Here we present SVScore, a tool for in silico structural variation (SV) impact prediction. SVScore aggregates per-base single nucleotide polymorphism (SNP) pathogenicity scores across relevant ...genomic intervals for each SV in a manner that considers variant type, gene features and positional uncertainty. We show that the allele frequency spectrum of high-scoring SVs is strongly skewed toward lower frequencies, suggesting that they are under purifying selection, and that SVScore identifies deleterious variants more effectively than alternative methods. Notably, our results also suggest that duplications are under surprisingly strong selection relative to deletions, and that there are a similar number of strongly pathogenic SVs and SNPs in the human population.
SVScore is implemented in Perl and available freely at {{ http://www.github.com/lganel/SVScore }} for use under the MIT license.
ihall@wustl.edu.
Supplementary data are available at Bioinformatics online.
CWD is an emergent prion disease that now affects cervid species on three continents. CWD is efficiently spread in wild and captive populations, likely through both direct animal contact and ...environmental contamination. Here, by longitudinally assaying in feces of CWD-exposed white-tailed deer by RT-QuIC, we demonstrate fecal shedding of prion seeding activity months before onset of clinical symptoms and continuing throughout the disease course. We also examine the impact of simulated environmental conditions such as repeated freeze-thaw cycles and desiccation on fecal prion seeding activity. We found that while multiple (n = 7) freeze-thaw cycles substantially decreased fecal seeding activity, desiccation had little to no effect on seeding activity. Finally, we examined whether RT-QuIC testing of landscape fecal deposits could distinguish two premises with substantial known CWD prevalence from one in which no CWD-infected animals had been detected. In the above pilot study, this distinction was possible. We conclude that fecal shedding of CWD prions occurs over much of the disease course, that environmental factors influence prion seeding activity, and that it is feasible to detect fecal prion contamination using RT-QuIC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monocytes contribute to the pro-inflammatory immune response during the blood stage of a Plasmodium falciparum infection, but their precise role in malaria pathology is not clear. Besides ...phagocytosis, monocytes are activated by products from P. falciparum infected erythrocytes (IE) and one of the activation pathways is potentially the NLR family pyrin domain containing 3 (NLRP3) inflammasome, a multi-protein complex that leads to the production of interleukin (IL)-1β. In cerebral malaria cases, monocytes accumulate at IE sequestration sites in the brain microvascular and the locally produced IL-1β, or other secreted molecules, could contribute to leakage of the blood-brain barrier. To study the activation of monocytes by IE within the brain microvasculature in an in vitro model, we co-cultured IT4var14 IE and the monocyte cell line THP-1 for 24 hours and determined whether generated soluble molecules affect barrier function of human brain microvascular endothelial cells, measured by real time trans-endothelial electrical resistance. The medium produced after co-culture did not affect endothelial barrier function and similarly no effect was measured after inducing oxidative stress by adding xanthine oxidase to the co-culture. While IL-1β does decrease barrier function, barely any IL-1β was produced in the co- cultures, indicative of a lack of or incomplete THP-1 activation by IE in this co-culture model.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The profound impact of the human microbiome on health and disease has captivated the interest of clinical and scientific communities. The human body hosts a vast array of microorganisms ...collectively forming the human microbiome, which significantly influences various physiological processes and profoundly shapes overall well-being. Notably, the gut stands out as an exceptional reservoir, harboring the most significant concentration of microorganisms, akin to an organ in itself. The gut microbiome's composition and function are influenced by genetics, environment, age, underlying conditions, and antibiotic usage, leading to dysbiosis and pathogenesis, such as Clostridioides difficile infection (CDI). Conventional CDI treatment, involving antibiotics like oral vancomycin and fidaxomicin, fails to address dysbiosis and may further disrupt gut microbial communities. Consequently, emerging therapeutic strategies are focused on targeting dysbiosis and restoring gut microbiota to advance CDI therapeutics. Fecal microbiota transplantation (FMT) has demonstrated remarkable efficacy in treating recurrent CDI by transferring processed stool from a healthy donor to a recipient, restoring gut dysbiosis and enhancing bacterial diversity. Moreover, 2 newer Food and Drug Administration (FDA)-approved live biotherapeutic products (LBP), namely, Fecal Microbiota Live-JSLM and Fecal Microbiota Spores Live-BRPK, have shown promise in preventing CDI recurrence. This review explores the role of the gut microbiota in preventing and treating CDI, with an emphasis on gut-based interventions like FMT and fecal microbiota-based products that hold potential for gut restoration and prevention of CDI recurrence. Understanding the microbiome's impact on CDI prevention and treatment offers valuable insights for advancing future CDI therapeutics.
Emerging strategies targeting dysbiosis to restore gut microbiota are currently advancing Clostridioides difficile infection (CDI) therapeutics. Two newly FDA-approved live biotherapeutic products have shown promise in preventing CDI recurrence. This review explores the role of the gut microbiota in CDI.
•Aid withdrawals/suspensions are qualitatively different from giving no aid, and frame development.•Aid suspensions follow a long chain of understudied political calculations and decisions by donors ...and recipients.•Further research is needed on the political calculations and options used by aid-receiving states to discipline donors.
In this introduction to the special issue, “Foreign Aid Withdrawals and Suspensions: Why, When and Are They Effective,” we both summarize the current state of the literature and outline a robust new agenda for studying aid suspensions and withdrawals. A common contribution of the papers in this special issue is that they emphasize that donors and aid-recipient states have more options available to them than previous literature has allowed and that it is the creative ways in which aid-recipient governments seek to discipline their donors that make the effective use of conditionality so challenging. In this introduction, we not only summarize what we know about aid suspensions and withdrawals but also begin to unpack the complex decision-making that underlies aid suspensions, providing a simplified decision tree that can guide future research. Overall, we emphasize that, far from being a niche issue, aid suspensions and withdrawals are a fundamental part of the political economy of foreign aid and that much more work is needed to understand how recipient governments make decisions about how to respond or not to respond to (threats of) aid suspensions and withdrawals and how donors factor such political calculations into their initial or subsequent decision-making. The article highlights both the challenges and the opportunities of unpacking the complex decision-making behind aid suspensions and withdrawals.
The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the ...aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
White-nose syndrome is a fungal disease that has decimated hibernating bats from multiple North American species. In 2014, the invasive fungus arrived at a hibernaculum of little brown bats (Myotis ...lucifugus) inside the spillway of Tippy Dam, located near Wellston, Michigan, USA, yet surprisingly, this population has not experienced the declines seen elsewhere. Unlike a typical subterranean hibernaculum, light enters the spillway through small ventilation holes. We hypothesized that this light causes the hibernating bats to maintain a circadian rhythm, thereby saving energy via social thermoregulation during synchronous arousals. To test this idea, we used high-resolution thermal cameras to monitor arousals from October 2019 to April 2020. We found that arousals followed a circadian rhythm, peaking after sunset, and that most observed arousals (>68%) occurred within a cluster of bats allowing for social thermoregulation. These findings are consistent with the hypothesis that light-induced synchronized arousals contribute to the unprecedented absence of mass mortality from white-nose syndrome in this large population. Using light to maintain a circadian rhythm in bats should be tested as a potential tool for mitigating mortality from white-nose syndrome. More generally, studying populations that have been largely unaffected by white-nose syndrome may provide insight into mitigation strategies for protecting the remaining populations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Food animals are known reservoirs of multidrug-resistant (MDR) Escherichia coli, but information regarding the factors influencing colonization by these organisms is lacking. Here we report the ...genomic analysis of 66 MDR E. coli isolates from non-redundant veal calf fecal samples. Genes conferring resistance to aminoglycosides, β-lactams, sulfonamides, and tetracyclines were the most frequent antimicrobial resistance genes (ARGs) detected and included those that confer resistance to clinically significant antibiotics (blaCMY-2, blaCTX-M, mph(A), erm(B), aac(6')Ib-cr, and qnrS1). Co-occurrence analyses indicated that multiple ARGs significantly co-occurred with each other, and with metal and biocide resistance genes (MRGs and BRGs). Genomic analysis also indicated that the MDR E. coli isolated from veal calves were highly diverse. The most frequently detected genotype was phylogroup A-ST Cplx 10. A high percentage of isolates (50%) were identified as sequence types that are the causative agents of extra-intestinal infections (ExPECs), such as ST69, ST410, ST117, ST88, ST617, ST648, ST10, ST58, and ST167, and an appreciable number of these isolates encoded virulence factors involved in the colonization and infection of the human urinary tract. There was a significant difference in the presence of multiple accessory virulence factors (VFs) between MDR and susceptible strains. VFs associated with enterohemorrhagic infections, such as stx, tir, and eae, were more likely to be harbored by antimicrobial-susceptible strains, while factors associated with extraintestinal infections such as the sit system, aerobactin, and pap fimbriae genes were more likely to be encoded in resistant strains. A comparative analysis of SNPs between strains indicated that several closely related strains were recovered from animals on different farms indicating the potential for resistant strains to circulate among farms. These results indicate that veal calves are a reservoir for a diverse group of MDR E. coli that harbor various resistance genes and virulence factors associated with human infections. Evidence of co-occurrence of ARGs with MRGs, BRGs, and iron-scavenging genes (sit and aerobactin) may lead to management strategies for reducing colonization of resistant bacteria in the calf gut.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Graft block copolymers (BCPs) with poly(4-methyl caprolactone)-block-poly(±-lactide) (P4MCL-PLA) side chains containing 80–100% PLA content were synthesized with the aim of producing tough and ...sustainable plastics. These graft BCPs experience physical aging and become brittle over time. For short aging times, t a, the samples are ductile and shear yielding is the primary deformation mechanism. A double-yield phenomenon emerges at intermediate t a where the materials deform by stress whitening followed by shear yielding. At long t a, the samples become brittle and fail after crazing. PLA content strongly governs the time to brittle failure, where a 100% PLA graft polymer embrittles in 1 day, an 86% PLA graft BCP embrittles in 35 days, and at 80% PLA, the material remains ductile after 210 days. Molecular architecture is also a factor in increasing the persistence of ductility with time; a linear triblock ages three times faster than a graft BCP with the same PLA content. Small-angle X-ray scattering and transmission electron microscopy analysis suggest that the rubbery P4MCL domains play a role in initiating crazing by cavitation. Prestraining the graft BCPs also significantly toughens these glassy materials. Physical aging-induced embrittlement is eliminated in all of the prestrained polymers, which remain ductile after aging 60 days. The prestrained graft BCPs also demonstrate shape memory properties. When heated above the glass-transition temperature (T g), the stretched polymer within seconds returns to its original shape and recovers the original mechanical properties of the unstrained material. These results demonstrate that graft BCPs can be used to make tough, durable, and sustainable plastics and highlight the importance of understanding the mechanical performance of sustainable plastics over extended periods of time following processing.
With the recent publication of regulatory guidelines from both the FDA and the CPMP addressing the investigation of immunotoxicity of new chemical entities has come the requisite increased ...application of immunotoxicology protocols. Importantly, the fulfillment of these protocols may require the use of different species, and while in many cases information concerning the structure and function of the immune system can be readily translated across species, there are numerous and significant species differences that need to be considered. In some cases, the generation of meaningful immunotoxicology data can be adversely affected by the choice of a species that does not adequately share the immune function of concern with man. Likewise immunotoxicology testing in one species may produce negative data in one species but positive data in another. Knowing the mechanistic basis through an understanding of species differences in the structure and function of the immune system is pivotal to success. This becomes especially true as pharmaceutical companies design and develop highly specific immunomodulatory molecules that demonstrate species-specific pharmacology. This review is an exploration of various species differences in the structure and function of the immune system and an attempt to identify those differences that may be important in the conduct of immunotoxicity tests.
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