uptake and toxicity of tattoo ink in human monocytes.

Macrophages play a critical role for the persistence of tattoo ink in human skin. However, a comparison to other skin-resident and blood circulating immune cells and a profound analysis of REACH-compliant tattoo ink are unmet medical needs. We hence characterized the size distribution of ink particles using physicochemical methods. We studied the uptake of tattoo ink by key human skin cells and blood-derived immune cells using optical and electron microscopy as well as flow cytometry. Scanning electron microscopy of ink revealed its crystalline structure, and a tendency towards aggregations was indicated by size changes upon diluting it. Flow cytometric analyses of skin and immune cells after incubation with tattoo ink demonstrated an increase in cellular granularity upon uptake and red ink additionally evoked fluorescent signals. Human macrophages were most potent in internalizing ink in full thickness 3D skin models. Macrophage cultures demonstrated that the ink did not lead to elevated inflammatory mediators, and showed no indications for toxicity, even after nice days. Strikingly, monocytes were most efficient in ink uptake, but displayed reduced viability, whereas granulocytes and lymphocytes showed only temporary ink uptake with flow cytometric signals declining after 1 day. Mechanistic studies on ink retention by corticosteroids or dexpanthenol in macrophage cultures demonstrated that these compounds do not lead to ink excretion, but even slightly increase the ink load in macrophages. The highly motile monocytes, precursors of macrophages, may play an underrated role for tattoo ink translocation from dermal blood vessels into internal organs.

BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir.

Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.

Accurate Collisional Cross Section Measurement by Multipass Cyclic Ion Mobility Spectrometry.

Ion mobility-mass spectrometry (IM-MS) is a powerful analytical tool for structural characterization. IM measurement provides collision cross section (CCS) values that facilitate analyte identification. While CCS values can be directly calculated from mobility measurements obtained using drift tube ion mobility spectrometry (DT-IMS), this method has limited mobility resolution due to the practical constraints on the length of the ion drift path. Consequently, DT-IMS cannot differentiate analytes with similar mobilities or resolve fine mobility features of individual ions. Cyclic IMS (cIMS) instruments leverage a cyclic path enabled by traveling wave ion mobility (TWIM) technology and offer increased mobility solution to address this challenge. While TWIM devices must first be calibrated to enable CCS measurements, current calibration strategies are primarily tailored for single-pass analyses. This preference is partly attributed to the challenges associated with multipass calibration methods, which require both calibrants and analytes to experience the same number of passes. Achieving this consistency can be complicated due to factors like peak splitting and diffusion, and may not be feasible for online IM-MS analyses. A recent report employed average ion velocities obtained from multiple measurements under different separation pathlengths as a path length-independent metric for CCS calibration. However, the ability to exploit this averaging approach is limited by observed variation in ion drift time/velocity in these measurements. In this study, we introduce a novel calibration strategy designed for multipass cIMS analyses, directly targeting the root cause for the path length- and mobility-dependent variations in ion drift time. With this method, we demonstrate that CCS values derived from multipass measurements closely align with those obtained from single-pass analyses, with an average deviation of 0.1%. We apply this method to characterize four isomeric trisaccharides. Our approach not only results in excellent agreement between our measured cIMSCCS values and the reported DTCCS values, with an average difference of only 0.5%, but also allows us to effectively identify subtle mobility characteristics of each compound and determine their respective CCS values. This level of detail and accuracy was previously unattainable using DT-IMS or single-pass cIMS measurements. We developed an algorithm for reconstructing arrival time distribution in cases where wrap-around has resulted in peak splitting. Collectively, the new calibration strategy and the reconstruction procedure maintain reproducibility and precision in CCS measurements while largely eliminating the need for meticulous selection of separation times. We expect that our method will empower researchers to harness the high mobility resolution offered by multipass cIMS analyses without compromising the accuracy of CCS measurement, making it appropriate for straightforward use across a wide range of applications.

Direct and Detailed Site-Specific Glycopeptide Characterization by Higher-Energy Electron-Activated Dissociation Tandem Mass Spectrometry.

Glycosylation is widely recognized as the most complex post-translational modification due to the widespread presence of macro- and microheterogeneities, wherein its biological consequence is closely related to both the glycosylation sites and the glycan fine structures. Yet, efficient site-specific detailed glycan characterization remains a significant analytical challenge. Here, utilizing an Orbitrap-Omnitrap platform, higher-energy electron-activated dissociation (heExD) tandem mass spectrometry (MS/MS) revealed extraordinary efficacy for the structural characterization of intact glycopeptides. HeExD produced extensive fragmentation within both the glycan and the peptide, including A-/B-/C-/Y-/Z-/X-ions from the glycan motif and a-/b-/c-/x-/y-/z-type peptide fragments (with or without the glycan). The intensity of cross-ring cleavage and backbone fragments retaining the intact glycan was highly dependent on the electron energy. Among the four electron energy levels investigated, electronic excitation dissociation (EED) provided the most comprehensive structural information, yielding a complete series of glycosidic fragments for accurate glycan topology determination, a wealth of cross-ring fragments for linkage definition, and the most extensive peptide backbone fragments for accurate peptide sequencing and glycosylation site localization. The glycan fragments observed in the EED spectrum correlated well with the fragmentation patterns observed in EED MS/MS of the released glycans. The advantages of EED over higher-energy collisional dissociation (HCD), stepped collision energy HCD (sceHCD), and electron-transfer/higher-energy collisional dissociation (EThcD) were demonstrated for the characterization of a glycopeptide bearing a biantennary disialylated glycan. EED can produce a complete peptide backbone and glycan sequence coverage even for doubly protonated precursors. The exceptional performance of heExD MS/MS, particularly EED MS/MS, in site-specific detailed glycan characterization on an Orbitrap-Omnitrap hybrid instrument presents a novel option for in-depth glycosylation analysis.

Highly Stretchable, Biodegradable, and Recyclable Green Electronic Substrates.

As a steady stream of electronic devices being discarded, a vast amount of electronic substrate waste of petroleum-based nondegradable polymers is generated, raising endless concerns about resource depletion and environmental pollution. With coupled reagent (CR)-grafted artificial marble waste (AMW@CR) as functional fillers, polylactic acid (PLA)-based highly stretchable biodegradable green composite (AMW@CR-SBGC) is prepared, with elongation at break up to more than 250%. The degradation mechanism of AMW@CR-SBGC is deeply revealed. AMW@CR not only contributed to the photodegradation of AMW@CR-SBGC but also significantly promoted the water degradation of AMW@CR-SBGC. More importantly, AMW@CR-SBGC showed great potential as sustainable green electronic substrates and AMW@CR-SBGC-based electronic skin can simulate the perception of human skin to strain signals. The outstanding programmable degradability, recyclability, and reusability of AMW@CR-SBGC enabled its application in transient electronics. As the first demonstration of artificial marble waste in electronic substrates, AMW@CR-SBGC killed three birds with one stone in terms of waste resourcing, e-waste reduction, and saving nonrenewable petroleum resources, opening up vast new opportunities for green electronics applications in areas such as health monitoring, artificial intelligence, and security.

Dressing Paraffin Wax/Boron Nitride Phase Change Composite with a Polyethylene "Underwear" for the Reliable Battery Safety Management.

Phase change material (PCM) can provide a battery system with a buffer platform to respond to thermal failure problems. However, current PCMs through compositing inorganics still suffer from insufficient thermal-transport behavior and safety reliability against external force. Herein, a best-of-both-worlds method is reported to allow the PCM out of this predicament. It is conducted by combining a traditional PCM (i.e., paraffin wax/boron nitride) with a spirally weaved polyethylene fiber fabric, just like the traditional PCM is wearing functional underwear. On the one hand, the spirally continuous thermal pathways of polyethylene fibers in the fabric collaborate with the boron nitride network in the PCM, enhancing the through-plane and in-plane thermal conductivity to 10.05 and 7.92 W m-1 K, respectively. On the other, strong polyethylene fibers allow the PCM to withstand a high puncture strength of 47.13 N and tensile strength of 18.45 MPa although above the phase transition temperature. After this typical PCM packs a triple Li-ion battery system, the battery can be promised reliable safety management against both thermal and mechanical abuse. An obvious temperature drop of >10 °C is observed in the battery electrode during the cycling charging and discharging process.

A Rapid, Scalable Laser-Scribing Process to Prepare Si/Graphene Composites for Lithium-Ion Batteries.

Silicon has gained significant attention as a lithium-ion battery anode material due to its high theoretical capacity compared to conventional graphite. Unfortunately, silicon anodes suffer from poor cycling performance caused by their extreme volume change during lithiation and de-lithiation. Compositing silicon particles with 2D carbon materials, such as graphene, can help mitigate this problem. However, an unaddressed challenge remains: a simple, inexpensive synthesis of Si/graphene composites. Here, a one-step laser-scribing method is proposed as a straightforward, rapid (≈3 min), scalable, and less-energy-consuming (≈5 W for a few minutes under air) process to prepare Si/laser-scribed graphene (LSG) composites. In this research, two types of Si particles, Si nanoparticles (SiNPs) and Si microparticles (SiMPs), are used. The rate performance is improved after laser scribing: SiNP/LSG retains 827.6 mAh g-1 at 2.0 A gSi+C -1, while SiNP/GO (before laser scribing) retains only 463.8 mAh g-1. This can be attributed to the fast ion transport within the well-exfoliated 3D graphene network formed by laser scribing. The cyclability is also improved: SiNP/LSG retains 88.3% capacity after 100 cycles at 2.0 A gSi+C -1, while SiNP/GO retains only 57.0%. The same trend is found for SiMPs: the SiMP/LSG shows better rate and cycling performance than SiMP/GO composites.

Development of Physiologically Relevant Skin Organoids from Human Induced Pluripotent Stem Cells.

The development of skin organs for studying developmental pathways, modeling diseases, or regenerative medicine purposes is a major endeavor in the field. Human induced pluripotent stem cells (hiPSCs) are successfully used to derive skin cells, but the field is still far from meeting the goal of creating skin containing appendages, such as hair follicles and sweat glands. Here, the goal is to generate skin organoids (SKOs) from human skin fibroblast or placental CD34+ cell-derived hiPSCs. With all three hiPSC lines, complex SKOs with stratified skin layers and pigmented hair follicles are generated with different efficacies. In addition, the hiPSC-derived SKOs develop sebaceous glands, touch-receptive Merkel cells, and more importantly eccrine sweat glands. Together, physiologically relevant skin organoids are developed by direct induction of embryoid body formation, along with simultaneous inactivation of transforming growth factor beta signaling, activation of fibroblast growth factor signaling, and inhibition of bone morphogenetic protein signaling pathways. The skin organoids created in this study can be used as valuable platforms for further research into human skin development, disease modeling, or reconstructive surgeries.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Thrombomodulin Improves Cognitive Deficits in Heat-Stressed Mice.

BACKGROUND: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed mice. METHODS: Adult male mice were exposed to HS (33 oC 2h daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble thrombomodulin (TM, 1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide, high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were measured biochemically. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. RESULTS: Compared to controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. CONCLUSIONS: The findings suggest that heat stress can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. Thrombomodulin, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.

Comparison of Mini Nutritional Assessment Tool and Geriatric Nutrition Risk Index in Predicting 12-Y Mortality Among Community-Dwelling Older Persons.

BACKGROUND: Malnutrition is a common and dangerous condition in older adults, which has been associated with increased risk of mortality. OBJECTIVES: This study aimed to evaluate and compare the abilities of Mini Nutritional Assessment short form (MNA-SF), MNA full form (MNA-FF), and geriatric nutritional risk index (GNRI) to predict all-cause and expanded cardiovascular disease (CVD)-related mortality in community-dwelling older adults. METHODS: This research was an observational cohort study conducted in a community setting, with a 12-y follow-up involving 1001 community-living older adults aged 65 y or older who were enrolled in 2009 and followed up until 2021. Nutritional status assessment was carried out in 2009 using MNA-SF, MNA-FF, and GNRI. Multivariate Cox proportional hazards regression was applied to determine adjusted hazard ratios of mortality with 95% CIs. RESULTS: A total of 368 deaths (36.76%) and 122 expanded CVD-related deaths (12.19%) were observed after a median follow-up of 12 y. Compared with normal nutritional status, poor nutritional status assessed by the MNA-SF, MNA-FF, and GNRI was found to be associated with an increased all-cause mortality in older persons. MNA-SF and MNA-FF, but not GNRI, were associated with expanded CVD-related mortality. The MNA-FF showed better discriminatory accuracy for all-cause (C-statistics: 0.77; 95% CI: 0.63, 0.79) and expanded CVD-related mortality (C-statistics: 0.79; 95% CI: 0.70, 0.83) than MNA-SF (C-statistics: 0.76; 95% CI: 0.73-0.79; and C-statistics: 0.76; 95% CI: 0.72-0.81, respectively) and GNRI (C-statistics: 0.75; 95% CI: 0.73-0.79; and C-statistics: 0.76; 95% CI: 0.72-0.80, respectively). CONCLUSIONS: Our findings indicate that MNA-SF, MNA-FF, and GNRI were all independent predictors of all-cause mortality. In particular, the MNA-FF may be the best nutritional assessment tool for predicting all-cause and CVD-related mortality among older persons residing in community, compared with MNA-SF and GNRI.