Inside-out: Synergising leaf biochemical traits with stomatal-regulated water fluxes to enhance transpiration modelling during abiotic stress.

As the global climate continues to change, plants will increasingly experience abiotic stress(es). Stomata on leaf surfaces are the gatekeepers to plant interiors, regulating gaseous exchanges that are crucial for both photosynthesis and outward water release. To optimise future crop productivity, accurate modelling of how stomata govern plant-environment interactions will be crucial. Here, we synergise optical and thermal imaging data to improve modelled transpiration estimates during water and/or nutrient stress (where leaf N is reduced). By utilising hyperspectral data and partial least squares regression analysis of six plant traits and fluxes in wheat (Triticum aestivum), we develop a new spectral vegetation index; the Combined Nitrogen and Drought Index (CNDI), which can be used to detect both water stress and/or nitrogen deficiency. Upon full stomatal closure during drought, CNDI shows a strong relationship with leaf water content (r2 = 0.70), with confounding changes in leaf biochemistry. By incorporating CNDI transformed with a sigmoid function into thermal-based transpiration modelling, we have increased the accuracy of modelling water fluxes during abiotic stress. These findings demonstrate the potential of using combined optical and thermal remote sensing-based modelling approaches to dynamically model water fluxes to improve both agricultural water usage and yields.

Fourth dose of microneedle array patch of SARS-CoV-2 S1 protein subunit vaccine elicits robust long-lasting humoral responses in mice.

The COVID-19 pandemic has underscored the pressing need for safe and effective booster vaccines, particularly in considering the emergence of new SARS-CoV-2 variants and addressing vaccine distribution inequalities. Dissolving microneedle array patches (MAP) offer a promising delivery method, enhancing immunogenicity and improving accessibility through the skin's immune potential. In this study, we evaluated a microneedle array patch-based S1 subunit protein COVID-19 vaccine candidate, which comprised a bivalent formulation targeting the Wuhan and Beta variant alongside a monovalent Delta variant spike proteins in a murine model. Notably, the second boost of homologous bivalent MAP-S1(WU + Beta) induced a 15.7-fold increase in IgG endpoint titer, while the third boost of heterologous MAP-S1RS09Delta yielded a more modest 1.6-fold increase. Importantly, this study demonstrated that the administration of four doses of the MAP vaccine induced robust and long-lasting immune responses, persisting for at least 80 weeks. These immune responses encompassed various IgG isotypes and remained statistically significant for one year. Furthermore, neutralizing antibodies against multiple SARS-CoV-2 variants were generated, with comparable responses observed against the Omicron variant. Overall, these findings emphasize the potential of MAP-based vaccines as a promising strategy to combat the evolving landscape of COVID-19 and to deliver a safe and effective booster vaccine worldwide.

Recent Progress in Phenoxazine-Based Thermally Activated Delayed Fluorescent Compounds and Their Full-Color Organic Light-Emitting Diodes.

Third-generation organic light-emitting diodes (OLEDs) based on metal-free thermally activated delayed fluorescent (TADF) materials have sparked tremendous interest in the last decade due to their nearly 100% exciton utilization efficiency, which can address the low-efficiency issue of the first-generation fluorescent emitters and the high-cost issue of the second-generation organometallic phosphorescent emitters. Construction of efficient and stable TADF-OLEDs requires utilizing TADF materials with a narrow singlet-triplet energy gap (ΔEST), high photoluminescence quantum yield (PLQY) and short TADF lifetime. A small ΔEST is necessary for an efficient reverse intersystem crossing (RISC) process, which can be achieved through the effective spatial separation of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). TADF emitters have been generally designed as intramolecular charge transfer (ICT) molecules with highly twisted donor-acceptor (D-A) molecular architectures. A wide variety of combinations of electron donors and acceptors have been explored. In this review, we shall focus on recent progress in organic TADF molecules incorporating strong electron-donor phenoxazine moiety and their application as emitting layer (EML) in OLEDs.

Second Boost of Omicron SARS-CoV-2 S1 Subunit Vaccine Induced Broad Humoral Immune Responses in Elderly Mice.

Currently approved COVID-19 vaccines prevent symptomatic infection, hospitalization, and death from the disease. However, repeated homologous boosters, while considered a solution for severe forms of the disease caused by new SARS-CoV-2 variants in elderly individuals and immunocompromised patients, cannot provide complete protection against breakthrough infections. This highlights the need for alternative platforms for booster vaccines. In our previous study, we assessed the boost effect of the SARS-CoV-2 Beta S1 recombinant protein subunit vaccine (rS1Beta) in aged mice primed with an adenovirus-based vaccine expressing SARS-CoV-2-S1 (Ad5.S1) via subcutaneous injection or intranasal delivery, which induced robust humoral immune responses (1). In this follow-up study, we demonstrated that a second booster dose of a non-adjuvanted recombinant Omicron (BA.1) S1 subunit vaccine with Toll-like receptor 4 (TLR4) agonist RS09 (rS1RS09OM) was effective in stimulating strong S1-specific immune responses and inducing significantly high neutralizing antibodies against the Wuhan, Delta, and Omicron variants in 100-week-old mice. Importantly, the second booster dose elicits cross-reactive antibody responses, resulting in ACE2 binding inhibition against the spike protein of SARS-CoV-2 variants, including Omicron (BA.1) and its subvariants. Interestingly, the levels of IgG and neutralizing antibodies correlated with the level of ACE2 inhibition in the booster serum samples, although Omicron S1-specific IgG level showed a weaker correlation compared to Wuhan S1-specific IgG level. Furthermore, we compared the immunogenic properties of the rS1 subunit vaccine in young, middle-aged, and elderly mice, resulting in reduced immunogenicity with age, especially an impaired Th1-biased immune response in aged mice. Our findings demonstrate that the new variant of concern (VOC) rS1 subunit vaccine as a second booster has the potential to offer cross-neutralization against a broad range of variants and to improve vaccine effectiveness against newly emerging breakthrough SARS-CoV-2 variants in elderly individuals who were previously primed with the authorized vaccines.

Synthesis, Characterization, Antiglycation Evaluation, Molecular Docking, and ADMET Studies of 4-Thiazolidinone Derivatives.

The design and development of new small-molecule glycation inhibitors are essential for preventing various chronic diseases, including diabetes mellitus, immunoinflammation, cardiovascular, and neurodegenerative diseases. 4-Thiazolidinone or thiazolidine-4-one is a well-known heterocyclic compound with the potential to inhibit the formation of advanced glycation end products. In the present work, we report the synthesis and characterization of four new 5-arylidene 3-cyclopropyl-2-(phenylimino)thiazolidin-4-one (1-4) compounds and their human serum albumin glycation inhibitory activity. One of the compounds 5-(2H-1,3-benzodioxol-5-ylmethylidene)-3-cyclopropyl-2-(phenylimino)-1,3-thiazolidin-4-one (3) showed potent inhibition in the synthesis of initial, intermediary, and final products of glycation reactions. Besides, conformational changes in the α-helix and ß-sheet (due to hyperglycemia) were also found to be reversed upon the addition of (3). Experimental findings were complemented by computational [molecular docking, ADME/Tox, and density functional theory (DFT)] studies. The docking scores of the compounds were in order 1 > 3 > 2 > 4, indicating the importance of the polar group at the 5-arylidene moiety. The results of ADME/Tox and DFT calculations revealed the safe nature of the compounds with high drug-likeness and stability. Overall, we speculate that the results of this study could provide valuable insights into the biological activity of 4-thiazolidinones.

Canine Model of Ischemia-Induced Ventricular Tachycardia.

INTRODUCTION: Despite advances in antiarrhythmia therapies, ventricular tachycardia (VT) is a leading cause of sudden cardiac death. Investigation into the characteristics and new treatments for this arrhythmia is required to improve outcomes and a reproducible model of VT would be useful in these endeavors. We therefore created a canine model of ischemia-induced VT. MATERIALS AND METHODS: A pacing lead was implanted in the right ventricle in canines (n = 13) and the left anterior descending artery was occluded in two locations for 2 h and subsequently released to create an ischemia-reperfusion injury. In the 10 dogs that survived the first 48 h following the initial study, a terminal study was conducted 4-7 d later and VT was induced using premature stimulation or burst pacing through the right ventricle lead. The arrhythmia was terminated using either antitachycardia pacing or a defibrillatory shock. Multiple inductions into sustained VT were attempted. RESULTS: Sustained VT was induced in eight of 10 dogs with an average cycle length of 335 ± 70 bpm. Multiple episodes of VT were induced. Episodes of VT exhibited different electrocardiogram morphologies and cycle lengths in individual animals. CONCLUSIONS: This canine model provides a consistent technique for inducing multiple episodes of sustained VT. It may be useful for investigating VT mechanisms and testing novel therapeutics and treatments for patients with VT.

In silico evaluation of 4-thiazolidinone-based inhibitors against the receptor for advanced glycation end products (RAGE).

Non-enzymatic glycation of biomolecules by reducing sugars led to several products, including the advanced glycation end products (AGEs), the accumulation of which has been linked to various life-threatening diseases. The binding of AGEs to their respective protein receptors for advanced glycation end products (RAGE) can initiate a cascade of reactions, which may alter physiological conditions. The present work investigates the potential of 4-thiazolidinones as RAGE inhibitors. We performed an extensive computational study to identify the structural requirements needed to act as RAGE inhibitors. To achieve this goal, 4-thiazolidinone-based compounds available in PubChem, ZINC15, ChEMBL, and ChEBI databases were screened against RAGE (PDB: 4LP5), leading to the identification of top five drug-like candidates with a high binding affinity to RAGE V-domain catalytic region. Drug likeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the top-scoring compounds have been studied and discussed. Global molecular descriptors, chemical reactivity, hardness, softness, etc., have been estimated. Finally, molecular dynamics (MD) simulations at 100 ns were carried out to check the stability and other properties. Overall, we believe that the identified compounds can potentially attenuate RAGE-AGE interactions.Communicated by Ramaswamy H. Sarma.

The WATCHMAN Device Review: A New Era for Stroke Prophylaxis.

Atrial fibrillation (AF) is a major risk factor for ischemic stroke, accounting for more than 37 million cases worldwide. In AF, the left atrial appendage (LAA) is the most common site of thrombus formation, and its ligation/closure with the WATCHMAN device is a good alternative to long-term oral anticoagulation, especially in patients with contraindications to warfarin. However, the implantation procedure is associated with various risks and complications. A short-term anticoagulant and antithrombotic administration are essential after implantation. However, no consensus has been reached on the optimal regimen. The WATCHMAN device is non-inferior to warfarin and is a safe alternative for the prevention of stroke and systemic embolization related to non-valvular atrial fibrillation (NVAF). Important procedure-related complications include pericardial effusion (PE), device embolization, procedure-related ischemic stroke, and device-related thrombosis (DRT) formation. It is essential to optimize post-implantation therapy according to individual patient bleeding risk, DRT formation, and contraindication to direct oral anticoagulants (DOACs). Recent studies have also shown that DOACs are a convenient and non-inferior substitute for warfarin. Furthermore, patients with absolute contraindications to OACs/DOACs can only be managed with dual antiplatelet therapy (DAPT). Transesophageal echocardiography (TEE) should be used to assess residual peridevice flow and possible DRT formation at days 45 and 12 months. Low molecular weight heparin (LMWH) and OAC are excellent choices for DRT treatment if detected. This review summarizes the most important complications of the WATCHMAN device in the existing literature and discusses various anticoagulation strategies and challenges post-implementation.

Tetravalent SARS-CoV-2 S1 subunit protein vaccination elicits robust humoral and cellular immune responses in SIV-infected rhesus macaque controllers.

IMPORTANCE: The study provides important insights into the immunogenicity and efficacy of a tetravalent protein subunit vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine induced both humoral and cellular immune responses in nonhuman primates with controlled SIVagm infection and was able to generate Omicron variant-specific antibodies without specifically vaccinating with Omicron. These findings suggest that the tetravalent composition of the vaccine candidate could provide broad protection against multiple SARS-CoV-2 variants while minimizing the risk of immune escape and the emergence of new variants. Additionally, the use of rhesus macaques with controlled SIVsab infection may better represent vaccine immunogenicity in humans with chronic viral diseases, highlighting the importance of preclinical animal models in vaccine development. Overall, the study provides valuable information for the development and implementation of coronavirus disease 2019 vaccines, particularly for achieving global vaccine equity and addressing emerging variants.

Exploring Celiac Disease: A Case Analysis of Multi-Systemic Symptoms and Effective Dietary Intervention in a Young Female.

This study presents the case of a 23-year-old woman diagnosed with celiac disease (CD), a condition triggered by an immune response to gluten, leading to inflammation in the small intestine. The patient manifested typical gastrointestinal symptoms, including diarrhea, abdominal pain, and vomiting, complemented by extra-intestinal signs such as fatigue and skin rashes. Diagnosis was corroborated through the presence of tTG-IgA antibodies and distinct histological changes in the duodenum. A notable finding was the patient's iron deficiency anemia, directly linked to the duodenal damage caused by CD. Effective management, encompassing a strict gluten-free diet and iron supplementation, resulted in marked improvement in her condition. This case accentuates the significance of early CD detection, especially in patients exhibiting a combination of gastrointestinal and extra-intestinal symptoms. Emphasis is placed on the pivotal role of timely diagnosis, adherence to a gluten-free regimen, and sustained monitoring to ensure patient well-being and prevent complications.

Two new red-emitting ternary europium(III) complexes with high photoluminescence quantum yields and exceptional performance in OLED devices.

Two new organo-europium complexes (OEuCs) [Eu(btfa)3(Bathphen)] (OEuC-1) and [Eu(tta)3(Bathphen)] (OEuC-2) where btfa and tta are the anions of 4,4,4-trifluoro-1-phenyl-1,3-butanedione and 2-thenoyltrifluoroacetone while Bathphen = Bathophenanthroline have been synthesized and characterized. Both complexes in the solid state exhibit strong red emissions with photoluminescence quantum yields (PLQYs) of 80% ± 10%. These complexes were tested as dopants in the emitting layer (EML) to fabricate red organic light emitting diodes (R-OLEDs). Through device engineering involving the amalgamation of appropriate host materials and complexes, we have achieved exceptional overall R-OLED performance for an OEuC-2 based device, with maximum current efficiency (CEmax) = 9.91 cd A-1, maximum power efficiency (PEmax) = 9.15 lm W-1, maximum external quantum efficiency (EQEmax.) = 6.24%, brightness (B) of 545 cd m-2, and (CIE)x,y = 0.620, 0.323 at J = 10 mA cm-2.

Antitachycardia pacing at the His bundle is safer than conventional right ventricular antitachycardia pacing in a canine myocardial ischemic injury model.

INTRODUCTION: Antitachycardia pacing (ATP) is used to terminate ventricular tachycardia (VT) by delivering rapid, low energy pacing to the right ventricle (RV). Unfortunately, ATP is not effective against all VT episodes and can result in adverse outcomes, such as VT acceleration and degeneration into ventricular fibrillation (VF). Improving ATP is therefore desirable. Our objective was to compare the efficacy and safety of ATP delivered at the His bundle to traditional ATP. METHODS: Six dogs were anesthetized and pacing leads were implanted in the RV and His bundle. The left anterior descending artery was occluded for 2 h to create an ischemic injury. In a study 4-7 days later, a 128-electrode sock was placed snugly around the ventricles and VT was induced using rapid pacing. ATP was delivered from either the His bundle or RV lead, then attempted at the other location if unsuccessful. Success rates and instances of VT acceleration and degeneration into VF were calculated. RESULTS: We induced 83 runs of VT and attempted ATP 128 times. RV ATP was successful in 36% of attempts; His ATP was successful in 38% of attempts. RV ATP resulted in significantly more adverse outcomes. RV and His ATP induced VT acceleration in 9% and 3% of trains, respectively, and induced degeneration into VF in 5% and 1% of trains, respectively. CONCLUSION: His bundle ATP is safer, but not significantly more effective, than RV ATP.

The learning curves of major laparoscopic and robotic procedures in urology: a systematic review.

BACKGROUND: Urology has been at the forefront of adopting laparoscopic and robot-assisted techniques to improve patient outcomes. This systematic review aimed to examine the literature relating to the learning curves of major urological robotic and laparoscopic procedures. METHODS: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic literature search strategy was employed across PubMed, EMBASE, and the Cochrane Library from inception to December 2021, alongside a search of the grey literature. Two independent reviewers completed the article screening and data extraction stages using the Newcastle-Ottawa Scale as a quality assessment tool. The review was reported in accordance with AMSTAR (A MeaSurement Tool to Assess systematic Reviews) guidelines. RESULTS: Of 3702 records identified, 97 eligible studies were included for narrative synthesis. Learning curves are mapped using an array of measurements including operative time (OT), estimated blood loss, complication rates as well as procedure-specific outcomes, with OT being the most commonly used metric by eligible studies. The learning curve for OT was identified as 10-250 cases for robot-assisted laparoscopic prostatectomy and 40-250 for laparoscopic radical prostatectomy. The robot-assisted partial nephrectomy learning curve for warm ischaemia time is 4-150 cases. No high-quality studies evaluating the learning curve for laparoscopic radical cystectomy and for robotic and laparoscopic retroperitoneal lymph node dissection were identified. CONCLUSION: There was considerable variation in the definitions of outcome measures and performance thresholds, with poor reporting of potential confounders. Future studies should use multiple surgeons and large sample sizes of cases to identify the currently undefined learning curves for robotic and laparoscopic urological procedures.

SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has raised concerns about reduced vaccine effectiveness and the increased risk of infection, and while repeated homologous booster shots are recommended for elderly and immunocompromised individuals, they cannot completely protect against breakthrough infections. In our previous study, we assessed the immunogenicity of an adenovirus-based vaccine expressing SARS-CoV-2 S1 (Ad5.S1) in mice, which induced robust humoral and cellular immune responses (E. Kim, F. J. Weisel, S. C. Balmert, M. S. Khan, et al., Eur J Immunol 51:1774-1784, 2021, https://doi.org/10.1002/eji.202149167). In this follow-up study, we found that the mice had high titers of anti-S1 antibodies 1 year after vaccination, and one booster dose of the nonadjuvanted rS1Beta (recombinant S1 protein of SARS-CoV-2 Beta [B.1.351]) subunit vaccine was effective at stimulating strong long-lived S1-specific immune responses and inducing significantly high neutralizing antibodies against Wuhan, Beta, and Delta strains, with 3.6- to 19.5-fold increases. Importantly, the booster dose also elicited cross-reactive antibodies, resulting in angiotensin-converting enzyme 2 (ACE2) binding inhibition against spikes of SARS-CoV-2, including Omicron variants, persisting for >28 weeks after booster vaccination. Interestingly, the levels of neutralizing antibodies were correlated not only with the level of S1 binding IgG but also with ACE2 inhibition. Our findings suggest that the rS1Beta subunit vaccine candidate as a booster has the potential to offer cross-neutralization against broad variants and has important implications for the vaccine control of newly emerging breakthrough SARS-CoV-2 variants in elderly individuals primed with adenovirus-based vaccines like AZD1222 and Ad26.COV2.S. IMPORTANCE Vaccines have significantly reduced the incidences of severe coronavirus disease 2019 (COVID-19) cases and deaths. However, the emergence of SARS-CoV-2 variants has raised concerns about their increased transmissibility and ability to evade neutralizing antibodies, especially among elderly individuals who are at higher risks of mortality and reductions of vaccine effectiveness. To address this, a heterologous booster vaccination strategy has been considered as a solution to protect the elderly population against breakthrough infections caused by emerging variants. This study evaluated the booster effect of an S1 subunit vaccine in aged mice that had been previously primed with adenoviral vaccines, providing valuable preclinical evidence for elderly people vaccinated with the currently approved COVID-19 vaccines. This study confirms the potential for using the S1 subunit vaccine as a booster to enhance cross-neutralizing antibodies against emerging variants of concern.

Prevalence and difference of COVID-19 symptoms, post-COVID conditions and duration of illness among the vaccinated and unvaccinated population: a cross-sectional study in Peshawar.

Studies on coronavirus disease 2019 (COVID-19) symptoms, post-coronavirus disease (COVID) conditions, and vaccination outcomes in Pakistan are limited and inconsistent. The study investigated differences in symptoms and post-COVID conditions between vaccinated and unvaccinated individuals and the impact of vaccination on illness duration based on existing literature. Methods: The study was a 3-month cross-sectional study conducted in Peshawar, Pakistan. It targeted individuals aged 16 and above who had contracted COVID-19 at least once during the recent pandemic, regardless of gender, and confirmed through reverse transcriptase polymerase chain reaction testing. The sample size was 250, determined using the WHO sample size calculator. Data were collected through questionnaires after obtaining verbal consent and analyzed using IBM SPSS version 26, taking into account their vaccination status along with other important variables. Results: Among the 250 respondents, 143 (57.2%) were unvaccinated, while 107 (42.8%) were vaccinated at the time of contracting COVID-19. Unvaccinated subjects developed a greater variety of symptoms that lasted for longer durations (P<0.001) with symptoms like dyspnea [55 (38.5%, P=0.011)], anosmia [76 (53.1%, P=0.001)], and chest pain [24 (16.8%, P=0.029)] occurring at greater percentages. Sixty-one (42.7%) unvaccinated subjects reported post-COVID conditions as opposed to 29 (27.1%) among the vaccinated group [P=0.011; odds ratio (OR)=0.5; 95% CI=0.29-0.86]. Conclusion: The study found that COVID-19 vaccination can reduce the duration and frequency of symptoms, as well as post-COVID conditions. This is the first research of its kind conducted in Peshawar, Pakistan, and may serve as a foundation for future research in this demographic.

Efficient Red Organic Light Emitting Diodes of Nona Coordinate Europium Tris(ß-Diketonato) Complexes Bearing 4'-Phenyl-2,2':6',2''-Terpyridine.

Two novel nona-coordinated Eu(III) complexes [Eu(btfa)3 (Ph-TerPyr)] (Eu-1) and [Eu(NTA)3 (Ph-TerPyr)] (Eu-2) have been synthesized and characterized. The structure of the complexes was elucidated by density functional theory (DFT) methods. The experimental photophysical properties of the complexes were investigated and complemented with theoretical calculations. Effective energy transfer (ET) pathways for the sensitized red luminescence is discussed. The complexes were tested as emitting layers (EML) in organic light emitting diodes (OLEDs). At the optimum doping concentration of 4 wt.%, the double-EML OLEDs of Eu-1 exhibited red electroluminescence (EL) with an EQE of 4.0 % and maximum brightness (B)=1179 cd/m2 , maximum current efficiency (ηc )=5.64 cd/A, and maximum power efficiency (ηp )=4.78 lm/W at the current density (J) of 10 mA/cm2 . Interestingly, the double-EML OLEDs of Eu-2 at the optimum concentration of 3 wt.%, displayed an outstanding EL performance with EQE of 7.32 % and B=838 cd/m2 , ηc =10.19 cd/A and ηp =10.33 lm/W at J=10 mA/cm2 . The EL performance of this device is among the best reported for devices incorporating a europium complex as a red emitter.

Tetravalent SARS-CoV-2 S1 Subunit Protein Vaccination Elicits Robust Humoral and Cellular Immune Responses in SIV-Infected Rhesus Macaque Controllers.

The COVID-19 pandemic has highlighted the need for safe and effective vaccines to be rapidly developed and distributed worldwide, especially considering the emergence of new SARS-CoV-2 variants. Protein subunit vaccines have emerged as a promising approach due to their proven safety record and ability to elicit robust immune responses. In this study, we evaluated the immunogenicity and efficacy of an adjuvanted tetravalent S1 subunit protein COVID-19 vaccine candidate composed of the Wuhan, B.1.1.7 variant, B.1.351 variant, and P.1 variant spike proteins in a nonhuman primate model with controlled SIVsab infection. The vaccine candidate induced both humoral and cellular immune responses, with T- and B cell responses mainly peaking post-boost immunization. The vaccine also elicited neutralizing and cross-reactive antibodies, ACE2 blocking antibodies, and T-cell responses, including spike specific CD4+ T cells. Importantly, the vaccine candidate was able to generate Omicron variant spike binding and ACE2 blocking antibodies without specifically vaccinating with Omicron, suggesting potential broad protection against emerging variants. The tetravalent composition of the vaccine candidate has significant implications for COVID-19 vaccine development and implementation, providing broad antibody responses against numerous SARS-CoV-2 variants.

A canine model of chronic ischemic heart failure.

Preclinical large animal models of chronic heart failure (HF) are crucial to both understanding pathological remodeling and translating fundamental discoveries into novel therapeutics for HF. Canine models of ischemic cardiomyopathy are historically limited by either high early mortality or failure to develop chronic heart failure. Twenty-nine healthy adult dogs (30 ± 4 kg, 15/29 male) underwent thoracotomy followed by one of three types of left anterior descending (LAD) coronary artery ligation procedures: group 1 (n = 4) (simple LAD: proximal and distal LAD ligation); group 2 (n = 14) (simple LAD plus lateral wall including ligation of the distal first diagonal and proximal first obtuse marginal); and group 3 (n = 11) (total LAD devascularization or TLD: simple LAD plus ligation of proximal LAD branches to both the right and left ventricles). Dogs were followed until chronic severe HF developed defined as left ventricular ejection fraction (LVEF) < 40% and NH2-terminal-prohormone B-type natriuretic peptide (NT-proBNP) > 900 pmol/L. Overall early survival (48-h postligation) in 29 dogs was 83% and the survival rate at postligation 5 wk was 69%. Groups 1 and 2 had 100% and 71% early survival, respectively, yet only a 50% success rate of developing chronic HF. Group 3 had excellent survival at postligation 48 h (91%) and a 100% success in the development of chronic ischemic HF. The TLD approach, which limits full LAD and collateral flow to its perfusion bed, provides excellent early survival and reliable development of chronic ischemic HF in canine hearts.NEW & NOTEWORTHY The novel total left anterior descending devascularization (TLD) approach in a canine ischemic heart failure model limits collateral flow in the ischemic zone and provides excellent early survival and repeatable development of chronic ischemic heart failure in the canine heart. This work provides a consistent large animal model for investigating heart failure mechanisms and testing novel therapeutics.

Trivalent SARS-CoV-2 S1 Subunit Protein Vaccination Induces Broad Humoral Responses in BALB/c Mice.

This paper presents a novel approach for improving the efficacy of COVID-19 vaccines against emergent SARS-CoV-2 variants. We have evaluated the immunogenicity of unadjuvanted wild-type (WU S1-RS09cg) and variant-specific (Delta S1-RS09cg and OM S1-RS09cg) S1 subunit protein vaccines delivered either as a monovalent or a trivalent antigen in BALB/c mice. Our results show that a trivalent approach induced a broader humoral response with more coverage against antigenically distinct variants, especially when compared to monovalent Omicron-specific S1. This trivalent approach was also found to have increased or equivalent ACE2 binding inhibition, and increased S1 IgG endpoint titer at early timepoints, against SARS-CoV-2 spike variants when compared monovalent Wuhan, Delta, or Omicron S1. Our results demonstrate the utility of protein subunit vaccines against COVID-19 and provide insights into the impact of variant-specific COVID-19 vaccine approaches on the immune response in the current SARS-CoV-2 variant landscape. Particularly, our study provides insight into effects of further increasing valency of currently approved SARS-CoV-2 vaccines, a promising approach for improving protection to curtail emerging viral variants.