Biology subjects

Ali, A.

Publications and source records attributed to Ali, A..

At least 127 records · Page 7Linked to original sources

bioRxiv2020

Increased demand for NAD+ relative to ATP drives aerobic glycolysis

Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is a hallmark of proliferative metabolism that is observed across many organisms and conditions. To better understand why aerobic glycolysis is associated with cell proliferation, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase mitochondrial pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the nicotinamide adenine dinucleotide cofactor ratio (NAD+/NADH). This change in NAD+/NADH ratio is caused by an increase in mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling mitochondrial respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when the demand for NAD+ to support oxidation reactions exceeds the demand for ATP consumption in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation despite available oxygen. This argues that cells engage in aerobic glycolysis when the cellular demand for NAD+ is in excess of the cellular demand for ATP.

biochemistry↗

bioRxiv2020

Subcellular localization of the J-protein Sis1 regulates the heat shock response

Cells exposed to heat shock induce a conserved gene expression program - the heat shock response (HSR) - encoding chaperones like Hsp70 and other protein homeostasis (proteostasis) factors. Heat shock also triggers proteostasis factors to form subcellular quality control bodies, but the relationship between these spatial structures and the HSR is unclear. Here we show that localization of the J-protein Sis1 - a co-chaperone for Hsp70 - controls HSR activation in yeast. Under nonstress conditions, Sis1 is concentrated in the nucleoplasm where it promotes Hsp70 binding to the transcription factor Hsf1, repressing the HSR. Upon heat shock, Sis1 forms an interconnected network with other proteostasis factors that spans the nucleolus and the surface of the cortical ER. We propose that localization of Sis1 to this network directs Hsp70 activity away from Hsf1 in the nucleoplasm, leaving Hsf1 free to induce the HSR. In this manner, Sis1 couples HSR activation to the spatial organization of the proteostasis network. One sentence summaryLocalization of the J-protein Sis1 to a subcellular network of proteostasis factors activates the heat shock response.

cell biology↗

bioRxiv2020

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.

cancer biology↗

bioRxiv2020

Ginseng Ameliorates Effect of Prolonged Use of Omeprazole in Rat Renal Cortex through Decreasing Inflammation, Fibrosis and Apoptosis

Omeprazole is used in acid-related gastrointestinal disorders but has prolonged usage adverse effects. The aim was to study changes in renal cortex following chronic Omeprazole administration and the possible protective role of ginseng. Rats were divided into control (C-), Ginseng (G-), omeprazole (OM-), and omeprazole-ginseng (OM-G) groups. Serum urea and creatinine levels and 24-hours urine-protein were determined. Kidneys were processed for histological study. Serum urea and creatinine and 24-hours protein were significantly higher in OM-group compared to controls and significantly decreased in OM-G group comparing to OM-group. OM-group showed significant glomerular and tubulointerstitial injury with vascular congestion, inflammatory cell infiltration, partial or complete damage of apical brush border of most tubules, interrupted basement membranes of glomerular capillaries and tubules, marked increase in collagen deposition, and significant increases in COX-2 and caspase-3 immune-expression. Co-administration of ginseng with omeprazole resulted in marked and significant improvement of these morphological changes. ConclusionOmeprazole induced renal functional and morphological changes through inflammatory reaction, induction of fibrosis, cellular degeneration and apoptosis. Co-administration of ginseng ameliorated these effects through its anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.

pathology↗

bioRxiv2020

Lipidomics of human adipose tissue reveals diversity between body areas

Background and aimsAdipose tissue plays a pivotal role in storing excess fat and its composition reflects the history of persons lifestyle and metabolic health. Broad profiling of lipids with mass spectrometry has potential for uncovering new knowledge on the pathology of obesity, metabolic syndrome, diabetes and other related conditions. Here, we developed a lipidomic method for analyzing human subcutaneous adipose biopsies. We applied the method to four body areas to understand the differences in lipid composition between these areas. Materials and methodsAdipose tissue biopsies from 10 participants were analyzed using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The method development included the optimization of the lipid extraction, the sample amount and the sample dilution factor to detect lipids in an appropriate concentration range. Lipidomic analyses were performed for adipose tissue collected from the abdomen, breast, thigh and lower back. Differences in lipid levels between tissues were visualized with heatmaps. ResultsLipidomic analysis on human adipose biopsies lead to the identification of 187 lipids in 2 mg of sample. Technical variation of the lipid-class specific internal standards were below 5 %, thus indicating acceptable repeatability. Triacylglycerols were highly represented in the adipose tissue samples, and lipids from 13 lipid classes were identified. Long polyunsaturated triacylglycerols in higher levels in thigh (q<0.05), when compared with the abdomen, breast and lower back, indicating that the lipidome was area-specific. ConclusionThe method presented here is suitable for the analysis of lipid profiles in 2 mg of adipose tissue. The amount of fat across the body is important for health but we argue that also the distribution and the particular profile of the lipidome may be relevant for metabolic outcomes. We suggest that the method presented in this paper could be useful for detecting such aberrations.

biophysics↗

bioRxiv2019

Factors Affecting Detection Of GMO Traces In Food And Crop Samples

Rice is one of the highly consumable and demanded food crops throughout the world. To meet this requirement, genetically modified (GM) crops were introduced, which were met with sturdy and frequently angry opposition by the user. To handle the situation labeling of GM food / crop was advised, thus demand for traceability and detection of unknown modified genes increased. Modified genes are detected by various methods; these methods are affected by several factors as reported in international standards. Those factors include presence / absence of shells, husk, and dust, method of DNA extraction and different PCR primers. These factors ultimately pose hindrance in detection of modified genes. This study was conducted to analyze the effects of the above mentioned factors on detection of GM rice samples. Furthermore two different sets of primers were used with same samples and their impact on the PCR detection was observed. The results showed a significant difference in DNA concentration between the rice samples with husk, without husk and after seed germination. Furthermore, the change of PCR primer set also affected the detection of genetic modifications. This allows analysis of the potential factors that may have impact on the final results.

plant biology↗

bioRxiv2019

Selection of HIV-1 for Resistance to Fourth Generation Protease Inhibitors Reveals Two Independent Pathways to High-Level Resistance

Darunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in the high drug concentrations that are achived in vivo. Little is known about the de novo resistance pathway for DRV. We have selected for resistance to high drug concentrations against ten PIs and their structural precursor DRV. Mutations accumulated through two pathways (anchored by protease mutations I50V or I84V). Small chemical changes in the inhibitor P1 side chain led to preferential use of one pathway over the other. Changes in the inhbitor P2 side chain determined differences in potency that were retained in the resistant viruses. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high level of selective pressure that is attainable with fourth generation PIs, and how features of the inhibitor affect both the resistance pathway and the residual potency in the face of resistance.

microbiology↗

bioRxiv2019

2′-5′-Oligoadenylate synthetase-like protein inhibits intracellular M. tuberculosis replication and promotes proinflammatory cytokine secretion

Host cytoplasmic surveillance pathways are known to elicit type I interferon (IFN) responses which are crucial to antimicrobial defense mechanisms. Oligoadenylate synthetase-like (OASL) protein has been extensively characterized as a part of the anti-viral mechanism, however a number of transcriptomic studies reveal its upregulation in response to infection with a wide variety of intracellular bacterial pathogens. To date, there is no evidence documenting the role (if any) of OASL during mycobacterium tuberculosis infection. Using two pathogenic strains differing in virulence only, as well as the non-pathogenic M. bovis BCG strain, we observed that pathogenicity and virulence strongly induced OASL expression after 24 h of infection. Further, we observed that OASL knock down led to a significant increase in M. tb CFU counts 96 h post-infection in comparison to the respective controls. Luminex revealed that OASL silencing significantly decreased IL-1{beta}, TNF- and MCP-1 secretion in THP-1 cells and had no effect on IL-10 secretion. We therefore postulate that OASL regulates pro-inflammatory mediators such as cytokines and chemokines which suppress intracellular mycobacterial growth and survival.

cell biology↗

bioRxiv2019

Multi Epitope Vaccine Prediction Against Aichi Virus using Immunoinformatic Approach

Aichi virus, AiV is single stranded negative sense RNA genome belonging to the genus Kobuviru, a family of Picornaviridae that causes severe gastroenteritis. There is no treatment or vaccine for it, thus the aim of this study is to design a peptide vaccine using immunoinformatic approaches to analyze the viral Protein VP1 of AiV-1 strain, to determine the conserved region which is further studied to predict all possible epitopes that can be used as a peptide vaccine. A total of 38 Aichi virus VP1 retrieved from NCBI database were aligned to determine the conservancy and to predict the epitopes using IEDB analysis resource. Three epitopes predicted as a peptide vaccine for B cell was (PLPPDT, PPLPTP, and LPPLPTP). For T cell, two epitopes showed high affinity to MHC class I (FSIPYTSPL and TMVSFSIPY) and high coverage against the whole world population. Also, in MHC class II, three epitopes that interact with most frequent MHC class II alleles (FTYIAADLR and YMAEVPVSA) with high coverage in the whole world population. For both MHCI and MHCII the T-cell peptide with the strongest affinity to the worldwide population was FSIPYTSPL.\n\nPeptide vaccine against AiV is powerfully displace the normal produced vaccines based on the experimental biochemistry tools, as it designed to handle with a wide range of mutated strains, which will effectively minimize the frequent outbreaks and their massive economical wastage consequences.

bioinformatics↗

bioRxiv2019

Persistent Prolate Polymersomes for Enhanced Co-Delivery of Hydrophilic and Hydrophobic Drugs

Self-assembled polymersomes encapsulate, protect, and deliver hydrophobic and hydrophilic drugs. Though spherical polymersomes are effective, early studies suggest that non-spherical structures may enhance specificity of delivery and uptake due to similarity to endogenous uptake targets. Here we describe a method to obtain persistent non-spherical shapes, prolates, via osmotic pressure and the effect of prolates on uptake behavior. Polyethylene glycol-b-poly(lactic acid) polymersomes change in diameter from 175 {+/-} 5nm to 200 {+/-} 5nm and increase in polydispersity from 0.06 {+/-} 0.02 to 0.122 {+/-} 0.01 nm after addition of 50 mM salt. Transmission and scanning electron microscopy confirm changes from spheres to prolates. Prolate-like polymersomes maintain their shape in 50 mM NaCl for seven days. Nile Red and bovine serum albumin(BSA)-Fluorescein dyes are taken up in greater amounts by SH-SY5Y neural cells when encapsulated in polymersomes. Prolate polymersomes may be taken up more efficiently in neural cells than spherical polymersomes.

bioengineering↗

bioRxiv2019

Interleukin-33 promotes type 1 cytokine expression via p38 MAPK in human natural killer cells

This study tests the hypothesis that activation of mitogen-activated protein kinase (MAPK) by physiologically-relevant concentrations of interleukin-33 (IL-33) contributes to enhanced cytokine expression by IL-12 stimulated human natural killer (NK) cells. While IL-33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL-12 to provoke interferon-gamma (IFN-{gamma}). We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-{gamma} by human NK cells that greatly exceeds responses to either cytokine alone. Nanogram doses of IL-33, potentially consistent with levels in tissue microenvironments, synergize with IL-12 to induce secretion of additional cytokines, including tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-{gamma} and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers ADAM17-mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL-12 in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/777847v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@c1f7c9org.highwire.dtl.DTLVardef@72d47dorg.highwire.dtl.DTLVardef@dc84d4org.highwire.dtl.DTLVardef@194b42f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

The effect of blue-blocking lenses on photostress recovery times for low and high contrast chromatic and achromatic stimuli

The selective reduction in visible wavelengths transmitted through commercially available blue-blocking lenses (BBLs) is known to influence the appearance and contrast detection of objects, particularly at low light levels which may impact the human retinal receptor response time to dynamic light changes during phostress events. In the present study, we assessed whether BBLs selectively affect photostress recovery times (PSRTs) in 12 participants for chromatic and achromatic stimuli presented under low and high contrast luminance conditions. Four types of commercially available BBLs were evaluated, and their effects on PSRTs were investigated. Our results showed that PSRTs required to detect high contrast chromatic and achromatic stimuli were unaffected by BBLs when compared to a clear control lens. However, PSRTs were significantly affected by BBLs and were longer when chromatic and achromatic stimuli were of low contrast. In addition, BBLs had the greatest impact on the PSRTs of blue coloured targets, and this was dependent on the spectral transmittance profile. These results indicate that wearing BBLs under low contrast conditions can have serious implications for visual behavior, particularly under low-light levels and in situations in which the observer is directly exposed to bright light sources. For example, during night time driving, the driver might be briefly exposed to bright lights by glancing at the headlights of a passing car. This increases the time required for vision to be restored after bright light exposure, resulting in delayed object detection, and therefore stoppage and reaction times, which might pose a safety risk for a driver.

physiology↗

bioRxiv2019

The Alkaliphilic side of Staphylococcus aureus

The genome of Staphylococcus aureus has eight structurally distinct cation/proton antiporters (CPA) that play significant roles in maintaining cytoplasmic pH and ions in extreme conditions. These antiporters enable S. aureus to persist under conditions that are favorable to the bacterium but unfavorable to animal host including humans. In this study, we report physiological roles and catalytic properties of NhaC (NhaC1, NhaC2 and NhaC3), CPA1 (CPA1-1 and CPA1-2) and CPA2 family antiporters and how these antiporters crosstalk with Mnh1, a CPA3 family antiporter, recently shown to play important roles in virulence and pH tolerance. Catalytic properties of antiporters were determined by Na+/H+ and K+/H+ antiport assays using everted membrane vesicles of a CPA-deficient E. coli KNabC host. NhaC and CPA1 candidates exhibited Na+/H+ and K+/H+ antiporter activity in the pH range between pH 7 to 9.5 but did not show significant role in halotolerance and osmotolerance alone. Interestingly, NhaC3 exhibited significant antiporter activity at alkaline pH and play major roles in pH and salt tolerance. CPA2 neither exhibited Na+or K+/H+ exchange nor showed any active role in pH and salt tolerance. Double deletion of mnhA1 with nhaC1, nhaC3, cpa1-1 or cpa1-2 respectively, made S. aureus severely sensitive at pH 7.5 under stress conditions indicating synergistic relationship of Mnh1 with these antiporters. The functional loss study of these antiporters in in-vivo mouse infection model, nhaC3 deletion showed significant loss of S. aureus virulence. Altogether, the current study indicates NhaC3 as a potential target against S. aureus virulence under extreme pH and salt conditions.\n\nImportanceIn this study, we established catalytic properties and physiological roles of S. aureus NhaC, CPA1 and CPA2 family antiporters and their importance under salt and alkaline stress conditions. Except CPA2, all five antiporters of both families were active for Na+/H+ and K+/H+ exchange. CPA1-1 showed significant role in pH homeostasis at pH 7.5 whereas CPA1-2 and NhaCs were major contributors to halotolerance and osmotolerance at alkaline pH. The severity of growth deficit in double knockouts of mnhA1 with each of nhaC1, nhaC2, nhaC3, cpa1-1 or cpa1-2 establishes their synergistic relationship in regulating pH and salt homeostasis. Deletion of cpa1-1, cpa1-2 and nhaC1, nhaC2, and nhaC3 were assessed in mice model and NhaC3 was shown to play a major role in S. aureus virulence.

microbiology↗

bioRxiv2019

Differential detection of Entamoeba species in stool samples collected from children in District Swat, Khyber Pakhtunkhwa Pakistan

BackgroundAmoebiasis is an intestinal disease caused by enteric protozoan called Entamoeba histolytica belongs to the Genus Entamoeba. The main reason of infection is the contamination of food and water due to the poor sanitation. Among Entamoeba species, Entamoeba histolytica is highly pathogenic while the other species are non-pathogenic and needs no medical treatment.\n\nMethodologyA total of 400 stool samples were collected from different areas of district Swat and were processed for screening of amoebic cells. Microscopically identified samples containing amoebic cells were stored at -20 {degrees}C till DNA extraction. Extracted DNA was used in a PCR reaction with specific reference primers to amplify the target DNA.\n\nResultsOut of all 400 stool samples 111 (27.7%) were found positive through microscopy while PCR reaction confirmed 80 out of microscope positive samples. Among 80 PCR positive samples, the infection with Entamoeba dispar was most common (57.5%) followed by E. histolytica (47.5%) and Entamoeba moshkovskii (20%). The positive cases for mono-infection of E. dispar were 33 (41.25%), followed by E.histolytica 25 (31.25%) and E. moshkovskii 7 (8.75%). The co-infection of E. histolytica with E. dispar and E. moshkovskii was 6 (7.5%) and 2 (2.5%), respectively. Similarly the co-infection of Entamoeba dispar with Entamoeba moshkovskii was also 2 (2.5%) while 5 (6.25%) samples were observed with mixed infection of E. histolytica, E. dispar and E. moshkovskii.\n\nSignificance of the studyThe aim of the study was to detect and differentiate the E. histolytica, Entamoeba dispar and Entamoeba moshkovskii using conventional microscopy and polymerase chain reaction. The results suggested that the use of PCR is necessary to differentiate E. histolytica from E. dispar and E. moshkovskii and therefore, to avoid unnecessary treatment the present study recommend the use of PCR for the routine diagnosis of amoebiasis in the study area. It is also suggested that further studies from this area may also facilitate the understanding of genetic diversity of these pathogens.

microbiology↗

bioRxiv2019

Molecular and structural mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir

Hepatitis C virus (HCV), causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82%. While older generation direct-acting antivirals (DAAs) had varying effectiveness against different genotypes, the newest NS3/4A protease inhibitors including glecaprevir (GLE) have pan-genotypic activity. The structural basis for pan-genotypic inhibition and effects of polymorphisms on inhibitor potency were not well known due to lack of crystal structures of GLE-bound NS3/4A or genotypes other than 1. In this study, we determined the crystal structures of NS3/4A from genotypes 1a, 3a, 4a and 5a in complex with GLE. Comparison with the highly similar grazoprevir (GZR) indicated the mechanism of GLEs drastic improvement in potency. We found that while GLE is highly potent against wild type NS3/4A of all genotypes, specific resistance-associated substitutions (RASs) confer orders of magnitude loss in inhibition. Our crystal structures reveal molecular mechanisms behind pan-genotypic activity of GLE, including potency loss due to RASs at D168. Our structures permit for the first time analysis of changes due to polymorphisms among genotypes, providing insights into design principles that can aid future drug development and potentially can be extended to other proteins.

biochemistry↗

bioRxiv2019

Comparative palatability of orally disintegrating tablets (ODTs) of Praziquantel (L-PZQ and Rac-PZQ) versus current PZQ tablet in African children: a randomized, single-blind, crossover study

BackgroundPraziquantel (PZQ) is currently the only recommended drug for infection and disease caused by the species of schistosome infecting humans; however, the current tablet formulation is not suitable for preschool age children mainly due to its bitterness and the size of the tablet. We assessed the palatability of two new orally disintegrating tablet (ODT) formulations of PZQ.\n\nMethodsThis randomized, single-blind, crossover, swill-and-spit palatability study (NCT02315352) was carried out at a single school in Tanzania in children aged 6-11 years old, irrespective of schistosomiasis infection. Children were stratified according to age group (6-8 years or 9-11 years) and gender, then randomized to receive each formulation in a pre-specified sequence. Over 2 days, the children assessed the palatability of levo-Praziquantel (L-PZQ) ODT 150 mg and Racemate Praziquantel (Rac-PZQ) ODT 150 mg disintegrated in the mouth without water on the first day, and L-PZQ and Rac-PZQ dispersed in water and the currently available PZQ 600 mg formulation (PZQ-Cesol(R)) crushed and dispersed in water on the second day. The palatability of each formulation was rated using a 100 mm visual analogue scale (VAS) incorporating a 5-point hedonic scale, immediately after spitting out the test product (VASt=0 primary outcome) and after 2-5 minutes (VASt=2-5).\n\nFindingsIn total, 48 children took part in the assessment. Overall, there was no reported difference in the VASt=0 between the two ODT formulations (p=0.106) without water. Higher VASt=0 and VASt=2-5 scores were reported for L-PZQ ODT compared with Rac-PZQ ODT in older children (p=0.046 and p=0.026, respectively). The VASt=0 and VASt=2-5 were higher for both ODT formulations compared with the current formulation (p<0.001 for both time points). No serious adverse events were reported.\n\nInterpretationThe new paediatric-friendly formulations dispersed in water were both found to be more palatable than the existing formulation of PZQ. There may be gender and age effects on the assessment of palatability.\n\nFundingThis study was funded by Merck KGaA, Darmstadt, Germany and the Global Health Innovative Technology (GHIT) Fund (Grant nos. 2013-212).\n\nAuthor summarySchistosomiasis or Bilharzia is among top debilitating parasitic diseases in endemic developing countries. It presents in two forms of either urinary or intestinal form. The diseases mode of transmission is waterborne through contact with infested water. The main group being affected in developing countries are women and children due to their frequent contact with water. WHO introduced mass drug administration program whereby drugs are distributed in endemic communities to cut off the transmission of NTDs schistosomiasis included.\n\nPraziquantel is the sole drug for treatment of all forms of Schistosomiasis currently and it has still been proven to be highly efficacious. Preventive chemotherapy program of WHO uses the same drug as a prophylactic tool to control the disease.\n\nThe biggest challenge for this drug is its availability as a 600mg tablet with a slightly bigger size and unpleasant taste, especially for younger children. This makes uneasy administering the correct dosage of drug to school children while making preschoolers totally neglected.\n\nThis study was done as swill and spit exercise (drug was not ingested) to assess the new orally disintegrating isomers of Praziquantel, L-PZQ and Rac-PZQ which have been prepared as a 150mg tablet and improved taste as compared to the existing Praziquantel formulation. Findings from 48 African children showed that both new formulations are more palatable to younger children as compared to the existing Praziquantel formulation.\n\nThese results provide evidence for further evaluation of the clinical efficacy and tolerability of the newer formulations towards the introduction of paediatric friendly Praziquantel tablets for Schistosomiasis treatment.

epidemiology↗

bioRxiv2018

Recruit symbiosis establishment and Symbiodiniceae composition influenced by adult corals and reef sediment

For most reef-building corals, the establishment of symbiosis occurs via horizontal transmission, where juvenile coral recruits acquire their algal symbionts (family Symbiodiniaceae) from their surrounding environment post-settlement. This transmission strategy allows corals to interact with a diverse array of symbionts, potentially facilitating adaptation to the newly settled environment. We exposed aposymbiotic Pseudodiploria strigosa recruits from the Flower Garden Banks to natal reef sediment (C-S+), symbiotic adult coral fragments (C+S-), sediment and coral fragments (C+S+), or seawater controls (C-S-) and quantified rates of symbiont uptake and Symbiodiniaceae community composition within each recruit using metabarcoding of the ITS2 locus. The most rapid uptake was observed in C+S+ treatments and this combination also led to the highest symbiont alpha diversity in recruits. While C-S+ treatments exhibited the next highest uptake rate, only one individual recruit successfully established symbiosis in the C+S-treatment, suggesting that sediment both serves as a direct symbiont source for coral recruits and promotes (or, potentially, mediates) transmission from adult coral colonies. In turn, presence of adult corals facilitated uptake from the sediment, perhaps via chemical signaling. Taken together, our results reinforce the key role of sediment in algal symbiont uptake by P. strigosa recruits and suggest that sediment plays a necessary, but perhaps not sufficient, role in the life cycle of the algal Symbiodinaceae symbionts.

zoology↗

bioRxiv2018

Structural Adaptation of Darunavir Analogs Against Primary Resistance Mutations in HIV-1 Protease

HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82 and I84 that line the S1/S1 pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogs to primary S1 mutations. The analogs had modifications at the hydrophobic P1 moiety to better occupy the unexploited space in the S1 pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analog with the largest P1 moiety, indicating interdependency between the S1 subsite and the flap region. Collective analysis of protease-inhibitor van der Waals (vdW) interactions in the crystal structures using principle component analysis indicated I84V mutation underlying the largest variation in the vdW contacts. Interestingly, the principle components were able to distinguish inhibitor identity and relative potency solely based on vdW interactions of active site residues in the crystal structures. Our results reveal the interplay between inhibitor P1 moiety and primary S1 mutations, as well as suggesting a novel method for distinguishing the interdependence of resistance through principle component analyses.

molecular biology↗