Mechanistic and Kinetic Insights into OH-Initiated Atmospheric Oxidation of Hymexazol: A Computational Study.

Hymexazol is a volatile fungicide widely used in agriculture, causing its abundance in the atmosphere; thus, its atmospheric fate and conversion are of great importance when assessing its environmental impacts. Herein, we report a theoretical kinetic mechanism for the oxidation of hymexazol by OH radicals, as well as the subsequent reactions of its main products with O2 and then with NO by using the Rice-Ramsperger-Kassel-Marcus-based Master equation kinetic model on the potential energy surface explored at the ROCBS-QB3//M06-2X/aug-cc-pVTZ level. The predicted total rate constants ktotal(T, P) for the reaction between hymexazol and OH radicals show excellent agreement with scarcely available experimental values (e.g., 3.6 × 10-12 vs (4.4 ± 0.8) × 10-12 cm3/molecule/s at T = 300 K and P = 760 Torr); thus, the calculated kinetic parameters can be confidently used for modeling/simulation of N-heterocycle-related applications under atmospheric and even combustion conditions. The model shows that 3,4-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-5-yl (IM2), 3,5-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-4-yl (IM3), and (3-hydroxy-1,2-oxazol-5-yl)methyl (P8) are the main primary intermediates, which form the main secondary species of (3,4-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)dioxidanyl (IM4), (3,5-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-4-yl)dioxidanyl (IM7), and ([(3-hydroxy-1,2-oxazol-5-yl)methyl]dioxidanyl (IM11), respectively, through the reactions with O2. The main secondary species then can react with NO to form the main tertiary species, namely, (3,4-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)oxidanyl (P19), (3,5-dihydroxy-5-methyl-4,5-dihydro-1,2-oxazol-4-yl)oxidanyl (P21), and [(3-hydroxy-1,2-oxazol-5-yl)methyl]oxidanyl (P23), respectively, together with NO2. Besides, hymexazol could be a persistent organic pollutant in the troposphere due to its calculated half-life τ1/2 of 13.7-68.1 h, depending on the altitude.

Developing and validating noninvasive prenatal testing for de novo autosomal dominant monogenic diseases in Vietnam.

Background: Over 60% of single-gene diseases in newborns are autosomal dominant variants. Noninvasive prenatal testing for monogenic conditions (NIPT-SGG) is cost-effective and timesaving, but not widely applied. This study introduces and validates NIPT-SGG in detecting 25 monogenic conditions. Methods: NIPT-SGG with a 30-gene panel applied next-generation sequencing and trio assays to confirm de novo variants. Diagnostic tests confirmed NIPT-detected cases. Results: Among 93 pregnancies with ultrasound findings, 11 (11.8%) fetuses were screened and diagnosed with monogenic diseases, mostly with Noonan syndrome. NIPT-SGG determined >99.99% of actual positive and negative cases, confirmed by diagnostic tests. No false-negatives or false-positives were reported. Conclusion: NIPT-SGG effectively identifies the fetuses affected with monogenic diseases, which is a promisingly safe and timely antenatal screening option for high-risk pregnancies.

Traveling to the left: A story of PKD1L1-containing vesicles.

The establishment of the left-right asymmetry in vertebrate animals is orchestrated by a series of tightly regulated events. In this issue of Developmental Cell, Tanaka et al. provide a tantalizing model to show how fluid flow in the mouse ventral node becomes integrated in a molecular cellular signature of asymmetry.

ING1 inhibits Twist1 expression to block EMT and is antagonized by the HDAC inhibitor vorinostat.

ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motility. ING1 expression had the opposite effect, promoting epithelial cell morphology and inhibiting basal and TGF-ß-induced motility in 3D organoid cultures. ING1 binds the Twist1 promoter and Twist1 was largely responsible for the ability of ING1 to reduce cell migration. Consistent with ING1 inhibiting Twist1 expression in vivo, an inverse relationship between ING1 and Twist1 levels was seen in breast cancer samples from The Cancer Genome Atlas (TCGA). The HDAC inhibitor vorinostat is approved for treatment of multiple myeloma and cutaneous T cell lymphoma and is in clinical trials for solid tumours as adjuvant therapy. One molecular target of vorinostat is INhibitor of Growth 2 (ING2), that together with ING1 serve as targeting subunits of the Sin3a HDAC complex. Treatment with sublethal (LD25-LD50) levels of vorinostat promoted breast cancer cell migration several-fold, which increased further upon ING1 knockout. These observations indicate that correct targeting of the Sin3a HDAC complex, and HDAC activity in general decreases luminal and basal breast cancer cell motility, suggesting that use of HDAC inhibitors as adjuvant therapies in breast cancers that are prone to metastasize may not be optimal and requires further investigation.

OH-initiated oxidation of vinyl butyrate: ab initio insights.

The widespread use of vinyl butyrate (CH2CHOC(O)CH2CH2CH3 or VB) in the polymer industry and daily-life materials inevitably results in its emission into the atmosphere. Therefore, understanding the mechanism and kinetics of the VB conversion is critical for evaluating its fate and environmental impacts. Herein, we theoretically investigate the chemical transformation of VB initiated by OH radicals in the atmosphere using the stochastic Rice-Ramsperger-Kassel-Marcus (RRKM)-based master equation kinetic model on the potential energy surface explored at the M06-2X/aug-cc-pVTZ level of theory. Showing excellent agreement with limited experimental kinetic data, the VB + OH kinetic model reveals that H-abstraction from Cß (i.e., -CßH2CH3) prevails over the OH-addition to the double bond (CC), even at low temperatures. The detailed analyses, including those of the time-resolved species profiles, reaction rate, and reaction flux, reveal the reaction mechanism shift with temperature (causing the U-shaped temperature dependence of k(T, P)) and the noticeable pressure dependence of k(T, P) at low temperatures. The secondary chemistry under atmospheric conditions (namely, the reaction of the main product with O2 and its subsequent reactions with NO) was then characterized within the same framework to reveal the detailed kinetic mechanism (e.g., [4-(ethenyloxy)-4-oxobutan-2-yl]oxidanyl (IM12) + NO2 is the dominant channel under atmospheric conditions), suggesting VB is not a persistent organic pollutant and a new environmental concern regarding the formed NO2. Also, the kinetic behaviors of vinyl butyrate and its oxidation products were extended from atmospheric to combustion conditions for further applications. Moreover, through TD-DFT calculations, it is shown that several related important species (i.e., 1-(ethenyloxy)-1-oxobutan-2-yl (P4), [4-(ethenyloxy)-4-oxobutan-2-yl]dioxidanyl (IM7), and IM12) can potentially undergo photolysis in the atmosphere.

Kinetics of photocatalytic degradation of organic compounds: a mini-review and new approach.

Organic compounds are widespread pollutants in wastewater, causing significant risks for living organisms. In terms of advanced oxidation processes, photocatalysis is known as an effective technology for the oxidation and mineralization of numerous non-biodegradable organic contaminants. The underlying mechanisms of photocatalytic degradation can be explored through kinetic studies. In previous works, Langmuir-Hinshelwood and pseudo-first-order models were commonly applied to fit batch-mode experimental data, revealing critical kinetic parameters. However, the application or combination conditions of these models were inconsistent or ignored. This paper briefly reviews kinetic models and various factors influencing the kinetics of photocatalytic degradation. In this review, kinetic models are also systemized by a new approach to establish a general concept of a kinetic model for the photocatalytic degradation of organic compounds in an aqueous solution.

A critical review on the bio-mediated green synthesis and multiple applications of magnesium oxide nanoparticles.

Nowadays, advancements in nanotechnology have efficiently solved many global problems, such as environmental pollution, climate change, and infectious diseases. Nano-scaled materials have played a central role in this evolution. Chemical synthesis of nanomaterials, however, required hazardous chemicals, unsafe, eco-unfriendly, and cost-ineffective, calling for green synthesis methods. Here, we review the green synthesis of MgO nanoparticles and their applications in biochemical, environmental remediation, catalysis, and energy production. Green MgO nanoparticles can be safely produced using biomolecules extracted from plants, fungus, bacteria, algae, and lichens. They exhibited fascinating and unique properties in morphology, surface area, particle size, and stabilization. Green MgO nanoparticles served as excellent antimicrobial agents, adsorbents, colorimetric sensors, and had enormous potential in biomedical therapies against cancers, oxidants, diseases, and the sensing detection of dopamine. In addition, green MgO nanoparticles are of great interests in plant pathogens, phytoremediation, plant cell and organ culture, and seed germination in the agricultural sector. This review also highlighted recent advances in using green MgO nanoparticles as nanocatalysts, nano-fertilizers, and nano-pesticides. Thanks to many emerging applications, green MgO nanoparticles can become a promising platform for future studies.

Reconstruction of Large Anterior Skull Base Defects After Resection of Sinonasal Tumors With Intracranial Extension by Using Pedicled Double Flap Techniques.

INTRODUCTION: The use of surgical resection for large anterior skull base (ASB) tumors and sinonasal malignancies with intracranial extension will result in a large skull base defect. Reconstruction of large ASB defects using traditional techniques is high risk and may lead to postoperative cerebral spinal fluid (CSF) leakage, meningitis, and an increase in mortality rate. The use of a pedicled double flap technique to reconstruct the ASB defect may decrease complications. This study presents the clinical outcomes of patients who underwent double flap reconstruction techniques after resection of their sinonasal malignancies with significant intracranial extension at Cho Ray hospital in Vietnam. METHODS: The case series study was conducted at Cho Ray hospital from September 2010 to September 2020. All patients with large sinonasal malignancies that invaded intracranially underwent transnasal endoscopic surgery and subfrontal craniotomy. Reconstruction of large skull base defects (>2 cm) were followed up by using the pedicled double flaps technique. This study was performed in line with the principles of the Declaration of Helsinki. Approval of the study was granted by the Independent Ethics Committee of Cho Ray Hospital (Date: March 3, 2014/No: 11/BVCRHDDD). RESULTS: During September 2010 to September 2020, there were 75 patients who underwent a modified multilayer, double flap reconstruction technique after the resection of their ASB tumor. Skull base defects were commonly seen along the horizontal plate of the ethmoid bone and the ethmoid roof (98.6%). Large skull base defects (>2 cm) accounted for 81.3% of cases. Overall, the risk of postoperative CSF leakage and meningitis after double flap repair was considerably low. Of all participants, only 1 experienced postoperative CSF leakage and 1 experienced postoperative meningitis. Despite the complications, these patients improved significantly and remained stable. CONCLUSION: The use of double vascularized pedicled flaps may decrease the incidence of postoperative CSF leakage and meningitis. This technique is an effective method for the reconstruction of ASB tumors with large defects.

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease.

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti-PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti-PD-1 antibody treatment improved the health span of podocytes. Administering the same anti-PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

Single-cell and spatial mapping Identify cell types and signaling Networks in the human ureter.

Tissue engineering offers a promising treatment strategy for ureteral strictures, but its success requires an in-depth understanding of the architecture, cellular heterogeneity, and signaling pathways underlying tissue regeneration. Here, we define and spatially map cell populations within the human ureter using single-cell RNA sequencing, spatial gene expression, and immunofluorescence approaches. We focus on the stromal and urothelial cell populations to enumerate the distinct cell types composing the human ureter and infer potential cell-cell communication networks underpinning the bi-directional crosstalk between these compartments. Furthermore, we analyze and experimentally validate the importance of the sonic hedgehog (SHH) signaling pathway in adult progenitor cell maintenance. The SHH-expressing basal cells support organoid generation in vitro and accurately predict the differentiation trajectory from basal progenitor cells to terminally differentiated umbrella cells. Our results highlight the essential processes involved in adult ureter tissue homeostasis and provide a blueprint for guiding ureter tissue engineering.

An evaluation of emergency pain management practices in fragility fractures of the pelvis.

BACKGROUND: Inadequately treated pain is associated with significant morbidity in older adults. We aimed to describe current pain management practices for patients with fragility pelvic fractures, a common emergency department (ED) presentation in older adults. METHODS: We performed a health records' review of adults ≥ 65 years old who presented to two academic EDs with nonoperative fragility pelvic fractures between 01/2014 and 09/2018. The primary outcome measures were type and timing of analgesic medications. Secondary outcome measures included ancillary service consultation, ED length of stay, admission rate and rate of return to ED at 30 days. Data were reported using descriptive statistics. RESULTS: We included 411 patients. The majority were female (339, 82.5%) with mean age 83.9 (SD 8.1) years. Nearly, one-third (130, 31.6%) did not receive any analgesia for their fracture. Analgesia was initiated in 123 (29.9%) patients through paramedic and nursing medical directives; 244 (59.4%) patients received physician-initiated opioids (hydromorphone 228 (55.5%); morphine 28 (6.8%)). Only 23.1% of patients received one or more ancillary services: physiotherapy (10.5%), social work (7.3%), geriatric nurse assessment (14.1%), and homecare (3.9%). Mean ED length of stay was 11.6 (SD 7.1) h; 210 (51.1%) patients were admitted; of those discharged, 45 (22.4%) returned to the ED within 30 days. CONCLUSION: One in three older adults presenting to the ED with nonoperative fragility pelvic fractures receive no analgesia during the course of their prehospital and ED care. Barriers to quality care must be identified and processes implemented to ensure adequate pain management for this population.

RéSUMé: CONTEXTE: La douleur insuffisamment traitée est associée à une morbidité importante chez les personnes âgées. Nous voulions décrire les pratiques actuelles de gestion de la douleur chez les patients souffrant de fractures pelviennes de fragilité, une présentation courante des services d'urgence (SU) chez les personnes âgées. MéTHODES: Nous avons effectué une revue des dossiers médicaux des adultes ≥ 65 ans qui se sont présentés à deux urgences universitaires avec des fractures pelviennes de fragilité non opérées entre 01/2014 et 09/2018. Les principaux critères d'évaluation étaient le type et le moment de la prise de médicaments analgésiques. Les critères d'évaluation secondaires comprennent la consultation des services auxiliaires, la durée moyenne de séjour aux urgences, le taux d'admission et le taux de retour aux urgences à 30 jours. Les données ont été rapportées en utilisant des statistiques descriptives. RéSULTATS: Nous avons inclus 411 patients. La majorité était des femmes (339, 82,5%) avec un âge moyen de 83,9 (écart-type 8,1) ans. Près d'un tiers (130, 31,6 %) n'ont reçu aucune analgésie pour leur fracture. L'analgésie a été initiée chez 123 (29,9%) patients par des directives médicales paramédicales et infirmières ; 244 (59,4%) patients ont reçu des opioïdes à l'initiative du médecin (hydromorphone 228 (55,5%) ; morphine 28 (6,8%)). Seuls 23,1% des patients ont bénéficié d'un ou plusieurs services auxiliaires : physiothérapie (10,5%), travail social (7,3%), évaluation infirmière gériatrique (14,1%) et soins à domicile (3,9%). La durée moyenne de séjour aux urgences était de 11,6 heures (écart-type : 7,1); 210 (51,1 %) patients ont été admis ; parmi ceux qui sont sortis, 45 (22,4 %) sont retournés aux urgences dans les 30 jours. CONCLUSION : Une personne âgée sur trois se présentant aux urgences avec des fractures du bassin non opératoires ne reçoit aucune analgésie au cours de ses soins préhospitaliers et aux urgences. Les obstacles à la qualité des soins doivent être identifiés et des processus doivent être mis en œuvre pour assurer une gestion adéquate de la douleur pour cette population.

Development of a paddy-based biorefinery approach toward improvement of biomass utilization for more bioproducts.

Improvement of biomass utilization productivity following cascading strategy is a priority for the biorefinery-based circular bioeconomy. In recent years, the field of energy research has seen an increasing interest in bio-products from paddy-based biorefinery, but the utilization of the entire value of paddy biomass to guide the commercial viability of its products has not been got feasible outcomes. Here we propose a potential pathway for a conceptual paddy biorefinery framework by addressing wastes for producing more products. The feasibility of the integrated biorefinery was demonstrated by the conversion of wastes into value-added products such as nano-silica and lignin. In particular, this is the first time that silica recovered from bioethanol system was continued to be reused to produce ZSM-5 and Ni/ZSM-5 as catalysts of rice straw lignin depolymerization achieving high conversion of lignin up to 95% and fair yield of phenolic products up to 41%. Material flow of an integrated biorefinery model was reported to give a future outlook for making most of the processing routes of rice residues. We also established a life cycle that follows the circular bioeconomy concept and discussed the relationship between each of potential bioproducts and their market opportunities.

Removal of total nitrogen from wastewater by a combination of Chlorella sp. and audible sound.

In developing countries, nitrogen in the traditional market wastewater is a critical environmental problem. In this study, the microalga Chlorella sp., which was isolated from wastewater, was used to remove the total nitrogen (TN) from conventional market wastewater in combination with audible sound (Vietnamese classical music). In addition, effects of sound exposure on removal efficiency at different initial cell densities were analyzed. Results revealed that music sound control demonstrates potential to improve the removal efficiency. TN removal efficiencies of 96%, 69.5%, and 4.3% were observed for treatments with Chlorella sp./audible sound, Chlorella sp., and without Chlorella sp., respectively. The significance of probability value (p-value) (<0.05) on the paired sample t-test confirmed the critical role of audible sound and Chlorella sp. density on the TN removal in screening experiments. The predicted optimal conditions for TN removal were as follows: a Chlorella sp. density of 4%, an audible sound of 52.5 dB, and a cultivation time of 4.6 days. Results based on statistical analysis revealed that the quadratic models for TN removal are significant at a low p-value (<0.05) and a high predicted coefficient of determination (R2 = 0.9452) value. The obtained statistical results also indicated that most of the variables are significant for the abatement of TN from market wastewater using Chlorella sp.

Outcomes in Patients Stratified by PRECISE-DAPT Versus DAPT Scores After Percutaneous Coronary Interventions.

The optimal length of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains debated. Current guidelines recommend individualized treatment with consideration of risk scores. We sought to evaluate the degree of agreement in treatment recommendations and the ability to predict ischemic and bleeding complications of the PRECISE-DAPT (predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) and DAPT scores. Consecutive patients receiving 12 months of DAPT were grouped based on score treatment recommendation at the time of PCI: PRECISE-DAPT prolonged or shortened (PRECISE DAPT <25 vs ≥25) and DAPT prolonged or shortened (DAPT ≥2 vs <2). One-year ischemic and bleeding outcomes were compared for each group. In 451 patients, the PRECISE-DAPT and DAPT score recommendations were concordant in 56.7% of patients (Cohen's kappa for agreement of k = 0.139, 95% confidence interval 0.065 to 0.212). There was no difference in composite major adverse cardiovascular and cerebrovascular events between patients with high versus low PRECISE-DAPT or DAPT scores. In patients with a high PRECISE-DAPT score versus a low score, there was an increased incidence of 1-year all-cause mortality (2.13% vs 0%, p = 0.04) and an increase in bleeding (Bleeding Academic Research Consortium ≥3a: 17.0% vs 2.8%; p <0.001; Bleeding Academic Research Consortium 3b/c and 5: 8.5% vs 1.4%; p = 0.001). There were no differences in rates of mortality or bleeding for patients with high versus low DAPT scores. In conclusion, when applied at the baseline, the PRECISE-DAPT and DAPT scores frequently make discordant DAPT duration recommendations. The PRECISE-DAPT, but not the DAPT score, demonstrated associations with all-cause mortality and bleeding in patients prescribed 12 months of DAPT after PCI.

Corneal perforation in ocular graft-versus-host disease.

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal "melt" in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies.

Controlling long-term SARS-CoV-2 infections can slow viral evolution and reduce the risk of treatment failure.

The rapid emergence and expansion of novel SARS-CoV-2 variants threatens our ability to achieve herd immunity for COVID-19. These novel SARS-CoV-2 variants often harbor multiple point mutations, conferring one or more evolutionarily advantageous traits, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we used a stochastic evolutionary modeling framework to explore the emergence of fitter variants of SARS-CoV-2 during long-term infections. We found that increased viral load and infection duration favor emergence of such variants. While the overall probability of emergence and subsequent transmission from any given infection is low, on a population level these events occur fairly frequently. Targeting these low-probability stochastic events that lead to the establishment of novel advantageous viral variants might allow us to slow the rate at which they emerge in the patient population, and prevent them from spreading deterministically due to natural selection. Our work thus suggests practical ways to achieve control of long-term SARS-CoV-2 infections, which will be critical for slowing the rate of viral evolution.

Iodine-Catalyzed Synthesis of Substituted Furans and Pyrans: Reaction Scope and Mechanistic Insights.

Substituted pyrans and furans are core structures found in a wide variety of natural products and biologically active compounds. Herein, we report a practical and mild catalytic method for the synthesis of substituted pyrans and furans using molecular iodine, a simple and inexpensive catalyst. The method described is performed under solvent-free conditions at an ambient temperature and atmosphere, thus offering a facile and practical alternative to currently available reaction protocols. A combination of experimental studies and density functional theory calculations revealed interesting mechanistic insights into this seemingly simple reaction.

Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein.

The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities.

Predator selection and predator-prey interactions for the biological control of mosquito dengue vectors in northern Vietnam.

Predators and their interactions with target prey influence the efficiency of control strategies. In the present study, we demonstrate the implementation of natural predator selection for controlling dengue vectors in northern Vietnam through field-based observation of aquatic insect predators in natural habitats and lab-based assessment of predatorial capacities for several aquatic insect predators. The selected species was then used to evaluate the predatory-prey interaction using functional responses (FRs) toward 3rd- and 4th-instar larvae of four major medical mosquito species (Aedes aegypti, Aedes albopictus, Culex quinquefasciatus, and Anopheles minimus). The preference of selected predators for Ae. aegypti larvae over other mosquito larvae was also investigated. Both field observation and lab experiments indicated that the giant water bug Diplonychus rusticus was abundant and exhibited the highest predatory capacity for mosquito larvae. The predator exhibited type II FRs when offered each of the four prey species, and the greatest attack rates were observed for Ae. aegypti and Ae. albopictus, with only negligible differences observed in the handling times of the prey species. Further, Manly's selectivity (α) values calculated from the prey choice experiments showed that Ae. aegypti was preferred over both Cx. quinquefasciatus and An. minimus. Together, these findings indicate that D. rusticus could be successfully used to facilitate the biological control of both Ae. aegypti and Ae. albopictus within the species' distributional overlap in Southeast Asia.