Dengue outbreaks in a city with recent transmission in São Paulo state, Brazil.

We investigated the distribution of dengue cases, solid waste deposits (SWDs), forest fragments, water drainage, population income, and the possible association with dengue outbreaks in Presidente Prudente, São Paulo, Brazil. An urban setting with recent transmission. Data were obtained from public agencies. Kernel density maps of the variables were constructed. From 2015 to 2021, 33026 cases of dengue were reported; the incidence and mortality rate were highest in 2016. The number of cases decreased during the COVID-19 pandemic (2020 and 2021) compared with 2019, but alarming rates were registered in 2022. In 2015, 56 points of SWDs were identified, with an increase of 1.6-fold in 2020 and 2021. Multivariate analysis showed a positive correlation between the density of dengue cases and SWDs with the highest correlation (0.70) in 2020. Identifying these areas could guide public health authorities in surveillance measures and improvements in health care infrastructure.

Kerbs and curbs, desire and damage: an affirmative account of children's play and being well during the COVID-19 pandemic

A dominant narrative around the impact of COVID-19 on children focuses on the risk of children being the pandemic's biggest victims. Without denying the severity of such damage, this article explores two examples of playing during the pandemic, alongside more affirmative Deleuzian accounts of desire, which can contribute to mitigating both the damage itself and what damage narratives perform. Using two fragments of data from research into children's play during the first COVID-19 UK lockdown, we show how, despite the tightest of restrictions, moments of playfulness emerged from encounters between children, other bodies and the materiality and affective atmospheres of the street to produce moments of being well. In both fragments children play with the kerbs on the street, deterritorialising the curbs of both striated street spaces and lockdown in ways that temporarily enact a playful politics of space and produce moments of being well. We read these fragments through contemporary Deleuzian accounts of desire as a productive force. In so doing, we contribute to debates in relational ontologies of children's geographies that address the micropolitics of children's spatial practices.

Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery.

Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be 'undruggable'. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.

Human Superantibodies to 3CLpro Inhibit Replication of SARS-CoV-2 across Variants.

Broadly effective and safe anti-coronavirus agent is existentially needed. Major protease (3CLpro) is a highly conserved enzyme of betacoronaviruses. The enzyme plays pivotal role in the virus replication cycle. Thus, it is a good target of a broadly effective anti-Betacoronavirus agent. In this study, human single-chain antibodies (HuscFvs) of the SARS-CoV-2 3CLpro were generated using phage display technology. The 3CLpro-bound phages were used to infect Escherichia coli host for the production the 3CLpro-bound HuscFvs. Computerized simulation was used to guide the selection of the phage infected-E. coli clones that produced HuscFvs with the 3CLpro inhibitory potential. HuscFvs of three phage infected-E. coli clones were predicted to form contact interface with residues for 3CLpro catalytic activity, substrate binding, and homodimerization. These HuscFvs were linked to a cell-penetrating peptide to make them cell-penetrable, i.e., became superantibodies. The superantibodies blocked the 3CLpro activity in vitro, were not toxic to human cells, traversed across membrane of 3CLpro-expressing cells to co-localize with the intracellular 3CLpro and most of all, they inhibited replication of authentic SARS-CoV-2 Wuhan wild type and α, ß, δ, and Omicron variants that were tested. The superantibodies should be investigated further towards clinical application as a safe and broadly effective anti-Betacoronavirus agent.

Antibody-receptor bioengineering and its implications in designing bioelectronic devices.

Antibodies play a crucial role in the defense mechanism countering pathogens or foreign antigens in eukaryotes. Its potential as an analytical and diagnostic tool has been exploited for over a century. It forms immunocomplexes with a specific antigen, which is the basis of immunoassays and aids in developing potent biosensors. Antibody-based sensors allow for the quick and accurate detection of various analytes. Though classical antibodies have prolonged been used as bioreceptors in biosensors fabrication due to their increased fragility, they have been engineered into more stable fragments with increased exposure of their antigen-binding sites in the recent era. In biosensing, the formats constructed by antibody engineering can enhance the signal since the resistance offered by a conventional antibody is much more than these fragments. Hence, signal amplification can be observed when antibody fragments are utilized as bioreceptors instead of full-length antibodies. We present the first systematic review on engineered antibodies as bioreceptors with the description of their engineering methods. The detection of various target analytes, including small molecules, macromolecules, and cells using antibody-based biosensors, has been discussed. A comparison of the classical polyclonal, monoclonal, and engineered antibodies as bioreceptors to construct highly accurate, sensitive, and specific sensors is also discussed.

De novo design and Rosetta-based assessment of high-affinity antibody variable regions (Fv) against the SARS-CoV-2 spike receptor binding domain (RBD).

The continued emergence of new SARS-CoV-2 variants has accentuated the growing need for fast and reliable methods for the design of potentially neutralizing antibodies (Abs) to counter immune evasion by the virus. Here, we report on the de novo computational design of high-affinity Ab variable regions (Fv) through the recombination of VDJ genes targeting the most solvent-exposed hACE2-binding residues of the SARS-CoV-2 spike receptor binding domain (RBD) protein using the software tool OptMAVEn-2.0. Subsequently, we carried out computational affinity maturation of the designed variable regions through amino acid substitutions for improved binding with the target epitope. Immunogenicity of designs was restricted by preferring designs that match sequences from a 9-mer library of "human Abs" based on a human string content score. We generated 106 different antibody designs and reported in detail on the top five that trade-off the greatest computational binding affinity for the RBD with human string content scores. We further describe computational evaluation of the top five designs produced by OptMAVEn-2.0 using a Rosetta-based approach. We used Rosetta SnugDock for local docking of the designs to evaluate their potential to bind the spike RBD and performed "forward folding" with DeepAb to assess their potential to fold into the designed structures. Ultimately, our results identified one designed Ab variable region, P1.D1, as a particularly promising candidate for experimental testing. This effort puts forth a computational workflow for the de novo design and evaluation of Abs that can quickly be adapted to target spike epitopes of emerging SARS-CoV-2 variants or other antigenic targets.

Particles and fragments in unused disposable face masks: A microscopic analysis

Introduction: In the context of the COVID-19 pandemic, many governments mandated the wearing of face masks by law. New research shows that these masks contain and release microplastics. Methods: In the present work, five samples of surgical masks were examined microscopically for the presence of particles and fragments. The masks were purchased from two of the largest supermarket chains in Switzerland. Results: Particles and fragments were found on the fibre surfaces in the inner layer of all face masks examined. The size of these objects varied in the range of about 2-40 μm, with dark spots and particles on the fibres having a smaller diameter than the more transparent fragments. Conclusion: In this work, it was shown that particles and fragments in the micrometer range can be found on the inside of commercially available surgical face masks purchased in supermarkets in Switzerland. The health significance of the presence of particles and fragments in the micrometer range as demonstrated by the current investigation of surgical face masks needs to be further investigated. © 2022 International Journal of Occupational Safety and Health (IJOSH). All rights reserved.

Host tRNA-Derived RNAs Target the 3'Untranslated Region of SARS-CoV-2.

The COVID-19 pandemic revealed a need for new understanding of the mechanisms regulating host-pathogen interactions during viral infection. Transfer RNA-derived RNAs (tDRs), previously called transfer RNA fragments (tRFs), have recently emerged as potential regulators of viral pathogenesis. Many predictive studies using bioinformatic approaches have been conducted providing a repertoire of potential small RNA candidates for further analyses; however, few targets have been validated to directly bind to SARS-CoV-2 sequences. In this study, we used available data sets to identify host tDR expression altered in response to SARS-CoV-2 infection. RNA-interaction-prediction tools were used to identify sequences in the SARS-CoV-2 genome where tDRs could potentially bind. We then developed luciferase assays to confirm direct regulation through a predicted region of SARS-CoV-2 by tDRs. We found that two tDRs were downregulated in both clinical and in vitro cell culture studies of SARS-CoV-2 infection. Binding sites for these two tDRs were present in the 3' untranslated region (3'UTR) of the SARS-CoV-2 reference virus and both sites were altered in Variants of Concern (VOCs) that emerged later in the pandemic. These studies directly confirm the binding of human tDRs to a specific region of the 3'UTR of SARS-CoV-2 providing evidence for a novel mechanism for host-pathogen regulation.

Predictive prognostic biomarkers in patients with COVID‑19 infection

The present study aimed to identify useful biomarkers to predict deterioration in patients with coronavirus disease 2019 (COVID‑19). A total of 201 COVID‑19 patients were classified according to their disease severity into non‑severe (n=125) and severe (n=76) groups, and the behavior of laboratory biomarkers was examined according to the prognosis. Neutrophil count, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase (LDH), C‑reactive protein (CRP), sialylated carbohydrate antigen KL‑6 (KL‑6), procalcitonin (PCT), presepsin (PSP) and D‑dimer levels were significantly higher, and lymphocyte count and platelet count were significantly lower in the non‑severe group compared with the severe group. In the non‑severe group, ROC analysis demonstrated that only four biomarkers, CRP, PSP, AST and LDH were useful for differentiating the prognosis between improvement and deterioration subgroups. No strong correlation was revealed for any of the markers. Multivariate analysis identified CRP as a significant prognostic factor in non‑severe cases (odds ratio, 41.45;95% confidence interval, 4.91‑349.24;P<0.001). However, there were no blood biomarkers that could predict the outcome of patients in the severe group. Overall, several blood markers changed significantly according to disease severity in the course of COVID‑19 infection. Among them, CRP, PSP, LDH and AST were the most reliable markers for predicting the patient's prognosis in non‑severe COVID‑19 cases.

Fragment-based drug discovery-the importance of high-quality molecule libraries.

Fragment-based drug discovery (FBDD) is now established as a complementary approach to high-throughput screening (HTS). Contrary to HTS, where large libraries of drug-like molecules are screened, FBDD screens involve smaller and less complex molecules which, despite a low affinity to protein targets, display more 'atom-efficient' binding interactions than larger molecules. Fragment hits can, therefore, serve as a more efficient start point for subsequent optimisation, particularly for hard-to-drug targets. Since the number of possible molecules increases exponentially with molecular size, small fragment libraries allow for a proportionately greater coverage of their respective 'chemical space' compared with larger HTS libraries comprising larger molecules. However, good library design is essential to ensure optimal chemical and pharmacophore diversity, molecular complexity, and physicochemical characteristics. In this review, we describe our views on fragment library design, and on what constitutes a good fragment from a medicinal and computational chemistry perspective. We highlight emerging chemical and computational technologies in FBDD and discuss strategies for optimising fragment hits. The impact of novel FBDD approaches is already being felt, with the recent approval of the covalent KRASG12C inhibitor sotorasib highlighting the utility of FBDD against targets that were long considered undruggable.

Cell Surface Transporters and Novel Drug Developments.

Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer drugs. Recent drug development has been in part guided by Lipinski's Rule of 5 (Ro5) even though many approved drugs do not comply to these rules. With Covid-19 vaccine development strategy dramatically accelerating drug development perhaps it is timely to question the generic drug development process itself to find a more efficient, cost effective, and successful approach. It is widely believed that drugs permeate cells via two methods: phospholipid bilayer diffusion and carrier mediated transporters. However, emerging evidence suggests that carrier mediated transport may be the primary mechanism of drug uptake and not diffusion as long believed. Computational biology increasingly assists drug design to achieve desirable absorption, distribution, metabolism, elimination and toxicity (ADMET) properties. Perfecting drug entry into target cells as a prerequisite to intracellular drug action is a logical and compelling route and is expected to reduce drug attrition rates, particularly gaining favour amongst chronic lifelong therapeutics. Novel drug development is rapidly expanding from the utilisation of beyond the rule of five (bRo5) to pulsatile drug delivery systems and fragment based drug design. Utilising transporters as drug targets and advocating bRo5 molecules may be the solution to increasing drug specificity, reducing dosage and toxicity and thus revolutionising drug development. This review explores the development of cell surface transporter exploitation in drug development and the relationship with improved therapeutic index.

Biting the Bullet: A Call for Action on Lead-Contaminated Meat in Food Banks

Even though the presence of ammunition-derived metallic lead fragments in donated firearms-hunted meat has been recognized for more than a decade, the vast majority of donated hunted meat is not inspected to discard meat containing lead fragments.1 An underlying lack of food safety standards for adulterated donated food increases risks to lowincome recipients, who are already disproportionately affected by elevated blood lead levels (BLLs).2 Primary prevention is needed for this overlooked source of lead exposure. LOW-LEVEL LEAD Primary prevention is recognized as the most effective way to address the epidemic of lead poisoning in the United States.3 The current blood lead reference level recognized by the Centers for Disease Control and Prevention is 3.5 micrograms per deciliter (mg/dL). A strong body of scientific research demonstrates that leadbased ammunition frequently contaminates hunted meat and increases BLLs of humans and animals who consume it.1,7-9 Lead-contaminated hunted meat has been identified as the most poorly acknowledged and addressed example of food lead contamination, and scientists have called for this source of lead exposure to be acknowledged and addressed with health-protective measures.8,9 A 2013 consensus statement of experts in human, environmental, and wildlife toxicology supports reducing and eventually eliminating the introduction of lead into the environment from lead-based ammunition, emphasizing that shooting lead ammunition into the environment poses significant risks of lead exposure to humans and wildlife.10 In 2016, Arnemo et al. found that more than 99% of 570 scientific articles about environmental and health consequences of lead in ammunition raised concerns about lead toxicity.7 The authors highlighted that nonlead ammunition is as effective as lead-based ammunition and is comparably priced. Despite the well-established scientific basis for regulation of lead ammunition for hunting, the topic has been politicized by misinformation campaigns portraying concerns about ingesting lead ammunition as a product of antihunting agendas.11 Lead Contamination in Donated Hunted Meat Donated hunted meat is a vital source of protein distributed by food banks at a time when food bank use remains far above pre-COVID-19 pandemic levels.12 Published evidence of leadcontaminated meat in food banks has existed for more than a decade (Figure A, available as a supplement to the online version of this article at https://www.ajph.org).13 Investigations in multiple states have confirmed the presence of lead in donated meat.

Using BERT model to Identify Sentences Paraphrase in the News Corpus

The paper analyzes the problems of semantic similarity identification of short text fragments and provides an overview of modern methods for solving them. The advantages of using the fine-tuned Sentence-BERT language model for paraphrased sentences classification over other modern models are proved. This paper presents the software implementation of the algorithm for automatic paraphrased sentences identification in a created corpus of English texts scraped from two news sites. The detailed information on designing and preprocessing of the news corpus on COVID-19 topic is provided. The operation of the created algorithm for automatic creation of the resulting corpus of semantically similar sentences is described in stages. The evaluation of the created algorithm based on the resulting corpus is calculated with the assistance of experts. The precision of the paraphrased sentences identification achieves 77 %. © 2022 Copyright for this paper by its authors.

Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease.

RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine, offering the opportunity to inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that target the active site cysteine of the 3C protease (3Cpro) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we re-purpose these hits towards the main protease (Mpro) of SARS-CoV-2 which shares the 3C-like fold and a similar active site. The hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity. We demonstrate that targeting the active site cysteine of Mpro can have profound allosteric effects, distorting secondary structures to disrupt the active dimeric unit.

Environmental hazard of polypropylene microplastics from disposable medical masks: acute toxicity towards Daphnia magna and current knowledge on other polypropylene microplastics.

The COVID-19 pandemic has increased the use of disposable plastics, including medical masks, which have become a necessity in our daily lives. As these are often improperly disposed of, they represent an important potential source of microplastics in the environment. We prepared microplastics from polypropylene medical masks and characterised their size, shape, organic chemical leaching, and acute toxicity to the planktonic crustacean Daphnia magna. The three layers of the masks were separately milled and characterised. Each of the inner frontal, middle filtering, and outer layers yielded different types of microplastics: fibres were obtained from the inner and outer layer, but irregular fragments from the middle layer. The shape of the obtained microplastics differed from the initial fibrous structure of the intact medical mask layers, which indicates that the material is deformed during cryo-milling. The chemical compositions of plastics-associated chemicals also varied between the different layers. Typically, the inner layer contained more chemicals related to antimicrobial function and flavouring. The other two layers also contained antioxidants and their degradation products, plasticisers, cross-linking agents, antistatic agents, lubricants, and non-ionic surfactants. An acute study with D. magna showed that these microplastics do not cause immobility but do physically interact with the daphnids. Further long-term studies with these microplastics are needed using a suite of test organisms. Indeed, studies with other polypropylene microplastics have shown numerous adverse effects on other organisms at concentrations that have already been reported in the environment. Further efforts should be made to investigate the environmental hazards of polypropylene microplastics from medical masks and how to handle this new source of environmental burden. PLEASE CHECK THE SI WORD DOCUMENT THE AUTHORS ARE NOT LISTED THERE I CANNOT EDIT THAT FILE PLEASE ADD THE AUTHORS SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43591-021-00020-0.

Global conserved RBD fraction of SARS-CoV-2 S-protein with T500S mutation in silico significantly blocks ACE2 and rejects viral spike.

BACKGROUND: SARS-CoV-2 developed global-pandemic with millions of infections/deaths. As it is urgently necessary it is assumed that some blockers/inhibitors of ACE2 could be helpful to resist the binding of viral-spike Receptor-Binding-Domain (RBD). METHODS: Here, conserved RBD from 186-countries were compared with WUHAN-Hu-1 wild-type (CLUSTAL-X2/Pymol). The RBD of ACE2-bound nCOV2 crystal-structure 6VW1 was analyzed by Haddock-PatchDock. Extensive structural study/trial to introduce point/double/triple mutations in the different locations of CUT4 (most-effective from total 4 proposed fragments; CUTs) were tested with Swiss-Model-Expacy. RESULTS: Blind-docking of mutated-CUTs in ACE2 completely rejected the nCOV2 binding to ACE2. Further, competitive-docking/binding-analyses (by PRODIGY) demonstrated few more bonding (LYS31-PHE490 and GLN42-GLN498) of CUT4 (than wild) and hindered TYR41-THR500 interaction with ACE2. Moreover, mutated-CUT4 even showed higher blocking effect against spike-ACE2 binding. CONCLUSION: In summary, CUT4-mutant rejects whole glycosylated-nCoV2 in all pre-dock, post-dock and competitive-docking conditions. The present work strategy is relevant because it could be able to block at the first level entry of the virus to the host cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41231-022-00109-5.

Recent Development in Small Molecules for SARS-CoV-2 and the Opportunity for Fragment-Based Drug Discovery.

The ongoing pandemic of Covid-19 caused by SARS-CoV-2 is a major threat to global public health, drawing attention to develop new therapeutics for treatment. Much research work is focused on identifying or repurposing new small molecules to serve as potential inhibitors by interacting with viral or host-cell molecular targets and understanding the nature of the virus in the host cells. Identifying small molecules as potent inhibitors at an early stage is advantageous in developing a molecule with higher potency and then finding a lead compound for the development of drug discovery. Small molecules can show their inhibition property by targeting either the SARS-CoV-2 main protease (Mpro) enzyme, papain-like protease (PLpro) enzyme, or helicase (Hel), or blocking the spike (S) protein angiotensin-converting enzyme 2 (ACE2) receptor. A very recent outbreak of a new variant (B.1.617.2-termed as Delta variant) of SARS-CoV-2 worldwide posed a greater challenge as it is resistant to clinically undergoing vaccine trials. Thus, the development of new drug molecules is of potential interest to combat SARS-CoV-2 disease, and for that, the fragment-based drug discovery (FBDD) approach could be one of the ways to bring out an effective solution. Two cysteine protease enzymes would be an attractive choice of target for fragment-based drug discovery to tune the molecular structure at an early stage with suitable functionality. In this short review, the recent development in small molecules as inhibitors against Covid-19 is discussed, and the opportunity for FBDD is envisioned optimistically to provide an outlook regarding Covid-19 that may pave the way in the direction of the Covid-19 drug development paradigm.

Preparation of different fragments of SARS-co V-2 urine protein and its application in fluorescent layer system

Expression and purification of different fragments of the new coronavirus nucleocapsid (N) protein, establish a new coronavirus total antibody fluorescence immunochromatographic method and evaluate the influence of different protein fragments on the method. Using bioinformatics technology to analyze, synthesize, express and purify the N protein sequence, prepare different N protein fragments;use 1-ethyl-(3-dimethylaminopropyl) carbodiimide (1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) method of fluorescent microspheres coupled with antigen was established to establish a sandwich fluorescence chromatography antibody detection method, and the performance was evaluated respectively. In the prepared 4 N protein fragments, the full-length N protein (N419) is preferably coated, and N412 is labeled with 0.5mol/L NaCl as the optimal combination;the 91-120th amino acid (N412) of the N-terminus of the N antigen is deleted It can reduce 87.5% of non-specific interference;the linear range is 0.312-80U/L, the lowest detection limit is 0.165U/L, and the accuracy is above 95%. The fluorescence immunochromatographic detection method for total antibodies of the new coronavirus established by pairing the N protein fragments has a total coincidence rate of 98% compared with the Guangzhou Wanfu test strip. The improvement provides experimental basis and reference.