Susceptibility Signatures Research Articles

Remote sensing and magnetic characterization of the Au mineralization and its structural implications: Meatiq dome, Eastern Desert, Egypt

This article examines hydrothermally altered ophiolitic ultramafic rocks (HAOU), specifically Listvenite, which are thrust over the Meatiq dome in the context of gold mineralization. These rocks represent gneissic complexes located in Egypt's eastern desert. The analyses presented herein are essential for understanding the distribution of sheared serpentinite on and beneath the surface and the underlying domal structure. This study offers critical insights into the distribution of serpentinite at Meatiq. It combines remote sensing, aerial and ground magnetic data with petrological, geochemical, and geological analyses to create precise geological maps of potential subsurface igneous structures commonly linked to gold mineralization. Remote sensing is used to test for rock differentiation; intensive field geological investigations were conducted along several traverses. Petrographic and geochemical analysis of selected samples confirmed Au content in some localities. Additionally, tomographic inversion of the collected magnetic land profiles has unveiled previously unidentified subsurface distributions of magnetic susceptibilities, which are essential for explaining the observed surface magnetic anomalies and for understanding the subsurface arrangement of various rock units. Results show that the HAOU rocks have a lower magnetic susceptibility signature relative to the adjacent serpentinites, the serpentinite from South Meatiq shows relatively high gold content, and the gold content decreases with carbonation and alteration of the serpentinite into talc-carbonate, as detected geochemically. The procedure followed in the present study can be regionally applied to studying HAOU rocks of similar geologic conditions. The novelty of this study, beyond the introduction of a novel workflow, lies in the revelation that the rocks forming the Meatiq dome are in thrust contact with steeply dipping suprastructure units.

Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.

The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults. We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m2), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative). In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance. A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.

Brain network integration underpins differential susceptibility of adolescent anxiety.

Parenting is a common and potent environmental factor influencing adolescent anxiety. Yet, the underlying neurobiological susceptibility signatures remain elusive. Here, we used a longitudinal twin neuroimaging study to investigate the brain network integration and its heritable relation to underpin the neural differential susceptibility of adolescent anxiety to parenting environments. 216 twins from the Beijing Twin Study completed the parenting and anxiety assessments and fMRI scanning. We first identified the brain network integration involved in the influences of parenting at age 12 on anxiety symptoms at age 15. We then estimated to what extent heritable sensitive factors are responsible for the susceptibility of brain network integration. Consistent with the differential susceptibility theory, the results showed that hypo-connectivity within the central executive network amplified the impact of maternal hostility on anxiety symptoms. A high anti-correlation between the anterior salience and default mode networks played a similar modulatory role in the susceptibility of adolescent anxiety to paternal hostility. Genetic influences (21.18%) were observed for the connectivity pattern in the central executive network. Brain network integration served as a promising neurobiological signature of the differential susceptibility to adolescent anxiety. Our findings deepen the understanding of the neural sensitivity in the developing brain and can inform early identification and personalized interventions for adolescents at risk of anxiety disorders.

Integrated multi-omic analyses provide insight into colon adenoma susceptibility modulation by the gut microbiota.

Colon cancer onset is strongly associated with the differences in microbial taxa in the gastrointestinal tract. Although recent studies highlight the role of individual taxa, the effect of a complex gut microbiome (GM) on the metabolome and host transcriptome is still unknown. We used a multi-omics approach to determine how differences in the GM affect the susceptibility to adenoma development in a rat model of human colon cancer. Ultra-high performance liquid chromatography mass spectrometry of feces collected prior to observable disease onset identified putative metabolite profiles that likely predict future disease severity. Transcriptome analyses performed after disease onset from normal colonic epithelium and tumor tissues show a correlation between GM and host gene expression. Integrated pathway analyses of the metabolome and transcriptome based on putatively identified metabolic features indicate that bile acid biosynthesis is enriched in rats with high tumors along with increased fatty acid metabolism and mucin biosynthesis. Targeted pyrosequencing of the Pirc allele indicates that the GM alters the mechanism of adenoma development and may drive an epigenetic pathway of tumor suppressor silencing. This study reveals how untargeted metabolomics identifies signatures of susceptibility and integrated analyses uncover pathways of differential mechanisms of loss of tumor suppressor gene function and for potential prevention and therapeutic intervention. IMPORTANCE The association between the gut microbiome and colon cancer is significant but difficult to test in model systems. This study highlights the association of differences in the pathogen-free gut microbiome to changes in the host transcriptome and metabolome that correlate with colon adenoma initiation and development in a rat genetic model of early colon cancer. The utilization of a multi-omics approach integrating metabolomics and transcriptomics reveals differences in pathways including bile acid biosynthesis and fatty acid metabolism. The study also shows that differences in gut microbiomes significantly alter the mechanism of adenoma formation, shifting from genetic changes to epigenetic changes that initiate the early loss of tumor suppressor function. These findings enhance our understanding of the gut microbiome's role in colon cancer susceptibility, offer insights into potential biomarkers and therapeutic targets, and may pave the way for future prevention and intervention strategies.

Zero-frequency supercurrent susceptibility signatures of trivial and topological zero-energy states in nanowire junctions

We propose a method to distinguish between trivial and topological, Majorana, zero-energy states (ZESs) in both short and long superconductor-normal-superconductor junctions based on Rashba nanowires using phase-biased equilibrium transport measurements. In particular, we show how the sawtooth profile of the supercurrent, due to the Majorana oscillation suppression in the topological phase for sufficiently long superconductor regions, leads to a strong signal in its zero-frequency susceptibility for a phase difference of . This signal is notably insensitive to the chemical potential in the normal region, while trivial ZESs only causes signals in the susceptibility that is highly varying with the chemical potential, thus turning gating of the normal region into a simple experimental control knob. Furthermore, we obtain that, by tuning the junction transparency, critical currents in both short and long junctions undergo a reduction in the number of oscillations as a function of magnetic field only in the topological phase, an effect that find to be intimately linked to Majorana non-locality. Finally, we show that our results also hold at finite temperatures, thus highlighting their potential measurability under realistic experimental conditions.

Prevalence and Antibiogram Signature of selected Vibrio species Recovered from Giant Shrimps (Penaeus Monodon) Samples in Malokun Sea, Ilaje, Ondo State, Nigeria

Background: Giant shrimps (Penaeus monodon), an important native of the aquatic food chain and abundant crustaceans in Malokun sea, Ilaje, Ondo state, serves as significant seafood recipe. This study investigated the incidence and antibiotic susceptibility signature of Vibrio species isolated from crayfish sample from Malokun sea, Ilaje, Ondo State so as to evaluate its potential as reservoir of Vibrio species in this environment. Method: A total of 30 fresh giant shrimp samples were obtained from Malokun sea and densities of Vibrio spp. were determined using MPN-PCR method. Shrimp samples were macerated in sterile blender and aliquots were processed using thiosulfate-citrate-bile salts-sucrose agar. The presumptive isolates were further confirmed as Vibrio spp. using PCR assay and then subjected to antibiotic susceptibility testing against a panel of 8 commonly used antibiotics using Kirby Bauer method. Results: Twenty (20) presumptive Vibrio isolates were randomly selected for molecular confirmation and 12 isolates were confirmed genotypically as Vibrio species. High antibiotic resistance was observed against penicillin (100%), ceftazidime (91.66%), cefepime (91.66%) doripenem while susceptibility to norfloxacin (75%), amikacin (100%), kanamycin (83.33%), streptomycin (66.66%) was likewise observed respectively. The multiple antibiotic resistance index (MARI) among Vibrio spp. ranged between MARindex 0.25-0.625 with highest MARI of 0.625 observed in 33.33% of Vibrio species showing resistance to five antibiotics. Conclusion: This study revealed high prevalence of Vibrio species and multiple antibiotics resistance among examined marine shrimps in Malokun sea, Ilaje, Ondo state. as well as raised resistance against samples. We therefore concluded that the shrimps might pose health risk if undercooked contaminated shrimps were consumed and are potential reservoir of Vibrio species which could cause Vibrio associated infections in sea animals in this marine environment. Keywords: Vibrio spp., Shrimps, Penaeus Monodon, antibiotic resistance, Nigeria

Health monitoring of bacterial concrete structure under dynamic loading using electro-mechanical impedance technique: a numerical approach.

Health monitoring of structures using techniques based on the smart material is an innovative concept that is exploding technological revolutions in the field of civil engineering. The electro-mechanical impedance (EMI) technique is used for structural health monitoring (SHM) and to investigate the damages in the structures. The bacterial incorporation in concrete produces calcite material through metabolism process in presence of moisture and carbon dioxide, which improves the mechanical properties of concrete. Hence, its application in construction of the buildings will improve the health of structures. In this research paper, dynamic behaviour of the bacterial concrete was investigated numerically. The beams of size 700 × 150 × 150mm of bacterial concrete and control concrete were modelled using finite element-based package ANSYS19. The beam of bacterial concrete was simulated as per the characteristics of the materials produced after the bacterial metabolism reactions. The EMI technique was applied to investigate the health of these beams. Admittance (conductance and susceptance) signatures were determined using piezo-ceramic lead zirconate titanate (PZT) sensors installed at mid-point on the top surface of concrete beams. The beams were exposed to dynamic loading and the intensity of dynamic loading was increased in four sub-steps. For the quantification of strength development in the concrete beam, the root mean square deviation (RMSD) statistical index had been applied. It was observed that the bacterial concrete beam has more resistance to the dynamic loading.

Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2) – the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

202 A CTS Team Approach to Immune Signatures of PTSD Susceptibility

OBJECTIVES/GOALS: Post-traumatic stress disorder (PTSD) develops in a subset of individuals (15-25%) exposed to trauma. We report our preliminary findings investigating underlying peripheral immune responses related to risk and resilience to PTSD. METHODS/STUDY POPULATION: Sprague-Dawley rats (half male) were exposed to predator scent stress in the form of the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) once for 10 minutes. Seven days later, rats were assessed for persistent anxiety-like behavior using the acoustic startle response task (ASR) and elevated plus maze (EPM). Tail blood was collected for later inflammation analysis at three time points: 1) prior to experiment start, 2) after TMT exposure, and 3) after ASR and EPM. Using a with-in subjects design, our experiment elucidates the connection between PTSD-like symptoms and baseline immune function, inflammatory stress responses, and chronic inflammatory state after stress exposure. RESULTS/ANTICIPATED RESULTS: In comparison to healthy controls, humans with PTSD show elevated blood levels of inflammatory markers. Human studies also show a relationship between baseline immune dysfunction and later PTSD development. In agreement with this literature, we anticipate PTSD-like rats will have increased blood levels of inflammation markers at all three time points compared to resilient and control rats. These findings will back-translate human findings in support of the predator scent stress preclinical model of PTSD. DISCUSSION/SIGNIFICANCE: Our findings will elucidate the temporal aspects of proinflammatory markers and PTSD development. This study will indicate if baseline peripheral immune dysfunction, inflammatory response immediately after stress exposure, and/or chronic inflammatory state predicts ptsd-like behavior in rats.

Inferring the impact of past climate changes and hunting on the South American sea lion

AbstractAimMany pinniped species have experienced drastic demographic changes due to their interaction with humans. Most studies, however, have failed to detect recent bottlenecks in otariids from genetic data. The South American Sea Lion Otaria flavescens have a long history of population changes associated with interglacial expansion and hunting to almost extinction. This study aimed at investigating these different demographic fluctuations integrating population genetics and phylogeographic approaches.LocationPacific coast of South America.MethodsEighty‐five samples from the Chilean coast were collected. Eight microsatellite loci were genotyped, and D‐Loop mitochondrial DNA (mtDNA) sequenced. Genetic diversity was assessed, and tests of recent genetic bottlenecks were performed. Past demographic changes were inferred based on neutrality tests, adjustment of a sudden expansion model and Bayesian skyline plots. The magnitude and timing of the different population size changes were further investigated through approximate Bayesian computation (ABC) of coalescent inferences.ResultsThe mtDNA shows relatively high diversity (h = 0.98 and π = 0.01) compared to most otariids, corroborates the divergence between Pacific and Atlantic populations, around 80,000 years ago (ya), and revealed a secondary contact zone in the Magellan strait. Microsatellite data support a second genetic discontinuity at 40°S, associated with post‐glacial colonization of Patagonia. ABC analyses confirmed that glaciation affected the effective population size (Ne) all along the Pacific Coast, between ~50,000 and 15,000 ya. A strong reduction of Ne was also inferred for the hunting period (73–66 ya from sampling).Main conclusionsO. flavescens shows clear signatures of susceptibility to climatic and anthropogenic disturbances and a spatial genetic structure that should be taken into account in the context of management and conservation policies. Yet, despite a recent history of demographic bottlenecks, the genetic diversity remains high, likely a consequence of the demographic dynamics in otariids, characterized by large and connected metapopulations.

Quantification of magnetic susceptibility fingerprint of a 3D linearity medical device.

The study investigates the numerical modelling as well as experimental validation of magnetic susceptibility effects with respect to a 3D linearity phantom used for the quantification of MR image distortions. Magnetic field numerical simulations based on finite difference methods were conducted to generate the susceptibility (χ) model of the MRID3D phantom. Experimental data was acquired and analyzed for eight different MR scanners to include a wide range of scanning parameters. Distortion vector fields were generated by applying a harmonic analysis based on finite elements methods. Phantom scans for the same setup but with opposite polarities of the frequency encoding gradient were processed in conjunction with the susceptibility modelling to separately quantify three field components due to gradient non-linearities (GNL), B0 inhomogeneities and χ perturbations. The numerical modelling showed a significant range of χ value of up to 8.23ppm, with a mean value of 2.9ppm. The χ perturbations were found to be mostly present at the end plates of the cylindrical phantom design. The simulations also showed that setup rotations of up to 10° introduced only negligible variations in the χ model of less than 0.1ppm. This allows for a straightforward practical implementation of the modelling as a single lookup table. After correcting for the χ perturbations, the B0 inhomogeneities were derived and found to be in good agreement with either the MR system manufacturer specifications or experimental data available in the literature. It is possible to accurately model the magnetic susceptibility signature of a 3D linearity device and remove it as a post-processing correction step. This is important as the procedure unlocks the ability of determining both the GNL field and B0 map of the scanner without the need of extra acquisitions or phantoms.

Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses.

Recurrent exertional rhabdomyolysis (RER) is a chronic muscle disorder of unknown etiology in racehorses. A potential role of intramuscular calcium (Ca2+) dysregulation in RER has led to the use of dantrolene to prevent episodes of rhabdomyolysis. We examined differentially expressed proteins (DEP) and gene transcripts (DEG) in gluteal muscle of Thoroughbred race-trained mares after exercise among three groups of 5 horses each; 1) horses susceptible to, but not currently experiencing rhabdomyolysis, 2) healthy horses with no history of RER (control), 3) RER-susceptible horses treated with dantrolene pre-exercise (RER-D). Tandem mass tag LC/MS/MS quantitative proteomics and RNA-seq analysis (FDR <0.05) was followed by gene ontology (GO) and semantic similarity of enrichment terms. Of the 375 proteins expressed, 125 were DEP in RER-susceptible versus control, with 52 ↑DEP mainly involving Ca2+ regulation (N = 11) (e.g. RYR1, calmodulin, calsequestrin, calpain), protein degradation (N = 6), antioxidants (N = 4), plasma membranes (N = 3), glyco(geno)lysis (N = 3) and 21 DEP being blood-borne. ↓DEP (N = 73) were largely mitochondrial (N = 45) impacting the electron transport system (28), enzymes (6), heat shock proteins (4), and contractile proteins (12) including Ca2+ binding proteins. There were 812 DEG in RER-susceptible versus control involving the electron transfer system, the mitochondrial transcription/translational response and notably the pro-apoptotic Ca2+-activated mitochondrial membrane transition pore (SLC25A27, BAX, ATP5 subunits). Upregulated mitochondrial DEG frequently had downregulation of their encoded DEP with semantic similarities highlighting signaling mechanisms regulating mitochondrial protein translation. RER-susceptible horses treated with dantrolene, which slows sarcoplasmic reticulum Ca2+ release, showed no DEG compared to control horses. We conclude that RER-susceptibility is associated with alterations in proteins, genes and pathways impacting myoplasmic Ca2+ regulation, the mitochondrion and protein degradation with opposing effects on mitochondrial transcriptional/translational responses and mitochondrial protein content. RER could potentially arise from excessive sarcoplasmic reticulum Ca2+ release and subsequent mitochondrial buffering of excessive myoplasmic Ca2+.

654. Core Antibiotic-Induced Transcriptional Signatures Reflect Susceptibility to All Members of an Antibiotic Class

BackgroundCurrent growth-based antibiotic susceptibility testing (AST) is too slow to guide key clinical decisions. We previously demonstrated a combined Genotypic and Phenotypic AST assay using RNA detection (GoPhAST-R) that can provide AST in < 4h directly from blood culture, 24-36h faster than standard growth-based methods. GoPhAST-R quantifies specific mRNA expression signatures using the multiplexed hybridization RNA-detection platform, NanoString. After brief antibiotic exposure, susceptible cells become stressed, eliciting transcriptional changes that distinguish them from unharmed resistant cells. Here, we assess the generalizability of transcriptional signatures of susceptibility within an antibiotic class.MethodsFor Escherichia coli and Klebsiella pneumoniae, we assessed the ability of the top ten antibiotic-responsive genes previously identified for ciprofloxacin, gentamicin, and meropenem to predict susceptibility to two other fluoroquinolones (FQ), two other aminoglycosides (AG), and six other beta-lactams (BL), respectively, across 6-8 clinical isolates for each drug for a total of 184 pathogen-drug pairs. After standardized antibiotic exposure (60m for FQs and AGs, 120m for BLs, each at its CLSI breakpoint MIC), samples were mechanically lysed and used as input for NanoString assays as previously described (Bhattacharyya, Nat Med 2019).ResultsIn both species, the top ten genes identified for AST of ciprofloxacin, gentamicin, and meropenem showed similar normalized fold-induction upon treatment with three FQs, three AGs, and seven BLs, respectively, allowing robust distinction of susceptible and resistant isolates (Fig 1).Figure 1 ConclusionWe show that a shared set of genes optimized for AST of one antibiotic can predict susceptibility to all members of that drug class, consistent with a conserved core transcriptional response related to mechanism of action. We demonstrate this phenomenon for two common pathogens with propensity for multidrug resistance treated with multiple members of three major antibiotic classes in common clinical use. This unified set of genes for susceptibility prediction would streamline GoPhAST-R implementation, in turn facilitating efficient deployment of antibiotics and reducing unnecessary broad-spectrum use.Disclosures All Authors: No reported disclosures

Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

A unique, protective cell envelope contributes to the broad drug resistance of the nosocomial pathogen Acinetobacter baumannii. Here we use transposon insertion sequencing to identify A. baumannii mutants displaying altered susceptibility to a panel of diverse antibiotics. By examining mutants with antibiotic susceptibility profiles that parallel mutations in characterized genes, we infer the function of multiple uncharacterized envelope proteins, some of which have roles in cell division or cell elongation. Remarkably, mutations affecting a predicted cell wall hydrolase lead to alterations in lipooligosaccharide synthesis. In addition, the analysis of altered susceptibility signatures and antibiotic-induced morphology patterns allows us to predict drug synergies; for example, certain beta-lactams appear to work cooperatively due to their preferential targeting of specific cell wall assembly machineries. Our results indicate that the pathogen may be effectively inhibited by the combined targeting of multiple pathways critical for envelope growth.

Fatigue damage and residual fatigue life assessment in reinforced concrete frames using PZT-impedance transducers

Structural health monitoring has contrived a path for ascertaining the condition of any structure under operating or critical loads. This paper investigates a possible application of the electro-mechanical impedance (EMI) technique in diagnosing high-cycle and low-strain fatigue damage in the reinforced concrete (RC) structures. The experimental study is conducted on a RC frame structure of overall size 1.45 m (width) x 1.22 m (height) using lead zirconate titanate (PZT) patches embedded in form of concrete vibration sensors (CVS), all operating in d-31 mode, for accessing fatigue damages till the structure fails at 5.5 million cycles. The damage dependent equivalent stiffness parameters (ESP) are obtained from the conductance and the susceptance signatures for each CVS at different damage states for enabling the estimation of residual fatigue life. For the first time, results have revealed a good comparison in obtaining flexural rigidity-based stiffness using global dynamic technique (GDT) and CVS-identified stiffness using EMI technique for the full-life span of the RC structure under high-cycle fatigue. A relation for estimating residual fatigue life of the structure with change in normalized damping has been also derived for this type of loading environment.

Challenges in diagnosing necrotizing enterocolitis.

One of the many challenges with necrotizing enterocolitis (NEC) remains our inability to make an accurate diagnosis of NEC. The lack of a unifying cause and multiple variations in presentations lead to great uncertainty with NEC. Separating out the needs of the researcher wanting to define NEC from the clinician and patient family's perspectives who want an accurate diagnosis for NEC is important. The need to augment and/or replace the outdated modified Bell staging criteria is crucial to improving NEC management. Emerging literature suggests that genetic susceptibility and stool microbiota signatures may help identify preterm infants at increased risk of the disease. Ongoing studies using single or multi-omic approaches may help to characterize biomarkers that will aid in the prediction or early diagnosis of NEC, as well as differentiate other causes of severe bowel injury. Bowel ultrasound shows promise in improving our diagnostic accuracy for NEC but has been slow in adoption. Patient family perspectives are key in accelerating our efforts to integrate newer diagnostic methods into practice.

Gene expression signature of antidepressant treatment response/non-response in Flinders Sensitive Line rats subjected to maternal separation

Neurobiological underpinnings of treatment-resistant depression, a debilitating condition associated with significant functional impairment, have not been elucidated. Consequently, the aim of this study was to use animal models of response and resistance to antidepressant treatment, in an attempt to identify differences in associated transcriptional responses. Flinders Sensitive Line rats were subjected to maternal separation (MS) and chronically treated with Escitalopram or Nortriptyline. Antidepressants reduced immobility time in the forced swim test in non-MS rats, while lack of antidepressant behavioural response was observed in MS animals. We developed a novel bioinformatic algorithm that enabled identification of transcriptional signatures in hippocampus and pre-frontal cortex that discriminate vehicle- and antidepressant-treated subjects in both MS and non-MS rats. Functional annotation analysis showed that in antidepressant-responder rats the most enriched pathways included IQGAPs activation, toll-like receptor trafficking, energy metabolism, and regulation of endopeptidase activity. The analysis of interacting proteins implicated synaptic vesicles and neurotransmitter release, ubiquitin regulation, cytoskeleton organisation and carbohydrate metabolism. In contrast, in treatment-resistant MS rats, main expression changes were revealed in ribosomal proteins, inflammatory responses, transcriptional/epigenetic regulation, and small GTPases. Susceptibility signature shared Rtn1, Zdhhc5, Igsf6, and Sim1 genes with the latest depression GWAS meta-analysis, while antidepressant resistance signature shared Ctnnd1, Rbms3, Atp1a3, and Pla2r1 genes. In conclusion, this study demonstrated that distinct transcriptional signatures are associated with behavioural response or non-response to antidepressant treatment. The identification of genes involved in antidepressant response will increase the comprehension of the neurobiological underpinnings of treatment-resistant depression, thus contributing to identification of novel therapeutic targets.

PNPLA3 and IL 28B signature for predicting susceptibility to chronic hepatitis C infection and fibrosis progression

Background Association studies identified genetic polymorphisms as predictive risk factors of rapid fibrosis progression in chronic hepatitis C (CHC). This study aims to assess the impact of IL28B rs8099917 polymorphism on CHC genotype 4 (G4) susceptibility and liver fibrosis progression individually; and in combination with PNPLA3 rs738409. Patients and methods IL28B rs8099917 and PNPLA3 rs738409 were genotyped in 150 Egyptian CHC patients and 175 healthy controls using real-time PCR. Results IL28B rs8099917 genotype distribution significantly differs in healthy individuals versus CHC patients (p = .018); and in low versus advanced fibrosis IL28B (p = .013). The haplotype CC –GG (PNPLA3-IL28B) is considered a high-risk signature for susceptibility to CHC infection. Similarly, GG–GG (PNPLA3-IL28B) is considered a high-risk signature for higher degree of fibrosis. Conclusion IL28B rs8099917 and PNPLA3 rs738409 introduce genetic signature to identify patients at higher risk for CHC susceptibility and fibrosis progression in CHC G4.

Preprotein signature for full susceptibility to the co-translational translocation inhibitor cyclotriazadisulfonamide.

Cyclotriazadisulfonamide (CADA) inhibits the co-translational translocation of human CD4 (huCD4) into the endoplasmic reticulum lumen in a signal peptide (SP)-dependent way. We propose that CADA binds the nascent huCD4 SP in a folded conformation within the translocon resembling a normally transitory state during translocation. Here, we used alanine scanning on the huCD4 SP to identify the signature for full susceptibility to CADA. In accordance with our previous work, we demonstrate that residues in the vicinity of the hydrophobic h-region are critical for sensitivity to CADA. In particular, exchanging Gln-15, Val-17 or Pro-20 in the huCD4 SP for Ala resulted in a resistant phenotype. Together with positively charged residues at the N-terminal portion of the mature protein, these residues mediate full susceptibility to the co-translational translocation inhibitory activity of CADA towards huCD4. In addition, sensitivity to CADA is inversely related to hydrophobicity in the huCD4 SP. In vitro translocation experiments confirmed that the general hydrophobicity of the h-domain and positive charges in the mature protein are key elements that affect both the translocation efficiency of huCD4 and the sensitivity towards CADA. Besides these two general SP parameters that determine the functionality of the signal sequence, unique amino acid pairs (L14/Q15 and L19/P20) in the SP hydrophobic core add specificity to the sensitivity signature for a co-translational translocation inhibitor.

ISC1, a new Leishmania donovani population emerging in the Indian sub-continent: Vector competence of Phlebotomus argentipes

Visceral leishmaniasis (VL), the most severe form of the disease, is caused by Leishmania donovani in the Indian sub-continent (ISC). Whole genome sequencing studies revealed that two parasite populations exist in the ISC: a main population named the Core Group (CG) found mostly in the lowlands, and a new, genetically different subpopulation called ISC1. Parasites belonging to the CG were shown to be responsible for the recent epidemics, while the ISC1 variant was originally identified in hilly districts of Nepal and was later on increasingly found in the lowlands. Importantly, the ISC1 and CG isolates differ in their drug susceptibility and virulence signatures, suggesting that ISC1 constitutes an emerging and functionally different variant of L. donovani. In present study we aimed to address the potential of ISC1 transmission by the natural vector of L. donovani in the lowlands, Phlebotomus argentipes. By experimental infection of sand flies with parasites of the different genotypes, we demonstrate that ISC1 and CG strains are developing similarly in P. argentipes, suggesting that P. argentipes is a fully competent vector for ISC1 parasites. Integration of previous and current findings shows thus that ISC1 is a new and different variant of L. donovani, fully adapted to spread in the ISC through the main vector. This information is directly useful for managers of the elimination program. Furthermore, integration of our successive studies (genotyping, phenotyping and vector competence) demonstrates the relevance of molecular surveillance and should be of interest for scientists working on vector borne diseases and control managers.