A New Shock Model for the Effect of Leptin on Body Weight Gain

The present study was designed to examine the dosage effect of the chronic Leptin infusion on body weight gain. Using a new shock model approach, the mean and variance for body weight gain were found. The results are consistent and the shock model concludes that if the dosage of the Leptin increases, the body weight gain decreases. Keywords: New Shock model, Leptin, neuroendocrine, neuropeptides. 2010 Mathematics Subject Classification: 97Mxx, 93A30, 74J4

A Study on Annaku Thooru Azharchi

AIM AND OBJECTIVES: “Prevention is better than cure” All of us know this way of living is better, but no body know how to prevent ourself from diseases. In this modern days “The children” the next generation of our country facing many problem physically as well as mentally. They are affected by diseases very easily because they are not good enough to protect against diseases. In childhood the cild easily affected by the Respiratory and Nutritional diseases. This is the common problem found among the children. If the disease of child is cured in childhood itself means, then the child place themselves in a better place in future to serve for our nation. So the author decided to take the child’s problem of respiratory systems. The disease Annakku Thooru Azharchi is the most common upper respiratory infection in childrens. The signs and symptoms of this disease correlate with Tonsillitis. If Annakku Thooru Azharchi was not properly treated it leads to the life threatening complications like Rheumatic fever, Acute glomerulo nephritis etc., The author has selected the disease Annakku Thooru Azharchi to safe guard the childrens from this disease and from the life threatening complications with the medicine Karpoora Valli Mathirai. The objectives are as follows, 1. To make a detailed study of Annakku Thooru Azharchi on the basis of Siddha literature. 2. To utilize and expose the unique diagnostic method mentioned by the siddhars and to know how the disease altered the normal conditions of Mukkutram, Pori pulangal, Ezhu Udal Kattukal and Envagai thervugal. 3. To divide a comparative clinical study with the particular medicines mentioned above. 4. To have an idea about the incidence of the disease with age, sex, socio economic status, Family history and seasonal variation. 5. To know the degree of correlation on aetiology, classifications, signs and symptoms of Annakku Thooru Azharchi in siddha medicine with that of modern medicine. 6. To evaluate the bio-chemical, pharmacological and anti microbial studies of the drugs used for the treatment of the disease. MATERIALS AND METHODS: MATERIALS: A Clinical trial on Annakku thooru Azarchi was carried out in Govt. Siddha Medical College Hospital, Palayamkottai. Cases are studied under the guidance of the professor and Lecturer of Post graduate Department of Kuzhanthai Maruthuvam both in Outpatients and In-patients ward. 20 cases with clinical signs and symptoms of Annakku thooru Azarchi of both sexes under the age of 12 were selected and treated with Karpooravalli mathirai – 1 twice daily with honey. Parameters of Case Selection: Cases were selected from out - patient department and the parameters of Case selection were, 1. Sore throat. 2. yellow (or) white coating of the tonsils. 3. Swelling of the tonsils (or) throat. 4. Fever. 5. Painful / difficult swallowing. 6. Cervical lymphadenitis. 7. Bad breath (halitosis). Patients aging under 12 years were only selected for this study. Clinical Examinations: Patients were subjected to Physical examination on Siddha Methodology “PINIYARI MURAIMAI” Piniyari Muraimai has three main principles: 1. Porialarithal. 2. Pulanalarithal and, 3. Vinathal. SUMMARY: In siddha system of medicine even though many disease of children were explained with their classification, symptoms and treatment. Annakku Thooru Azharchi was not explained elaborately. Siddhars had mentioned many medicines for this disease. So from the available text. Annakku thooru Azharchi signs, symptoms and clinical features were collected and the medicines mentioned are taken for the study. Majority of childrens has annakkuthorru azharchi as common problem in their early stage of life. Annakku thooru Azharchi. Clinical feature reveals that this is a disease of tonsils and has close association with the immunity of the children. It is one of the common upper respiratory infection affecting children. Among 20 cases, diagnosis established by siddha and modern methodology reveals that the incidence of Annakku thooru Azharchi is greater in childrens with age group of 6 -11 years. During this study the incidence of disease was more common in Elavenil and Munpani. In elavenil sour taste gets thannilai valarchi and astrigent tastes gets vetrunilai valarchi which increases kabam. This makes high incidence of Annakuru Thooru Azharchi. In munpani kaalam sugar tastes gets tannilai varlarchi and pungent taste gets vetrunilai valarchi which makes the Annakku Thooru Azharchi. The Envaai thervugal helped to diagnose disease to a large extent. To confirm the diagnosis the available modern techniques, described previously were employed. Regarding the treatment, all the patients were treated with Karpoora valli mathirai. internally for an average of 5-6 days. The observation made during this study showed that the trial medicine was clinically effective. Their blood tests also showed encouraging improvement. The pharmacological action of the trial drug has moderate acute anti–inflammatory, analgesic and chronic anti –inflammatory actions. The anti pyretic action of karpooravalli mathirai was mild. Anti bacterial activity of the trial drug was sensitive against Group A streptococcus,staphylococcus aureus, pseudomonas aeruginosa. Biochemical analysis revealed the trial drugs contains calcium, sulphate, ferrous and Tannic acid. The improvement in the conditions of the patients was observed from the second day of treatment itself in general. All the patients showed very good response. no patients developed any adverse side effect. The action of the drug and progress in patients symptoms encouraging. CONCLUSION: The treatment of Karpooravalli Mathirai for Annakku Thooru Azharchi showed good results. The trial drug is easily palatable to children. Raw drugs of this trial medicine is easily available and the preparation of medicine is also simple. The cost of trial medicine is comparatively very low. Drug is safe for the treatment of childrens as though all the ingredients are herbals. No adverse effects were noticed during the course of treatment. So it is concluded that in developing country like India, the therapy of Karpooravalli Mathirai can be very good in the view of efficacy, safety and cost, in the chemotheraphy for Annakku Thooru Azharchi

INSIGHTS ON DRUG TARGETING OF TOXOPLASMA GONDII HOST INVASION PROTEINS: A REVIEW

Toxoplasma gondii is an obligate intracellular parasite that infects homoeothermic animals. It is also the major cause of retinochoroiditis in humans.Drugs targeting T. gondii proteins involved in the establishment of host-pathogen interactions is well documented to be an efficient way to combatthe infections. Basically, parasitic invasion of T. gondii occurs by the sequential secretion of apical membrane antigen 1 and rhoptry neck proteins onthe parasite and host cell surfaces, respectively. These proteins operate synergistically and form the moving junction (MJ) complex, thereby, enablingattachment and penetration of the parasite into the host cell. Better understanding of molecular interactions of these proteins is essential to develophighly efficient therapeutic modalities. Hence, by this review it is intended to update the current status of rhoptry and other MJ complex proteins asideal candidates for targeting T. gondii.Keywords: Toxoplasma gondii, Rhoptry proteins, Moving junction complex, Toxoplasmosis

Pathological and physiological functions of presenilins

Mutations in PSEN1 and PSEN2 genes account for the majority of cases of early-onset familial Alzheimer disease. Since the first prediction of a genetic link between PSEN1 and PSEN2 with Alzheimer's disease, many research groups from both academia and pharmaceutical industry have sought to unravel how pathogenic mutations in PSEN cause presenile dementia. PSEN genes encode polytopic membrane proteins termed presenilins (PS1 and PS2), which function as the catalytic subunit of γ-secretase, an intramembrane protease that has a wide spectrum of type I membrane protein substrates. Sequential cleavage of amyloid precursor protein by BACE and γ-secretase releases highly fibrillogenic β-amyloid peptides, which accumulate in the brains of aged individuals and patients with Alzheimer's disease. Familial Alzheimer's disease-associated presenilin variants are thought to exert their pathogenic function by selectively elevating the levels of highly amyloidogenic Aβ42 peptides. In addition to Alzheimer's disease, several recent studies have linked PSEN1 to familiar frontotemporal dementia. Here, we review the biology of PS1, its role in γ-secretase activity, and discuss recent developments in the cell biology of PS1 with respect to Alzheimer's disease pathogenesis

Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components

gamma-Secretase, which is responsible for the intramembranous cleavage of Alzheimer beta-amyloid precursor protein and the signaling receptor Notch, is a multiprotein complex consisting of at least four components: presenilin ( PS); nicastrin (Nct); APH-1 ( anterior pharynx-defective-1); and presenilin enhancer-2 (PEN-2). Presenilin 1 (PS1) is known to be essential for the stability, interaction, and trafficking of the other PS1/gamma-secretase components. However, the precise functions of the other components remain elusive. Here, we investigated the functions of Nct within the PS1/gamma-secretase complex. We demonstrated that the loss of Nct expression in the embryonic fibroblast cells ( Nct KO cells) results in dramatically decreased levels of APH-1, PEN-2, and PS1 fragments accompanied by a significant accumulation of full-length PS1. In the absence of Nct, PEN-2 and full-length PS1 are subjected to proteasome-mediated degradation, whereas the degradation of APH-1 is mediated by both proteasomal and lysosomal pathways. Unlike the case of wild type cells in which the gamma-secretase complex mainly locates in the trans-Golgi network, the majority of residual PEN-2, APH-1, and the uncleaved full-length PS1 in Nct KO cells reside in the endoplasmic reticulum, which remain associated with each other in the absence of Nct. Interestingly, significant amounts of full-length PS1 and PEN-2, but not APH-1, are detected on the plasma membrane in Nct KO cells, suggesting the Nct-independent cell surface delivery of the PEN-2 center dot PS1. Finally, the diminished PEN-2 protein level in Nct-deficient cells can be partially restored by overexpression of exogenous PS1, APH-1, or PEN-2 individually or collectively, indicating a dispensable role for Nct in controlling PEN-2 level. Taken together, our study demonstrates a critical role of Nct in the stability and proper intracellular trafficking of other components of the PS1/ gamma-secretase complex but not in maintaining the association of PEN-2, APH-1, and full-length PS1

RETRACTED ARTICLE: Age-dependent Increase in Desmosterol Restores DRM Formation and Membrane-related Functions in Cholesterol-free DHCR24−/− Mice

Cholesterol is a prominent modulator of the integrity and functional activity of physiological membranes and the most abundant sterol in the mammalian brain. DHCR24-knock-out mice lack cholesterol and accumulate desmosterol with age. Here we demonstrate that brain cholesterol deficiency in 3-week-old DHCR24−/− mice was associated with altered membrane composition including disrupted detergent-resistant membrane domain (DRM) structure. Furthermore, membrane-related functions differed extensively in the brains of these mice, resulting in lower plasmin activity, decreased β-secretase activity and diminished Aβ generation. Age-dependent accumulation and integration of desmosterol in brain membranes of 16-week-old DHCR24−/− mice led to the formation of desmosterol-containing DRMs and rescued the observed membrane-related functional deficits. Our data provide evidence that an alternate sterol, desmosterol, can facilitate processes that are normally cholesterol-dependent including formation of DRMs from mouse brain extracts, membrane receptor ligand binding and activation, and regulation of membrane protein proteolytic activity. These data indicate that desmosterol can replace cholesterol in membrane-related functions in the DHCR24−/− mouse

Putative DHHC-Cysteine-Rich Domain S-Acyltransferase in Plants

Protein S-acyltransferases (PATs) containing Asp-His-His-Cys within a Cys-rich domain (DHHC-CRD) are polytopic transmembrane proteins that are found in eukaryotic cells and mediate the S-acylation of target proteins. S-acylation is an important secondary and reversible modification that regulates the membrane association, trafficking and function of target proteins. However, little is known about the characteristics of PATs in plants. Here, we identified 804 PATs from 31 species with complete genomes. The analysis of the phylogenetic relationships suggested that all of the PATs fell into 8 groups. In addition, we analysed the phylogeny, genomic organization, chromosome localisation and expression pattern of PATs in Arabidopsis, Oryza sative, Zea mays and Glycine max. The microarray data revealed that PATs genes were expressed in different tissues and during different life stages. The preferential expression of the ZmPATs in specific tissues and the response of Zea mays to treatments with phytohormones and abiotic stress demonstrated that the PATs play roles in plant growth and development as well as in stress responses. Our data provide a useful reference for the identification and functional analysis of the members of this protein family

Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles

A large body of evidence has implicated amyloid precursor protein (APP) and its proteolytic derivatives as key players in the physiological context of neuronal synaptogenesis and synapse maintenance, as well as in the pathology of Alzheimer's Disease (AD). Although APP processing and release are known to occur in response to neuronal stimulation, the exact mechanism by which APP reaches the neuronal surface is unclear. We now demonstrate that a small but relevant number of synaptic vesicles contain APP, which can be released during neuronal activity, and most likely represent the major exocytic pathway of APP. This novel finding leads us to propose a revised model of presynaptic APP trafficking that reconciles existing knowledge on APP with our present understanding of vesicular release and recycling

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

RNA-Seq of untreated wastewater to assess COVID-19 and emerging and endemic viruses for public health surveillance

BackgroundThe COVID-19 pandemic showcased the power of genomic sequencing to tackle the emergence and spread of infectious diseases. However, metagenomic sequencing of total microbial RNAs in wastewater has the potential to assess multiple infectious diseases simultaneously and has yet to be explored.MethodsA retrospective RNA-Seq epidemiological survey of 140 untreated composite wastewater samples was performed across urban (n = 112) and rural (n = 28) areas of Nagpur, Central India. Composite wastewater samples were prepared by pooling 422 individual grab samples collected prospectively from sewer lines of urban municipality zones and open drains of rural areas from 3rd February to 3rd April 2021, during the second COVID-19 wave in India. Samples were pre-processed and total RNA was extracted prior to genomic sequencing.FindingsThis is the first study that has utilised culture and/or probe-independent unbiased RNA-Seq to examine Indian wastewater samples. Our findings reveal the detection of zoonotic viruses including chikungunya, Jingmen tick and rabies viruses, which have not previously been reported in wastewater. SARS-CoV-2 was detectable in 83 locations (59%), with stark abundance variations observed between sampling sites. Hepatitis C virus was the most frequently detected infectious virus, identified in 113 locations and co-occurring 77 times with SARS-CoV-2; and both were more abundantly detected in rural areas than urban zones. Concurrent identification of segmented virus genomic fragments of influenza A virus, norovirus, and rotavirus was observed. Geographical differences were also observed for astrovirus, saffold virus, husavirus, and aichi virus that were more prevalent in urban samples, while the zoonotic viruses chikungunya and rabies, were more abundant in rural environments.InterpretationRNA-Seq can effectively detect multiple infectious diseases simultaneously, facilitating geographical and epidemiological surveys of endemic viruses that could help direct healthcare interventions against emergent and pre-existent infectious diseases as well as cost-effectively and qualitatively characterising the health status of the population over time