Thermodynamic bounds on ultrasensitivity in covalent switching

Switch-like motifs are among the basic building blocks of biochemical networks. A common motif that can serve as an ultrasensitive switch consists of two enzymes acting antagonistically on a substrate, one making and the other removing a covalent modification. To work as a switch, such covalent modification cycles must be held out of thermodynamic equilibrium by continuous expenditure of energy. Here, we exploit the linear framework for timescale separation to establish tight bounds on the performance of any covalent-modification switch, in terms of the chemical potential difference driving the cycle. The bounds apply to arbitrary enzyme mechanisms, not just Michaelis-Menten, with arbitrary rate constants, and thereby reflect fundamental physical constraints on covalent switching.Comment: 29 pages, 6 figure

Tissue Determinants of Human NK Cell Development, Function, and Residence.

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT

ANTI CANCEROUS EFFICACY OF AYURVEDIC MILK EXTRACT OF SEMECARPUS ANACARDIUM NUTS ON HEPATOCELLULAR CARCINOMA IN WISTAR RATS

The objective of the study was to determine the anticancerous efficacy of Ayurvedic preparation made of Semecarpus anacardium (SA) nuts. Five groups of rats were used for the study. Group I served as water control. Hepatocellular carcinoma (HCC) was induced in groups II, III and IV animals using N-nitrosodiethylamine as inducing agent followed by phenobarbitone as promoter for 13 weeks. Group-II animals were kept untreated as hepatocellular carcinoma control. Group-III animals were treated with Ayurvedic milk extract of Semecarpus anacardium nuts at dose mentioned in Ashtangahridaya, an authentic book of Ayurveda for 49 days and group-IV animals were treated with doxorubicin as reference drug at dose of 1mg/kg twice a week for 7 weeks. Group V animals were kept as drug (SA nut milk extract) control for studying the effect of nut milk extract on normal rats. After 154 days of experiment, all animals were subjected to screening for HCC by estimation of liver enzymes, HCC marker (alpha-2 macroglobulin) and histopathology. Both liver enzymes and HCC marker were increased in hepatocellular carcinoma control along with neoplastic changes in liver and were decreased in Semecarpus anacardium nut milk extract treated group. The Ayurvedic drug showed positive correlation with the action of doxorubicin. This study demonstrated the efficacy of Semecarpus anacardium nut milk extract for the treatment of hepatocellular carcinoma either alone or along with chemotherapy

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases

Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations. Methods: Female C57Bl/6J mice at 6 weeks old were given free access to open voluntary running wheels for a period of 28 days and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls. Results: Following 5 days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina. Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype

Assessing potential locations for flood-based farming using satellite imagery: a case study of Afar region, Ethiopia

The dry lowlands of Ethiopia are seasonally affected by long periods of low rainfall and, coinciding with rainfall in the Amhara highlands, flood waters which flow onto the lowlands resulting in damage to landscapes and settlements. In an attempt to convert water from storm generated floods into productive use, this study proposes a methodology using remote sensing data and geographical information system tools to identify potential sites where flood spreading weirs may be installed and farming systems developed which produce food and fodder for poor rural communities. First, land use land cover maps for the study area were developed using Landsat-8 and MODIS temporal data. Sentinel-1 data at 10 and 20m resolution on a 12-day basis were then used to determine flood prone areas. Slope and drainage maps were derived from Shuttle RADAR Topography Mission Digital Elevation Model at 90m spatial resolution. Accuracy assessment using ground survey data showed that overall accuracies (correctness) of the land use/land cover classes were 86% with kappa 0.82. Coinciding with rainfall in the uplands, March and April are the months with flood events in the short growing season (belg) and June, July and August have flood events during the major (meher) season. In the Afar region, there is potentially >0.55m ha land available for development using seasonal flood waters from belg or meher seasons. During the 4 years of monitoring (2015–2018), a minimum of 142,000 and 172,000 ha of land were flooded in the belg and meher seasons, respectively. The dominant flooded areas were found in slope classes of <2% with spatial coverage varying across the districts. We concluded that Afar has a huge potential for flood-based technology implementation and recommend further investigation into the investments needed to support new socio-economic opportunities and implications for the local agro-pastoral communities

Rationale for Stereotactic Body Radiation Therapy in Treating Patients with Oligometastatic Hormone-Naïve Prostate Cancer

Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT) is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease

Benzothiazole analogues and their biological aspects: A Review

Heterocyclic compounds analogues have attracted strong interest in medicinal chemistry due to their pharmacological properties. Benzothiazole belongs to the heterocyclic class of bicyclic compounds. It is a combination of two rings six membered and five membered and both the rings are responsible for the therapeutic activity. Different methods are used to synthesize benzothiazole compounds and have been found to have numerous biological activities like – anticancer, antimicrobial, anti-inflammatory, anti-leishmanial, antidiabetic activity. This review is mainly an attempt to present the work reported in literature on pharmacological activity of benzothiazole compounds

Benzothiazole analogues and their biological aspects: A Review

1659-1669Heterocyclic compounds analogues have attracted strong interest in medicinal chemistry due to their pharmacological properties. Benzothiazole belongs to the heterocyclic class of bicyclic compounds. It is a combination of two rings six membered and five membered and both the rings are responsible for the therapeutic activity. Different methods are used to synthesize benzothiazole compounds and have been found to have numerous biological activities like – anticancer, antimicrobial, anti-inflammatory, anti-leishmanial, antidiabetic activity. This review is mainly an attempt to present the work reported in literature on pharmacological activity of benzothiazole compounds