Search

Background Non-polio Enteroviruses (EV) are important neonatal CNS pathogens. Multiple EV genotypes have been detected in pediatric CSF, e.g. Echovirus (E) 6 and E30. CSF innate immune responses to EV genotypes remain poorly defined. Most data are from EV-A71 or E30 CNS infections and do not compare responses between these or other EV types. We sought to better define innate immune responses to EV genotypes in CSF. Methods Salvaged standard of care CSF samples from ≤6 month olds (real time EV PCR(+) or EV PCR(-) controls) from Jan 2010 - Dec 2020 were tested in duplicate on a 21- cytokine bead panel (MilliporeSigma). EV positive samples were previously genotyped by sequencing the viral capsid gene. Cytokine levels calculated from the standard curve were compared by Kruskal-Wallis and post-hoc analysis (GraphPad Prism 8.4.3). Natural partitioning of participants was explored using principal component analysis and cluster analysis (IBM SPSS v27). The utility of cytokine signatures in predicting EV status was explored using discriminant analysis and ROC analysis (IBM SPSS v27). Results Data from 72 CSF with E6 (N=16), E9 (N= 9), E18 (N=9), and E30 (N=21) showed significant differences among EV genotypes vs. controls for 20 cytokines (IL-17 was excluded). Significant differences in cytokine levels in EV CSF vs controls were seen: E6 for all 20 cytokines; E9 for Fractalkine, IP10, and MCP1; E18 for Fractalkine and MCP1; E30 19 cytokines (not GM-CSF). PCA revealed only minor overlap of controls and EV positives; EV types overlapped, except E30, differing most from E9 and E18 but overlapping E6. The most important type-differentiating cytokines by PCA were MCP1, Fractalkine, IL-8, and IL-10. Patterns in DA resembled PCA; controls clearly separated from EV CSF, E30 being the most distinct. Overall, the discriminant model correctly classified EV type or controls at a 63% rate - highest for controls (94.1%) and E30 (74.1%). In the DA model, the most important cytokines were IP-10, IL-2, IL-1Ra, and Fractalkine. Discriminant scores had the largest area under the curve (AUC), 0.990. Among cytokines, IFNa2 had the largest AUC, 0.987. Conclusion Preliminary data show significant EV-genotype differences in innate immune response to CNS infections. Cytokine patterns may serve as a key predictor for discerning EV genotypes. Disclosures Brian R. Lee, PhD, MPH, CDC: Grant/Research Support|Merck: Grant/Research Support Christopher J Harrison, MD, Astellas: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|Pediatric news: Honoraria|Pfizer: Grant/Research Support Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, F(AAM), BioFire: Grant/Research Support|Luminex: Grant/Research Support.

This study aims to explore the effects of Garcinia mangostana (mangosteen) and Curcuma longa independently and synergistically in modulating induced inflammation and impaired brain neurotransmitters commonly observed in high-fat diet-induced obesity in rodent models. Male albino Wistar rats were divided into four experimental groups. Group I, control, obese, fed on a high-fat diet (HFD), and Group II-IV, fed on HFD then given mangosteen extract (400 mg/kg/day) and/or Curcuma (80 mg/kg/day), or a mixture of both for 6 weeks. Plasma pro-inflammatory cytokines, leptin, and brain serotonin, dopamine, and glutamate were measured in the five studied groups. G. mangostana and Curcuma longa extracts demonstrate antioxidant and DPPH radical scavenging activities. Both induced a significant reduction in the weight gained, concomitant with a non-significant decrease in the BMI (from 0.86 to 0.81 g/cm2). Curcuma either alone or in combination with MPE was more effective. Both extracts demonstrated anti-inflammatory effects and induced a significant reduction in levels of both IL-6 and IL-12. The lowest leptin level was achieved in the synergistically treated group, compared to independent treatments. Brain dopamine was the most affected variable, with significantly lower levels recorded in the Curcuma and synergistically treated groups than in the control group. Glutamate and serotonin levels were not affected significantly. The present study demonstrated that mangosteen pericarp extract (MPE) and Curcuma were independently and in combination effective in treating obesity-induced inflammation and demonstrating neuroprotective properties.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that clinically presented as impaired social interaction, repetitive behaviors, and weakened communication. The use of bee pollen as a supplement rich in amino acids amino acids, vitamins, lipids, and countless bioactive substances may lead to the relief of oxidative stress, neuroinflammation, glutamate excitotoxicity, and impaired neurochemistry as etiological mechanisms autism. Thirty young male Western albino rats were randomly divided as: Group I-control; Group II, in which autism was induced by the oral administration of 250 mg propionic acid/kg body weight/day for three days followed by orally administered saline until the end of experiment and Group III, the bee pollen-treated group, in which the rats were treated with 250 mg/kg body weight of bee pollen for four weeks before autism was induced as described for Group II. Markers related to oxidative stress, apoptosis, inflammation, glutamate excitotoxicity, and neurochemistry were measured in the brain tissue. Our results indicated that while glutathione serotonin, dopamine, gamma-aminobutyric acid (GABA), GABA/Glutamate ratio, and vitamin C were significantly reduced in propionic acid-treated group (p < 0.05), glutamate, IFN-γ, IL-1A, IL-6, caspase-3, and lipid peroxide levels were significantly elevated (p < 0.05). Bee pollen supplementation demonstrates protective potency presented as amelioration of most of the measured variables with significance range between (p < 0.05)–(p < 0.001).

Neuropeptides play a major role in maintaining normal brain development in children. Dysfunction of some specific neuropeptides can lead to autism spectrum disorders (ASD) in terms of social interaction and repetitive behavior, but the exact underlying etiological mechanisms are still not clear. In this study, we used an animal model of autism to investigate the role of bee pollen and probiotic in maintaining neuropeptide levels in the brain. We measured the Alpha-melanocyte-stimulating hormone (α-MSH), Beta-endorphin (β-End), neurotensin (NT), and substance P (SP) in brain homogenates of six studied groups of rats. Group I served as control, given only PBS for 30 days; Group II as an autistic model treated with 250 mg PPA/kg BW/day for 3 days after being given PBS for 27 days. Groups III-VI were denoted as intervention groups. G-III was treated with bee pollen (BP) 250 mg/kg body weight/day; G-IV with Lactobacillus paracaseii (LB) (109 CFU/mL) suspended in PBS; G-V with 0.2 g/kg body weight/day Protexin®, a mixture of probiotics (MPB); and G-VI was transplanted with stool from normal animals (FT) for 27 days prior to the induction of PPA neurotoxicity on the last 3 days of study (days 28–30). The obtained data were analyzed through the use of principal component analysis (PCA), discriminant analysis (DA), hierarchical clustering, and receiver operating characteristic (ROC) curves as excellent statistical tools in the field of biomarkers. The obtained data revealed that brain levels of the four measured neuropeptides were significantly reduced in PPA-treated animals compared to healthy control animals. Moreover, the findings demonstrate the ameliorative effects of bee pollen as a prebiotic and of the pure or mixed probiotics. This study proves the protective effects of pre and probiotics against the neurotoxic effects of PPA presented as impaired levels of α-MSH, β-End, NT, and SP.

Obesity and the brain are linked since the brain can control the weight of the body through its neurotransmitters. The aim of the present study was to investigate the effect of high-fat diet (HFD)-induced obesity on brain functioning through the measurement of brain glutamate, dopamine, and serotonin metabolic pools. In the present study, two groups of rats served as subjects. Group 1 was fed a normal diet and named as the lean group. Group 2 was fed an HFD for 4 weeks and named as the obese group. Markers of oxidative stress (malondialdehyde, glutathione, glutathione-s-transferase, and vitamin C), inflammatory cytokines (interleukin [IL]-6 and IL-12), and leptin along with a lipid profile (cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein levels) were measured in the serum. Neurotransmitters dopamine, serotonin, and glutamate were measured in brain tissue. Fecal samples were collected for observing changes in gut flora. In brain tissue, significantly high levels of dopamine and glutamate as well as significantly low levels of serotonin were found in the obese group compared to those in the lean group (P > 0.001) and were discussed in relation to the biochemical profile in the serum. It was also noted that the HFD affected bacterial gut composition in comparison to the control group with gram-positive cocci dominance in the control group compared to obese. The results of the present study confirm that obesity is linked to inflammation, oxidative stress, dyslipidemic processes, and altered brain neurotransmitter levels that can cause obesity-related neuropsychiatric complications.

Background Syphilis is one of the most common sexually transmitted infections (STIs), and it remains a significant public health concern, particularly in low-resource settings including sub-Saharan Africa. There are limited data on the prevalence of syphilis among pregnant women living with HIV in South Africa. This study determined the prevalence of syphilis infection in pregnant women living with HIV by the polymerase chain reaction (PCR). Methods This was a cross-sectional study that included 385 pregnant women living with HIV recruited from the antenatal clinic at the King Edward VIII Hospital in Durban, South Africa between October 2020 and April 2021. Treponema pallidum was detected using the Applied BiosystemsTM TaqMan® Assays from stored DNA samples extracted from vaginal swabs. Results The prevalence of syphilis was 5.2% (20/385). The overall median (Q1–Q3) age of the women was 30.0 years (25.0–36.0). Of the women who tested positive for syphilis, 60.0% had reported STI symptoms ( p = 0.030) and of those, 65.0% did not perceive themselves at risk of contracting STIs ( p = 0.019). Women who reported having STI symptoms were more likely to test positive for syphilis when compared to women who reported not having any STI symptoms (OR: 2.810; 95% CI 1.119–7.052; p = 0.028). Women who perceived themselves as being at risk of contracting STIs were less likely to test positive for syphilis when compared to women who did not perceive themselves at risk of contracting STIs (OR: 0.328; 95% CI 0.128–0.842; p = 0.020). Conclusion The study has indicated syphilis is prevalent among pregnant women living with HIV in Durban, South Africa however STI risk perception is low. Educational programs on STIs are essential among pregnant women attending antenatal care clinics in Durban.

Obesity prevalence is rising globally, as are the number of chronic disorders connected with obesity, such as diabetes, non-alcoholic fatty liver disease, dyslipidemia, and hypertension. Bariatric surgery is also becoming more common, and it remains the most effective and long-term treatment for obesity. This study will assess the influence of Laparoscopic Sleeve Gastrectomy (LSG) on gut microbiota in people with obesity before and after surgery. The findings shed new light on the changes in gut microbiota in Saudi people with obesity following LSG. In conclusion, LSG may improve the metabolic profile, resulting in decreased fat mass and increased lean mass, as well as improving the microbial composition balance in the gastrointestinal tract, but this is still not equivalent to normal weight microbiology. A range of factors, including patient characteristics, geographic dispersion, type of operation, technique, and nutritional and caloric restriction, could explain differences in abundance between studies. This information could point to a novel and, most likely, tailored strategy in obesity therapy, which could eventually be incorporated into health evaluations and monitoring in preventive health care or clinical medicine.

1. The Qilian Mountains represent one of the key livestock‐raising grasslands in China. The two main herbivore species raised in this area – yaks and sheep – are of critical economical value. Grasshoppers compete with these animals for available nutrients, creating multifaceted relationships between livestock, grasshoppers and plants. A clear understanding of such relationships is lacking and is urgently needed to guide conservation efforts. 2. This study aims to document the effects of yak and sheep grazing on grasshopper assemblages and to elucidate the underlying mechanisms of such effects. 3. It is shown here that yaks and sheep impact grasshopper assemblages differently. Grasshopper assemblages exhibited lower density, biodiversity, richness, and evenness of distribution in yak‐grazed pastures than in grazing‐free grasslands. Sheep‐grazed pastures exhibited a dramatically divergent picture, with elevated density, biodiversity and richness, and a slightly decreased evenness of distribution. Grasshoppers were generally larger in grazed pastures than in grazing‐free grasslands, especially in yak‐grazed plots. 4. The present study suggests that differences between yak and sheep pastures in plant assemblage structure and plant traits are probably the underlying forces driving the differences in grasshopper assemblage structure and grasshopper traits, respectively. 5. The study shows that the grasshopper habitat indicator species differ between yak and sheep pastures, raising the possibility that such indicators can be used to monitor grassland usage and degradation in the Qilian Mountains. 6. These results provide novel insights into the dynamic interactions of common domesticated herbivore species, grasshoppers and plants in Qilian Mountains, which augment current knowledge and may ultimately lead to better conservation practices.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and restricted, repetitive behavior. Multiple studies have suggested mitochondrial dysfunction, glutamate excitotoxicity, and impaired detoxification mechanism as accepted etiological mechanisms of ASD that can be targeted for therapeutic intervention. In the current study, blood samples were collected from 40 people with autism and 40 control participants after informed consent and full approval from the Institutional Review Board of King Saud University. Sodium (Na+), Potassium (K+), lactate dehydrogenase (LDH), glutathione-s-transferase (GST), and mitochondrial respiratory chain complex I (MRC1) were measured in plasma of both groups. Predictive models were established to discriminate individuals with ASD from controls. The predictive power of these five variables, individually and in combination, was compared using the area under a ROC curve (AUC). We compared the performance of principal component analysis (PCA), discriminant analysis (DA), and binary logistic regression (BLR) as ways to combine single variables and create the predictive models. K+ had the highest AUC (0.801) of any single variable, followed by GST, LDH, Na+, and MRC1, respectively. Combining the five variables resulted in higher AUCs than those obtained using single variables across all models. Both DA and BLR were superior to PCA and comparable to each other. In our study, the combination of Na+, K+, LDH, GST, and MRC1 showed the highest promise in discriminating individuals with autism from controls. These results provide a platform that can potentially be used to verify the efficacy of our models with a larger sample size or evaluate other biomarkers.

Microorganisms and associated conditions make up some of the world’s leading causes of death and have the potential to cause a significant societal effect during pandemic states. Despite such significance in the healthcare field, attention and funding directed towards microbiological research lags its cohorts in cancer and cardiovascular disease. In the current SAR-CoV-2 pandemic, the importance of practicing clinicians and providers to remain knowledgeable on antimicrobial therapy for their patients is higher than ever before. The scope of this review is to provide clinicians a semi-comprehensive, up-to-date understanding of the mechanisms of action among antimicrobial agents as well as key distinctions in clinical manifestations of pathogens.

Brevibacillus laterosporus (B. laterosporus) is an aerobic gram-positive bacillus that is rarely associated with human infection. A review of multiple online databases revealed no other cases of bacteremia in an adult involving this organism. Historically, this "canoe-shaped" microbe has been characterized as a pathogen in invertebrates, and information regarding human infection is scarce. We present a clinical vignette of what we believe to be the first reported case of B. laterosporus bacteremia in an adult human subject.

BackgroundEnterovirus (EV) and parechovirus type A3 (PeV-A3) cause infections ranging from asymptomatic to life-threatening. Host immune responses in children, particularly innate responses to PeV-A3, remain largely unknown. The aim of this study was to determine aspects of the cytokine/chemokine responses to EV and PeV-A3 in cerebrospinal fluid (CSF) and plasma obtained from children with systemic/central nervous system infection.MethodsA total of 74 salvaged CSF samples (27 with EV, 23 with PeV-A3, and 24 with neither EV nor PeV-A3) and 35 paired blood samples (10 with EV, 14 with PeV-A3, and 11 with neither) were studied. Concentrations of cytokines and chemokines were measured using a customized 21-plex MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel. Additionally, clinical characteristics data for all the patients were collected from electronic medical records to evaluate the potential association between the immune response and presentations.ResultsWe demonstrate that EV and PeV-A3 infections induce different cytokine/chemokine immune responses in children. EV induces more robust responses in CSF with significantly elevated levels of fractalkine, interferon (IFN)-α2, IFN-γ, interleukin (IL)-1Rα, IL-4, IL-8, and tumor necrosis factor α; PeV-A3 induces less robust or absent responses in CSF but robust responses in plasma, with significantly higher concentrations of IFN-α2, IL-15, IL-1Rα, interferon-γ-inducible protein–10, and monocyte chemoattractant protein–1.ConclusionsHigh cytokine/chemokine concentrations in the plasma of PeV-A3 patients compared with EV patients could explain higher/more prolonged fever in PeV-A3 patients, whereas relatively low cytokine/chemokine concentrations in PeV-A3 CSF might explain the absence of CSF pleocytosis.

Chronic diseases constitute a major global burden with significant impact on health systems, economies, and quality of life. Chronic diseases include a broad range of diseases that can be communicable or non-communicable. Chronic diseases are often associated with modifications of normal physiological levels of various analytes that are routinely measured in serum and other body fluids, as well as pathological findings, such as chronic inflammation, oxidative stress, and mitochondrial dysfunction. Identification of at-risk populations, early diagnosis, and prediction of prognosis play a major role in preventing or reducing the burden of chronic diseases. Biomarkers are tools that are used by health professionals to aid in the identification and management of chronic diseases. Biomarkers can be diagnostic, predictive, or prognostic. Several individual or grouped biomarkers have been used successfully in the diagnosis and prediction of certain chronic diseases, however, it is generally accepted that a more sophisticated approach to link and interpret various biomarkers involved in chronic disease is necessary to improve our current procedures. In order to ensure a comprehensive and unbiased coverage of the literature, first a primary frame of the manuscript (title, headings and subheadings) was drafted by the authors working on this paper. Second, based on the components drafted in the preliminary skeleton a comprehensive search of the literature was performed using the PubMed and Google Scholar search engines. Multiple keywords related to the topic were used. Out of screened papers, only 190 papers, which are the most relevant, and recent articles were selected to cover the topic in relation to etiological mechanisms of different chronic diseases, the most recently used biomarkers of chronic diseases and finally the advances in the applications of multivariate biomarkers of chronic diseases as statistical and clinically applied tool for the early diagnosis of chronic diseases was discussed. Recently, multivariate biomarkers analysis approach has been employed with promising prospect. A brief discussion of the multivariate approach for the early diagnosis of the most common chronic diseases was highlighted in this review. The use of diagnostic algorithms might show the way for novel criteria and enhanced diagnostic effectiveness inpatients with one or numerous non-communicable chronic diseases. The search for new relevant biomarkers for the better diagnosis of patients with non-communicable chronic diseases according to the risk of progression, sickness, and fatality is ongoing. It is important to determine whether the newly identified biomarkers are purely associations or real biomarkers of underlying pathophysiological processes. Use of multivariate analysis could be of great importance in this regard.

Tibetan Plateau grasslands embody an important ecosystem featuring vibrant biogeochemical cycles. Soil fauna, particularly nematodes, play an important role in maintaining the integrity, function, and homeostasis of such ecosystem. In the Tibetan Plateau, studies exploring the influence of frequent fertilization practices on nematode communities and subsequent repercussions impacting the entire ecosystem are scarce. To investigate the effect of long-term fertilization on nematode communities in the eastern Tibetan Plateau of China, we monitored such communities under fertilization treatments ranging from 0 to 120 g m−2 year−1. To gain broader insights into the dynamic interrelationships within the ecosystem, we also monitored plant communities and modeled their bidirectional relationships with soil nematodes. Our data show that with higher fertilization intensities, overall plant productivity increases. Such gains are accompanied by reduction in plant community richness and predominance of grasses on the expense of sedges, legumes, and forbs. Fertilization also impacted the abundance and species richness of nematode communities; this effect was manifest in a hump-shaped relationship with both abundance and species richness of nematode communities peaking at 60 g m−2 year−1. The relationship between nematode biodiversity and aboveground plant production also exhibited a predominantly hump-shaped trajectory. Our model suggests that soil acidity and the ratio of available nitrogen-to-available phosphorus had indirect, yet strong, effects on the nematode community abundance and species richness, indicating that the decline of nematode communities beyond a 60 g m−2 year−1 treatment could, at least in part, be attributed to unfavorable soil conditions. Our findings augment our understanding of the responses of soil fauna to nitrogen and phosphorus additions in alpine grasslands and provide scientific basis for future management of grassland fertilization.

Fertilization greatly impacts grassland ecosystems as it alters plant communities, soil fauna, and microbiota although few studies have looked at these interactions on the Tibetan plateau. Soil nematodes are ideal bioindicators for the status of below-ground ecosystems. To explore how nematode communities are impacted by the use of fertilization, we studied the top layer of soil in land that had been fertilized annually with diammonium phosphate for over 10 years. We tested effects of long term fertilization treatment at 300, 600 kg ha−1 yr−1 (F300, F600) compared to unfertilized control (F0) on soil nematode community at the 0–15 cm depth. Soil samples for analysis of nematode community were collected on September 2012 and on September 2013. We show that fertilization was associated with increased plant and microbial biomass, and decreased plant biodiversity. Fertilization increased microbial biomass C and N; grass biomass and total plant biomass, but decreased plant species richness, plant community biodiversity and the biomass of sedges, legumes and forbs. Fertilization increased nematode communities increased over the entire course of the study. We show that the amount of fertilizer used and the duration of its use significantly impacted the dynamics and composition of nematode communities. The changes in nematode community were associated with both changes in soil factors and shifts in the plant community that were caused by fertilization. According to the structural equation model (SEM), fertilization had strong effects on soil microorganisms and plant community composition, whereas plant community was the main determinant of nematode community changes. Our findings highlight the importance of soil fertilization in regulating both plant and soil fauna communities, and provide a better understanding of the responses of plants and soils to fertilization and the linkages between structure and functioning of above-ground and below-ground in the Tibetan Plateau.

Background Autism spectrum disorder (ASD) is a complex group of heterogeneous neurodevelopmental disorders the prevalence of which has been in the rise in the past decade. In an attempt to better target the basic causes of ASD for diagnosis and treatment, efforts to identify reliable biomarkers related to the body’s metabolism are increasing. Despite an increase in identifying biomarkers in ASD, there are none so far with enough evidence to be used in routine clinical examination, unless medical illness is suspected. Promising biomarkers include those of mitochondrial dysfunction, oxidative stress, energy metabolism, and apoptosis. Methods and participants Sodium (Na+), Potassium (K+), glutathione (GSH), glutathione-s-transferase (GST), Creatine kinase (CK), lactate dehydrogenase (LDH), Coenzyme Q10, and melatonin (MLTN) were evaluated in 13 participants with ASD and 24 age-matched healthy controls. Additionally, five ratios, which include Na+/K+, GSH:GST, CK:Cas7, CoQ10: Cas 7, and Cas7:MLTN, were tested to measure their predictive values in discriminating between autistic individuals and controls. These markers, either in absolute values, as five ratios, or combined (9 markers + 5 ratios) were subjected to a principal component analysis and multidimensional scaling (MDS), and hierarchical clustering, which are helpful statistical tools in the field of biomarkers. Results Our data demonstrated that both PCA and MDS analysis were effective in separating autistic from control subjects completely. This was also confirmed through the use of hierarchical clustering, which showed complete separation of the autistic and control groups based on nine biomarkers, five biomarker ratios, or a combined profile. Excellent predictive value of the measured profile was obtained using the receiver operating characteristics analysis, which showed an area under the curve of 1. Conclusion The availability of an improved predictive profile, represented by nine biomarkers plus the five ratios, inter-related different etiological mechanisms in ASD and would be valuable in providing greater recognition of the altered biological pathways in ASD. Our predictive profile could be used for the diagnosis and intervention of ASD.

The complexity of immune responses limits the usefulness of univariate methods in answering complex immunology questions. To demonstrate the utility of a multivariate approach, we employ such approach to compare T cells of African green monkeys (AGMs) and rhesus macaques (RMs). Among the most prominent distinguishing features we found were lower CD3 and higher CD28 surface expression in AGMs compared to RMs. After in vitro stimulation, a larger proportion of AGM T cells secreted cytokines, especially those producing more than one cytokine (i.e. multifunctional cells). To find out whether multifunctional responses associate with protection in other species, we compared T cells of cynomolgus macaques (CMs) infected with wild-type Simian Immunodeficiency Virus (SIV) to those of CMs infected (vaccinated) with a replication-defective virus. Wild-type SIV infection in macaques leads to simian Acquired Immunodeficiency Syndrome (AIDS), which does not happen in animals previously vaccinated with a replication-defective virus. Interestingly, after in vitro stimulation, multifunctional cells were more abundant among T cells of vaccinated CMs. Our results propose T-cell multifunctionality as a potentially useful marker of immunity, although additional verification is needed. Finally, we hope our multivariate model and its associated validation methods will inform future studies in the field of immunology.

Multiple gene expression alterations have been linked to Alzheimer’s disease (AD), implicating multiple metabolic pathways in its pathogenesis. However, a clear distinction between AD-specific gene expression changes and those resulting from non-specific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human β-amyloid peptide (Aβ) in a Caenorhabditis elegans Alzheimer’s disease model. Aβ-induced gene expression alterations were compared to those caused by a synthetic aggregating protein to identify Aβ-specific effects. Both Aβ-specific and non-specific alterations were observed. Among Aβ-specific genes were those involved in aging, proteasome function, and mitochondrial function. An intriguing observation was the significant overlap between gene expression changes induced by Aβ and those induced by Cry5B, a bacterial pore-forming toxin. This led us to hypothesize that Aβ exerts its toxic effect, at least in part, by causing damage to biological membranes. We provide in vivo evidence consistent with this hypothesis. This study distinguishes between Aβ-specific and non-specific mechanisms and provides potential targets for therapeutics discovery.

It is critical to be able to identify longitudinally changing genes in temporal data so that studies can be focused on how gene expression changes in a dynamic way. While biological networks continue to play a significant role in modeling and characterizing complex relationships in biological systems, most network modeling studies in biomedical research focus on snapshot or “static” network-based analysis to identify genes of interest. In this study, we use a temporal non-sampling network-based approach to identify and rank genes that exhibit significant co-expression variation over time. We use in the C. elegans gene correlation network obtained from mRNA expression profiles to illustrate the value of the proposed approach. We compare the results of this method to results obtained from traditional statistical analysis that focuses on identifying simple differentially expressed genes. We show that rank-based temporal network analysis can identify genes that contribute to changes in the network structure and consequently contribute to changes in the genetic regulatory machine.

Many bioinformatics algorithms attempt to extract relevant biological information from datasets obtained at specific data points. However, it is critical to identify changing genes in temporal data so that studies can focus on the dynamics of gene expression. While networks continue to play a significant role in characterising biological relationships, most biomedical network modelling studies focus on 'static' network-based analysis. In this study, we use a temporal, network-based approach to identify and rank genes that exhibit variation in short-course gene expression. We use a Caenorhabditis elegans (C. elegans) gene correlation network obtained from mRNA expression to illustrate the value of the proposed approach, and compare the results of this method to results obtained from traditional differential gene expression analysis. We show that temporal network analysis identifies genes that are inherently different from differentially expressed genes, raising new questions about structural meaning in expression networks and how changes in expression are observed.

Background Autism is a neurodevelopmental disorder that displays significant heterogeneity. Comparison of subgroups within autism, and analyses of selected biomarkers as measure of the variation of the severity of autistic features such as cognitive dysfunction, social interaction impairment, and sensory abnormalities might help in understanding the pathophysiology of autism. Methods and Participants In this study, two sets of biomarkers were selected. The first included 7, while the second included 6 biomarkers. For set 1, data were collected from 35 autistic and 38 healthy control participants, while for set 2, data were collected from 29 out of the same 35 autistic and 16 additional healthy subjects. These markers were subjected to a principal components analysis using either covariance or correlation matrices. Moreover, libraries composed of participants categorized into units were constructed. The biomarkers used include, PE (phosphatidyl ethanolamine), PS (phosphatidyl serine), PC (phosphatidyl choline), MAP2K1 (Dual specificity mitogen-activated protein kinase kinase 1), IL-10 (interleukin-10), IL-12, NFκB (nuclear factor-κappa B); PGE2 (prostaglandin E2), PGE2-EP2, mPGES-1 (microsomal prostaglandin synthase E-1), cPLA2 (cytosolic phospholipase A2), 8-isoprostane, and COX-2 (cyclo-oxygenase-2). Results While none of the studied markers correlated with CARS and SRS as measure of cognitive and social impairments, six markers significantly correlated with sensory profiles of autistic patients. Multiple regression analysis identifies a combination of PGES, mPGES-1, and PE as best predictors of the degree of sensory profile impairment. Library identification resulted in 100% correct assignments of both autistic and control participants based on either set 1 or 2 biomarkers together with a satisfactory rate of assignments in case of sensory profile impairment using different sets of biomarkers. Conclusion The two selected sets of biomarkers were effective to separate autistic from healthy control subjects, demonstarting the possibility to accurately predict the severity of autism using the selected biomarkers. The effectiveness of the identified libraries lied in the fact that they were helpful in correctly assigning the study population as control or autistic patients and in classifying autistic patients with different degree of sensory profile impairment.

Multiple neurodegenerative diseases are causally linked to aggregation-prone proteins. Cellular mechanisms involving protein turnover may be key defense mechanisms against aggregating protein disorders. We have used a transgenic Caenorhabditis elegans Alzheimer's disease model to identify cellular responses to proteotoxicity resulting from expression of the human beta amyloid peptide (Abeta). We show up-regulation of aip-1 in Abeta-expressing animals. Mammalian homologues of AIP-1 have been shown to associate with, and regulate the function of, the 26S proteasome, leading us to hypothesize that induction of AIP-1 may be a protective cellular response directed toward modulating proteasomal function in response to toxic protein aggregation. Using our transgenic model, we show that overexpression of AIP-1 protected against, while RNAi knockdown of AIP-1 exacerbated, Abeta toxicity. AIP-1 overexpression also reduced accumulation of Abeta in this model, which is consistent with AIP-1 enhancing protein degradation. Transgenic expression of one of the two human aip-1 homologues (AIRAPL), but not the other (AIRAP), suppressed Abeta toxicity in C. elegans, which advocates the biological relevance of the data to human biology. Interestingly, AIRAPL and AIP-1 contain a predicted farnesylation site, which is absent from AIRAP. This farnesylation site was shown by others to be essential for an AIP-1 prolongevity function. Consistent with this, we show that an AIP-1 mutant lacking the predicted farnesylation site failed to protect against Abeta toxicity. Our results implicate AIP-1 in the regulation of protein turnover and protection against Abeta toxicity and point at AIRAPL as the functional mammalian homologue of AIP-1.

Acute SIV infection is characterized by explosive infection of memory CD4 T cells in peripheral and mucosal tissues. Interestingly, relatively few memory CD4 T cells are infected until as late as days 7–8 after challenge. However, by day 10 postinfection, most of the memory CD4 T cells are infected and carry viral DNA. The rapidity with which infection expands within 2–3 days to encompass virtually the entire memory CD4 T cell compartment suggests significant alterations in the susceptibility of memory CD4 T cells to infection during this period. The mechanism(s) underlying this increased permissiveness to infection is not known. In this study, we show that IL-15 secretion significantly correlates with the up-regulated expression of CD4 on memory CD4 T cells that is associated with increased permissiveness to SIV infection. Activation and proliferation of memory CD8, but not memory CD4 T cells, preceded the amplification of viral infection. Although memory CD4 T cells did not express normal activation markers, they displayed a significant up-regulation in the density of CD4 but not CCR5 expression between days 7 and 10 postinfection that correlated with increased plasma IL-15 levels and infection in these cells. Culture of purified CD4 T cells with IL-15 and/or SIV was associated with a significant increase in the expression of CD4 and infection of these sorted cells. Our results demonstrate that IL-15 contributes to the increased susceptibility of memory CD4 T cells to SIV during the early phase of acute SIV infection.

The goal of the study was to determine which similarity coefficient and statistical method to use to produce the highest rate of correct assignment (RCA) in repetitive extragenic palindromic PCR-based bacterial source tracking. In addition, the use of standards for deciding whether to accept or reject source assignments was investigated. The use of curve-based coefficients Cosine Coefficient and Pearson's Product Moment Correlation yielded higher RCAs than the use of band-based coefficients Jaccard, Dice, Jeffrey's x, and Ochiai. When enterococcal and Escherichia coli isolates from known sources were used in a blind test, the use of maximum similarity produced consistently higher RCAs than the use of average similarity. We also found that the use of a similarity value threshold and/or a quality factor threshold (the ratio of the average fingerprint similarity within a source to the average similarity of this source's isolates to an unknown) to decide whether to accept source assignments of unknowns increases the reliability of source assignments. Applying a similarity value threshold improved the overall RCA (ORCA) by 15 to 27% when enterococcal fingerprints were used and 8 to 29% when E. coli fingerprints were used. Applying the quality factor threshold resulted in a 22 to 32% improvement in the ORCA, depending on the fingerprinting technique used. This increase in reliability was, however, achieved at the expense of decreased numbers of isolates that were assigned a source.

In the human stomach, the oxyntic epithelium includes numerous tubular invaginations consisting of short pits opening into long glands. The pit is lined by pit cells, whereas the gland is composed of three regions: the base, containing zymogenic cells; the neck, containing neck cells; and the isthmus, composed of little known immature cells and of parietal cells, which are also scattered through the neck and base. The aim of this study was to examine the ultrastructure of the immature cells and to determine their relation to mature cells. To do so, normal oxyntic mucosal biopsies from subjects ranging from 20-43 years old were fixed in aldehydes and postfixed in reduced osmium for electron microscopy and morphometric analysis. The immature cells were sorted out into four classes, whose roles were clarified by comparison with the thoroughly investigated mouse oxyntic epithelium. The first class was composed of the least differentiated immature cells, which were rare and characterized by minute, dense, or cored secretory granules and were accordingly named mini-granule cells. Their function was not clarified. The second class consisted of pre-pit cells, which were characterized by few dense mucous granules and give rise to pit cells that ascend the pit wall and, after reaching the luminal surface, die or are extruded. Both pre-pit and pit cells underwent continuous renewal and, therefore, together constituted a renewal system referred to as pit cell lineage. The third class, or pre-neck cells, characterized by cored secretory granules, give rise to neck cells that descend toward the base region and differentiate further into pre-zymogenic cells, which finally become zymogenic cells. The latter eventually degenerate and die. Thus pre-neck cells and their progeny constitute a renewing system, designated zymogenic cell lineage. The fourth class, or pre-parietal cells, characterized by long microvilli and few tubulovesicles, differentiate into parietal cells that descend along the neck and base regions and eventually degenerate and die. Pre-parietal and parietal cells represent a renewing system referred to as parietal cell lineage. While the origin of the last three classes of progenitor cells has not been elucidated, it is likely that they arise either from an unidentified multipotential stem cell, possibly the mini-granule cell itself, or from the mitotic activity of pre-pit and pre-neck cells. In conclusion, the human oxyntic epithelium is composed of continually renewing cells organized in distinct cell lineages.

The rectal mucosa is a major site for human immunodeficiency virus entry and CD4 T-cell depletion. The early and near-total loss of these cells from the rectal mucosa severely compromises the ability of the mucosal immune system to control various opportunistic infections. Protecting these cells from infection and destruction can delay disease progression, leading to a better long-term outcome. Here we show that effective suppression of viral infection in memory CD4 T cells from the rectal mucosa and peripheral blood to a very low level with antiretroviral therapy (ART) initiated prior to the peak of infection is associated with opposite outcomes in these tissues. A near-total loss of CD4 T cells in the rectal mucosa contrasted with preservation of most memory CD4 T cells in peripheral blood during the course of treatment. Interestingly, ART significantly reduced viral infection in memory CD4 T cells from both rectal mucosa and peripheral blood. Although early ART was of limited value in protecting the CD4 T cells in the rectal mucosa, the significant preservation of peripheral CD4 T cells could contribute to maintaining immune competence, leading to a better long-term outcome.

Aims: The goal of the study was to improve the fidelity of library-dependent bacterial source tracking efforts in determining sources of faecal pollution. The first objective was to compare the fidelity of source assignments using Escherichia coli vs Enterococcus spp. The second objective was to determine the efficacy of using thresholds during source assignments to reduce the rate of misassignments when nonlibrary isolates (i.e. isolates from animals not used in building the identification library) are present. Methods and Results: E. coli and Enterococcus isolates from 784 human, cow, deer, dog, chicken, and gull faecal samples were fingerprinted using BOX-PCR. Jack-knife analysis of the fingerprints showed that the overall rate of correct assignment (ORCA) of 867 E. coli isolates was 67% compared with 82% for 1020 Enterococcus isolates. In a separate blind test using similarity value and quality factor thresholds, the ORCA of 130 E. coli and 131 Enterococcus isolates were 70% and 98%, respectively. The use of these thresholds reduced misassignment of 262 nonlibrary enterococcal isolates from horses, goats, pigs, bats, squirrels, ducks, geese, and migratory song birds. Misassignment was reduced from 100% when thresholds were not used, to 47% using similarity threshold alone, and to 12% when both thresholds were used. Conclusions: The use of enterococci provides higher rates of correct source assignment compared with E. coli. The use of similarity thresholds to decide whether to accept source assignments made by computer programmes reduces the rate of misassignment of nonlibrary isolates. Significance and Impact of the Study: Although both E. coli and Enterococcus spp. are still used in microbial source tracking, the use of enterococci should be preferred over the use of E. coli in DNA fingerprint-based efforts. In addition, because environmental isolates are not limited to those from animals used to build source tracking libraries, similarity thresholds should be used during source assignments to reduce the rate of misassignments.

Background and Aim: In mice and humans, the gastric epithelial progenitors undergo proliferation and bipolar migration from the isthmus associated with their differentiation into mucus-, acid- and pepsinogen-secreting cell lineages. Little is known about factors that control the dynamics of these isthmal progenitor cells. Retinoids have long been known as chemopreventive agents against gastric mucosal damage and carcinogenesis. The aim of the present study was to examine the cellular localization of the various retinoid receptors proteins (RAR and RXR) in the gastric epithelium of mice and humans. Methods: Gastric antral biopsies of normal individuals and the oxyntic and antral regions of the mouse stomach were processed for immunohistochemistry using anti-RAR and anti-RXR antibodies. To label the progenitor cell zone, some sections were also probed with antibodies specific for proliferating cell nuclear antigen. Results: The immunoprobed oxyntic mucosal sections of the mice showed that RXRβ protein was present in the epithelial isthmal cells, neck cells, zymogenic cells and some pit and parietal cells. In addition, RARβ was found in isthmal and neck cells, and RARγ was mainly found in neck cells. In the mouse antrum, only RXRβ was detected in the isthmal cells and their pit and gland cell descendents. In humans, immunoprobed antral sections showed that RARβ, RARγ, RXRα and RXRγ proteins are expressed in the isthmal, pit and gland cells. Conclusions: Retinoid receptors are expressed in multiple cell lineages of the mouse and human gastric epithelium and may, therefore, account for the possible effects of retinoids on gastric epithelial cell proliferation and differentiation.