A Review on the Development of Novel Heterocycles as α-Glucosidase Inhibitors for the Treatment of Type-2 Diabetes Mellitus.

One of the most effective therapeutic decencies in the treatment of Type 2 Diabetes Mellitus is the inhibition of α-glucosidase enzyme, which is present at the brush border of the intestine and plays an important role in carbohydrate digestion to form mono-, di-, and polysaccharides. Acarbose, Voglibose, Miglitol, and Erniglitate have been well-known α-glucosidase inhibitors in science since 1990. However, the long synthetic route and side effects of these inhibitors forced the researchers to move their focus to innovate simple and small heterocyclic scaffolds that work as excellent α-glucosidase inhibitors. Moreover, they are also effective against the postprandial hyperglycemic condition in Type 2 Diabetes Mellitus. In this aspect, this review summarizes recent progress in the discovery and development of heterocyclic molecules that have been appraised to show outstanding inhibition of α-glucosidase to yield positive effects against diabetes.

Rab35 is required for embryonic development and kidney and ureter homeostasis through regulation of epithelial cell junctions.

Background: Rab35 is a member of a GTPase family of endocytic trafficking proteins. Studies in cell lines have indicated that Rab35 participates in cell adhesion, polarity, cytokinesis, and primary cilia length and composition. Additionally, sea urchin Rab35 regulates actin organization and is required for gastrulation. In mice, loss of Rab35 in the CNS disrupts hippocampal development and neuronal organization. Outside of the CNS, the functions of mammalian Rab35 in vivo are unknown. Methods: We generated and analyzed the consequences of both congenital and conditional null Rab35 mutations in mice. Using a LacZ reporter allele, we assessed Rab35 expression during development and postnatally. We assessed Rab35 loss in the kidney and ureter using histology, immunofluorescence microscopy, and western blotting. Results: Congenital Rab35 loss of function caused embryonic lethality: homozygous mutants arrested at E7.5 with cardiac edema. Conditional loss of Rab35, either during gestation or postnatally, caused hydronephrosis. The kidney and ureter phenotype were associated with disrupted actin cytoskeletal architecture, altered Arf6 epithelial polarity, reduced adherens junctions, loss of tight junction formation, defects in EGFR expression and localization, disrupted cell differentiation, and shortened primary cilia. Conclusion: Rab35 is essential for mammalian development and the maintenance of kidney and ureter architecture. Loss of Rab35 leads to non-obstructive hydronephrosis, making the Rab35 mutant mouse a novel mammalian model to study mechanisms underlying this disease.

Linker-assisted engineering of chimeric xylanase-phytase for improved thermal tolerance of feed enzymes.

Biological enzymes are multifunctional macromolecules that can perform hundreds of reactions simultaneously. An enzyme must possess specific characteristics to meet industrial needs, such as stability over a wide pH and temperature range and high specific activity. A phytase and xylanase mixture is generally added to poultry feed to improve the bird's health and productivity. Despite this, animal farmers have noticed no difference in productivity, and a leading cause is the high temperature at which feed is pulverized, which inactivates enzymes. A thermo-stable enzyme system can overcome these hitches. Commonly, coatings and immobilization reduce losses caused by physical-chemical factors in feed processing and digestion. To this end, we engineered the multifunctional xylanase-phytase domains on a single polypeptide fused by a helical linker. First, the ideal linker sequence was chosen by computing each selected linker's root mean square deviation (RMSD). The selected helical linker provides sufficient structural flexibility for substrate binding and product release evaluated by molecular docking and molecular dynamic simulation studies. Furthermore, a domain-domain interaction has stabilized the bridging partners, attaining the thermal optima for xylanase and phytase at 90 °C. Even at the above-optimal temperature (100 °C), the recombinant PLX was relatively stable and retained 64.2% and 59.2% activity for xylanase and phytase, respectively, when surveyed for ten hours. So far, to this date, this is the highest degree of thermostability achieved by any recombinant phytase or xylanase.Communicated by Ramaswamy H. Sarma.

Evaluation of geothermal water and assessment of corrosive and scaling potential of water samples in Tulsishyam Geothermal Region, Gujarat, India.

The purpose of this study was to evaluate and analyse the water quality in the Tulsishyam region in terms of corrosive and scaling properties. Thermal water samples (TWS), groundwater samples (GWS), and riverwater samples (RWS) were collected and analysed for a variety of geochemical parameters in various locations throughout the Tulsishyam region. The pH of such thermal springs ranges between 7.1 and 7.4, suggesting that they are neutral, and the temperature ranges between 39 and 42 °C. To determine the corrosive and scaling properties of water, various indices such as the Langelier Saturation Index (LSI), the Puckorius Scaling Index (PSI), the Ryznar Stability Index (RSI), and the Larson Index (LaI) are used. According to the indices described previously, all water samples are extremely corrosive to intolerably corrosive with a significant abrasion rate. The chemical composition of the fluids is also investigated in relation to the weathering processes. Sulphate has a significant negative link with chlorine and a weak correlation with bicarbonate, whereas chlorine has a moderate correlation with bicarbonate, according to multivariate analysis. Industrial usage of water samples from the study area should be limited due to the aggressive nature of the water samples.

pCold-assisted expression of a thermostable xylanase from Bacillus amyloliquefaciens: cloning, expression and characterization.

The biotechnological application of bacterial xylanases requires a high thermostability, a catalytically active state for a broad pH range. The Bacillus amyloliquefaciens (MTCC 1270) xynA gene was amplified and cloned into the pCold vector and was expressed in Escherichia coli to evaluate the expressed proteins' thermostability. The pCold, compared to other similar vectors, has unique properties-including pH and temperature tolerance due to the presence of the cspA promoter. The recombinant xynA-pCold (rxynApC) showed the expression of xynA gene with a molecular weight of ~ 27 kDa, confirmed on SDS-PAGE. The rxynApC exhibits optimal activity at 70 °C and pH 8.0. The residual activity of the recombinant enzyme was 90% at pH 8.0. The thermal decomposition temperature (T d) value for the rxynApC enzyme was 93.33 °C obtained from the thermogravimetric analysis, indicating the potent stability of the cloned enzyme. The specific activity of native xylanase and rxynApC under optimal conditions was 32.35 and 105.5 U/mg, respectively. The structural model of the xynA gene was predicted using the in silico tool along with the active site (containing four important Tyr-166, Gly-7, Try-69 and Arg-112 amino acids). The predicted biophysical parameters of the in silico model were similar to the experimental results. The unique feature of the cspA promoter is that it gave a high expression of rxynApC enzyme having alkali and thermostable properties with high yield in surrogate host E. coli. Thus, the recombinant xynA gene can potentially be applied to different industrial needs by looking at its thermostability and enhanced enzyme activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03315-y.

A Case of Lymphomatoid Granulomatosis in a Lymph Node with Unique Clinical and Histopathologic Features.

BACKGROUND Lymphomatoid granulomatosis (LyG) is a rare lymphoproliferative disorder associated with Epstein-Barr virus (EBV) in which there is an infection of B cells and numerous reactive T cells. The lymphoproliferative disorder progresses to organ infiltration and resultant dysfunction of affected organs. Histologically, it is characterized by a triad of polymorphic lymphoid infiltrate, angiitis, and granulomatosis. The lungs are the most commonly involved sites for lymphomatoid granulomatosis, but other sites that can be involved include the liver, skin, and central nervous system. The signs and symptoms of LyG can vary, and can produce generalized symptoms such as cough, shortness of breath, and chest tightness, but can vary depending on the location of LyG. CASE REPORT We report a case of a 60-year-old man who presented with altered mental status. Cross-sectional imaging of the brain was negative for any acute intracranial process, but a fine-needle biopsy of a retroperitoneal lymph node revealed nodular polymorphous mononuclear infiltrates containing atypical large EBV-positive B cells with positive EBER and CD30, consistent with lymphomatoid granulomatosis. The patient was started on a regimen of brentuximab/bendamustine, and instructed to follow up with Oncology on an outpatient basis. CONCLUSIONS Treatment options for lymphomatoid granulomatosis are based on the disease grading. Lymphomatoid granulomatosis can be classified by using a grading system determined by the number of EBV-positive large B cell malignant cells, along with necrosis. The most effective treatment for lymphomatoid granulomatosis is unknown, but at this time treatment protocols are based on the grade of the disease. The clinical and histological features of lymphomatoid granulomatosis are discussed in this case report.

Acute Abdomen from Spontaneous Splenic Artery Rupture with Coincidental Metastatic Disease: A Case Report.

BACKGROUND Splenic artery rupture is a rare surgical occurrence, often with fatal results. The reported prevalence is 0.1-0.2%. Splenic artery rupture can be from atraumatic or traumatic causes. Clinical presentation can vary from being asymptomatic to having an acute abdomen presentation if the splenic artery ruptures. Various imaging studies such as computed tomography, magnetic resonance imaging, and Doppler ultrasound can be used to determine the morphology and location of the aneurysm. Surgical treatment options are aneurysm resection or simple ligation and splenectomy. CASE REPORT We present the case of an 84-year-old man who presented to the Emergency Department after having an episode of syncope. Upon admission, the patient had an acute rupture of the splenic artery aneurysm with large-volume hemoperitoneum, with extensive hepatic and periportal nodal metastases. Interventional radiology was immediately consulted for an emergent splenic artery embolization. He then underwent a liver biopsy, showing poorly differentiated carcinoma, with elevated AFP, CA 19-9, and CEA. The patient was discharged, and was scheduled to follow up with gastroenterology for an outpatient colonoscopy and with oncology for further staging and treatment. CONCLUSIONS This is a rare case where a patient had an acute splenic artery rupture with underlying hepatic and periportal metastasis, with a primary within the gastroenterology tract, specifically the colon. It is imperative to consider splenic artery aneurysm as a differential diagnosis in patients who present with acute abdomen. This case will bring to light a traumatic cause leading to a delayed diagnosis of metastatic malignancy, with the colon as the primary location.

Linkers: A synergistic way for the synthesis of chimeric proteins.

In the cell, the protein domains are attached with the short oligopeptide, commonly known as linker peptide. Besides bridging, the linker assists in the domain-domain interaction and protein folding into the peculiar conformations. Linkers allow or control the movement of protein domains in the dynamic cellular environment. The recent advances in the recombinant DNA technology enable the construction of multiple gene constructs in an open reading frame. The express sequences can work in a cascade to cater for myriad functions. This trend has given momentum to incorporating bridge sequences (linker) that essentially separates the independent domains. According to the cellular need, the bridging partner can be spaced at a secure gap or requires attaching or interacting physically. The flexible or rigid linker can help to achieve such conformations in chimeric fusion proteins. The linker can improve solubility, proteolytic resistance and stability of such fusion proteins. Recently, linker aided protein switches and antibody-drug conjugates are gaining the attention of researchers worldwide. Here, we thoroughly reviewed the types of the linker, strategies for linker engineering and the composition of a linker.

Engineering of thermostable phytase-xylanase for hydrolysis of complex biopolymers.

Industrial processing of enzymes requires higher heating that affects the thermal stability of the enzyme and increases the production cost. In this study, xylanase-phytase (XP) fusion protein was generated via co-expression in a single vector with a cold-shock promoter, leading to improved activity at optimal pH, temperature and the thermal behaviour of the protein. Xylanase-phytase (XP) fusion and phytase proteins were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The XP fusion was thermally stable up to 124 °C, higher than phytase which was steady up to 113.5 °C. XP fusion exhibits higher stability at its thermal transition midpoint (T m) 108 °C, higher than the T m value of phytase which is 90 °C. Industrially efficient and environment-friendly proteins with low production cost and higher stability can be generated by 'fusion protein' technology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02936-z.

A Rare Case of Hypereosinophilic Syndrome-Induced Shower Thrombus Responsive to Nilotinib.

Hypereosinophilic syndrome (HES) is a rare clinical disease that affects 0.036/100,000 patients, with a minority of patients having associated genetic markers which can encompass PDGFRA/B or FGFR1 mutations. The prognosis is dependent on the timing of diagnosis and early treatment, with a mortality rate ranging from 48% to 75% if there is a delayed diagnosis. Eosinophilic myocarditis is characterized by invasion of the myocardium with eosinophils. Myeloid neoplasms are a rare, but known cause of HES induced myocarditis. Signs and symptoms can range from being asymptomatic to retrosternal pain, arrhythmias, and even sudden death. HES myocarditis is a diagnosis of exclusion that is made via endomyocardial biopsy. Peripheral eosinophilia is the only specific sign to suggest eosinophilic myocarditis with traditional biomarkers, electrocardiogram, and echocardiogram. Treatment modalities include systemic corticosteroids and symptomatic management. Complications from HES myocarditis may include embolic events, eosinophilic vegetations, and dysrhythmias, or conduction disturbances. We present a case of a 62-year-old male who initially presented with epigastric pain, and then suffered a myocardial infarction. After testing, the probable diagnosis of eosinophilic myocarditis was made. His clinical course was complicated by the development of shower thrombus associated with acute encephalopathy. Although HES has classically been treated with imatinib, in this case, an alternative biologic agent was used, resulting in a good prognosis and ultimate patient survival. This case details the importance of early clinical suspicion, diagnosing the condition, and early initiation of treatment to prevent worsening clinical status.

Extraosseus Ewing's Sarcoma in Pancreas: A Review.

Primitive neuroectodermal tumors (PNET, previously referred to as peripheral neuroepithelioma) are rare malignant tumors with various degrees of differentiation belonging to the Ewing's family of sarcomas. They are classified as round cell tumors arising from soft tissues. In rare instances, PNETs may arise from solid organs containing neuroendocrine cells of kidney, bladder, heart, lungs, parotid glands and pancreas. Most cases occur in the second decade of life with a slight preponderance in males. PNET of the pancreas is an aggressive tumor with multiple recurrences and a relatively poor prognosis. These tumors should be considered in the differential diagnosis, especially in a diagnosed pancreatic tumor in individuals less than 35 years of age. Due to the nature of the tumor, surgery with subsequent chemoradiation are widely accepted modalities despite the poor prognosis. In this article, we review 25 cases of extraosseous Ewing's sarcoma (ES) of the pancreas which to the best of our knowledge, enlists most cases reported in the literature thus far.

A Rare Case of Non-Small Cell Lung Cancer with BRAF V600E Gene: Case Report and Literature Review.

Non-small cell lung cancer is one of the leading causes of mortality in the United States. The BRAF mutation, which has been associated with malignant melanoma, has been documented in only 3.5-5% of the non-small cell lung cancer (NSCLC) patient population.The involvement of the BRAF mutation in NSCLC and the treatment for tumors with such mutations is still an evolving topic of interest, which is why more in depth information is warranted. We present a rare case of stage IV non-small cell lung adenocarcinoma, who presented first with a complicated pericardial effusion with evidence of malignant effusion. He had genetic testing done, revealing he had a positive BRAF V600E mutation. He was put on multiple chemotherapy regimens, but was most responsive to Vemurafenib. This case will shed light into the importance of the BRAF V600E gene and its importance in NSCLC for better prognosis value.

Actinomyces turicensis: An unusual cause of cervicofacial actinomycosis presenting as ludwig angina in an immunocompromised host - Case report and literature review.

Actinomyces is an anaerobic, gram-positive bacillus that is known to cause chronic granulomatous infections. Common risk factors predisposing patients to this life-threatening infection are recent dental procedures, immunosuppression from malignancy, or history of smoking and alcohol use. Actinomyces, commonly found in the normal flora of the oral cavity, is one of the pathogens that can cause Ludwig's angina. Ludwig's angina is diffuse cellulitis and edema of the soft tissues of the neck and floor of the mouth. Cervicofacial actinomyces is an invasive infection that can form life-threatening abscesses through its rapid spread. Actinomyces turicensis is an isolate that has emerged recently to cause infections in humans. There are few reported cases of this species causing abdominal and genital infections; however, there is no report of it invading the cervicofacial space. A feared complication of Ludwig's angina and cervicofacial actinomyces is airway compromise. Therefore, prompt initiation of intravenous antibiotics is required for the treatment and prevention of deadly complications. We present a patient with left-sided neck swelling after a recent oral surgical procedure and was found to grow Actinomyces turicensis on wound culture. The patient was treated with intravenous ampicillin-sulbactam, which not only decreased the swelling but improved the necrotic appearance of his abscess wound.

Spontaneous Fungal Peritonitis as a Rare Complication of Ascites Secondary to Cardiac Cirrhosis: A Case Report.

BACKGROUND Spontaneous fungal peritonitis (SFP) is a life-threatening infection which occurs more commonly in patients with liver failure. SFP is not as common as spontaneous bacterial peritonitis (SBP) and has higher mortality rates due to late recognition and difficulty in differentiation between SFP and SBP. Spontaneous fungal peritonitis is extremely uncommon in patients with cardiac ascites due to a high protein content, which predisposes to a low risk of infections. CASE REPORT This report presents a rare case of spontaneous fungal peritonitis in a patient with cardiogenic ascites. To the best of our knowledge, this is the second known case of SFP occurring in a patient with cardiac cirrhosis. The patient did not respond to initiation of SBP treatment and after ascitic fluid grew Candida glabrata, the diagnosis of SFP was made. The patient's clinical status improved after initiation of intravenous caspofungin. CONCLUSIONS SFP should be a differential diagnosis in patients who have cardiac or liver cirrhosis, who are not improving with empirical antibiotic therapy for spontaneous bacterial peritonitis.

A time-motion analysis of the mothers staying in the neonatal care unit.

CONTEXT: In addition to various barriers studied for kangaroo mother care (KMC), time opportunities for better implementation of KMC need to be studied. AIM: Time-motion analysis of the mother's daily activities was carried out to identify scope to improve KMC. SETTINGS AND DESIGN: This is a 24-h recall-based questionnaire study. Mothers were interviewed whose newborns were admitted at a tertiary and secondary care neonatal care unit of western India over a period of 9 months from November 2015 to July 2016. MATERIALS AND METHODS: Mothers were approached when the preterm neonate and mother dyad was eligible for KMC, that is, when mothers were physically healthy and newborns were physiologically stable. A total of 60 mothers were enrolled in the study. Mothers' daily activities were noted, and time spent in each activity was charted for 3 consecutive days. Missed time opportunities which could be used to increase daily KMC hours were studied. STATISTICAL ANALYSIS USED: To compare quantitative variables, two-sample unpaired t-test and one-way analysis of variance were used. RESULTS: The average time of activities which consumed most was 8.24 h for sleep/rest, 3.46 h for meals/snacks, 4.89 h for breastfeeding, and a daily average of only 1.4 h was used for KMC. A quite a significant proportion, that is, 3.89 h, was spent for meeting relatives which could be used for KMC as well without affecting social meetings. CONCLUSION: Time-motion analysis was helpful to find out weak links in KMC implementation. Providing family-centered environment in terms of implementing KMC during meeting hours with family may augment KMC hours.

Delftia acidovorans: A rare cause of septic pulmonary embolism from catheter-related infection: Case report and literature review.

Septic pulmonary emboli is a rare condition due to the dislodgement of an infected thrombus traveling to the pulmonary vasculature via the venous system. Staphylococcus spp. and Candida spp. are the most common causative agents. The most common risk factor is intravenous drug abuse, but there has been an association with intravenous catheters. Delftia acidovorans (DA) is a rare organism causing catheter-related infection, which has a tendency to embolize and clog up major vessels. It is highly resistant to all available aminoglycoside agents. There are only a few cases reported in children showing DA as a cause of septic emboli with none of the cases reported in a young patient. We report a similar case but in a young adult who developed septic emboli due to DA that was caused by an infected peripherally inserted central catheter (PICC) line. Since the organism is highly susceptible to recurrent embolization, the PICC line was removed and the patient was treated successfully with an appropriate antibiotic regime.

The Medical Termination of Pregnancy Act: Need to keep pace with technology.

In the summer of 2017, the Supreme Court of India denied permission to abort a 26-week-old foetus, detected with Down syndrome at 22 weeks, to a family which already had a child with special needs, on the grounds that the 20-week mark specified in The Medical Termination of Pregnancy Act of 1971 had been crossed. An Act well formulated and ahead of its time at inception seems not to have kept pace with technology and to be in need of change. We argue that by denying the abortion the Court did not adhere to the core principle of ethics-respect for autonomy, beneficence, non-malfeasance, and justice-as the mother was not allowed to decide for herself and was forced to abide by the decision taken by the court.

RAHI-SATHI Indo-U.S. Collaboration: The Evolution of a Trainee-Led Twinning Model in Global Health Into a Multidisciplinary Collaborative Program.

BACKGROUND: In recent years there has been a surge in the number of global health programs operated by academic institutions. However, most of the existing programs describe partnerships that are primarily faculty-driven and supported by extramural funding. PROGRAM DESCRIPTION: Research and Advocacy for Health in India (RAHI, or "pathfinder" in Hindi) and Support and Action Towards Health-Equity in India (SATHI, or "partnership" in Hindi) are 2 interconnected, collaborative efforts between the University of Massachusetts Medical School (UMMS) and Charutar Arogya Mandal (CAM), a medical college and a tertiary care center in rural western India. The RAHI-SATHI program is the culmination of a series of student/trainee-led research and capacity strengthening initiatives that received institutional support in the form of faculty mentorship and seed funding. RAHI-SATHI's trainee-led twinning approach overcomes traditional barriers faced by global health programs. Trainees help mitigate geographical barriers by acting as a bridge between members from different institutions, garner cultural insight through their ability to immerse themselves in a community, and overcome expertise limitations through pre-planned structured mentorship from faculty of both institutions. Trainees play a central role in cultivating trust among the team members and, in the process, they acquire personal leadership skills that may benefit them in their future careers. CONCLUSION: This paradigm of trainee-led twinning partnership promotes sustainability in an uncertain funding climate and provides a roadmap for conducting foundational work that is essential for the development of a broad, university-wide global health program.