Biology subjects

Shah, A. M.

Publications and source records attributed to Shah, A. M..

13 recordsLinked to original sources

bioRxiv2026

Somatosensory gating dysfunction is masked by cognitive variability in cognitively impaired individuals

Disruptions in somatosensory processing have been observed in cognitive impairment (CI), suggesting that alterations in sensory processing may emerge earlier during cognitive decline than previously recognized. Somatosensory gating (SG) is an automatic inhibitory mechanism that protects neural resources by suppressing responses to redundant, non-behaviorally relevant stimuli. Prior work has demonstrated exaggerated gamma SG and response amplitudes in the primary somatosensory cortex (S1) of individuals with Alzheimers disease-confirmed pathology, and these effects were masked by variability in attention/executive function performance. However, whether similar relationships are present during earlier stages of cognitive decline, such as CI, remains unclear. Herein, 63 cognitively healthy older adults (CH; mean age = 59.9 {+/-} 8.6 years) and 32 individuals with CI (mean age = 62.4 {+/-} 8.8 years) underwent magnetoencephalography (MEG) while completing a paired-pulse SG paradigm designed to probe inhibitory sensory processing. MEG oscillatory responses were source-imaged using a beamformer. Time series data were extracted from the peak voxel to quantify oscillatory dynamics and SG. Neuropsychological testing was conducted to assess attention/executive function. After controlling for attention/executive function variance, exaggerated gamma SG was observed in adults with CI compared with CH adults (p < 0.05). Additionally, adults with CI exhibited increased beta peak frequency following the second stimulation (p < 0.01) and a group-by-age interaction for theta SG in S1 (p < 0.05). Together, these results suggest somatosensory abnormalities are present in earlier stages of cognitive decline and highlight a dynamic interaction between sensory processing and cognitive systems during this decline.

neuroscience↗

bioRxiv2026

Reduced Somatosensory Oscillatory Dynamics and Inhibition in Moderate-to-Severe Nociceptive Pain

Nociceptive pain is the most common pain condition, and moderate-to-severe nociceptive pain substantially impacts daily functioning, constituting a significant public health burden. Despite this, most studies investigating the neural mechanisms underlying somatosensory processing and inhibition have focused on other pain conditions (e.g., neuropathic, nociplastic, or mixed pain). Thus, the extent to which neural aberrancies detected in these other populations extend to or differentiate from nociceptive pain conditions remains largely unknown. In this study, 29 individuals with moderate-to-severe nociceptive pain (MSNP) and 47 pain-free (PF) controls underwent magnetoencephalography (MEG) alongside a paired-pulse somatosensory stimulation paradigm to examine somatosensory cortical processing and functional inhibition. Pain status and intensity were determined using validated pain questionnaires, painDETECT and PROMIS-29, respectively. MEG oscillatory responses were source localized via a beamformer to the primary somatosensory cortex (S1) and time series data were extracted from the peak voxel to quantify the dynamics of somatosensory gating (SG; index of cortical inhibitory processing), oscillatory response power, and spontaneous power. We found that adults with MSNP exhibit aberrant theta SG in contralateral S1 compared to PF controls, reflecting reduced functional inhibition of innocuous stimulus processing in this region. Additionally, individuals with MSNP demonstrated exaggerated gamma responses but blunted alpha responses in contralateral S1 to innocuous stimulation. Finally, individuals with MSNP were characterized by weaker spontaneous alpha in contralateral S1 that scaled with self-reported pain intensity. Together, these findings suggest that experiencing MSNP is associated with disrupted somatosensory and cortical inhibitory processing.

neuroscience↗

bioRxiv2026

Age-Related Alterations in Multispectral Somatosensory Gating: Evidence for Partial Compensation in Attentional Performance

Healthy cognitive aging involves selective changes, with relative preservation of some domains and decline in others, particularly attention, inhibitory control, and executive function. Somatosensory gating (SG) refers to the brains ability to suppress neural responses to redundant tactile input, conserving resources for relevant stimuli and reflects pre-attentive and inhibitory mechanisms. Prior region-of-interest studies have shown age-related reductions in gamma SG within contralateral primary somatosensory cortex (S1), and modulation of theta, alpha, and beta SG by attention in young adults. However, whole-brain, multispectral age effects remain unclear. In this study, 63 middle-to-older aged adults (38 females; mean age = 59.9 {+/-} 8.6 years) underwent magnetoencephalography during a paired-pulse somatosensory paradigm. SG was quantified as attenuation of the neural response to the second stimulus relative to the first. Time-frequency analyses identified theta (4-7 Hz), alpha (8-13 Hz), beta (15-25 Hz), and gamma (30-90 Hz) oscillatory responses, and band-specific voxel-wise whole-brain gating maps assessed age-related effects. Attention/executive function was also measured. Results showed significant age-related increases in gamma SG in the contralateral supplementary motor area. Mediation analyses suggested this increase partially offsets age-related declines in attention/executive function, consistent with a partial compensatory mechanism. Additionally, theta SG in contralateral S1 increased with age. These findings demonstrate frequency- and region-specific age-related alterations in SG, suggesting that older adults may recruit enhanced inhibitory mechanisms, particularly in higher-order sensorimotor regions, to support cognitive function.

neuroscience↗

bioRxiv2025

Dietary glutamine supplementation alleviates age-related cardiac dysfunction by reducing elevated H3K27me3

BackgroundChanges to the epigenetic landscape play an important role in cardiovascular aging, where alterations in histone modifications influence gene expression by regulating DNA accessibility and chromatin structure. Our investigation into epigenetic changes during myocardial aging revealed that the repressive epigenetic mark H3K27me3 is significantly upregulated in aged mice and humans. This increase in H3K27me3 was shown to impair cardiomyocyte autophagy and drive metabolic reprogramming, key features of myocardial aging and causatively linked to dysfunction. Notably, by alleviating this repressive mark through a modified diet, we successfully mitigated the aged myocardial phenotype. MethodsHeart tissue from young and aged mice and humans was analyzed for H3K27me3 levels using immunoblotting and immunofluorescence staining. Genes regulated by H3K27me3 were identified through CUT&RUN-Seq and RNA-Seq, while metabolites were profiled using metabolomics. In neonatal rat ventricular myocytes (NRVMs), H3K27me3 levels were elevated by siRNA-mediated knockdown of UTX. Cellular metabolism was investigated using a Seahorse analyzer in cardiomyocytes with basal or elevated H3K27me3 levels. In further human studies, we assessed how circulating glutamine levels associate with the incidence of heart failure and the association of genetic variants within the SLC1A5 region with heart disease. In aged mice, H3K27me3 levels were reduced through a modified diet, and heart function was evaluated using echocardiography. Subsequently, hearts were processed for biochemical analysis, and autophagy was assessed using electron microscopy. ResultsH3K27me3 was significantly elevated in the aged mouse and human myocardium. This observed elevation in H3K27me3 was found to be attributed to impaired glutamine metabolism, resulting from reduced expression of the glutamine transporter SLC1A5 in the aged myocardium. Furthermore, elevation in H3K27me3 was found to contribute to impaired cardiomyocyte autophagy and metabolic dysfunction. In aged mice supplemented with a high glutamine diet this attenuated myocardial H3K27me3 and improved cardiac function. Furthermore, a high-glutamine diet reversed H3K27me3-mediated impairment in cardiac autophagy in aged mice. ConclusionsReduction in SLC1A5 during aging is likely to lead to increased myocardial H3K27me3 that results in impaired autophagy and metabolic reprogramming that contribute to the aged cardiac phenotype. Our findings also suggest glutamine may improve cardiac health in the aged population by lowering H3K27me3. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIElevation in H3K27me3 during aging is likely to lead to impaired myocardial autophagy and metabolic reprogramming. C_LIO_LIReduction in SLC1A5 during aging in humans is likely to contribute to myocardial dysfunction C_LIO_LIDietary supplementation of glutamine improves cardiac function in aged mice. C_LI What are the clinical implications?O_LITargeting H3K27me3 in the aged population may to mitigate cardiovascular disease C_LIO_LIDietary glutamine supplementation offers a promising strategy to improve cardiac function during aging. C_LI

cell biology↗

bioRxiv2025

Targeting C42 in PKGIα alleviates diastolic dysfunction in HFpEF

BackgroundIn our exploration of novel therapeutic strategies for treating heart failure with preserved ejection fraction (HFpEF), we focused on cysteine 42 (C42) in cGMP-dependent protein kinase I (PKGI), which plays a crucial role in regulating blood pressure and diastolic relaxation. Our findings demonstrate that targeting C42 on PKGI with urolithin A effectively limits diastolic dysfunction and cardiac remodeling in a multi-hit mouse model of HFpEF, while also improving the kinetics of relaxation and contraction in human-engineered heart tissue. MethodsWe evaluated various polyphenols, including urolithin A, for their capacity to oxidize and activate PKGI. This assessment involved recombinant protein, isolated rat aortic smooth muscle cells, and myography experiments using isolated mesenteric vessels. Additionally, we investigated the ability of urolithin A to stimulate PKGI-dependent phosphorylation of phospholamban (PLN) in neonatal rat ventricular myocytes (NRVMs). A multi-hit mouse model was employed to induce HFpEF in wild-type and C42S PKGI knock-in (KI) mice. Following this, the mice were given vehicle or urolithin A by gavage, and heart function was evaluated using echocardiography. The relevance to human physiology was assessed using human-engineered heart tissue. ResultsThe polyphenols quercetin, fisetin, and urolithin A were shown to induce C42-dependent activation of PKGI. This mechanism of kinase activation led to vasorelaxation, which was attenuated in mesenteric vessels isolated from KI mice. Additionally, urolithin A treatment promoted PKGI-dependent phosphorylation of phospholamban in isolated cardiomyocytes. In a multi-hit model of HFpEF, urolithin A reversed diastolic dysfunction and cardiac remodeling in wild-type mice, but not in KI mice. These findings were shown to be likely relevant to humans, as urolithin A also enhanced the kinetics of relaxation and contraction in human-engineered heart tissue. ConclusionsTargeting C42 in PKGI with urolithin A presents a promising new strategy for the treatment of HFpEF.

biochemistry↗

bioRxiv2023

NRF2 activation in the heart induces glucose metabolic reprogramming and mediates cardioprotection via upregulation of the pentose phosphate pathway.

RationaleThe transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 protects mouse hearts during chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. ObjectiveTo investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress. Methods and ResultsCardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 upregulated key enzymes of the Pentose Phosphate Pathway (PPP), redirected glucose metabolism towards the PPP and protected the heart against pressure overload-induced cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP. Activation of NRF2 also protected the heart against myocardial infarction-induced DNA damage, dysfunction, and adverse remodeling. ConclusionsThese results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby providing cardiac protection during stress by generating NADPH and providing nucleotides to prevent stress-induced DNA damage.

physiology↗

bioRxiv2022

Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity

The microvasculature plays a key role in tissue perfusion, transport of mediators, and exchange of gases and metabolites to and from tissues. Microvascular dysfunction has emerged as an important contributor to cardiovascular diseases. In this study we used human blood vessel organoids (BVOs) as a model of the microvasculature to delineate the mechanisms of microvascular dysfunction caused by metabolic rewiring. BVOs fully recapitulated key features of the normal human microvasculature, including reliance of mature endothelial cells (ECs) on glycolytic metabolism, as concluded from metabolic flux assays using 13C-glucose labelling and mass spectrometry-based metabolomics. Treatment of BVOs with PFK15, a pharmacological inhibitor of glycolysis, resulted in rapid tissue restructuring, vessel regression with reduced pericyte coverage and alterations in tight junction morphology. Proteomic analysis of the BVO secretome revealed remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovered tight junction formation and increased pericyte coverage in microvessels. Our metabolic and proteomics findings demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.

cell biology↗

bioRxiv2021

Development and validation of a cellular host response test as an early diagnostic for sepsis

Sepsis must be diagnosed quickly to avoid morbidity and mortality. However, the clinical manifestations of sepsis are highly variable and emergency department (ED) clinicians often must make rapid, impactful decisions before laboratory results are known. We previously developed a technique that allows the measurement of the biophysical properties of white blood cells as they are stretched through a microfluidic channel. In this study we describe and validate the resultant output as a model and score - the IntelliSep Index (ISI) - that aids in the diagnosis of sepsis in patients with suspected or confirmed infection from a single blood draw performed at the time of ED presentation. By applying this technique to a high acuity cohort with a 23.5% sepsis incidence (n=307), we defined specific metrics - the aspect ratio and visco-elastic inertial response - that are more sensitive than cell size or cell count in predicting disease severity. The final model was trained and cross-validated on the high acuity cohort, and the performance and generalizability of the model was evaluated on a separate low acuity cohort with a 6.4% sepsis incidence (n=94) and healthy donors (n=72). For easier clinical interpretation, the ISI is divided into three interpretation bands of Green, Yellow, and Red that correspond to increasing disease severity. The ISI agreed with the diagnosis established by retrospective physician adjudication, and accurately identified subjects with severe illness as measured by SOFA, APACHE-II, hospital-free days, and intensive care unit admission. Measured using routinely collected blood samples, with a short run-time and no requirement for patient or laboratory information, the ISI is well suited to aid ED clinicians in rapidly diagnosing sepsis.

bioengineering↗

bioRxiv2020

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

Cancer therapies have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of cancer. ACT-iPSC-CM generated from individuals with CD20+ B-cell lymphoma cancer who had received high doses of DOX and suffered cardiac dysfunction were observed to be persistently more susceptible to DOX toxicity compared to control-iPSC-CM. ACT-iPSC-CM exhibited increased DOX-dependent disorganized myofilament structure and cell death, as well as higher reactive oxygen species (ROS) compared to controls. Importantly, analysis of engineered heart muscle (EHM) from ACT-iPSC-CM showed an impaired DOX-dependent mechanical functionality. Transcriptome profiles of EHM are in line with a disturbed adjustment to DOX-dependent alteration of Ca2+ homeostasis in ACT-iPSC-CM. Furthermore, genetic variants in different cardiac key regulators were uncovered. In conclusion, we developed the first human iPSC-CM and EHM model of DOX-induced cardiac dysfunction in patients with B-cell lymphoma. Our results suggest that DOX-related stress resulted in decreased contractile activity and finally in heart failure in ACT patients. Brief summaryDevelopment of the first human iPSC-CM model of DOX-induced cardiac dysfunction in patients with aggressive B cell lymphoma and high-dose DOX treatment.

cell biology↗

bioRxiv2019

Relationship between True Digestibility of dietary Phosphorus and Gastrointestinal Bacteria of Goats

The present research was conducted to evaluate the connection between the true digestibility of Phosphorus (TDP) in diet and bacterial community structure in the gastrointestinal tract (GIT) of goats. Twenty-eight Nubian goats were chosen and metabolic experiment was conducted to analyze TDP of research animals. Eight goats were grouped into the high digestibility of phosphorus (HP) phenotype, and another 8 were grouped into the low digestibility of phosphorus (LP) phenotype. And from the rumen, abomasum, jejunim, cecum and colon content of the goats, bacterial 16S rRNA gene amplicons were sequenced. In the rumen 239 genera belonging to 23 phyla, in abomasum 319 genera belonging to 30 phyla, in jejunum 248 genera belonging to 36,in colon 248 genera belonging to 25 phyla and in cecum 246 genera belonging to 23 phyla were noticed. In addition, there was a significant correlation between the TDP and the abundance of Ruminococcaceae_UCG-010, Ruminococcus_2, Ruminococcaceae_UCG-014, Selenomonas_1 and Prevotella in the rumen, Lachnospiraceae_ND3007_group, Saccharofermentans, Ruminococcus_1, Ruminococcaceae_UCG-014, Lachnospiraceae_XPB1014_group and Desulfovibrio in the abomasum, Prevotella, Clostridium_sensu_stricto_1, Fibrobacter, Desulfovibrio and Ruminococcus_2 in the jejunum, Ruminococcaceae_UCG-014 in the colon, and Desulfovibrio in the cecum. Present research trial recommended that the community of gastrointestinal microbiota is a factor affecting TDP in goats.

microbiology↗

bioRxiv2019

Effects of active dry yeast on growth performance, rumen fermentation characteristics and slaughter performance in beef cattle

This study aimed to investigate the effects of active dry yeast (ADY) on rumen microbial composition and slaughter performance of beef cattle. Thirty-two finishing beef cattle (simmental crossbred cattle [male] x cattle-yaks [female]), with an average body weight of 110 {+/-} 12.85 kg, were randomly assigned to one of four treatments: the low plane of nutrition group (Control), low plane of nutrition group + ADY 2 g/head/d (ADY2), low plane of nutrition group + ADY 4 g/head/d (ADY4) and high plane of nutrition group (HPN). ADY supplementation increased average daily gain (P<0.001), and the carcass weight of ADY4 group had no significant difference with HPN group (P>0.05). The serum glutamic-pyruvic transaminase activity in control and ADY4 group was higher than HPN group (P=0.001). The neutral detergent fiber (P=0.022) and acid detergent fiber (P=0.043) digestibility in HPN group was greater than control, but no difference was obtained among ADY2, ADY4 and HPN group (P>0.05). The rumen ammonium nitrogen content in control was greater than ADY2 and ADY4 group (P=0.003), and no difference was obtained ADY2, ADY4 and HPN group (P>0.05). The propionic acid content in the rumen in ADY2, ADY4, and HPN group were greater than control group (P<0.001). The simpson (P=0.014) and shannon (P=0.045) indexes in control and HPN group were greater than ADY4 group. At the phylum level, the relative abundance of Firmicutes in the HPN group was higher than ADY4 group (P=0.015). At the genus level, HPN and ADY4 were clustered together, and the relative abundance of Ruminococcaceae UCG-002 in ADY4 group was higher than control and HPN group (P=0.004). In conclusion, supplementation ADY 4 g/head/d shift the rumen microbial composition of beef cattle fed low plane of nutrition to a more similar level with cattle fed with HPN diet, produced comparable carcass weight with HPN diet.

zoology↗

bioRxiv2018

Accumulation of prelamin A drives inflammation in the heart with implications for treatment of inherited and acquired cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited e.g. dilated cardiomyopathy resulting from LMNA gene mutations, or acquired, e.g. cardiomyopathy associated with HIV. In both cases the lamin A precursor, prelamin A, may play a central role: mutations in LMNA and certain HIV protease inhibitors acting via the enzyme ZMPSTE24 both inhibit prelamin A processing. Firstly, we show that myocardial prelamin A accumulation occurs in both these cardiomyopathies in patients. Secondly, we developed a novel mouse model of cardiac specific prelamin A accumulation which mimicked tissue and molecular features of HIV associated cardiomyopathy, including inflammation. These findings: (1) confirm a central pathological role of prelamin A common to genetic and acquired cardiomyopathies; (2) have implications for the management of HIV patients with cardiac disease in whom protease inhibitors with low/no binding to ZMPSTE24 may be preferred; and (3) suggest that targeting inflammation may be a useful treatment strategy for some forms of inherited cardiomyopathy.

pathology↗

bioRxiv2017

Hydrogen peroxide formation by Nox4 limits malignant transformation

Reactive oxygen species (ROS) can cause cellular damage and are thought to promote cancer-development. Nevertheless, under physiological conditions, all cells constantly produce ROS, either as chemical by-products or for signaling purpose. During differentiation cells induce the NADPH oxidase Nox4, which constitutively produces low amounts of H2O2. We infer that this constitutive H2O2 is unlikely to be carcinogenic and may rather maintain basal activity of cellular surveillance systems.\n\nUtilizing two different murine tumor models we demonstrate that Nox4 prevents malignant transformation and facilitated the recognition of DNA-damage. Upon DNA-damage repair is initiated as consequence of phosphorylation of H2AX ({gamma}H2AX). Repair only occurs if nuclear activity of the {gamma}H2AX-dephosphorylating phosphatase PP2A is kept sufficiently low, a task fulfilled by Nox4: Nox4 continuously oxidizes AKT, and once oxidized AKT captures PP2A in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of {gamma}H2AX. Simultaneously the proportion of active, phosphorylated AKT is increased. Thus, DNA-damage is not recognized and the increase in AKT activity promotes proliferation. The combination of both events resulted in genomic instability and tumor initiation.\n\nWith the identification of the first cancer-protective source of reactive oxygen species, Nox4, the paradigm of reactive-oxygen species-induced initiation of malignancies should be revised.\n\nSignificanceThe stereotype of ROS produced by NADPH oxidases as cause of malignant diseases persists generalized since decades. We demonstrate that the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.\n\nPrecisBy oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.

cancer biology↗