Biology subjects

Jacob, M.

Publications and source records attributed to Jacob, M..

9 recordsLinked to original sources

bioRxiv2025

Synthesis and biological evaluation of glutathione-responsive 2-alkoxycarbonyl allyl niclosamide prodrugs as anticancer agents

Reprogrammed mitochondrial metabolism is recognized as an important target for anticancer therapy. Niclosamide, an FDA approved anthelmintic agent with mitochondrial uncoupling activity, has shown promise as an anticancer agent. However, off target mitochondrial toxicity has rendered the utility of this agent at clinically effective doses. Here, we synthesize a variety of prodrugs on the niclosamide template based on the Baylis-Hillman (BH) reaction, with the hypothesis that niclosamide will be released upon the reaction with cellular nucleophiles, including thiols. Consistent with this hypothesis, the BH-prodrugs release the parent niclosamide in the presence of cysteine and glutathione, and the cancer cell proliferation inhibition properties of the lead candidates are retained when compared to the parent niclosamide. Mitochondrial respiration assays illustrate that niclosamide acutely uncouples the mitochondria, and the lead BH-prodrug 6b does not, providing evidence of this prodrug strategy in mitigating off target toxicities. In a dose escalation study, the lead candidate 6b is generally well tolerated in healthy mice as evidenced by zero mortality, normal grooming pattern, and normal weight gains. Finally, 6b exhibits 54% volume tumor growth inhibition properties in a syngraft model of breast cancer in mice. The studies herein provide a novel methodology for the application of BH prodrugs on the niclosamide template and the anticancer applications.

pharmacology and toxicology↗

bioRxiv2023

Characteristics of antimicrobial resistance in Escherichia coli isolated from retail meat products in North Carolina

BackgroundEscherichia coli is commonly used as an indicator for antimicrobial resistance (AMR) in food, animal, environment, and human surveillance systems. Our study aimed to characterize AMR in E. coli isolated from retail meat purchased from grocery stores in North Carolina, USA as part of the National Antimicrobial Resistance Monitoring System (NARMS). MethodsRetail chicken (breast, n=96; giblets, n=24), turkey (n=96), and pork (n=96) products were purchased monthly from different counties in North Carolina during 2022. Label claims on packages regarding antibiotic use were recorded at collection. E. coli was isolated from meat samples using culture-based methods and isolates were characterized for antimicrobial resistance using whole genome sequencing. Multi-locus sequence typing, phylogroups, and a single nucleotide polymorphism (SNP)-based maximum-likelihood phylogenic tree were generated. Data were analyzed statistically to determine differences between antibiotic use claims and meat type. ResultsOf 312 retail meat samples, 138 (44.2%) were positive for E. coli, with turkey (78/138; 56.5%) demonstrating the highest prevalence. Prevalence was lower in chicken (41/138; 29.7%) and pork (19/138;13.8%). Quality sequence data was available from 84.8% (117/138) of the E. coli isolates, which included 72 (61.5%) from turkey, 27 (23.1%) from chicken breast, and 18 (15.4%) from pork. Genes associated with AMR were detected in 77.8% (91/117) of the isolates and 35.9% (42/117) were defined as MDR ([≥]3 distinct classes of antimicrobials). Commonly observed AMR genes included tetB (35%), tetA (24.8%), aph(3)-lb (24.8%), and blaTEM-1 (20.5%), the majority of which originated from turkey isolates. Antibiotics use claims had no statistical effect on MDR E. coli isolates from the different meat types (X2=2.21, p =0.33). MDR was observed in isolates from meat products with labels indicating "no claims" (n=29; 69%), "no antibiotics ever" (n=9; 21.4%), and "organic" (n=4; 9.5%). Thirty-four different replicon types were observed. AMR genes were carried on plasmids in 17 E. coli isolates, of which 15 (88.2%) were from turkey and two (11.8%) from chicken. Known sequence types (STs) were described for 81 E. coli isolates, with ST117 (8.5%), ST297 (5.1%), and ST58 (3.4%) being the most prevalent across retail meat types. The most prevalent phylogroups were B1 (29.1%) and A (28.2%). Five clonal patterns were detected among isolates. ConclusionsE. coli prevalence and the presence of AMR and MDR were highest in turkey retail meat. The lack of an association between MDR E. coli in retail meat and antibiotic use claim, including those with no indication of antimicrobial use, suggests that additional research is required to understand the origin of resistance. The presence of ST117, an emerging human pathogen, warrants further surveillance. The isolates were distinctly diverse suggesting an instability in population dynamics.

microbiology↗

bioRxiv2023

EEG spectral attractors identify a geometric core of resting brain activity

Spectral analysis of electroencephalographic (EEG) data simplifies the characterization of periodic band parameters but can obscure underlying dynamics. By contrast, reconstruction of neural activity in state-space preserves geometric complexity in the form of a multidimensional, global attractor. Here we combine these perspectives, inferring complexity and shared dynamics from eigen-time-delay embedding of periodic and aperiodic spectral parameters to yield unique dynamical attractors for each EEG parameter. We find that resting-state alpha and aperiodic attractors show low geometric complexity and shared dynamics with all other frequency bands, what we refer to as geometric cross-parameter coupling. Further, the geometric signatures of alpha and aperiodic attractors dominate spectral dynamics, identifying a geometric core of brain activity. Non-core attractors demonstrate higher complexity but retain traces of this low-dimensional signal, supporting a hypothesis that frequency specific information differentiates out of an integrative, dynamic core. Older adults show lower geometric complexity but greater geometric coupling, resulting from dedifferentiation of gamma band activity. The form and content of resting-state thoughts were further associated with the complexity of core dynamics. Thus, the hallmarks of resting-state EEG in the frequency domain, the alpha peak and the aperiodic backbone, reflect a dynamic, geometric core of resting-state brain activity. This evidence for a geometric core in EEG complements evidence for a regionally defined dynamic core from fMRI-based neuroimaging, further supporting the utility of geometric approaches to the analysis of neural data.

neuroscience↗

bioRxiv2022

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Infantile Spasms syndrome (ISS) is a childhood epilepsy syndrome characterized by infantile or late onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IS are not well understood. Multiple human ISS risk genes are linked to Wnt/{beta}-catenin signaling, a pathway which controls developmental transcriptional programs and promotes glutamatergic excitation via {beta}-catenins role as a synaptic scaffold. We previously showed that deleting adenomatous polyposis coli (APC), a component of the {beta}-catenin destruction complex, in excitatory neurons (APC cKO mice, APCfl/fl x CaMKIICre) in mice increased {beta}-catenin levels in developing glutamatergic neurons and led to infantile behavioral spasms, abnormal neonatal EEG, and adult epilepsy. Here, we tested the hypothesis that the development of inhibitory GABAergic interneurons (INs) is disrupted in APC cKOs. IN dysfunction is implicated in human ISS, is a feature of other rodent models of ISS and may contribute to the manifestation of spasms and seizures. We found that parvalbumin positive INs (PV+INs), an important source of cortical inhibition, were decreased in number, underwent disproportionate developmental apoptosis, and had altered dendrite morphology at P9, the peak time of behavioral spasms. PV+INs received excessive excitatory input and their intrinsic ability to fire action potentials was reduced at all timepoints examined (P9, P14, P60). Subsequently, synaptic inhibition of pyramidal neurons was uniquely altered in the somatosensory cortex of APC cKO mice at all ages, with both decreased inhibition at P14 and enhanced inhibition at P9 and P60. These results indicate that inhibitory circuit dysfunction occurs in APC cKOs and, along with known changes in excitation, may contribute to ISS-related phenotypes. Significance StatementInfantile spasms syndrome (ISS) is a devastating epilepsy with limited treatment options and poor clinical outcomes. The molecular, cellular, and circuit disruptions that cause infantile spasms and seizures are largely unknown, but inhibitory GABAergic interneuron dysfunction has been implicated in rodent models of ISS and may contribute to human ISS. Here, we utilize a rodent model of ISS, the APC cKO mouse, in which {beta}-catenin signaling is increased in excitatory neurons. This results in altered parvalbumin-positive GABAergic interneuron development and inhibitory synaptic dysfunction throughout life, showing that pathology arising in excitatory neurons can initiate long-term interneuron dysfunction. Our findings further implicate GABAergic dysfunction in ISS, even when pathology is initiated in other neuronal types.

neuroscience↗

bioRxiv2021

Insulin resistance and adipose tissue inflammation induced by a high-fat diet are attenuated in the absence of hepcidin

Increased body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying basis of these associations are unclear. In order to assess this, we studied how IR and associated inflammation in adipose tissue developed in the presence of increased body iron stores. Male hepcidin knock-out (Hamp1-/-) mice, which have increased body iron stores, and wild-type (WT) mice were fed a high-fat diet (HFD) for 12 and 24 weeks. Development of IR and metabolic parameters linked to this, insulin signaling in tissue, and inflammation and iron-related parameters in visceral adipose tissue were studied in these animals. HFD-feeding resulted in impaired glucose tolerance in both genotypes of mice. In response to the HFD for 24 weeks, Hamp1-/- mice gained less body weight and developed less IR than corresponding WT mice. This was associated with less lipid accumulation in the liver and decreased inflammation and lipolysis in the adipose tissue in the knock-out mice, than in the WT animals. Fewer macrophages infiltrated the adipose tissue in the knockout mice than in wild-type mice, with these macrophages exhibiting a predominantly anti-inflammatory (M2-like) phenotype. These observations suggest a novel role of hepcidin (central regulator of systemic iron homeostasis) in the development of inflammation in adipose tissue and insulin resistance, in response to a high-fat diet. CLINICAL PERSPECTIVESO_LIElevated body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying molecular mechanisms linking them are unclear. C_LIO_LIIn response to high-fat diet (HFD)-feeding (to induce IR), mice that lacked hepcidin (Hamp1-/-) (and hence had elevated body iron stores) gained less body weight and developed less insulin resistance than wild-type (WT) mice. Inflammation and infiltration of macrophages into adipose tissue of HFD-fed Hamp1-/- mice were less than in WT mice, with the macrophages exhibiting an anti-inflammatory M2-like phenotype. C_LIO_LIThese findings suggest a novel role of iron and hepcidin in HFD-induced inflammation in adipose tissue and development of insulin resistance. They raise the possibility that modulation of body iron may represent a potential way to inhibit these processes. C_LI

immunology↗

bioRxiv2021

Aperiodic measures of neural excitability are associated with anticorrelated hemodynamic networks at rest: a combined EEG-fMRI study

The hallmark of resting EEG spectra are distinct rhythms emerging from a broadband, aperiodic background. This aperiodic neural signature accounts for most of total EEG power, although its significance and relation to functional neuroanatomy remains obscure. We hypothesized that aperiodic EEG reflects a significant metabolic expenditure and therefore might be associated with the default mode network while at rest. During eyes-open, resting-state recordings of simultaneous EEG-fMRI, we find that aperiodic and periodic components of EEG power are only minimally associated with activity in the default mode network. However, a whole-brain analysis identifies increases in aperiodic power correlated with hemodynamic activity in an auditory-salience-cerebellar network, and decreases in aperiodic power are correlated with hemodynamic activity in prefrontal regions. Desynchronization in residual alpha and beta power is associated with visual and sensorimotor hemodynamic activity, respectively. These findings suggest that resting-state EEG signals acquired in an fMRI scanner reflect a balance of top-down and bottom-up stimulus processing, even in the absence of an explicit task. HIGHLIGHTSO_LIPeriodic and aperiodic EEG parameters associated with distinct resting-state networks C_LIO_LIIncreases in aperiodic power associated with an auditory-salience-cerebellar network C_LIO_LIDecreases in aperiodic power associated with prefrontal regions C_LIO_LIGlobal neural excitability may reflect stimulus processing or arousal attributable to the uniqueness of the resting-state MR-scanner environment C_LI

neuroscience↗

bioRxiv2020

Biodiverse food plants in the semiarid region of Brazil have unknown potential: A systematic review

Food biodiversity presents one of the most significant opportunities to enhance food and nutrition security today. The lack of data on many plants, however, limits our understanding of their potential and the possibility of building a research agenda focused on them. Our objective with this systematic review was to identify biodiverse food plants occurring in the Caatinga biome, Brazil, strategic for the promotion of food and nutrition security. We selected studies from the following databases: Web of Science, Medline/PubMed (via the National Library of Medicine), Scopus and Embrapa Agricultural Research Databases (BDPA). Eligible were original articles, published since 2008, studying food plants occurring in the Caatinga. We assessed the methodological quality of the studies we selected. We reviewed a total of fifteen studies in which 65 plants that met our inclusion criteria were mentioned. Of this amount, 17 species, including varieties, subspecies, and different parts of plants, had data on chemical composition, in addition to being mentioned as food consumed by rural communities in observational ethnobotanical studies. From the energy and protein data associated with these plants, we produced a ranking of strategic species. The plants with values higher than the average of the set were: Dioclea grandiflora Mart. ex Benth (mucuna), Hymenaea courbaril L. (jatoba), Syagrus cearensis Noblick (coco-catole), Libidibia ferrea (Mart. ex Tul.) L.P.Queiroz (juca), Sideroxylon obtusifolium (Roem. & Schult.) T.D.Penn. (quixabeira). We suggest that the scientific community concentrates research efforts on tree legumes, due to their resilience and physiological, nutritional, and culinary qualities.

scientific communication and education↗

bioRxiv2019

Characterization of C. difficile strains isolated from companion animals and the associated changes in the host fecal microbiota

BackgroundClostridioides difficile is an enteric pathogen historically known to cause hospital associated (HA)-infections in humans. A major risk factor for CDI in humans is antibiotic usage as it alters the gut microbiota and there is a loss of colonization resistance against C. difficile. In recent years there has been an increase in community associated (CA)-C. difficile infection that does not have the same risk factors as HA-CDI. Potential sources of CA-CDI have been proposed and include animals, food, water, and the environment, however these sources remain poorly investigated. Here, we define the prevalence of C. difficile strains found in different companion animals (canines, felines, and equines) to investigate a potential zoonotic link. C. difficile strains were identified by toxin gene profiling, fluorescent PCR ribotyping, and antimicrobial susceptibility testing. 16s rRNA gene sequencing was done on animal feces to investigate the relationship between the presence of C. difficile and the gut microbiota in different hosts.\n\nResultsHere, we show that C. difficile was recovered from 20.9% of samples (42/201), which included 33 canines, 2 felines, and 7 equines. Over 69% (29/42) of the isolates were toxigenic and belonged to 14 different ribotypes, with overlap between HA- and CA-CDI cases in humans. The presence of C. difficile results in a shift in the fecal microbial community structure in both canines and equines. Commensal Clostridia C. hiranonis was negatively associated with C. difficile in canines. Further experimentation showed a clear antagonistic relationship between the two strains in vitro, suggesting that commensal Clostridia might play a role in colonization resistance against C. difficile in different hosts.\n\nConclusionsIn this study we investigated a potentially important source of C. difficile transmission: the companion animal population. C. difficile carriage was common in dogs, cats, and horses. C. difficile isolates from companion animals included many of the same ribotypes known to cause HA- and CA-CDI in humans, and had similar antimicrobial resistance profiles as those isolated from human populations. These data contribute to our understanding of non-hospital exposure to C. difficile in the human population and suggest new avenues for reducing C. difficile prevalence in companion animals and, perhaps, thereby reducing CA-CDI in humans.

microbiology↗

bioRxiv2018

Non-academic employability of life science PhDs: the importance of training beyond the bench

To better understand how PhD graduates have prepared for the non-academic job market, we surveyed life science PhD and postdoctoral graduates from the University of Toronto who were employed in non-academic sectors. We also surveyed life science PhD and postdoctoral trainees to assess their engagement in career preparation activities. PhD professionals employed in non-academic sectors had engaged in various career preparation activities during their training. Some activities had a higher perceived impact on the path to employment than others. Trainees had also engaged in such activities, but those rated by professionals as having a highly positive impact on their path to employment were engaged in by only a minority of trainees. The proportion of trainees who wished to work in a non-academic sector was higher among those who were closer to program completion. Like professionals, many trainees reported facing barriers to pursuing career development activities. Our findings suggest that PhD trainees seeking to work in non-academic sectors should engage in career preparation activities, particularly those that involve experiential learning. By supporting co-curricular programming and reducing barriers to participation in career development activities, academic administrators and faculty have the opportunity to support trainees professional development beyond the laboratory.

scientific communication and education↗