Biology subjects

Garcia, V.

Publications and source records attributed to Garcia, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Postprandial hypertriglyceridemia activates microglia to promote satiety via an ASC dependent signaling.

Reactive microglia are commonly considered neurotoxic and detrimental for brain functioning. Chronic consumption of a high-fat diet strongly activates microglia, disrupts the central control of energy metabolism, contributes to obesity, and promotes cognitive decline. In this study we report an unexpected beneficial function of microglia reaction at the time scale of a meal, whereby they promote satiety in a macronutrient-dependent manner. We show that murine microglia react to ingested dietary fat within three hours. Specifically, postprandial hypertriglyceridemia induced microglial hyper-ramification alongside with a transcriptional reprogramming promoting communication with neurons. This effect occurs in discrete brain areas, including the hypothalamus and the brainstem, which control hunger. Remarkably, microglia-specific genetic ablation of Apoptosis-associated Speck-like protein containing a CARD (named ASC), a master regulator of metabolism, immune function and cell shape, profoundly alters satiety following high-fat food consumption. These results reveal that microglia engage an immune signaling pathway to rapidly alert the neural circuits and activate an anorectic response that limits overconsumption of dietary fat. Unexpectedly, this regulatory process is sexually dimorphic, present in males only. Furthermore, we found that the postprandial microglial reaction is bypassed during obesity, providing a new therapeutic target to treat maladaptive eating disorders.

neuroscience↗

bioRxiv2026

Deformability screening identifies NUDT5 as a mediator of cellular mechanobiology

How cells deform, sense, and respond to mechanical cues drives physiological and disease processes ranging from development to cancer metastasis; however, unbiased approaches to identify mechanical mediators are lacking. We screened 1280 compounds to identify modulators of cancer cell deformability using a cellular filtration assay and identified 92 compounds that significantly reduced deformability of ovarian cancer cells; top hits also reduced migration and invasion. Connectivity mapping of the top 21 compounds identified NUDT5 (Nudix hydrolase 5) as a predicted mechanical mediator; transcriptomic analyses implicated NUDT5 in mechanobiology and metabolic processes. We confirmed that NUDT5 mediates intracellular ATP and cellular mechanical behaviors, including morphology and deformability. In ovarian cancer, increased NUDT5 levels were associated with higher tumor stage and worse patient survival; NUDT5 inhibition reduced migration and colony formation in vitro and peritoneal tumor burden in mice. These findings establish deformability-based screening as a platform for discovering mechanical mediators and identify NUDT5 as a therapeutic target in ovarian cancer. TeaserScreening cells based on deformability provides an unbiased approach to identify NUDT5 as a mediator of cell mechanics

cell biology↗

bioRxiv2026

APPNL-F knock-in Alzheimer's Disease model mice reveal etiological convergence of aging and amyloidosis

Alzheimers disease (AD) is the leading cause of dementia worldwide, with a steadily increasing prevalence. Despite the advent of some plaque-degrading therapies, early intervention strategies are still suboptimal, largely due to an incomplete understanding of how early pathological events of amyloid-{beta} (A{beta}) plaque deposition entail or accompany the neuroinflammatory processes that ensue. The APPNL-F mouse line is a second-generation endogenous-promoter knock-in AD model that represents a valuable tool to dissect disease mechanisms and evaluate therapeutic strategies. However, the early prodromal stage remains poorly characterized. Here we performed in-depth analyses in both homozygous (APPNL-F/NL-F) and heterozygous (APPNL-F/WT) mice at 3, 6, 9 and 12 months of age. Among a battery of behavioural tests, the first phenotype was observed at 9 months with defects in spatial memory. Using hypersensitive MSD-ELISA technology assays we quantified distinct A{beta} species and found that A{beta}42 oligomers, protofibrils, and fibrillar aggregates were detectable as early as 6 months of age in homozygous APPNL-F/NL-F mice. By 9 months, their A{beta}42 levels increased markedly and overt A{beta} plaques were detected, histologically associated with recruited glial cells. Targeted RT-qPCR analysis of neuroinflammation-related genes in the cortex also identified 9 months as a molecular tipping point in these middle aged APPNL-F mice. To characterize the etiological signal transduction at the cellular level, we isolated microglia, the brain resident immune cells, whose contribution to AD pathogenesis is now well established. Sequencing around 5,000 individual cells from both 12-month-old APPNL-F/NL-F and APPWT/WT CD11b+ myeloid cells revealed that the buildup of amyloidosis was associated with an accelerated shift of microglia from a homeostatic toward a senescent-like state. Together, these findings highlight the 6-12 month period of the APPNL-F/NL-F model as a powerful system to study the interdependence between microglial senescence and amyloidosis in driving AD progression.

neuroscience↗

bioRxiv2026

Non-HLA antibodies worsen the histological phenotype and prognosis of antibody mediated rejection in kidney allografts

IntroductionAntibody-mediated rejection (AMR) remains a leading cause of kidney allograft failure, with both HLA and non-HLA antibodies implicated in its pathogenesis. The contribution of non-HLA antibodies (non-HLA Abs) to microvascular inflammation (MVI) and graft outcome, particularly in cases lacking donor-specific anti-HLA antibodies (HLA-DSAs), remains incompletely understood. MethodsWe analyzed 571 post-transplant serum samples from 326 patients with histological features of AMR (AMRh) and 164 stable controls. Non-HLA Abs were detected using the previously developed Non-HLA Antibody Detection Immunoassay (NHADIA), and associations were examined with histological lesions, AMRh persistence, and graft outcomes. Biopsies were scored according to Banff 2022 criteria, and patients were stratified by HLA-DSA and NHADIA status. ResultsNHADIA values were significantly higher in AMRh patients compared to controls (P=0.0001), regardless of HLA-DSA status. NHADIA values correlated with the severity of glomerulitis, peritubular capillaritis and global MVI scores. In AMRh patients with HLA-DSAs, non-HLA Abs remained independently associated with MVI severity. Follow-up biopsies revealed persistent AMR lesions in patients with both HLA-DSAs and non-HLA Abs. Allograft survival was lowest in double-positive patients, and NHADIA positivity independently predicted graft loss (HR=2.25, 95% CI: 1.03-4.92, P=0.042). Incorporating NHADIA into the Banff classification reclassified 61% of AMRh cases as "double-positive AMRh," and identified new subgroups with significant prognostic differences. ConclusionPost-transplant detection of non-HLA antibodies identifies a distinct subset of AMR with more severe histology and worse graft prognosis, particularly when coexisting with HLA-DSAs. Integrating non-HLA Ab testing into current diagnostic frameworks may refine AMR classification and improve risk stratification. TRANSLATIONAL STATEMENTThis study highlights the clinical relevance of non-HLA antibodies, identified using our innovative endothelial cell-based assay (NHADIA), in kidney transplant recipients. Their presence is associated with more severe antibody-mediated rejection (AMR) and poorer graft outcomes, even in the absence of donor-specific HLA antibodies. Incorporating non-HLA antibody detection into routine post-transplant evaluation may allow clinicians to better identify high-risk patients, including those previously classified as DSA-negative AMR. This expanded immunological profiling refines AMR diagnosis, improves risk stratification, and opens new avenues for personalized immunosuppressive strategies, ultimately enhancing long-term graft survival and patient care.

pathology↗

bioRxiv2025

Effects of Experimental Autoimmune Encephalomyelitis on Bladder Function and Properties of Pelvic Ganglion Neurons

Multiple sclerosis (MS) has substantial impacts on autonomic function. In part, MS results in loss of normal autonomic activity that contributes to disease-associated pathology such as neurogenic bladder, bowel, and sexual dysfunction. Yet little is known of the impacts of MS on peripheral autonomic neurons that directly innervate these target organs. In this study, we measured changes in properties of neurons of the mouse major pelvic ganglion (MPG) associated with two different levels of severity in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. Our data show that bladder function and physiological properties of MPG neurons are altered in association with EAE, and differ between less and more severe clinical scores associated with disease progression. EAE results in decreased bladder function measured by decreased urine output and increased micturition pressures. In the most severely affected animals, action potentials (APs) in MPG neurons show increased half-widths as a result of decreased maximum decay slopes leading to overall broader and longer APs and lower maximum firing frequency. These changes in AP properties are associated with differences in ion channel subunit expression as well. KCNA1-4, KCNN3 and SCN2A1 and SCN3A mRNA levels in MPGs decreased with disease severity. Taken together, our data indicate that peripheral autonomic neurons are fundamentally altered in EAE, suggesting that longer-term therapeutic approaches for MS could target these neurons directly to potentially help ameliorate neurogenic target organ dysfunction.

neuroscience↗

bioRxiv2025

Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer s disease

Early synaptic dysfunction is a hallmark of Alzheimers disease (AD), yet the astrocytic mechanisms underlying these alterations remain poorly defined. Here, we identify astrocyte perisynaptic processes (PAPs) as subcellular hotspots of early translational dysregulation in AD. Soluble A{beta}-2 rapidly enhanced global and local protein synthesis in primary astrocytes. In 5.5-month-old APP/PS1-dE9 (APP) mice, translating ribosome affinity purification (TRAP) revealed widespread remodeling of the PAP translatome, while whole-astrocyte translation remained largely unchanged. Dysregulated mRNAs were linked to neuroinflammation, synaptic remodeling, and endoplasmic reticulum stress, and alterations emerged prior to amyloid plaque deposition. Among them, Serpina3n exhibited increased mRNA abundance in PAPs, uncovering spatially restricted translational control. Mechanistically, early Serpina3n upregulation was partially driven by JAK-STAT3 signaling, with preferential effects in astrocyte processes. These findings reveal that local translation in astrocyte PAPs is an early and compartment-specific mechanism that may contribute to synaptic dysfunction and disease initiation in AD.

neuroscience↗

bioRxiv2025

Esca Disease triggers local transcriptomic response and systemic DNA methylation changes in grapevine

Woody plants such as grapevine are vulnerable to trunk diseases caused by pathogens that colonize the wood, disrupt vascular function, and induce recurrent leaf symptoms associated with major metabolic disturbances and canopy decline. Over time, these diseases can irreversibly alter plant physiology and phenotype, ultimately reducing vine longevity. One of the most predominant of such diseases is esca, which is a major cause of vineyard dieback, with rising incidence worldwide over the past decade. However, the molecular mechanisms underlying esca symptom development remain unclear. In this study, we leveraged the heterogeneous expression of esca-symptoms within individual grapevines to investigate molecular responses in both symptomatic and asymptomatic leaf tissues. By combining metabolite profiling, RNA-seq and whole genome bisulfite sequencing, we show that metabolic alterations and extensive transcriptomic reprogramming are restricted to symptomatic leaves and are partially associated with local changes in DNA methylation. Asymptomatic leaves display distinct DNA methylation changes, some of which are shared with symptomatic tissues, suggesting a systemic response to the disease at the epigenetic level. Notably, subset of these methylation marks are observable prior to symptom emergence, highlighting the potential of epigenetic biomarkers for the early detection of trunk diseases in perennial plants.

plant biology↗

bioRxiv2025

G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway

The G1 and G2 variants of the gene encoding Apolipoprotein L1 (APOL1) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1. We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor -difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.

cell biology↗

bioRxiv2025

Negative epistasis limits current codon optimization approaches

Demand for high-yield protein production in biotechnological applications is driving efforts to maximize heterologous protein expression in scalable microorganisms such as E. coli. While codon optimization techniques employed by contemporary sequence providers promise high-expression products, expression levels are often unsatisfactory. Whether the causes for this performance unreliability are due to fundamental constraints on the predictability of protein yields, or whether they stem from differences in theoretical approaches, is unknown. Here, we performed a comparative analysis to address this question. We assessed the performance of twelve different optimization approaches at enhancing expression of a sequence encoding a cinnamyl alcohol dehydrogenase. Six approaches stemmed from commercial providers and six from freely available sources. Through analysis of their elongation time profiles and multidimensional scaling we assessed which algorithms follow a unique optimization approach. We found that codon-optimized sequences are, on average, capable to raise protein expression levels with respect to the nonoptimised source sequence. However, variation in the protein expression levels was large. Simple, non-proprietary optimization techniques were capable of achieving protein expression levels that fall within the top expression range amongst candidate sequences. Lastly, we found that negative epistasis influences a sequences protein expression level. Since therefore the protein expression landscape arising from synonymous sequence space must exhibit a non-negligible degree of ruggedness, standard approaches will be limited in their capacity to predict protein expression levels of sequences.

molecular biology↗

bioRxiv2025

LAVR-289, a new acyclo-nucleoside phosphonate having broad-spectrum activity against herpesviruses.

Human herpesviruses are latent opportunistic large dsDNA viruses that can have deleterious effect in immunocompromised patients by triggering life-threatening infections. Over the past years, different antivirals have been developed against a variety of herpesviruses, including Acyclovir for herpes simplex viruses (HSV1 and 2) and ganciclovir and letermovir for human cytomegalovirus (hCMV). However, broad-spectrum inhibitors of herpesvirus infections are still missing. Here we report the efficacy of LAVR-289, a new acyclic nucleoside analog, on a broad variety of herpesviruses from human and animal origin. LAVR-289 displays nanomolar efficiency in vitro, is active on viral strains resistant to gold standard antivirals and ex vivo on reconstituted human skin infected with HSV1. Combined with its anti-poxvirus and anti-adenovirus activity, LAVR-289 can become the next gold standard for the management of opportunistic virus infections in immunocompromised patient.

microbiology↗

bioRxiv2024

The Zinc Finger protein SlZFP2 is essential for tomato fruit locular tissue morphogenesis

In tomato (Solanum lycopersicum L.) fruit, the locular tissue (LT) is a unique jelly-like tissue that differentiates from the central axis of the fruit after ovule fertilization. LT is essential for seed development and dispersal by preventing early germination and initiating fruit ripening. In this work, we studied a "gel-less" mutant and identified the underlying mutation in the coding sequence of the C2H2 zinc finger transcription factor (TF) SlZFP2. Histological, cytological and molecular characterization from knockout-CRISPR/Cas9 lines for this gene revealed the strong and early impact of zfp2 mutation on cell cycle and endocycle in LT. Additionally, model-based analysis of cellular data revealed that cell cycle was the main altered process, explaining the zfp2 mutant phenotype. Further laser capture microdissection coupled with RNA-Seq analysis of young LT highlighted global expression changes between WT and zfp2 mutant and led to a preliminary list of potential direct targets of the SlZFP2 TF. This multifaceted approach not only uncovered a new role for SlZFP2 TF as an essential regulator of LT morphogenesis, but also provides a foundation for future works aimed at deciphering the intricate regulatory networks governing fruit tissue development in tomato. One sentence summaryAlteration of cell division and endoreduplication in a gel-less mutant reveals the role of the transcription factor SlZFP2 in tomato locular tissue morphogenesis

plant biology↗

bioRxiv2024

Grapevine cell response to carbon deficiency requires transcriptome and methylome reprogramming

Sugar limitation has dramatic consequences on plant cells, which include a profound reorganization of the cell metabolism, transcriptional reprogramming, and the recycling of cellular components to maintain fundamental cell functions. There is so far no description of the possible contribution of epigenetic regulations in the adaptation of plant cells to limited carbon availability. We investigated this question using non-photosynthetic grapevine cells (Vitis vinifera, cv Cabernet Sauvignon) cultured in vitro with contrasted glucose concentrations. As expected, limited sugar availability in the culture medium led to a rapid cell growth arrest. This was associated with a major metabolic shift characterized by depletion in soluble sugar and total amino acids, an increase in malate content and changes in the cell redox status. Consistently, flux modeling showed a dramatic slowdown of many pathways required for biomass accumulation such as cell wall polymers and total protein content. In contrast, anaplerotic fluxes, the synthesis of some amino acids, redox and polyamine metabolism were enhanced. Carbon deprivation also resulted in a major transcriptional reprogramming characterized by the induction of genes involved in photosynthesis, and the repression of those related to sucrose mobilization or cell cycle control. Similarly, the epigenetic landscape was deeply modified. Glucose-depleted cells showed a higher global DNA methylation level than those grown with glucose. Changes in DNA methylation mainly occurred at transposable elements, but also at genes including differentially expressed genes, suggesting that DNA methylation could participate in the adaptation of cells to limited sugar availability. In addition, genes encoding histone modifiers were differentially expressed suggesting that additional epigenetic mechanisms may be at work during the response of plant cells to carbon shortage.

plant biology↗

bioRxiv2023

Genomic signatures of adaptation in native lizards exposed to human-introduced fire ants

Understanding the process of genetic adaptation in response to human-mediated ecological change will help elucidate the eco-evolutionary impacts of human activity. Red fire ants (Solenopsis invicta) spread across Southeastern USA since their accidental introduction via Port Mobile, Alabama in the 1930s, serving today as both novel venomous predator and novel toxic prey to native eastern fence lizards (Sceloporus undulatus). To identify potential signatures of genetic adaptation in lizards to invasive fire ants, we generated whole genome sequencing data from 420 native fence lizards sampled across three populations, two of which had not been invaded by fire ants (in Tennessee and Arkansas) and one which had been invaded for [~]70 years (Alabama). We detected signatures of positive selection exclusive to the exposed Alabama population for genetic variants overlapping genes related to the membrane attack complex of the complement immune system, growth factor pathways, and morphological development. Prior work identified a relationship between increased lizard survival of fire ant attack and longer hind limbs, which lizards use to remove ants from their bodies. Furthermore, we conducted a genome-wide association study with 381 Alabama lizards to identify 24 hind limb length-associated genetic loci. For two loci, positive-effect alleles occur in high frequency and overlap genomic regions that are highly differentiated from the populations naive to fire ants. Collectively, these findings represent plausible genetic adaptations in response to fire ant invasion, whereby morphological differentiation may increase survival against swarming ants and altered immune responses may allow the exploitation of a novel, toxic food resource. Significance statementHuman activity can force interactions between species from distinct ecological backgrounds. These interactions can consequently impose novel selective pressures on endemic populations via predation or disruption of ecological niches through community-wide effects. While some endemic taxa have been able to adapt biologically to these disruptions, we do not have a full understanding of the underlying genetic processes that may allow it. Here we identify genomic signatures of recent adaptation nearby genes involved in morphological and immunological processes in native fence lizards that are consistent with pressures imposed by the venomous, predatory fire ants introduced by humans. These signatures are largely absent from lizard populations that are naive to fire ants.

evolutionary biology↗

bioRxiv2023

Comparative analysis of myoglobin in Cetaceans and humans reveals novel regulatory elements and evolutionary flexibility

Cetacea and other diving mammals have undergone numerous adaptations to their aquatic environment, among them high levels of the oxygen-carrying intracellular hemoprotein myoglobin in skeletal muscles, especially those responsible for swimming. Hypotheses regarding the mechanisms leading to these high myoglobin levels often invoke exercise, hypoxia, and other physiological pathways that impact gene regulation, and increase myoglobin gene expression. Here we explore an alternative hypothesis: that Cetacean myoglobin genes have evolved high levels of transcription driven by the intrinsic developmental mechanisms that drive muscle cell differentiation. We have used luciferase assays in differentiated C2C12 cells to test this hypothesis. Contrary to our hypothesis, we find that the myoglobin gene from the minke whale, Balaenoptera acutorostrata, has a low level of expression, less than 10% that of humans. This low expression level is broadly shared among Cetaceans, and Artiodactylans. Previous work on regulation of the human gene has identified a core muscle-specific enhancer comprised of two regions, the "AT element" and a C-rich sequence 5 of the AT element termed the "CCAC-box". Comparative analysis of the minke whale gene supports the importance of the AT element, but the minke whale CCAC-box ortholog has little effect. Instead, critical positive input has been identified in a G-rich region 3 of the AT element. Also, a conserved E-box in exon 1 positively affects expression, despite having been assigned a repressive role in the human gene. Last, a novel region 5 of the core enhancer has been identified, which we hypothesize may function as a boundary element. These results illustrate regulatory flexibility during evolution. They also support the hypothesis that the induction of transcription by physiological signaling pathways, and evolved protein stability are important in leading to the high myoglobin protein levels found in Cetaceans.

molecular biology↗

bioRxiv2023

Transplantation-based screen uncovers inducers of muscle progenitor cell engraftment across vertebrate species

Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited due to the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small molecule screening platform employing zebrafish and mouse, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to identify those that could increase myogenic engraftment in vivo in zebrafish and mice. Two lipids, lysophosphatidic acid (LPA) and niflumic acid (NFA), are linked to activation of intracellular calcium ion flux, which showed conserved, dose-dependent and synergistic effects in promoting muscle engraftment across these vertebrate species.

cell biology↗

bioRxiv2022

Withdrawal from repeated nicotine vapor exposure increases somatic signs of physical dependence, anxiety-like behavior, and brain reward thresholds in adult male rats.

In recent years, there has been a dramatic increase in nicotine vapor consumption via electronic nicotine delivery systems (i.e., e-cigarettes), particularly in adolescents. While recent work has focused on the health effects of nicotine vapor exposure, its effects on the brain and behavior remain unclear. In this study, we assessed the effects that cessation from repeated nicotine vapor exposure had on behavioral and neuronal measures of withdrawal. For Experiment 1, fifty-six adult male rats were tested for plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior in the elevated plus maze, immediately following precipitated withdrawal from repeated exposure to 12 or 24 mg/mL nicotine vapor. In Experiment 2, twelve adult male rats were tested for intracranial self-stimulation (ICSS) across 14 days of exposure to 24 mg/mL nicotine vapor and across the 14 days immediately following nicotine exposure. Results revealed that plasma cotinine, somatic signs, anxiety-like behavior, and ICSS stimulation thresholds were all observed to be elevated during withdrawal in the 24 mg/mL nicotine group, when compared to vehicle controls (50/50 vegetable glycerin/propylene glycol). The data suggest that cessation from repeated nicotine vapor exposure using our preclinical model leads to nicotine dependence and withdrawal, and demonstrates that the vapor system described in these experiments is a viable pre-clinical model of e-cigarette use in humans. Further characterization of the mechanisms driving nicotine vapor abuse and dependence is needed to improve policies and educational campaigns related to e-cigarette use. HighlightsO_LIA rodent model of nicotine e-cigarette vapor use was utilized to assess effects of cessation from repeated nicotine vapor exposure on behavioral and neuronal measures of drug withdrawal. C_LIO_LICessation of repeated nicotine vapor exposure resulted in increased plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior. C_LIO_LICessation of repeated nicotine vapor exposure resulted in elevations of ICSS reward threshold. C_LIO_LIElectrode implantations for ICSS were mapped by location and threshold to a standardized reference atlas of the rat brain to facilitate comparisons with the published literature. C_LI

neuroscience↗

bioRxiv2021

Circadian Clock Core Component Bmal1 Dictates Cell Cycle Rhythm of Proliferating Hepatocytes during Liver Regeneration

Following partial hepatectomy (PH), the majority of remnant hepatocytes synchronously enter and rhythmically progress through the cell cycle for three major rounds to regain lost liver mass. Whether and how the circadian clock core component Bmal1 modulates this process remains elusive. We performed PH on Bmal1+/+ and hepatocyte-specific Bmal1 knockout (Bmal1hep-/-) mice and compared the initiation and progression of the hepatocyte cell cycle. After PH, Bmal1+/+ hepatocytes exhibited three major waves of nuclear DNA synthesis. In contrast, in Bmal1hep-/-hepatocytes, the first wave of nuclear DNA synthesis was delayed by 12 h, and the third such wave was lost. Following PH, Bmal1+/+ hepatocytes underwent three major waves of mitosis, whereas Bmal1hep-/-hepatocytes fully abolished mitotic oscillation. These Bmal1-dependent disruptions in the rhythmicity of hepatocyte cell cycle after PH were accompanied by suppressed expression peaks of a group of cell cycle components and regulators, and dysregulated activation patterns of mitogenic signaling molecules c-Met and EGFR. Moreover, Bmal1+/+ hepatocytes rhythmically accumulated fat as they expanded following PH, whereas this phenomenon was largely inhibited in Bmal1hep-/-hepatocytes. In addition, during late stages of liver regrowth, Bmal1 absence in hepatocytes caused the activation of redox sensor Nrf2, suggesting an oxidative stress state in regenerated liver tissue. Collectively, we demonstrated that during liver regeneration, Bmal1 partially modulates the oscillation of S-phase progression, fully controls the rhythmicity of M-phase advancement, and largely governs fluctuations in fat metabolism in replicating hepatocytes, and eventually determines the redox state of regenerated livers. New and NoteworthyWe demonstrated that Bmal1 centrally controls the synchronicity and rhythmicity of the cell cycle and lipid accumulation in replicating hepatocytes during liver regeneration. Bmal1 plays these roles, at least in part, by ensuring formation of the expression peaks of cell cycle components and regulators, as well as the timing and levels of activation of mitogenic signaling molecules. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/455958v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@16dc661org.highwire.dtl.DTLVardef@1fb1a65org.highwire.dtl.DTLVardef@820e1dorg.highwire.dtl.DTLVardef@6cc264_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

pathology↗

bioRxiv2021

Identification of novel human derived influenza viruses in pigs with zoonotic potential.

In 2009, a novel swine influenza A virus (IAV) emerged causing a global pandemic that highlighted the role of swine as a reservoir. To date, there is limited information about swine IAV circulating in Latin America. We identified two swine H1N2 and one divergent swine H3N2 viruses that co-circulated in Chilean swine together with the 2009 H1N1 pandemic strain (A(H1N1)pdm09). Phylogenetic analysis revealed several human-to-swine IAV introductions occurring as early as the mid-1980s, and since 2009, several introductions of the A(H1N1)pdm09 strain. Antigenic cartography confirmed that these viruses were antigenically unique and identified drifted variants within the clusters. Human sera from the Chilean general population showed an age dependent mid to low-level antibody mediated protection against swine H1N2 and A(H1N1)pdm09-like viruses and a poor protection against the swine H3N2 virus, highlighting the zoonotic potential of this strain. Our results underscore the epidemiological importance of studying swine IAV in Latin America for epidemic and pandemic preparedness.

microbiology↗