Preliminary Structural Data Revealed That the SARS-CoV-2 B.1.617 Variant's RBD Binds to ACE2 Receptor Stronger Than the Wild Type to Enhance the Infectivity.

The evolution of new SARS-CoV-2 variants around the globe has made the COVID-19 pandemic more worrisome, further pressuring the health care system and immunity. Novel variations that are unique to the receptor-binding motif (RBM) of the receptor-binding domain (RBD) spike glycoprotein, i. e. L452R-E484Q, may play a different role in the B.1.617 (also known as G/452R.V3) variant's pathogenicity and better survival compared to the wild type. Therefore, a thorough analysis is needed to understand the impact of these mutations on binding with host receptor (RBD) and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to explore the impact of specific mutations (L452R-E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2. Our analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic-stability, residual flexibility and structural compactness. Moreover, the new variant had altered the bonding network and structural-dynamics properties significantly. MM/GBSA technique was used, which further established the binding differences between the wild type and B.1.617 variant. In conclusion, this study provides a strong impetus to develop novel drugs against the new SARS-CoV-2 variants.

Abnormal vocal cord movement in patients with and without airway obstruction and asthma symptoms.

BACKGROUND: Abnormal vocal cord movements can cause laryngeal extrathoracic airway obstruction (often called vocal cord dysfunction - VCD) leading to asthma-like symptoms. These aberrant movements are characteristically present during inspiration and termed paradoxical vocal cord movement (PVCM). We have reported PVCM in up to 40% of severe asthmatics, but it is not known if PVCM is detectable in all patients with asthma-like symptoms and if the condition is more often associated with abnormal lung function. OBJECTIVE: We hypothesized that PVCM is frequently associated with asthma symptoms accompanied by airflow limitation. Studies examined whether PVCM is solely linked to experiencing asthma symptoms, or if PVCM is related to airflow limitation and/or other disease characteristics. METHODS: Patients with asthma symptoms were recruited from general practice and severe asthma clinics (n = 155). Pulmonary function measurements were conducted, asthma control and Nijmegen (dysfunctional breathing) questionnaires were administered and skin prick testing was carried out. PVCM was quantified using dynamic 320-slice computerized tomography of the larynx. Groups were divided into patients with FEV1 ≥ 80% predicted or FEV1 < 80% predicted and FEV1 /FVC < 0.7. ATS/ERS definitions of severity were also applied and evaluated. Detection of PVCM in the groups was compared and analyses performed to identify features associated with PVCM. RESULTS: Overall (n = 155), PVCM was detected in 42 cases (27.1%). Patients with FEV1 < 80% predicted had PVCM more often (25/68, 36.8%) than individuals with normal spirometry (17/87, 19.5%; P = 0.016). PVCM was associated with older age (P = 0.003) and with Nijmegen scores > 20 (P = 0.04). Patients with FEV1 < 80% predicted plus Nijmegen scores > 20 were more likely to have PVCM (OR = 9.3, P = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Paradoxical vocal cord movement is more often associated with asthma symptoms accompanied by airflow limitation and dysfunctional breathing. Further studies are needed to determine whether PVCM is induced by dysfunctional breathing practices and/or airway obstruction. How PVCM links with symptomatic asthma and VCD also requires evaluation.

Effects of oyster mushroom (Pleurotus ostreatus) stem residue supplementation on growth performance, meat quality and health status of broilers.

Oyster mushroom stem residue, a by-product with medicinal and nutritive values, might be a prospective feed supplement in poultry nutrition. The study focused on evaluating the impact of oyster mushroom (Pleurotus ostreatus) stem residue (OMSR) powder supplementation on growth performance, carcass traits, meat quality, blood characteristics, and the cecal bacterial count in Arbor Acres broilers raised 35 d. A total of 144 day-old chicks, with an average weight of 40.27± 2.45 g, were divided into 3 groups: control (received a standard basal diet), antibiotic (basal diet + 75 mg/kg chlortetracycline), and OMSR (fed a basal diet with 300 mg/kg OMSR), where each group comprises 8 replications of 6 chicks. Supplementation of 300 mg/kg of OMSR powder in the broiler diet significantly (P < 0.05) enhanced the average daily gain (ADG) and final body weight as opposed to the control and antibiotic treatments, though the average daily feed intake was not influenced by OMSR supplementation during the whole experimental period. However, in comparison to the control and antibiotic groups, OMSR significantly reduced the postmortem breast meat drip loss percentage (P < 0.05) at 24 hours and on the seventh d. Furthermore, the OMSR group reported significantly elevated levels of Hb and RBC counts (P < 0.05), and decreased levels of serum triglyceride (TG) and total cholesterol (TC) concentrations (P < 0.05) on d 35 in comparison to broilers in the control and antibiotic groups. Additionally, the OMSR group exhibited an improved Heterophil/Lymphocytes (H/L) ratio (P < 0.05) relative to the broilers of the control and antibiotic groups. In contrast, the inclusion of OMSR in the broiler diet did not significantly (P > 0.05) influence other serum biochemical and hematological values tested. Broilers in OMSR group had reduced number (P < 0.05) of E. coli and Salmonella spp., but higher presence of Lactobacillus spp. (P < 0.05) in contrast to the control broilers. To summarize, the study's findings revealed that 300 mg of OMSR powder supplementation per kg of basal diet could be act as a natural growth promoter, and confer favorable effects on health and meat quality of broilers.

A Case Series on Endometrial Cancer, Despite Endometrial Thickness Being Less than Four Millimetres and A Brief Review of Recent Literature on Endometrial Cancer.

The most common presentation of the most common gynaecological malignancy (Endometrial Cancer) is abnormal PV bleeding. Transvaginal sonography (TVS) is the first line investigation to assess the endometrial nature. Four to five (4-5) millimetre endometrial thicknesses is considered as the normal cut off in post menopausal women. But endometrial cancer can be present while endometrial thickness is less than 4mm. The author describes three cases of isolated endometrial cancer in Glangwili General Hospital in Wales, UK that was diagnosed despite endometrial thickness being less than 4mm and a brief review of the literature on its prevalence, risk factors, clinical presentation, diagnosis and therapeutic approach.

A Simulation Study of Triband Low SAR Wearable Antenna.

The proposed paper presents a flexible antenna that is capable of operating in several frequency bands, namely 2.45 GHz, 5.8 GHz, and 8 GHz. The first two frequency bands are frequently utilized in industrial, scientific, and medical (ISM) as well as wireless local area network (WLAN) applications, whereas the third frequency band is associated with X-band applications. The antenna, with dimensions of 52 mm × 40 mm (0.79 λ × 0.61 λ), was designed using a 1.8 mm thick flexible kapton polyimide substrate with a permittivity of 3.5. Using CST Studio Suite, full-wave electromagnetic simulations were conducted, and the proposed design achieved a reflection coefficient below -10 dB for the intended frequency bands. Additionally, the proposed antenna achieves an efficiency value of up to 83% and appropriate values of gain in the desired frequency bands. In order to quantify the specific absorption rate (SAR), simulations were conducted by mounting the proposed antenna on a three-layered phantom. The SAR1g values recorded for the frequency bands of 2.45 GHz, 5.8 GHz, and 8 GHz were 0.34, 1.45, and 1.57 W/Kg respectively. These SAR values were observed to be significantly lower than the 1.6 W/Kg threshold set by the Federal Communication Commission (FCC). Moreover, the performance of the antenna was evaluated by simulating various deformation tests.

First demonstration of a fiber optic bolometer on a tokamak plasma (invited).

A fiber optic bolometer (FOB) was demonstrated observing a fusion plasma for the first time at the DIII-D tokamak. A FOB uses a fiber optics-based interferometric technique that is designed to have a high sensitivity to temperature changes [75 mK/(W/m2) responsivity in high vacuum with 0.38 mK noise level] with a negligible susceptibility to electromagnetic interference (EMI) that can be problematic for resistive bolometers in a tokamak environment. A single-channel test apparatus was installed on DIII-D consisting of a measurement FOB and shielded reference FOB. The single-channel FOB showed a negligible increase in the noise level during typical plasma operations (0.39 mK) compared to the benchtop results (0.38 mK), confirming an insignificant EMI impact to the FOB. Comparisons to DIII-D resistive bolometers showed good agreement with the single-channel FOB, indicating that the FOB is comparable to a resistive bolometer when the impulse calibration is applied. The noise-equivalent power density of the calibrated FOB during a plasma operation was 0.55 W/m2 with an average sampling time of 20 ms. The major potential effect of ionizing radiation on the FOB would be the radiation-induced attenuation, which can be efficiently compensated for by adjusting the probing light power.

Abrogation of SARS-CoV-2 interaction with host (NRP1) neuropilin-1 receptor through high-affinity marine natural compounds to curtail the infectivity: A structural-dynamics data.

The evolution of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants around the globe has made the coronavirus disease 2019 (COVID-19) pandemic more worrisome, pressuring the health care system and resulting in an increased mortality rate. Recent studies recognized neuropilin-1 (NRP1) as a key facilitator in the invasion of the new SARS-CoV-2 into the host cell. Therefore, it is considered an imperative drug target for the treatment of COVID-19. Hence, a thorough analysis was needed to understand the impact and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to identify novel marine natural products which could block this receptor and stop the virus entry. We discovered that the binding affinity of CMNPD10175, CMNPD10017, CMNPD10114, CMNPD10115, CMNPD10020. CMNPD10018, CMNPD10153, CMNPD10149 CMNPD10464 and CMNPD10019 were substantial during the virtual screening (VS). We further explored these compounds by analyzing their absorption, distribution, metabolism, and excretion and toxicity (ADMET) properties and structural-dynamics features. Free energy calculations further established that all the compounds exhibit stronger binding energy for NRP1. Consequently, we hypothesized that these compounds might be the best lead candidates for therapeutic interventions hindering virus binding to the host cell. This study provides a strong impetus to develop novel drugs against the SARS-CoV-2 by targeting NRP1.

Genome-wide screening of vaccine targets prioritization and reverse vaccinology aided design of peptides vaccine to enforce humoral immune response against Campylobacter jejuni.

Campylobacter jejuni, gram-negative bacteria, is an infectious agent of foodborne disease-causing bloody diarrhea, abdominal pain, fever, Guillain-Barré syndrome (GBS) and Miller Fisher syndrome in humans. Campylobacter spp. with multidrug resistance to fluoroquinolones, tetracycline, and erythromycin are reported. Hence, an effective vaccine candidate would provide long-term immunity against C. jejuni infections. Thus, we used a subtractive proteomics pipeline to prioritize essential proteins, which impart a critical role in virulence, replication and survival. Five proteins, i.e. Single-stranded DNA-binding protein, UPF0324 membrane protein Cj0999c, DNA translocase FtsK, 50S ribosomal protein L22, and 50S ribosomal protein L1 were identified as virulent proteins and selected for vaccine designing. We reported that the multi-epitopes subunit vaccine based on CTL, HTL and B-cell epitopes combination possess strong antigenic properties and associates no allergenic reaction. Further investigation revealed that the vaccine interacts with the immune receptor (TLR-4) and triggered the release of primary and secondary immune factors. Moreover, the CAI and GC contents obtained through codon optimization were reported to be 0.93 and 53% that confirmed a high expression in the selected vector. The vaccine designed in this study needs further scientific consensus and will aid in managing C. jejuni infections.

The SARS-CoV-2 B.1.618 variant slightly alters the spike RBD-ACE2 binding affinity and is an antibody escaping variant: a computational structural perspective.

Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2-RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further in vitro and in vivo studies that will facilitate the development of possible therapies for new variants such as B.1.618.

Annotation of Potential Vaccine Targets and Design of a Multi-Epitope Subunit Vaccine against Yersinia pestis through Reverse Vaccinology and Validation through an Agent-Based Modeling Approach.

Yersinia pestis is responsible for plague and major pandemics in Asia and Europe. This bacterium has shown resistance to an array of drugs commonly used for the treatment of plague. Therefore, effective therapeutics measurements, such as designing a vaccine that can effectively and safely prevent Y. pestis infection, are of high interest. To fast-track vaccine development against Yersinia pestis, herein, proteome-wide vaccine target annotation was performed, and structural vaccinology-assisted epitopes were predicted. Among the total 3909 proteins, only 5 (rstB, YPO2385, hmuR, flaA1a, and psaB) were shortlisted as essential vaccine targets. These targets were then subjected to multi-epitope vaccine design using different linkers. EAAK, AAY, and GPGPG as linkers were used to link CTL, HTL, and B-cell epitopes, and an adjuvant (beta defensin) was also added at the N-terminal of the MEVC. Physiochemical characterization, such as determination of the instability index, theoretical pI, half-life, aliphatic index, stability profiling, antigenicity, allergenicity, and hydropathy of the ensemble, showed that the vaccine is highly stable, antigenic, and non-allergenic and produces multiple interactions with immune receptors upon docking. In addition, molecular dynamics simulation confirmed the stable binding and good dynamic properties of the vaccine-TLR complex. Furthermore, in silico and immune simulation of the developed MEVC for Y. pestis showed that the vaccine triggered strong immune response after several doses at different intervals. Neutralization of the antigen was observed at the third day of injection. Conclusively, the vaccine designed here for Y. pestis produces an immune response; however, further immunological testing is needed to unveil its real efficacy.

Computational Modeling of Immune Response Triggering Immunogenic Peptide Vaccine Against the Human Papillomaviruses to Induce Immunity Against Cervical Cancer.

Papillomaviruses are placed within the family Papillomaviride, and the members of this family have a double-stranded circular DNA genome. Every year, ∼30% of cancers are reported to be human papillomavirus (HPV) related, which represents 63,000 cancers of all infectious agent-induced cancers. HPV16 and HPV18 are reported to be associated with 70% of cervical cancers. The quest for an effective drug or vaccine candidate still continues. In this study, we aim to design B cell and T cell epitope-based vaccine using the two structural major capsid protein L1 and L2 as well as other three important proteins (E1, E2, and E6) against HPV strain 16 (HPV16). We used a computational pipeline to design a multiepitope subunit vaccine and tested its efficacy using in silico computational modeling approaches. Our analysis revealed that the multiepitope subunit vaccine possesses antigenic properties, and using in silico cloning method revealed proper expression and downstream processing of the vaccine construct. Besides this, we also performed in silico immune simulation to check the immune response upon the injection. Our results strongly suggest that this vaccine candidate should be tested immediately for the immune response against the cervical cancer-causing agent. The safety, efficacy, expression, and immune response profiling makes it the first choice for experimental and in vivo setup.

Immunogenomics guided design of immunomodulatory multi-epitope subunit vaccine against the SARS-CoV-2 new variants, and its validation through in silico cloning and immune simulation.

Reports of the novel and more contagious strains of SARS-CoV-2 originating in different countries have further aggravated the pandemic situation. The recent substitutions in spike protein may be critical for the virus to evade the host's immune system and therapeutics that have already been developed. Thus, this study has employed an immunoinformatics pipeline to target the spike protein of this novel strain to construct an immunogenic epitope (CTL, HTL, and B cell) vaccine against the new variant. Our investigation revealed that 12 different epitopes imparted a critical role in immune response induction. This was validated by an exploration of physiochemical properties and experimental feasibility. In silico and host immune simulation confirmed the expression and induction of both primary and secondary immune factors such as IL, cytokines, and antibodies. The current study warrants further lab experiments to demonstrate its efficacy and safety.

Enhanced Energy Localization in Hyperthermia Treatment Based on Hybrid Electromagnetic and Ultrasonic System: Proof of Concept with Numerical Simulations.

This paper proposes a hybrid hyperthermia treatment system, utilizing two noninvasive modalities for treating brain tumors. The proposed system depends on focusing electromagnetic (EM) and ultrasound (US) energies. The EM hyperthermia subsystem enhances energy localization by incorporating a multichannel wideband setting and coherent-phased-array technique. A genetic algorithm based optimization tool is developed to enhance the specific absorption rate (SAR) distribution by reducing hotspots and maximizing energy deposition at tumor regions. The treatment performance is also enhanced by augmenting an ultrasonic subsystem to allow focused energy deposition into deep tumors. The therapeutic faculty of ultrasonic energy is assessed by examining the control of mechanical alignment of transducer array elements. A time reversal (TR) approach is then investigated to address challenges in energy focus in both subsystems. Simulation results of the synergetic effect of both modalities assuming a simplified model of human head phantom demonstrate the feasibility of the proposed hybrid technique as a noninvasive tool for thermal treatment of brain tumors.

Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor.

Despite ionizing radiation (IR) is being widely used as a standard treatment for lung cancer, many evidences suggest that IR paradoxically promotes cancer malignancy. However, its molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that exposure to fractionated radiation (2 Gy per day for 3 days) induces the secretion of granulocyte-colony-stimulating factor (G-CSF) that has been commonly used in cancer therapies to ameliorate neutropenia. Intriguingly, radiation-induced G-CSF promoted the migratory and invasive properties by triggering the epithelial-mesenchymal cell transition (EMT) in non-small-cell lung cancer cells (NSCLCs). By irradiation, G-CSF was upregulated transcriptionally by ß-catenin/TCF4 complex that binds to the promoter region of G-CSF as a transcription factor. Importantly, irradiation increased the stability of ß-catenin through the activation of PI3K/AKT (phosphatidylinositol 3-kinase/AKT), thereby upregulating the expression of G-CSF. Radiation-induced G-CSF is recognized by G-CSFR and transduced its intracellular signaling JAK/STAT3 (Janus kinase/signal transducers and activators of transcription), thereby triggering EMT program in NSCLCs. Taken together, our findings suggest that the application of G-CSF in cancer therapies to ameliorate neutropenia should be reconsidered owing to its effect on cancer progression, and G-CSF could be a novel therapeutic target to mitigate the harmful effect of radiotherapy for the treatment of NSCLC.

No evidence for a significant non-nitrergic, hyperpolarising factor contribution to field stimulation-induced relaxation of the mouse anococcygeus.

1. The aim of the study was to determine whether a nerve-derived hyperpolarizing factor (NDHF) might contribute to non-adrenergic, non-cholinergic (NANC) relaxations of the mouse anococcygeus when low concentrations of contractile agent are used to raise tone and low frequencies of field stimulation applied; such a non-nitrergic NDHF has been proposed to contribute to NANC relaxations of the rat anococcygeus and guinea-pig taenia coli. 2. Phenylephrine (0.1-100 microM) produced concentration-related contractions of the mouse isolated anococcygeus muscle; 0.2 microM phenylephrine (EC26) was used to raise tone in subsequent experiments. 3. Field stimulation (0.5, 1.0 and 5.0 Hz) produced frequency-dependent relaxations of phenylephrine-induced tone. In the presence of the nitric oxide synthase inhibitor L-NG-nitro-arginine (L-NOARG; 100 microM), the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-1-one (ODQ; 5 microM), or a combination of these two drugs, relaxations to field stimulation were abolished at all frequencies studied. Relaxations to sodium nitroprusside (0.01-5 microM) were unaffected by L-NOARG but strongly inhibited by ODQ; neither enzyme inhibitor affected relaxations to 8-Br-cyclic GMP (10 microM). 4. Nifedipine (1 microM) reduced the contractile response to 0.2 microM phenylephrine by 38%; however, it had no effect on NANC relaxations. 5. It is concluded that NANC relaxations of the mouse anococcygeus are purely nitrergic and that there is no significant contribution from a putative NDHF.

Clinical utility of ¹8F FDG-PET/CT in the detection of bone marrow disease in Hodgkin's lymphoma.

OBJECTIVE: The aim of the study was to evaluate the potential role of fludeoxyglucose (FDG)-positron emission tomography (PET)/CT in the detection of bone/bone marrow disease in patients with Hodgkin's lymphoma (HL). METHODS: We retrospectively reviewed ((18)F)-FDG-PET/CT scans of 122 newly diagnosed, biopsy-proven cases of HL performed between November 2009 and June 2010. All the patients were staged before treatment by both PET/CT and bone marrow biopsy (BMB). Patients were subdivided into three groups based on the findings of FDG-PET/CT. Group A consisted of patients showing diffuse FDG uptake, Group B consisted of patients showing unifocal FDG uptake and Group C patients showed multifocal FDG-avid foci on PET/CT scans. Bone marrow results were also reviewed and considered positive if lymphomatous involvement was detected on bone marrow trephine biopsy. BMB results were correlated with FDG-PET/CT findings. RESULTS: There were 122 patients in total-81 (66.4%) were male and 41 (33.6%) were female. The age range was from 6 years to 78 years (mean 35.70 years). PET/CT was reported as negative for bone/bone marrow involvement in 85 (69.7%) patients, while the remaining 37 showed abnormal FDG uptake. The sensitivity of FDG-PET/CT was calculated to be 100%, the specificity was 76.57%, the negative predictive value was 76.57%, the positive predictive value was 29.72% and the diagnostic accuracy was 78.62%. CONCLUSION: (18)F-FDG-PET/CT and BMB are complementary in the evaluation of bone marrow disease.

Management of breast lesions by breast physicians in a heavily populated South asian developing country.

BACKGROUND: In Asia, from 1998 to 2002, the highest annual-age standardized incidence rates of breast cancer per 100,000 women were recorded as follows: in the Karachi South district of Pakistan 69.0 and in the Israeli Jews 96.8. At Shaukat Khanum Memorial Cancer Hospital and Research Center in Lahore, Pakistan, in 15-years from Dec. 1995-Dec. 2009, among adult females, approximately 46% (8,915) of malignancies were recorded as breast tumors. Further, according to Pakistan's population estimates (2009), the total population of the country is 177 million; females 85 million (40-69 years: 13.6 million). DISCUSSION: Screening of asymptomatic women: Basing the recommendations on biennial mammograhic screening for average-risk women in the 40-69 year age-band, about 6.8 million women will have to be screened every year. In a resource-constrained country like Pakistan, early detection by this method is not possible. As most symptomatic women present with advanced disease, clinicians skilled in breast diseases are required. The Australasian Society of Breast Physicians has developed a formal three year training model for General Practitioners to qualify as breast physicians by: i) developing their skills in the areas of clinical breast-examination, interpretation of mammography and breast ultrasound; performance of image-guided interventional procedures; counseling of and planning/coordinating treatment of females with breast cancer and assessment/monitoring of women at potentially 'high-risk' of cancer; and ii) working in consultation with surgeons, radiologists, pathologists, oncologists, and other members of the multidisciplinary team. SUMMARY: Easily accessible one-stop breast clinics staffed by trained breast physicians can help reduce morbidity/mortality from breast cancer in developing countries, and improve the quality of life and survival.