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The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.

Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states. Applying the approach to KRAS, we discovered CLAMPs that recognize the open conformation of KRAS

The understanding of the inferior turbinate (IT) function, role in nasal obstruction, and its management for symptomatic relief has evolved. We aim to provide a comprehensive review of the anatomy, contribution to nasal function and response of the IT to sinonasal disease. Techniques to study the nasal physiology are expanding; these include the computational flow dynamics that has allowed a better understanding of the function and role of the inferior turbinate in normal respiration and airway obstruction. The IT function includes warming, moisturizing, and filtering the air prior to the entrance to the lower airways. More sophisticated techniques have been developed to study the nasal physiology, though not widely used in clinical practice.

The present experiment was conducted by executing detailed tests on performance, combustion, and emission characteristics to prove that the Nerium biodiesel emulsified fuel can be an eco-friendly fuel. The emulsified biodiesel was formed by mixing with a small proportion of water in the limits of 5%, 10%, and 15% by volume. This study also assessed the stability of different emulsified blends. The properties were tested according to ASTM requirements. The blend of 60% diesel, 20% biodiesel, 15% water, and 5% surfactant showed the higher brake thermal efficiency and in-cylinder pressure by 13.72% and 12.6%, respectively, when related to base fuel. Also, carbon monoxide, oxides of nitrogen, opacity of smoke and hydrocarbon emission of the above blend decreased by 42.87%, 6.5%, 12.96%, and 31.94%, respectively, when related to base fuel. This can be attributed due to the micro-explosion and availability of the oxygen content in the fuel. The results noticed a significant improvement and advantage of using the eco-friendly emulsified fuel in traditional engines without any modifications. Micro-explosion during combustion stage guaranteed a reduction in emission of nitrogen oxides (NOx).

At present, IC engines are the primary power source in transit and must never be modified. The palm oil was collected from the palm tree and used in an internal combustion engine as an alternative fuel. In the present investigation, the palm oil is preheated to 110 °C using a heat exchanger to get a homogeneous mixture. The two additives, i.e., butylated hydroxytoluene (BHT) and n-butanol, were combined with preheated palm oil. The four fuels were prepared PN100, PND20, PND20 mixing with the 2000 ppm BHT of 1000 mL oil and other blends preheated PND20 palm oil mixing with the 2000 ppm n-butanol of 1000 mL oil. The blend 20 brake thermal efficiency was increased by 11.70% when compared with the mineral fuel, because the proper air–fuel mixture takes place. The oxides of nitrogen and smoke opacity were decreased by 15.32% and14.53%, respectively, for the blend of preheated palm oil and n-butanol as compared to mineral fuel due to the burning of more fuel through the combustion process. The hydrocarbon and carbon monoxide emissions were decreased for PND20AB and PNDAN blends by 35.71% and 14.53%, respectively, as compared to diesel. The preheated palm oil mixed with antioxidants was utilized as the alternative fuel in the conventional engine.

Although many studies have investigated how well government websites have implemented website accessibility standards, such as Section 508 and WCAG 2.0, very little research has been conducted exploring what factors influence the level of implementation. Based on the organizational innovation model proposed by Frances Berry, this study examines 342 county government websites in the USA and analyzes how several factors, such as budget resources, local demographics and forms of county government, influence the accessibility of the sites. The result of the OLS estimate indicates that the complexity of the websites and the county population density are the most important predictors of web accessibility. County budget is also a marginal predictor, while the percentage of the population with disabilities is a negative predictor. Given the slow progress in the implementation of higher accessibility standards in the USA, the findings of this study provide timely implications for policymakers and governments to improve the quality of their websites.

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

Introduction Psoriasis is estimated to affect 0.44–2.8% of the Indian population. Moisturizers are a key adjuvant psoriasis treatment strategy, but data regarding their effectiveness, safety and compliance pattern in an Indian context are lacking. Hence, this real-world study on an intensive plant-based butter moisturizing cream (Venusia ® Max) was conducted among Indian patients with psoriasis. Methods This was an observational, patient-reported outcomes (PRO) study in patients with psoriasis aged 18–75 years who were prescribed the cream in routine clinical practice, as per clinician’s discretion, over 4 weeks. The primary outcome measure was improvement from baseline in quality of life assessed using the Dermatology Quality of Life Index (DLQI) at 4 weeks of the study period. The secondary outcome measures were improvement in dryness using the Dry Skin/Ichthyosis Area and Severity Index (DASI) score at 4 weeks, safety and compliance. The DLQI and DASI scores were recorded by the clinicians at baseline and after 2 (optional) and 4 weeks of starting the cream. Safety was assessed throughout the study. Results The study included 400 patients from 9 outpatient dermatology centers across India. Of 400 patients, 384 completed the study. A significant reduction in both the mean DLQI score (66.7%; p

Introduction Although hydroxyzine is widely used for symptom relief in pruritus, its clinical safety and efficacy data in the Indian setting are scarce. We conducted a study to assess the effectiveness and tolerability of hydroxyzine in the management of Indian patients with chronic pruritus in a real-world setting. Methods This was a prospective, observational, patient-reported outcomes (PRO) study in patients with chronic pruritus due to dermatological causes treated with hydroxyzine as per the clinician’s discretion for a period of up to 12 weeks. The primary outcome was improvement in quality of life from baseline, assessed using the 10-point Dermatology Quality of Life Index (DLQI) at week 12 of the study period. Secondary outcomes were improvement in the pruritus scores (5-D itch scale) at 12 weeks, improvements in the DLQI and 5-D itch scores at 2, 4 and 8 weeks and safety. Results The study included 400 patients (179 males, 221 females) from 7 dermatology centres across India. Of the 400 patients recruited, 391 patients completed at least 2 weeks of treatment. There was significant (p

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen., Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Arthroscopy for acetabular labral tears has minimal impact on pain and function in older patients, especially in the setting of concomitant osteoarthritis. Still, many physicians seek this diagnosis with MR arthrography. Our purpose is to assess the frequency of acetabular labral tears in older patients with hip pain and correlate likelihood of labral pathology with severity of osteoarthritis as visualized on conventional radiograph. From 2004 to 2013, 208 hip MRI arthrograms and corresponding radiographs on patients aged 50 years and older were identified. Age, gender, grade and location of labral tear, alpha angle, Tonnis grade, and joint space width were documented. Labral tears and alpha angle were identified and measured on MR arthrogram. Tonnis grade and joint space width were measured on radiographs. On MR arthrography, true labral tearing was identified in 73 % of patients. There was some degree of labral pathology in 93.3 % of patients, and this increased to 100 % in patients with moderate to severe osteoarthritis, as defined by Tonnis grade 2–3 or joint space width ≤ 2 mm. There were no statistically significant correlations between labral tear grade and Tonnis grade or joint space width. Given the high frequency of labral pathology and the questionable efficacy of arthroscopic surgical intervention in older patients, MR arthrography should be primarily for those with minimal arthritis on radiograph and potential to benefit from surgery. If further imaging beyond radiographs is necessary in these patients, standard MRI may be a more appropriate imaging tool.

Nasal obstruction is a common presenting complaint, with many possible etiologies. Herein, we provide an introductory anatomic description, clinical relevance, and proposed nomenclature for an underappreciated soft tissue focus in the nasal vestibule-the nasal vestibular body (NVB)-that can contribute to nasal obstruction in a subset of patients. This is a small mound of dynamic soft tissue in the lateral aspect of the internal nasal valve, situated inferior and anterior to the head of the inferior turbinate that can be missed on routine examination for many salient reasons. In well-selected patients, whose symptoms of nasal obstruction may in part be secondary to the presence of this soft tissue focus, directed testing and tissue reduction can be performed.

The recent verdict of the Supreme Court recognising Securities Exchange Board of India’s (SEBI) jurisdiction to regulate matters pertaining to Global Depository Receipts (GDRs) emanates as a remarkable decision. The judgment although, is reliant on facts of the case, it clarifies the scope of SEBI’s territorial jurisdiction. It enunciates that even though GDRs are issued abroad entirely, they qualify as a form of securities and cannot escape SEBI’s jurisdiction. If a corporation deploys the GDR route to raise its foreign capital and in the process it manipulates the Indian securities market, adversely affecting the interests of investors in India, SEBI possesses the requisite authority to intercede and take coercive actions. With increased cross-border trading in securities, there is a risk of heightened abuse by entities, both Indian and foreign, that can have deleterious effects on the Indian markets. Therefore, this judgement comes as a respite for SEBI which enables it to regulate financial products even if they do not fall exactingly within its regulatory purview, as long as manipulation resulting to adverse impact on securities market is established. This case note thus, appraises this judgment as it appears to have commenced a novel legal doctrine.

This study is a comparative evaluation of nonlinear classification methods with a focus on nonlinear decision functions and the standard method of support vector machines for seizure detection. These nonlinear classification methods are used on key features that were extracted on subdural EEG data after a thorough evaluation of all the frequency bands from 1 to 44 Hz. The sensitivity, specificity, and accuracy of seizure detection reveal that the gamma frequencies (36-44 Hz) are most suitable for detecting seizure files using a unique 2D decisional plane. We evaluated 157 intracranial EEG files from 14 patients by calculating the spectral power using nonoverlapping 1-s windows on different frequency bands. A key finding is in establishing a 2D decision plane, where duration of the seizure is used as the first dimension (x coordinate) and the maximum of the gamma frequency components is used as the second dimension (y coordinate). Within this 2D plane, the best results were observed when the nonlinearity degree is three for the proposed nonlinear decision functions, with a sensitivity of 96.3%, a specificity of 96.8%, and accuracy of 96.7%.

Overall survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has not improved appreciably over the past few decades. Because standard treatments have not controlled this disease with sufficiently high success rates, novel therapeutic approaches, such as immunotherapy, are under investigation. Cancer immunotherapy involves various techniques used to expand and activate the immune system to control tumor growth in vivo; to date, clinical evaluation has demonstrated low toxicity. An emerging form of SCCHN immunotherapy involves the use of antibodies that target growth factor receptors (where immune activation appears to enhance tumor lysis), resulting in improved clinical outcome. So far, immunotherapy appears to have the most applicability after other therapeutic interventions; however, its vast potential clinical value has yet to be fully explored. This article reviews immunotherapeutic strategies currently in clinical trials or under development for patients with SCCHN.

Anti-diabetic, anti-hyperlipidemic and spermatogenic effects were studies with methanolic extract of stem of Amaranthus spinosus Linn (Family: Amaranthaceae) in diabetic rats. In streptozotocin (STZ)-induced diabetic rats, it was observed that both the standard drug (Glibenclamide) and methanolic extract of Amaranthus spinosus Linn. significantly exhibited control of blood glucose level on a 15 day model. Further, the methanolic extract also showed significant anti-hyperlipidemic and spermatogenic effects in STZ-induced diabetic rats. The methanolic extract has also accelerated the process of spermatogenesis by increasing the sperm count and accessory sex organ weights. The present investigation of the plant established some pharmacological evidence to support the folklore claim that it is used as an anti-diabetic.

Medically refractory epilepsy is a significant cause of morbidity and mortality in pediatric neurology. Surgical intervention has been well established as a viable treatment option in certain cases. This article reviews the process of selecting appropriate patients using the latest advances in neuroimaging and electrophysiologic techniques. It also discusses the various surgical techniques currently available, including recent advances in minimally invasive approaches.

Undescended testis is a relatively common condition in boys. The standard treatment is orchiopexy. In adults, orchiopexy is done only if sufficient length can be mobilized. Otherwise, orchiectomy is ideal as undescended testis predisposes to carcinoma. The incidence of carcinoma increases with age. The aim of this study is to highlight the value of laparoscopy in treatment of impalpable testis and simultaneously repair associated hernias. This is our experience in a rural tertiary hospital. In our rural hospital, it is not uncommon to see men aged 30 years or more presenting with unilateral absence of testis/empty hemiscrotum. A total of 35 patients were studied. Ultrasonography of the abdomen was done to localize the exact position of the testis; it was detected in 12 cases. A computed tomography (CT) scan was done in the other 23 cases and was positive in 16. The testis was found in the retroperitoneum (close to the internal inguinal ring) in 12 cases and in the inguinal canal in 23 cases. There were associated hernias in 9 patients. Laparoscopy accurately identified the exact location of the missing testis and resection was also accomplished and associated hernias were repaired laparoscopically. In countries like India, the majority of the population is poor and illiterate. By the time a boy or young man with an undescended testis arrives at the hospital, it is already too late to do orchiopexy. Even though most of our patients had no symptoms, orchiectomy had to be done because of the risk of torsion and malignant transformation. By using laparoscopy in these patients, the advantages of minimally invasive surgery can be utilized. Laparoscopic orchiectomy seems to be advantageous and well received by patients. We preferred the laparoscopic approach for the obvious benefits of less pain, better cosmesis, and early discharge.

This study integrates a spectral analysis of key frequency bands (Alpha, Beta, Delta, and Theta) with an eigensystem-based study in order to validate brain functional mappings associated with the characterization effects of an Auditory/Comprehension paradigm. This numerical characterization supported by topographic functional maps brings added insight in the involvement of the Wernicke and Broca's brain areas to language comprehension. A thorough examination of EEG recordings through the eigensystem reveals that eigenvectors associated with the largest eigenvalues produce an interesting activity pattern located in the frontal area of the brain directly attributable to those characteristic behaviors found in the Alpha, Beta, Delta, and Theta frequency bands. An evaluation of spectral arrays is performed using topographic maps of the induced brain activities during both listening and answering phases. This evaluation is then augmented with quantifying measures using the eigensystem study while results are validated through integration of EEG activity and eigensystem modalities. Such a representation can provide insightful information on how different patients react during an auditory and response phases, and in the ability to detect the presence of potential neurological disorders by assessing similar/dissimilar behaviors with respects to all former patients already included in the database. The algorithm as developed in this study could be extended in its application to other brain functional mapping tasks given its simple but effective practical mathematical foundation.

This study evaluates the utility of 3-D localization of interictal spike activity on the electroencephalographs (EEG) superimposed on magnetic resonance imagery (MRI) in a pediatric population with extra-temporal lesional epileptic foci. 3-D software programming based on the CURRY platform (a multimodal neuro-imaging software) was adapted for analyzing scalp EEG data and reconstructing superimposed images in 10 children who underwent extensive pre-surgical evaluation for intractable partial seizures. The results of 3-D spike source localization were assessed in relationship to focal lesions evident on the patient's MRI scans. Calculated spike sources were closest to the lesions during intervals corresponding to the spike peaks. The information was useful in surgical planning in six children that underwent successful resections.