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Abstract Background The paucity of SARS-CoV-2-specific virulence factors has greatly hampered the therapeutic management of patients with COVID-19 disease. Although available vaccines and approved therapies have shown tremendous benefits, the continuous emergence of new variants of SARS-CoV-2 and side effects of existing treatments continue to challenge therapy, necessitating the development of a novel effective therapy. We have previously shown that our developed novel single-stranded DNA aptamers not only target the trimer S protein of SARS-CoV-2, but also block the interaction between ACE2 receptors and trimer S protein of Wuhan origin, Delta, Delta plus, Alpha, Lambda, Mu, and Omicron variants of SARS-CoV-2. We herein performed in vivo experiments that administer the aptamer to the lungs by intubation as well as in vitro studies utilizing PBMCs to prove the efficacy and safety of our most effective aptamer, AYA2012004_L. Methods In vivo studies were conducted in transgenic mice expressing human ACE2 (K18hACE2), C57BL/6J, and Balb/cJ. Flow cytometry was used to check S-protein expressing pseudo-virus-like particles (VLP) uptake by the lung cells and test the immuogenicity of AYA2012004_L. Ames test was used to assess mutagenicity of AYA2012004_L. RT-PCR and histopathology were used to determine the biodistribution and toxicity of AYA2012004_L in vital organs of mice. Results We measured the in vivo uptake of VLPs by lung cells by detecting GFP signal using flow cytometry. AYA2012004_L specifically neutralized VLP uptake and also showed no inflammatory response in mice lungs. In addition, AYA2012004_L did not induce inflammatory response in the lungs of Th1 and Th2 mouse models as well as human PBMCs. AYA2012004_L was detectable in mice lungs and noticeable in insignificant amounts in other vital organs. Accumulation of AYA2012004_L in organs decreased over time. AYA2012004_L did not induce degenerative signs in tissues as seen by histopathology and did not cause changes in the body weight of mice. Ames test also certified that AYA2012004_L is non-mutagenic and proved it to be safe for in vivo studies. Conclusions Our aptamer is safe, effective, and can neutralize the uptake of VLPs by lung cells when administered locally suggesting that it can be used as a potential therapeutic agent for COVID-19 management.

The function of an antibody is intrinsically linked to the epitope it engages. Clonal clustering methods, based on sequence identity, are commonly used to group antibodies that will bind to the same epitope. However, such methods neglect the fact that antibodies with highly diverse sequences can exhibit similar binding site geometries and engage common epitopes. In a previous study, we described SPACE1, a method that structurally clustered antibodies in order to predict their epitopes. This methodology was limited by the inaccuracies and incomplete coverage of template-based modeling. In addition, it was only benchmarked at the level of domain-consistency on one virus class. Here, we present SPACE2, which uses the latest machine learning-based structure prediction technology combined with a novel clustering protocol, and benchmark it on binding data that have epitope-level resolution. On six diverse sets of antigen-specific antibodies, we demonstrate that SPACE2 accurately clusters antibodies that engage common epitopes and achieves far higher dataset coverage than clonal clustering and SPACE1. Furthermore, we show that the functionally consistent structural clusters identified by SPACE2 are even more diverse in sequence, genetic lineage, and species origin than those found by SPACE1. These results reiterate that structural data improve our ability to identify antibodies that bind to the same epitope, adding information to sequence-based methods, especially in datasets of antibodies from diverse sources. SPACE2 is openly available on GitHub (https://github.com/oxpig/SPACE2).

Abstract Background Shotgun metagenome analysis provides a robust and verifiable method for comprehensive microbiome analysis of fungal, viral, archaeal and bacterial taxonomy, particularly with regard to visualization of read mapping location, normalization options, growth dynamics and functional gene repertoires. Current read classification tools use non-standard output formats, or do not fully show information on mapping location. As reference datasets are not perfect, portrayal of mapping information is critical for judging results effectively. Results Our alignment-based pipeline, Wochenende, incorporates flexible quality control, trimming, mapping, various filters and normalization. Results are completely transparent and filters can be adjusted by the user. We observe stringent filtering of mismatches and use of mapping quality sharply reduces the number of false positives. Further modules allow genomic visualization and the calculation of growth rates, as well as integration and subsequent plotting of pipeline results as heatmaps or heat trees. Our novel normalization approach additionally allows calculation of absolute abundance profiles by comparison with reads assigned to the human host genome. Conclusion Wochenende has the ability to find and filter alignments to all kingdoms of life using both short and long reads, and requires only good quality reference genomes. Wochenende automatically combines multiple available modules ranging from quality control and normalization to taxonomic visualization. Wochenende is available at https://github.com/MHH-RCUG/nf_wochenende .

Abstract Tannins and tanniferous plant extracts have been discussed as sustainable means for helminth control in the past two decades in response to a dramatic increase of resistances towards standard anthelmintics. While their bioactivities have been broadly investigated in vitro and in vivo, less is known about their mode of action in nematodes, apart from their protein binding properties. In the current study we therefore investigated the impact of a phytochemically well characterized plant extract from Combretum mucronatum, known to contain procyanidins as the active compounds, on the model organism Caenorhabditis elegans. By different microscopic techniques, the cuticle was identified as the main binding site for tannins, whereas underlying tissues did not seem to be affected. In addition to disruptions of the cuticle structure, molting defects occurred at all larval stages. Finally, an increased rigidity of the nematodes’ cuticle due to binding of tannins was confirmed by force spectroscopic measurements. This could be a key finding to explain several anthelmintic activities reported for tannins, especially impairment of molting or exsheathment as well as locomotion.

Studies have shown that plants possess medicinal properties and compounds are beneficial in managing and treating diseases, including high blood pressure and related cardiovascular conditions. Simarouba glauca (SG) has been widely reported to possess antibacterial activity, anti-oxidant, anti-proliferative and hemolytic activity; amongst others. However, there is paucity of data on its effect on blood pressure. Hence, the study research aimed at assessing the hypotensive prospect inherent in the aqueous leaf extract of Simarouba glauca (AESG) on normotensive male Wistar rats. The study was conducted using adult male Wistar rats (n = 3), a urethane/thiopental (1205/20 mg/kg) anesthesia and a chart paper attached to Ugo Basile Uni-recorder Model 400700 data capsule. Under full anesthesia, the rat’s trachea and the carotid artery were cannulated for assisted respiration and blood pressure measurement. At stable variables; following the administration of 0.2 mL normal saline, the AESG was administered intravenously via the caudal vein at 2.5 and 5.0 mg/kg body weight dose respectively. The data was recorded on a chart; indicated the characteristic dose-dependent hypotensive effect of AESG on normotensive rats; at doses of 2.5 mg/kg and 5.0 mg/kg, with marked decreases in the systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) from basal levels of 127.83 ± 1.01 mmHg, 91.00 ± 1.00 mm Hg and 103.27 ± 0.99 mm Hg respectively. The outcome of the preliminary investigation indicates that the AESG demonstrated a hypotensive effect on the BP of normotensive male Wistar rats dependent on varying doses administered; indicative of further evaluation.

We present WearMoCap, an open-source library to track the human pose from smartwatch sensor data and leveraging pose predictions for ubiquitous robot control. WearMoCap operates in three modes: 1) a Watch Only mode, which uses a smartwatch only, 2) a novel Upper Arm mode, which utilizes the smartphone strapped onto the upper arm and 3) a Pocket mode, which determines body orientation from a smartphone in any pocket. We evaluate all modes on large-scale datasets consisting of recordings from up to 8 human subjects using a range of consumer-grade devices. Further, we discuss real-robot applications of underlying works and evaluate WearMoCap in handover and teleoperation tasks, resulting in performances that are within 2 cm of the accuracy of the gold-standard motion capture system. Our Upper Arm mode provides the most accurate wrist position estimates with a Root Mean Squared prediction error of 6.79 cm. To evaluate WearMoCap in more scenarios and investigate strategies to mitigate sensor drift, we publish the WearMoCap system with thorough documentation as open source. The system is designed to foster future research in smartwatch-based motion capture for robotics applications where ubiquity matters. www.github.com/wearable-motion-capture. [ABSTRACT FROM AUTHOR]

Abstract Background The evolutionary history of biodiversity in South America has been poorly studied in the seasonal dry tropical forest (SDTF). Species diversification in this ecosystem may have a twofold explanation. First, intermittent connections in the middle and late Pleistocene promoted species dispersal and/or genetic connectivity between lineages isolated in disjunct patches of forest. Second, allopatric speciation proceeded immediately after the formation and colonization of the SDTF in the Neogene. Here we studied the diversification of Psammolestes, a genus endemic of the SDTF and naturally infected with Trypanosoma cruzi (agent of Chagas disease), using a combination of phylogenetic, population genetics and niche model methods, and evaluated the reliability of the three morphospecies currently recognized. Results Our multilocus analyses recovered P. coreodes and P. tertius in a monophyletic clade sister to P. arthuri. Species delimitation tests recovered these lineages as different species despite the shared genetic variation observed between P. coreodes and P. tertius in five genes. Also, genetic variation of the genus clustered in three groups that were consistent with the three morphospecies. Our demographic model predicted a scenario of divergence in absence of gene flow, suggesting that mixed haplotypes may be the result of shared ancestral variation since the divergence of the subtropical-temperate species P. coreodes and P. tertius. In contrast, the tropical species P. arthuri was highly differentiated from the other two in all tests of genetic structure, and consistently, the Monmonier’s algorithm identified a clear geographical barrier that separates this species from P. coreodes and P. tertius. Conclusions We found three genetically structured lineages within Psammolestes that diverged in absence of gene flow in the late Miocene. This result supports a scenario of species formation driven by geographical isolation rather than by divergence in the face of gene flow associated with climatic oscillations in the Pleistocene. Also, we identified the Amazon basin as a climatic barrier that separates tropical from subtropical-temperate species, thus promoting allopatric speciation after long range dispersion. Finally, each species of Psammolestes occupies different climatic niches suggesting that niche conservatism is not crucial for species differentiation. These findings influence the current vector surveillance programs of Chagas disease in the region.

No abstract available.

BackgroundBlood cultures (BC) are critical for the diagnosis of bloodstream infections, pathogen identification, and resistance testing. Guidelines recommend a blood volume of 8-10 mL per bottle as lower volumes result in decreased sensitivity. We aimed to evaluate factors for non-adherence to recommended volumes and assess the effects on diagnostic performance.MethodsFrom February to April 2020, we measured collected blood volumes by weighing all BC containers from inpatient samples at the University Hospital Basel. Information on BC volumes was merged with clinical and microbiological data, as well as nursing staff schedules. We analyzed factors associated with (i) BC sampling volume, (ii) reaching recommended volumes (≥8 mL), (iii) BC positivity, and (iv) time to positivity using linear and generalized linear mixed effect models.ResultsWe evaluated a total of 4'118 BC bottles collected from 686 patients. A total of 1'495 (36.3%) of all bottles contained the recommended filling volume of ≥8 mL. Using a central venous and arterial catheter for drawing blood resulted in an increase of filling volume by 0.26 mL (95% CI 0.10, 0.41) and 0.50 mL (95% CI 0.31, 0.69) compared to peripheral venipuncture, respectively. Each additional nursing staff working at the time of blood drawing was associated with 6% higher odds of achieving the recommended filling volume. We found no significant correlation between the filling volume and the positivity rate.ConclusionOur results indicate critical pre-analytical quality markers linked to BC collection procedures to reach recommended collection volumes. No significant impact on the positivity rate was found.

The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses’ health threats. The parasites’ frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the Tb enzymes (0.2 μM < IC50 < 85.1 μM) and ten against the respective Lm enzymes (0.6 μM < IC50 < 84.5 μM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target.

Abstract Virus-like particles are an emerging class of nano-biotechnology with the Tobacco Mosaic Virus (TMV) having found a wide range of applications in imaging, drug delivery, and vaccine development. TMV is typically produced in planta, and, as an RNA virus, is highly susceptible to natural mutation that may impact its properties. Over the course of 2 years, from 2018 until 2020, our laboratory followed a spontaneous point mutation in the TMV coat protein—first observed as a 30 Da difference in electrospray ionization mass spectrometry (ESI–MS). The mutation would have been difficult to notice by electrophoretic mobility in agarose or SDS-PAGE and does not alter viral morphology as assessed by transmission electron microscopy. The mutation responsible for the 30 Da difference between the wild-type (wTMV) and mutant (mTMV) coat proteins was identified by a bottom-up proteomic approach as a change from glycine to serine at position 155 based on collision-induced dissociation data. Since residue 155 is located on the outer surface of the TMV rod, it is feasible that the mutation alters TMV surface chemistry. However, enzyme-linked immunosorbent assays found no difference in binding between mTMV and wTMV. Functionalization of a nearby residue, tyrosine 139, with diazonium salt, also appears unaffected. Overall, this study highlights the necessity of standard workflows to quality-control viral stocks. We suggest that ESI–MS is a straightforward and low-cost way to identify emerging mutants in coat proteins.

Abstract Fingers facilitate number learning and arithmetic processing in early childhood. The current study investigated whether images of early-learned, culturally-typical (canonical), finger montring patterns presenting smaller (2,3,4) or larger (7,8,9) quantities still facilitate adults’ performance and neural processing in a math verification task. Twenty-eight adults verified solutions to simple addition problems that were shown in the form of canonical or non-canonical finger-number montring patterns while measuring Event Related Potentials (ERPs). Results showed more accurate and faster sum verification when sum solutions were shown by canonical (versus non-canonical) finger patterns. Canonical finger montring patterns 2–4 led to faster responses independent of whether they presented correct or incorrect sum solutions and elicited an enhanced early right-parietal P2p response, whereas canonical configurations 7–9 only facilitated performance in correct sum solution trials without evoking P2p effects. The later central-parietal P3 was enhanced to all canonical finger patterns irrespective of numerical range. These combined results provide behavioral and brain evidence for canonical cardinal finger patterns still having facilitating effects on adults’ number processing. They further suggest that finger montring configurations of numbers 2–4 have stronger internalized associations with other magnitude representations, possibly established through their mediating role in the developmental phase in which children acquire the numerical meaning of the first four number symbols.

One of the most evident sources of phenotypic diversity within a population is colouration, as exemplified by colour polymorphism. This is relevant to a greater extent in animals with visually biased sensory systems. There is substantial evidence suggesting that different colour morphs can access a broader range of habitats or niches, leading to larger geographic range sizes. However, this hypothesis has been tested in few lineages, comprising species where colour is likely to be involved in sexual selection. Furthermore, some available evidence considers geographical variation as polymorphism, thus limiting our comprehension of how sympatric colour polymorphism can influence a species' geographic range. Through an extensive systematic literature review and a comparative analysis, we examined the relationship between colour polymorphism and range size or niche breadth in web-building spiders. We identified 140 colour polymorphic spider species, belonging mainly to the families Araneidae and Theridiidae. We found no evidence that colour polymorphic species differ significantly from non-polymorphic species in terms of range size and niche breadth, after accounting for phylogenetic relationships and other covariates. However, we did observe that colour polymorphic species were more likely to be found on islands compared to non-polymorphic species. Overall, our results indicate that the association between colour polymorphism and geographic range size may not exist among web-building spiders, or be as pronounced as in other lineages. This suggests that the strength of the association between colour polymorphism and ecological success might depend on the ecological role that colouration plays in each clade. [ABSTRACT FROM AUTHOR]

Iron oxide nanoparticles hold great potential for future biomedical applications but, to date, usually suffer from reduced magnetic properties compared to their bulk counterparts. The replacement of Fe(III) ions with Zn(II) ions can enhance their magnetic properties while keeping their biocompatibility characteristics. Yet, common synthesis methods for these highly magnetic particles require using environmentally harmful solvents, multiple steps, and postfunctionalization, all while being affected by poor scalability and high polydispersity. To address these challenges, in this study, a single‐step coprecipitation‐based method is developed to fabricate gelatin‐coated, zinc‐substituted, sub‐10 nm‐sized iron oxide nanoparticles exhibiting high saturation magnetization. This single‐step synthesis benefits from simplicity and robustness, capable of yielding large amounts of highly magnetic nanoparticles without the utilization of environmentally harmful or highly toxic reagents. Furthermore, in situ gelatin coating during the synthesis ensures particle stability in aqueous solutions over a wide range of pH and enhances cell compatibility. Systematic investigations show a direct correlation between the particles' magnetization and the concentrations of Zn(II) and NaOH, where particles with a zinc‐to‐iron ratio of Zn:Fe = 0.18:2.82 reach a maximum saturation magnetization of 91.2 emu g−1. Thus, these particles are promising candidates for biomedical applications. [ABSTRACT FROM AUTHOR]

The initial delivery of small‐scale magnetic devices such as microrobots is a key, but often overlooked, aspect for their use in clinical applications. The deployment of these devices within the dynamic environment of the human body presents significant challenges due to their dispersion caused by circulatory flows. Here, a method is introduced to effectively deliver a swarm of magnetic nanoparticles in fluidic flows. This approach integrates a magnetically navigated robotic microcatheter equipped with a reservoir for storing the magnetic nanoparticles. The microfluidic flow within the reservoir facilitates the injection of magnetic nanoparticles into the fluid stream, and a magnetic field gradient guides the swarm through the oscillatory flow to a target site. The microcatheter and reservoir are engineered to enable magnetic steering and injection of the magnetic nanoparticles. To demonstrate this approach, experiments are conducted utilizing a spinal cord phantom simulating intrathecal catheter delivery for applications in the central nervous system. These results demonstrate that the proposed microcatheter successfully concentrates nanoparticles near the desired location through the precise manipulation of magnetic field gradients, offering a promising solution for the controlled deployment of untethered magnetic micro‐/nanodevices within the complex physiological circulatory systems of the human body. [ABSTRACT FROM AUTHOR]

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Stabilizing lipid nanoparticles and lipidprotein assemblies is challenging owing to lipid dynamics and protein instability. Here, the authors report on the reversible encapsulation of liposomes and proteoliposomes in a metalorganic framework permitting months-long room temp storage.

Abstract Tonality is one of the most central theoretical concepts for the analysis of Western classical music. This study presents a novel approach for the study of its historical development, exploring in particular the concept of mode. Based on a large dataset of approximately 13,000 musical pieces in MIDI format, we present two models to infer both the number and characteristics of modes of different historical periods from first principles: a geometric model of modes as clusters of musical pieces in a non-Euclidean space, and a cognitively plausible Bayesian model of modes as Dirichlet distributions. We use the geometric model to determine the optimal number of modes for five historical epochs via unsupervised learning and apply the probabilistic model to infer the characteristics of the modes. Our results show that the inference of four modes is most plausible in the Renaissance, that two modes–corresponding to major and minor–are most appropriate in the Baroque and Classical eras, whereas no clear separation into distinct modes is found for the 19th century.

This research investigated the prevalence of waterborne infections (WBIs) and the risks associated with household drinking water choices, knowledge, and practices. A cross-sectional multi-stage sampling research design was employed. A well-structured questionnaire was used to sample 403 individuals representing 115 household; and stool samples collected and subjected to standard parasitic and bacterial diagnostic methods. From the 403 samples, 344 (85.4%) were positive for at least one waterborne pathogen of nine isolates: E. coli (38.0%), Giardia lamblia (35.2%), E. histolytica (33.0%), Salmonella typhi (19.9%), Proteus spp. (13.2%), Shigella dysentery (9.4%), Klebsiella spp. (7.4%), Enterobacter spp. (5.5%), and Cryptosporidium spp. (5.2%). Prevalence of WBIs was >75% in all age groups, but decreased with age. Prevalence of WBIs was >80% in all communities. Risk was not biased by gender. Odds of infection from public well (OR = 2.487; CI95: 1.296–4.774) and borehole/vendor (OR = 2.175; CI95: 1.231–3.843) users was over two times greater than non-users. Risk of WBDs was significantly reduced by 60% in sachet water drinkers (OR = 0.392; CI95: 0.217–0.709; p < 0.05). Surprisingly, river/stream water users had a significant reduced risk of WBDs than non-users (OR = 0.335; CI95: 0.150–0.749; p < 0.05). Poor hygiene was the most important determinant of WBIs; poor sanitary practice increased odds of WBIs by 400% (OR = 4.945; CI95: 2.358–10.371; p < 0.05). This study shows that most household water choices are vulnerable to contamination at many points in their journey from source to mouth; and advocates adequate provision of safe water, “point of use” household water treatment, and good storage methods to effectively curb WBIs.

The precise subcellular location of ion channels is a key determinant of their functions. Here, subcellular patch-clamp recordings demonstrate that an axon-specific expression of HCN channels facilitates the initiation and propagation of action potentials in parvalbumin-expressing basket cells.

Major invasions of Indo-Pacific lionfish (Pterois volitans and P. miles) are underway in the Western Atlantic Ocean and the Mediterranean Sea. While the establishment of lionfish in the Western Atlantic is perhaps the most well-studied marine fish invasion to date, the rapidly expanding invasion in the Mediterranean is more recent and has received less attention. Here we review and synthesize successes and failures from two decades of lionfish management in the Western Atlantic to give policy recommendations for their management in the Mediterranean. Two failed approaches that were attempted multiple times in the Western Atlantic and that we advise against are (1) feeding lionfish to native fish to promote predation and (2) implementing bounty programs to incentivize lionfish harvest. Broadly, the most important management lessons that we recommend include (1) conducting routine removals by spearfishing with scuba, which can effectively suppress local abundances of lionfish; (2) encouraging the development of recreational and commercial lionfish fisheries, which can promote long-term, sustainable lionfish population control; and, (3) engaging local communities and resource users (e.g., with lionfish removal tournaments), which can concurrently achieve multiple objectives of promoting lionfish removals, market-development, research, and public education. Managers in the Western Atlantic often needed to adapt current conservation policies to enable lionfish removals in areas where spearfishing with scuba was otherwise prohibited for conservation purposes. The risk of abusing these policies was mitigated through the use of gear restrictions, diver trainings, and through participatory approaches that integrated scuba divers and stakeholder organizations in lionfish research and management. Our review of policies and practices in the Mediterranean Sea found that many of our recommended lionfish management approaches are not being done and indicate potential opportunities to implement these. We expect and fully recommend that work continues towards multinational cooperation to facilitate regional coordination of research, control, and management efforts with respect to the Mediterranean lionfish invasion. As with other major biological invasions, lionfish are unconstrained by political borders and their control will require rapid and strategic management approaches with broad cooperation among and between governments and stakeholders.