Vigilin protein Vgl1 is required for heterochromatin-mediated gene silencing in Schizosaccharomyces pombe.

Heterochromatin is a conserved feature of eukaryotic genomes and regulates various cellular processes, including gene silencing, chromosome segregation, and maintenance of genome stability. In the fission yeast Schizosaccharomyces pombe, heterochromatin formation involves methylation of lysine 9 in histone H3 (H3K9), which recruits Swi6/HP1 proteins to heterochromatic loci. The Swi6/HP1-H3K9me3 chromatin complex lies at the center of heterochromatic macromolecular assemblies and mediates many functions of heterochromatin by recruiting a diverse set of regulators. However, additional factors may be required for proper heterochromatin organization, but they are not fully known. Here, using several molecular and biochemical approaches, we report that Vgl1, a member of a large family of multiple KH-domain proteins, collectively known as vigilins, is indispensable for the heterochromatin-mediated gene silencing in S. pombe ChIP analysis revealed that Vgl1 binds to pericentromeric heterochromatin in an RNA-dependent manner and that Vgl1 deletion leads to loss of H3K9 methylation and Swi6 recruitment to centromeric and telomeric heterochromatic loci. Furthermore, we show that Vgl1 interacts with the H3K9 methyltransferase, Clr4, and that loss of Vgl1 impairs Clr4 recruitment to heterochromatic regions of the genome. These findings uncover a novel role for Vgl1 as a key regulator in heterochromatin-mediated gene silencing in S. pombe.

Analysis of antibacterial and cytotoxic potential of medicinal plants from Cholistan desert, Pakistan.

This study aimed to investigate the antibacterial and cytotoxic activity of 03 medicinal plants, Calligonum polygonides, Farsetia hamiltonii, and Pulcaria crispa, from Cholistan desert, Pakistan. The active constituents of plants species were extracted in 05 different solvents and the extracts were tested against various bacterial strains and brine shrimps. Although all Calligonum polygonides's extracts except chloroform were active against Staphylococcus aureus the most active was the acetone extract (21 ± 0.00 mm at 200 µg/disc) and activity was better than Caricef (p-value 0.03). While its water extract was more potent (18 ± 1.45 mm at 200 µg/disc) than Augmentin and Caricef (p-value < 0.005). The methanol extract's activity (15 ± 0.39 mm in 200 µg/disc) was comparable to Fucidin against Proteus vulgaris (p-value > 0.99) and activity of diethyl ether extract against Escherichia coli (10 ± 1.16 mm in 200 µg/disc) was same as of Urixin (p-value 0.91). Farsetia hamiltonii's acetone extract against Pseudomonas aeruginosa (10 ± 0.15 mm in 1 µg/disc) was more active than Augmentin Caricef and Cefotax (p-value < 0.02) and against Staphylococcus aureus (15 ± 1.15 mm in 200 µg/disc) activity was higher than Caricef (p-value 0.03). All Pulicaria crispa's extracts except water extract were found active against Staphylococcus aureus. However, the diethyl ether extract was most effective (25 + 0.00 mm at 150 µg /disc) and activity was more than Augmentin, Oxy-tetracycline, Fucidin, Urixin, Ceftriaxone (p-value < 0.05). Although all extracts were exhibited cytotoxic activity, the Calligonum polygonides's acetone extract (100%), Farsetia hamiltonii's diethyl ether extract (90%) and Pulicaria crispa's methanol extract (100%) were most active at 1000 µg/ml concentration. This study validated the medicinal significance of the studied plants and thus opens the way for their therapeutic applications.

Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes.

Introduction: Type 2 diabetes (T2DM), which is more prevalent (more than 90% of all diabetes cases) and the main driver of the diabetes epidemic, now affects 5.9% of the world's adult population, with almost 80% of the total in developing countries. At present, 537 million adults (20−79 years) are living with diabetes­1 in 10. This number is predicted to rise to 643 million by 2030 and 783 million by 2045. In India, reports show that 69.2 million people are living with diabetes (8.7%) as per 2015 data. Long-term metformin treatment is a known pharmacological cause of vitamin B12 (Vit B12) deficiency, as was evident within the first 10−12 years after it started to be used. Methods: This was a cross-sectional study conducted in the Postgraduate Department of Medicine in one of the tertiary hospitals in Kashmir. A total of 1600 consecutive patients with T2DM were taken for the study. Out of which 700 patients met the inclusion criteria. These 700 patients were divided into two groups: those taking metformin, and those who were not on metformin. Cumulative metformin doses were recorded in patients taking metformin, using history of dose and duration of treatment. Serum Vit B12 levels were taken for all patients. Based on the results of Vit B12 levels, patients were classified into normal levels (20 pmol/L), possible B12 deficiency (150−220 pmol/l), and definite deficiency (<150 pmol/L). Results: Our results depicted that patients on prolonged metformin therapy showed an increase in Vit B12 deficiency by 11.16%. The prevalence of clinical neuropathy in the metformin-exposed group was 45%, whereas, a prevalence of 31.8% was found in the non-metformin group. The mean age of patients with neuropathy was higher than those without neuropathy (59.01 ± 7.14 vs. 49.95 ± 7.47) (p-value < 0.514, statistically insignificant). Conclusions: In our study, we found that metformin use is associated with Vit B12 deficiency, which is dependent upon the cumulative dose of metformin. Importantly, prolonged metformin use is also associated with an increase in the prevalence of clinical neuropathy.

COVID-19: Diagnostics, Therapeutic Advances, and Vaccine Development.

PURPOSE OF REVIEW: Human race is currently facing the wrath of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly transmittable and pathogenic RNA virus, causing coronavirus disease 2019 (COVID-19), the worst ever global pandemic. Coronaviruses (CoVs) have emerged as a major public health concern. Urgent global response to COVID-19 outbreak has been to limit spread of SARS-CoV-2 via extensive monitoring and containment. Various treatment regimens have been adopted to manage COVID-19, with known drugs and drug combinations used to decrease the morbidity and mortality associated with COVID-19. Intensive research on various fronts including studying molecular and structural aspects of these viruses and unraveling the pathophysiology and mechanistic basis of COVID-19 aimed at developing effective prophylactic, therapeutic agents and vaccines has been carried out globally. RECENT FINDINGS: No approved antiviral treatment except remdesivir exists for SARS-CoV-2 till date though novel drug targets have been identified. However, worldwide frantic and competitive vaccine development pharmaceutical race has borne fruit in the form of a number of promising candidate vaccines, out of which few have already received emergency use authorization by regulatory bodies in record time. SUMMARY: This review highlights the painstaking efforts of healthcare workers and scientific community to successfully address the COVID-19 pandemic-though damage in the form of severe illness, loss of lives, and livelihood has left a serious mark. Focusing on extensive research on various therapeutic options and antiviral strategies including neutralizing antibodies, potential drugs, and drug targets, light has been shed on various diagnostic options and the amazing vaccine development process as well.

Managing the COVID-19 Pandemic: Research Strategies Based on the Evolutionary and Molecular Characteristics of Coronaviruses.

Coronavirus disease 2019 (COVID-19), an ongoing global health emergency, is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging in Wuhan, China, in December 2019, it spread widely across the world causing panic-worst ever economic depression is visibly predictable. Coronaviruses (CoVs) have emerged as a major public health concern having caused three zoonotic outbreaks; severe acute respiratory syndrome-CoV (SARS-CoV) in 2002-2003, Middle East respiratory syndrome-CoV (MERS-CoV) in 2012, and currently this devastating COVID-19. Research strategies focused on understanding the evolutionary origin, transmission, and molecular basis of SARS-CoV-2 and its pathogenesis need to be urgently formulated to manage the current and possible future coronaviral outbreaks. Current response to the COVID-19 outbreak has been largely limited to monitoring/containment. Although frantic global efforts for developing safe and effective prophylactic and therapeutic agents are on, no licensed antiviral treatment or vaccine exists till date. In this review, research strategies for coping with COVID-19 based on evolutionary and molecular aspects of coronaviruses have been proposed.

Diagnostic utility of epigenetics in breast cancer - A review.

Epigenetic alterations are clearly involved in cancer initiation and progression as recent epigenetic studies of genomic DNA, histone modifications and micro-RNA alterations suggest that these are playing an important role in the incidence of breast cancer. Epigenetic information has recently gained the attention of researchers because epigenetic modification of the genome in breast cancer is still an evolving area for researchers. Several active compounds present in foods, poisons, drugs, and industrial chemicals may as a result of epigenetic mechanisms increase or decrease the risk of breast cancer. Epigenetic regulation is critical in normal growth and development and closely conditions the transcriptional potential of genes. Epigenetic mechanisms convey genomic adaption to an environment thereby ultimately contributing towards given phenotype. In addition to the use of epigenetic alterations as a means of screening, epigenetic alterations in a tumor or adjacent tissues or peripheral blood may also help clinicians in determining prognosis and treatment of breast cancer. As we understand specific epigenetic alterations contributing to breast tumorigenesis and prognosis, these discoveries will lead to significant advances for breast cancer treatment, like in therapeutics that target methylation and histone modifications in breast cancer and the newer versions of the drugs are likely to play an important role in future clinical treatment.

Generalized Tetanus Initially Presenting with Dysmasesis.

A 58-year-old male farmer, with no significant history of any chronic morbidity, was admitted via the Emergency Department of SMHS Hospital, Srinagar, with a history of an injury to the hand 20 days earlier followed by a three-day history of dysmasesis (difficulty chewing), progressing to trismus and generalized stiffness interfering with his daily activities. The patient was clinically managed as tetanus on grounds of high clinical suspicion. The patient was treated for a week and discharged without any sequelae to follow-up in the Neurology Outpatient Department of the SMHS Hospital and is currently doing well. After a week of successful management, we received the blood and wound culture reports of the patient that had been sent at the time of his admission to the hospital, which overwhelmingly tested positive for Clostridium tetani. Tetanus is a disease to be suspected post-trauma in patients, especially in developing countries like India. Despite active and passive immunization, it continues to be a significant public health problem in developing countries and should be readily suspected and treated. Although prevention is important for tetanus, the outcomes can be improved by early clinical diagnosis and treatment.

Correction: Generalized Tetanus Initially Presenting with Dysmasesis.

[This corrects the article DOI: 10.7759/cureus.644.].

Extra pontine osmotic demyelination syndrome.

The osmotic demyelination syndrome (ODS) has been identified as a complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium which cause a rapid changes in osmolality of the interstitial (extracellular) compartment of the brain leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Slow correction of the serum sodium concentration and additional administration of corticosteroids seems to be a major prevention step in ODS patients. In the current report we aimed to share a rare case which we observed in our hospital. A 65 year old female admitted as altered sensorium with history of vomiting, diarrhea was managed with intravenous fluids for 2 days at a peripheral health centre. Patient was referred to our centre with encephalopathy, evaluated and found to have hyponatremia and hypokalemia rest of biochemical parameters and septic profile were normal. Patient's electrolyte disturbances were managed as per guidelines but encephalopathy persisted. Supportive treatment was continued and patient was discharged after 2 wks of stay in hospital after gaining full sensorium and neurological functions.

Non-Hyperammonemic valproate encephalopathy.

A 21-year-old male known case of primary hypothyroidism, Seizure disorder sequelae of an old trauma receiving sodium valproate, clobazam and phenobarbitone for control of Generalized tonic clonic seizures reported to neurology OPD with history of altered sensorium and gait unsteadiness for 1 week with history of hike in valproate dose 2 weeks before. On examination he was drowsy. Neurological examination was unremarkable except for gait unsteadiness and ataxia. Patient was admitted and evaluated for acute worsening. All (the) biochemical parameters including complete blood count, liver function tests, kidney function tests, routine urine examination, arterial blood gas analysis, blood and urine culture tests were normal. CSF analysis was also normal. Repeat MRI brain was also done which depicted all old changes with no fresh changes which will account for worsening of his sensorium. EEG was suggestive of diffuse encephalopathy. Thyroid function tests were also normal. Valproate encephalopathy was suspected and Valproate was empirically stopped and he was put on levetiracetam and phenytoin. His sensorium improved rapidly after stoppage of valproate with normalization of EEG. Serum valproate Levels were high with serum ammonia levels were in the normal range. We made the inference of nonhyperammoneamic valproate encephalopathy. This case highlights the existence of non-hyperammonemic valproate induced encephalopathy, suggesting mechanisms other than hyperammonemia responsible for this encephalopathy.

Comparative study on ELISA, IFA and direct methods in diagnosis of giardiasis.

A total of 200 cases aged 1-13 years complaining of symptoms suggestive of giardiasis in addition to thirty normal healthy children as a control group was examined clinically and laboratory using stool examination and detection of Giardia coproantigen in faeces by Dot ELISA and direct IFA. Stool examination detected 39 cases (19.5%) while Dot ELISA and direct IFA detected 49 cases (24.5%) with 100% sensitivity and 93.8% specificity. The common clinical findings were diarrhea, abdominal cramps, anorexia, underweight, pallor and manifestations of vitamin deficiency. The results were discussed.