Aging is associated with a modality-specific decline in taste.

Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders, including Alzheimer's disease (AD). The fruit fly, Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging and neurodegeneration on taste function remain largely unexplored. Aging impaired response to sugars, but not medium-chain fatty acids that are sensed by a shared population of neurons. Selective expression of the human amyloid beta (Aß) peptide phenocopied the effects of aging. Functional imaging of gustatory axon terminals revealed reduced response to sugar, but not fatty acids. Axonal innervation of the fly taste center was largely intact in aged flies; however, axonal innervation was reduced upon expression of Aß. A comparison of transcript expression within the sugar-sensing taste neurons revealed age-related changes in 66 genes. Together, these findings suggest that different mechanisms underly taste deficits in aged and AD model flies.

Platelet factors ameliorate thoracic aortic aneurysm and dissection by inhibiting the FGF-FGFR cascade activation in aortic-endothelial cell.

Thoracic aortic aneurysm and dissection (TAAD) is closely associated with vascular endothelial dysfunction. Platelet factor 4 (PF4) is crucial for maintaining vascular endothelial cell homeostasis. However, whether PF4 can influence the progression of TAAD remains unknown. In the present study, we constructed a liposome-encapsulated PF4 nanomedicine and verified its effect on BAPN-induced TAAD in vivo. We found that liposome PF4 nanoparticles (Lipo-PF4), more effectively than PF4 alone, inhibited the formation of TAAD. In vitro, PF4 improved endothelial cell function under pathological conditions by inhibiting migratory and angiogenic abilities of human aortic endothelial cells (HAECs). Mechanically, PF4 inhibited the development of TAAD and improved HAECs function by combining with heparin sulfate and blocking fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling. Taken together, we developed a nano-drug (Lipo-PF4) that effectively ameliorates the progression of TAAD by improving endothelial function. Lipo-PF4 is expected to be a therapeutic option for TAAD in the future.

An inhibitory acetylcholine receptor gates context-dependent mechanosensory processing in C. elegans.

An animal's current behavior influences its response to sensory stimuli, but the molecular and circuit-level mechanisms of this context-dependent decision-making are not well understood. Caenorhabditis elegans are less likely to respond to a mechanosensory stimulus by reversing if the stimuli is received while the animal turns. Inhibitory feedback from turning associated neurons are needed for this gating. But until now, it has remained unknown precisely where in the circuit gating occurs and which specific neurons and receptors receive inhibition from the turning circuitry. Here, we use genetic manipulations, single-cell rescue experiments, and high-throughput closed-loop optogenetic perturbations during behavior to reveal the specific neuron and receptor responsible for receiving inhibition and altering sensorimotor processing. Our measurements show that an inhibitory acetylcholine-gated chloride channel comprising LGC-47 and ACC-1 expressed in neuron type RIM disrupts mechanosensory evoked reversals during turns, presumably in response to inhibitory signals from turning-associated neuron SAA.

Population genomic analysis reveals a polygenic sex determination system in Apostichopus japonicus.

The sea cucumber Apostichopus japonicus, a key species in Chinese aquaculture, plays a significant evolutionary role within the Echinodermata phylum. However, the sex determination mechanism in this species remains poorly understood. Here, we conducted extensive sex surveys and sampling of eight wild populations, investigating the sex-related SNPs and insertion or deletions (indels) through bulk segregation analysis (BSA) and genome-wide association study (GWAS) analysis. Our findings suggest that A. japonicus employs a polygenic sex determination (PSD) system, with solute carrier family 8 (SLC8A) being the candidate gene for sex determination, encoding sodium-calcium exchanger (NCX1). The analysis of normalized sequencing depth reveals variations across chromosomes 6, 13, 14, 16, and 18, supporting the PSD system. We also identified 541.656 kb of male-specific sequences and screened five markers (C77185, C98086, C64977, C125, and C876) for molecular sex identification. Overall, this study provides new insights into A. japonicus sex determination, highlighting a complex multi-gene mechanism rather than a simple XX/XY system.

Engineering branched ionizable lipid for hepatic delivery of clustered regularly interspaced short palindromic repeat-Cas9 ribonucleoproteins.

The delivery of the CRISPR/Cas ribonucleoprotein (RNP) has received attention for clinical applications owing to its high efficiency with few off-target effects. Lipid nanoparticles (LNPs) are potential non-viral vectors for the delivery of RNPs. Herein, we report the engineering of a branched scaffold structure of ionizable lipids for the hepatic delivery of RNPs. Both the total carbon number and branching position were critical for the functional delivery of RNPs. The optimal ionizable lipid exhibited a more than 98% reduction in transthyretin protein after a single dose with no obvious signs of toxicity. The mechanistic study has revealed that optimal LNPs have a unique "flower-like structure" that depends on both the lipid structure and the payload and that these LNPs accumulate in hepatocytes in an apolipoprotein E-independent manner. These results represent a major step toward the realization of in vivo genome editing therapy via RNP delivery using chemically synthesizable LNP formulations.

Sirtuin 1/sirtuin 3 are robust lysine delactylases and sirtuin 1-mediated delactylation regulates glycolysis.

Lysine lactylation (Kla), an epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, bridges metabolism and gene regulation. Enzymes such as p300 and HDAC1/3 have been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Here, we identify SIRT1 and SIRT3 as key "erasers" of Kla, shedding light on their selective regulation of both histone and non-histone proteins. Proteomic analysis in SIRT1/SIRT3 knockout HepG2 cells reveals distinct substrate specificities toward Kla, highlighting their unique roles in cellular signaling. Notably, we highlight the role of specific Kla modifications, such as those on the M2 splice isoform of pyruvate kinase (PKM2), in modulating metabolic pathways and cell proliferation, thereby expanding Kla's recognized functions beyond epigenetics. Therefore, this study deepens our understanding of Kla's functional mechanisms and broadens its biological significance.

Effects of breast-fed infants-derived Limosilactobacillus reuteri and Bifidobacterium breve ameliorate DSS-induced colitis in mice.

Studies have shown that breastfeeding can reduce the risk and severity of inflammatory bowel disease (IBD) in children and adults. Probiotics in breast milk have also been isolated and their effects on IBD have been studied. However, based on current evidence, the exact efficacy and mechanisms of probiotics in the treatment of IBD cannot be determined. In this study, Bifidobacterium breve FPHC4024 (BB FPHC4024) and Limosilactobacillus reuteri FPHC2951 (LR FPHC2951) were isolated from feces of exclusively breastfed healthy infants and administered by gavage to dextran sulfate sodium (DSS)-induced IBD mice. The results showed that LR FPHC2951 improved the symptoms of DSS-induced IBD, increased the expression of interleukin (IL)-10 mRNA and upregulated the abundance of Verrucomicrobiaceae Akkermansia. Combined with Kyoto Encyclopedia of Genes and Genomes (KEGG)-based Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) function prediction results, we hypothesized that LR FPHC2951 improved DSS-induced colitis symptoms in mice by increasing of IL-10 mRNA, altering the structure of intestinal flora, and reducing proinflammatory pathways and enhancing pathways associated with anti-inflammatory and intestinal protection.

Expectations guide predictive eye movements and information sampling during face recognition.

Context information has a crucial impact on our ability to recognize faces. Theoretical frameworks of predictive processing suggest that predictions derived from context guide sampling of sensory evidence at informative locations. However, it is unclear how expectations influence visual information sampling during face perception. To investigate the effects of expectations on eye movements during face anticipation and recognition, we conducted two eye-tracking experiments (n = 34, each) using cued face morphs containing expected and unexpected facial features, and clear expected and unexpected faces. Participants performed predictive saccades toward expected facial features and fixated expected more often and longer than unexpected features. In face morphs, expected features attracted early eye movements, followed by unexpected features, indicating that top-down as well as bottom-up information drives face sampling. Our results provide compelling evidence that expectations influence face processing by guiding predictive and early eye movements toward anticipated informative locations, supporting predictive processing.

Highly efficient generation of self-renewing trophoblast from human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) represent a powerful model system to study early developmental processes. However, lineage specification into trophectoderm (TE) and trophoblast (TB) differentiation remains poorly understood, and access to well-characterized placental cells for biomedical research is limited, largely depending on fetal tissues or cancer cell lines. Here, we developed novel strategies enabling highly efficient TE specification that generates cytotrophoblast (CTB) and multinucleated syncytiotrophoblast (STB), followed by the establishment of trophoblast stem cells (TSCs) capable of differentiating into extravillous trophoblast (EVT) and STB after long-term expansion. We confirmed stepwise and controlled induction of lineage- and cell-type-specific genes consistent with developmental biology principles and benchmarked typical features of placental cells using morphological, biochemical, genomics, epigenomics, and single-cell analyses. Charting a well-defined roadmap from hPSCs to distinct placental phenotypes provides invaluable opportunities for studying early human development, infertility, and pregnancy-associated diseases.

Rosiglitazone retards the progression of iron overload-induced osteoarthritis by impeding chondrocyte ferroptosis.

Ferroptosis is implicated in several diseases, including iron overload-induced osteoarthritis (IOOA), which is marked by oxidative stress, iron imbalance, and lipid peroxidation. Given rosiglitazone's (RSG) ability to inhibit lipid peroxidation and ferroptosis, this study aims to assess its therapeutic potential for treating IOOA. Our in vitro results show that RSG targets acyl-CoA synthetase long-chain family member 4 to mitigate impairments induced by interleukin-1 beta and ferric ammonium citrate, including cell apoptosis, senescence, inflammatory responses, extracellular matrix degradation, and ferroptosis. RSG reduced intracellular iron content, alleviated oxidative stress and lipid peroxidation, mitigated damage to membrane-bound organelles, and enhanced glucose transport. Additionally, pre-treatment with RSG imparted anti-ferroptotic properties to chondrocytes. In vivo, RSG alleviated cartilage degradation, inflammatory responses, and ferroptosis in mice with IOOA. In conclusion, RSG exhibits chondroprotective and anti-ferroptotic effects by suppressing lipid peroxidation and restoring iron homeostasis, highlighting its potential for treating IOOA.

Endocrine gland size is proportional to its target tissue size.

Endocrine glands secrete hormones into the circulation to target distant tissues and regulate their functions. The qualitative relationship between hormone-secreting organs and their target tissues is well established, but a quantitative approach is currently limited. Quantification is important, as it could allow us to study the endocrine system using engineering concepts of optimality and tradeoffs. In this study, we collected literature data on 24 human hormones secreted from dedicated endocrine cells. We find that the number of endocrine cells secreting a hormone is proportional to the number of its target cells. A single endocrine cell serves approximately 2,000 target cells, a relationship that spans 6 orders of magnitude of cell numbers. This suggests an economic principle of cells working near their maximal capacity, and glands that are no bigger than they need to be.

Cronobacter sakazakii induced sepsis-associated arrhythmias through its outer membrane vesicles.

Sepsis-induced arrhythmia, linked to sudden cardiac death, is associated with gut microbiota, though the exact relationship is unclear. This study aimed to elucidate the relationship between Cronobacter sakazakii (C. sakazakii) and arrhythmia. The relative abundance of C. sakazakii was increased in cecal ligation and puncture (CLP)-induced septic mice. Live C. sakazakii, supernatant, and outer membrane vesicles (OMVs) resulted in premature ventricular beat (PVB), sinus arrhythmia (SA), and increased arrhythmia and mortality in sepsis model through dysregulated ion channel proteins. Moreover, short-chain fatty acids (SCFAs) showed antibacterial effects in vitro. We confirmed sodium acetate (C2) and sodium butyrate (C4) protect from C. sakazakii-induced arrhythmia, and C2 and C4 protected from septic arrhythmia by activating free fatty acid receptor 2 and 3 (FFAR2 and FFAR3) in mice. These findings point to how C. sakazakii's OMVs trigger arrhythmia, and SCFAs may be a treatment for septic arrhythmia.

Specified functions of the first two fixations in face recognition: Sampling the general-to-specific facial information.

Visual perception is enacted and constrained by the constantly moving eyes. Although it is well known that the first two fixations are crucial for face recognition, the function of each fixation remains unspecified. Here we demonstrate a central-to-divergent pattern of the two fixations and specify their functions: Fix I clustered along the nose bridge to cover the broad facial information; Fix II diverged to eyes, nostrils, and lips to get the local information. Fix II correlated more than Fix I with the differentiating information between faces and contributed more to recognition responses. While face categories can be significantly discriminated by Fix II's but not Fix I's patterns alone, the combined patterns of the two yield better discrimination. Our results suggest a functional division and collaboration of the two fixations in sampling the general-to-specific facial information and add to understanding visual perception as an active process undertaken by structural motor programs.

Human RP105 monoclonal antibody enhances antigen-specific antibody production in unique culture conditions.

Detecting antibodies, particularly those targeting donor human leukocyte antigens in organ transplantation and self-antigens in autoimmune diseases, is crucial for diagnosis and therapy. Radioprotective 105 (RP105), a Toll-like receptor family protein, is expressed in immune-competent cells, such as B cells. Studies in mice have shown that the anti-mouse RP105 antibody strongly activates B cells and triggers an adjuvant effect against viral infections. However, the anti-human RP105 antibody (ɑhRP105) weakly activates human B cells. This study established new culture conditions under, which human B cells are strongly activated by the ɑhRP105. When combined with CpGDNA, specific antibody production against blood group carbohydrates, ɑGal, and SARS-CoV-2 was successfully detected in human B cell cultures. Furthermore, comprehensive analysis using liquid chromatography-electrospray ionization tandem mass spectrometry, single-cell RNA sequencing, and quantitative real-time PCR revealed that ɑhRP105 triggered a different activation stimulus compared to CpGDNA. These findings could help identify antibody-producing B cells in cases of transplant rejection and autoimmune diseases.

An ensemble deep learning model for predicting minimum inhibitory concentrations of antimicrobial peptides against pathogenic bacteria.

The rise of antibiotic resistance necessitates effective alternative therapies. Antimicrobial peptides (AMPs) are promising due to their broad inhibitory effects. This study focuses on predicting the minimum inhibitory concentration (MIC) of AMPs against whom-priority pathogens: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853. We developed a comprehensive regression model integrating AMP sequence-based and genomic features. Using eight AI-based architectures, including deep learning with protein language model embeddings, we created an ensemble model combining bi-directional long short-term memory (BiLSTM), convolutional neural network (CNN), and multi-branch model (MBM). The ensemble model showed superior performance with Pearson correlation coefficients of 0.756, 0.781, and 0.802 for the bacterial strains, demonstrating its accuracy in predicting MIC values. This work sets a foundation for future studies to enhance model performance and advance AMP applications in combating antibiotic resistance.

FNIP1 suppresses colorectal cancer progression through inhibiting STAT3 phosphorylation and nuclear translocation.

Folliculin interacting protein 1 (FNIP1) primarily participates in regulating cellular energy metabolism and is associated with Birt-Hogg-Dubé (BHD) syndrome. Although FNIP1 has been demonstrated to function as both a tumor suppressor and promoter, its role in colorectal cancer (CRC) remains unclear. Our study demonstrated a significant downregulation of FNIP1 in CRC, correlating with shorter overall and disease-specific survival. FNIP1 may potentially serve as an independent prognostic factor in CRC. Moreover, FNIP1 inhibited CRC progression in vitro and in vivo. Mechanistically, FNIP1 bound to phosphorylated signal transducer and activator of transcription-3 (p-STAT3) and downregulated its expression. FNIP1 deletion increased STAT3 phosphorylation and nuclear localization, thereby promoting CRC progression. The use of p-STAT3-specific chemical inhibitors successfully mitigated excessive tumorigenesis resulting from FNIP1 absence. Thus, our results suggest that FNIP1 hinders CRC progression by suppressing STAT3 phosphorylation and nuclear translocation. FNIP1 may be a candidate prognostic indicator and a therapeutic target for intervention in CRC.

Asymmetry in synaptic connectivity balances redundancy and reachability in the Caenorhabditis elegans connectome.

The brain is overall bilaterally symmetrical, but also exhibits considerable asymmetry. While symmetry may endow neural networks with robustness and resilience, asymmetry may enable parallel information processing and functional specialization. How is this tradeoff between symmetrical and asymmetrical brain architecture balanced? To address this, we focused on the Caenorhabditis elegans connectome, comprising 99 classes of bilaterally symmetrical neuron pairs. We found symmetry in the number of synaptic partners between neuron class members, but pronounced asymmetry in the identity of these synapses. We applied graph theoretical metrics for evaluating Redundancy, the selective reinforcement of specific neural paths by multiple alternative synaptic connections, and Reachability, the extent and diversity of synaptic connectivity of each neuron class. We found Redundancy and Reachability to be stochastically tunable by the level of network asymmetry, driving the C. elegans connectome to favor Redundancy over Reachability. These results elucidate fundamental relations between lateralized neural connectivity and function.

Cordycepin exhibits both antiviral and anti-inflammatory effects against dengue virus infection.

Cordycepin, a natural derivative of adenosine from Cordyceps militaris, can inhibit the replication of the dengue virus (DENV). Here, we investigated its antiviral and anti-inflammatory effects in DENV infected cells. Cordycepin significantly inhibited DENV-2 infection, virion production, and viral protein synthesis. It also reduced DENV-induced cytokine/chemokine production, including RANTES, IP-10, IL-6, and TNF-α. Mechanistically, cordycepin targeted the DENV NS5 protein, suppressing RANTES expression and hindering viral replication. Additionally, it inhibited the NF-κB pathway, leading to reduced nuclear translocation and signaling deactivation. PCR array analysis revealed cordycepin's suppression of 46 genes associated with DENV-induced inflammation. These findings highlight cordycepin's dual potential as an antiviral and anti-inflammatory agent against DENV, making it as a promising candidate for dengue treatment, targeting both viral and host factors.

A functional role for glycosylated B7-H5/VISTA immune checkpoint protein in metastatic clear cell renal cell carcinoma.

Increased expression of the B7 family of immune checkpoint proteins hinders tumor elimination by the immune system. Expression levels of the B7-H5 protein were found to be upregulated in clear cell renal cell carcinomas (ccRCC). We here report the molecular, functional, and clinical characterization of B7-H5 from renal cancer cells and metastatic ccRCC tumors. B7-H5 was highly glycosylated and mainly expressed in the cell membrane. Mutagenic studies on B7-H5 identified the residues targeted by N-glycosylation and revealed an impact of B7-H5 glycosylation on protein expression levels and localization. B7-H5 knockdown decreased the cell proliferation and viability of renal cancer cells. We analyzed B7-H5 expression on tumor cells and tumor-infiltrated leukocytes (TILs) in samples from metastatic ccRCC patients and found that B7-H5 expression on TILs correlated with syncronous metastases and poor outcomes. These results provide insights into the molecular properties and clinical impact of B7-H5 and support B7-H5 as a new immunotherapeutic target in metastatic ccRCC.

Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.

Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins. Here, we showed that overexpressed M1 spastin localizes in ER-mitochondria intersections and that endogenous spastin accumulates in MERCs. We demonstrated in different cellular models that downregulation of spastin enhances the number of MERCs, alters mitochondrial morphology, and impairs ER and mitochondrial calcium homeostasis. These effects are associated with reduced mitochondrial membrane potential, oxygen species levels, and oxidative metabolism. These findings extend our knowledge on the role of spastin in the ER and suggest MERCs deregulation as potential causes of SPG4-HSP disease.