The eight members of the FAM83 (FAMily with sequence similarity 83) family of poorly characterised proteins are only present in vertebrates and are defined by the presence of the conserved DUF1669 ...domain of unknown function at their N-termini. The DUF1669 domain consists of a conserved phospholipase D (PLD)-like catalytic motif. However, the FAM83 proteins display no PLD catalytic (PLDc) activity, and the pseudo-PLDc motif present in each FAM83 member lacks the crucial elements of the native PLDc motif. In the absence of catalytic activity, it is likely that the DUF1669 domain has evolved to espouse novel function(s) in biology. Recent studies have indicated that the DUF1669 domain mediates the interaction with different isoforms of the CK1 (casein kinase 1) family of Ser/Thr protein kinases. In turn, different FAM83 proteins, which exhibit unique amino acid sequences outside the DUF1669 domain, deliver CK1 isoforms to unique subcellular compartments. One of the first protein kinases to be discovered, the CK1 isoforms are thought to be constitutively active and are known to control a plethora of biological processes. Yet, their regulation of kinase activity, substrate selectivity and subcellular localisation has remained a mystery. The emerging evidence now supports a central role for the DUF1669 domain, and the FAM83 proteins, in the regulation of CK1 biology.
Abstract
Study question
To evaluate modified Applebaum uterine scoring system in predicting the uterine receptivity and clinical pregnancy rate?
Summary answer
The modified version of Applebaum ...uterine scoring system has sensitivity of 0.9411 and specificity of 0.5869 in predicting the uterine receptivity in embryo transfer cycle.
What is known already
The endometrial receptivity have been accepted to be major limiting factors in the establishment of pregnancy. Different techniques have been developed to evaluate endometrial receptivity, such as endometrial receptivity array or histological dating. The advantage of Ultrasound is it’s non-invasiveness, repeatability, real time monitoring and predictability.
Study design, size, duration
It is a prospective observational study. Study group comprises of 200 female with primary infertility over a period of 6 month.
Participants/materials, setting, methods
Exclusion criteria was patients associated with male sub-fertility or having uterine anomalies. The study was conducted at D.Y.Patil fertility centre, unit of Bloom IVF. All the patients were given uterine scoring before FET based on Endometrial thickness, morphology, vascularisation, myometrial echogenicity, uterine artery PI and EDF, myometrial blood flow.
Main results and the role of chance
The overall pregnancy rate was 54%. A perfect score of 20 was associated with 97.4% pregnancy rate. Scores of 17 to 19 was associated with the pregnancy rate of 85.4% and scores of 14 to 16 was associated with the pregnancy rate of 28.6%. Score less than 13 is not associated with any pregnancy. The Modified Applebaum scoring system showed the sensitivity of 0.9411 and specificity of 0.5869 in predicting the outcome of the cycle.
On an individual basis, endometrial morphology, end diastolic blood flow(EDF) and Pulsatility index(PI) of uterine artery and myometrial blood flow were found to be significant for a pregnancy on the basis of Z score and p value of < 0.01
Limitations, reasons for caution
As there were no case of secondary infertility, Grade III/IV endometriosis, endocrine disorder and uterine anomalies. The scoring system might not replicate the same results.
Wider implications of the findings
As the sensitivity and specificity of this uterine scoring system is quite good. It could be a good tool in assessing endometrium before embryo transfer.
Trial registration number
Not applicable
Small molecule inhibitors of type 1 receptor serine threonine kinases (ALKs1-7), the mediators of TGFß and BMP signals, have been employed extensively to assess their physiological roles in cells and ...organisms. While all of these inhibitors have been reported as “selective” inhibitors of specific ALKs, extensive specificity tests against a wide array of protein kinases have not been performed. In this study, we examine the specificities and potencies of the most frequently used small molecule inhibitors of the TGFß pathway (SB-431542, SB-505124, LY-364947 and A-83-01) and the BMP pathway (Dorsomorphin and LDN-193189) against a panel of up to 123 protein kinases covering a broad spectrum of the human kinome. We demonstrate that the inhibitors of the TGFß pathway are relatively more selective than the inhibitors of the BMP pathway. Based on our specificity and potency profile and published data, we recommend SB-505124 as the most suitable molecule for use as an inhibitor of ALKs 4, 5 and 7 and the TGFß pathway. We do not recommend Dorsomorphin, also called Compound C, for use as an inhibitor of the BMP pathway. Although LDN-193189, a Dorsomorphin derivative, is a very potent inhibitor of ALK2/3 and the BMP-pathway, we found that it potently inhibited a number of other protein kinases at concentrations sufficient to inhibit ALK2/3 and its use as a selective BMP-pathway inhibitor has to be considered cautiously. Our observations have highlighted the need for caution when using these small molecule inhibitors to assess the physiological roles of BMP and TGFß pathways.
► Selectivity and potency of common BMP and TGFß pathway inhibitors profiled against 123 human kinases. ► TGFß pathway inhibitors relatively more selective than BMP pathway inhibitors. ► SB-505124 recommended for use as TGFß pathway inhibitor. ► Dorsomorphin not suitable as a BMP-pathway inhibitor. ► Caution recommended when using LDN-193189 as a BMP pathway inhibitor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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•Little is known about antibiotics and herbicides in household greywater.•Samples were tested with LC/MS-MS for a wide suite of these compounds.•Antibiotics and herbicides were widely ...found in greywater influent.•Off-grid greywater reuse systems did not consistently remove these contaminants.•Concentrations were generally lower in irrigation pond water.
Greywater is increasingly treated and reused for agricultural irrigation in off-grid communities in the Middle East and other water scarce regions of the world. However, there is a dearth of data regarding levels of antibiotics and herbicides in off-grid greywater treatment systems. To address this knowledge gap, we evaluated levels of these contaminants in two types of greywater treatment systems on four farms in the West Bank, Palestinian Territories. Samples of household greywater (influent, n = 23), treated greywater effluent intended for agricultural irrigation (n = 23) and pumped groundwater held in irrigation water ponds (n = 12) were collected from October 2017 to June 2018. Samples were analyzed using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) for the following antibiotics and herbicides: alachlor, ampicillin, atrazine, azithromycin, ciprofloxacin, erythromycin, linezolid, oxacillin, oxolinic acid, penicillin G, pipemidic acid, sulfamethoxazole, triclocarban, tetracycline, triflualin, and vancomycin. All tested antibiotics and herbicides were detected in greywater influent samples at concentrations ranging from 1.3 to 1592.9 ng/L and 3.1–22.4 ng/L, respectively. When comparing influent to effluent concentrations, removal was observed for azithromycin, alachlor, linezolid, oxacillin, penicillin G, pipemidic acid, sulfamethoxazole, triclocarban, and vancomycin. Removal was not observed for atrazine, ciprofloxacin, erythromycin, oxolinic acid, tetracycline, and trifluralin. Pond water also contained the majority of tested contaminants, but at generally lower concentrations. To our knowledge, this is the first description of an extensive array of antibiotics and herbicides detected in household greywater from off-grid treatment systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nepal is one of the highest recipients of remittances (percentage of GDP) in the world. For a small land-locked economy battered by a decade-long Maoist insurgency (1996-2006), prolonged political ...instability, slow growth rate and large exodus of youths for employment overseas, high inflow of remittances bears a huge significance both at micro and macro levels. Exploring various facets of high migration and remittances, this article shows remittance-induced Dutch disease effects and policy laxity to improve investment climate in Nepal. Since it is costly to sterilise the impact of remittances each year, it might be prudent to learn to live with it and gradually channel remittances to productive usages with a goal to boost productivity.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Targeted protein degradation (TPD) is an exciting new modality for inducing target protein destruction in cells by harnessing cellular degradation pathways. However, to develop effective and ...selective degraders with clinical potential, there are many challenges, ranging from developing an effective, tissue-penetrant, and selective degrader to understanding its mode of action.Integrating cutting-edge proteomic workflows during degrader development and application can overcome many challenges facing TPD.Chemoproteomics aids degrader development and refinement through dissection of ligand–protein interactions, ligandability of targets, degrader–target engagement, and specificity of binding.Quantitative proteomics aids TPD by delineating the specificity of protein-of-interest (POI) degradation, off-target effects of degraders, biological consequences of POI degradation, and mechanism of degradation.Technological advances in instrumentation, sample preparation workflows, and data-processing power are poised to enable proteomics approaches to be more effective and accessible for TPD applications.
Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action.
Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining to both the development of effective, selective, and tissue-penetrant degraders and understanding their mode of action. In this review, we focus on progress made in addressing these challenges. In particular, we discuss the utility and application of recent proteomic approaches as indispensable tools to enable insights into degrader development, including target engagement, degradation selectivity, efficacy, safety, and mode of action.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infections with nontyphoidal Salmonella cause an estimated 19,336 hospitalizations each year in the United States. Sources of infection can vary by state and include animal and plant-based foods, as ...well as environmental reservoirs. Several studies have recognized the importance of increased ambient temperature and precipitation in the spread and persistence of Salmonella in soil and food. However, the impact of extreme weather events on Salmonella infection rates among the most prevalent serovars, has not been fully evaluated across distinct U.S. regions.
To address this knowledge gap, we obtained Salmonella case data for S. Enteriditis, S. Typhimurium, S. Newport, and S. Javiana (2004-2014; n = 32,951) from the Foodborne Diseases Active Surveillance Network (FoodNet), and weather data from the National Climatic Data Center (1960-2014). Extreme heat and precipitation events for the study period (2004-2014) were identified using location and calendar day specific 95
percentile thresholds derived using a 30-year baseline (1960-1989). Negative binomial generalized estimating equations were used to evaluate the association between exposure to extreme events and salmonellosis rates.
We observed that extreme heat exposure was associated with increased rates of infection with S. Newport in Maryland (Incidence Rate Ratio (IRR): 1.07, 95% Confidence Interval (CI): 1.01, 1.14), and Tennessee (IRR: 1.06, 95% CI: 1.04, 1.09), both FoodNet sites with high densities of animal feeding operations (e.g., broiler chickens and cattle). Extreme precipitation events were also associated with increased rates of S. Javiana infections, by 22% in Connecticut (IRR: 1.22, 95% CI: 1.10, 1.35) and by 5% in Georgia (IRR: 1.05, 95% CI: 1.01, 1.08), respectively. In addition, there was an 11% (IRR: 1.11, 95% CI: 1.04-1.18) increased rate of S. Newport infections in Maryland associated with extreme precipitation events.
Overall, our study suggests a stronger association between extreme precipitation events, compared to extreme heat, and salmonellosis across multiple U.S. regions. In addition, the rates of infection with Salmonella serovars that persist in environmental or plant-based reservoirs, such as S. Javiana and S. Newport, appear to be of particular significance regarding increased heat and rainfall events.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Commentary: Aotearoa New Zealand’s Parliament grounds have been reclaimed. All the streets around the buildings are again open to the public. Te Āti Awa have held a karakia to reinstall the mauri of ...the land. There is currently a rāhui over the Parliament grounds. It is time for healing. And moving on, writes a Māori Television videographer on reflection about the unprecedented hate directed at news media during the three-week occupation by anti-public health measures protesters. But after the unprecedented chaos that ended in a riot on Day 23—2 March 2022—he quotes a journalist who said, ‘I was feeling sad ... And then I look at Ukraine and realise there are bombs going off next to all these journalists and camera operators. I got hit with a camping chair and am I going to sit around and complain about it?
•Recommended and newer techniques of pharmaceutical waste management are presented.•Pharmaceutical waste generation, disposal and management techniques are discussed.•Objective evaluation of ...sustainability and eco-friendliness profiles is discussed.
Most households and healthcare facilities usually dispose of contaminated, unused, or expired (CUE) medicines with municipal wastes, the disposal of which usually amounts to $790/ton in the USA and £450/ton in the UK. Solid (e.g., tablets, capsules, powders) and semi-solid (e.g., ointment, creams) pharmaceuticals are managed with incineration/pyrolysis, encapsulation, and engineered landfills, whereas wastewater treatment plants (WWTPs) are recommended for liquid pharmaceutical wastes (PWs). However, to date, the sustainability and eco-friendliness profile of these techniques are only subjectively ensured, leading to controversial viewpoints in many guidelines. Each technique has relative strengths and weaknesses, and their comparative weighting to maximize these profiles is sought after. The present comprehensive review aims to fulfil knowledge gaps in this regard. Four electronic databases (e.g., PubMed/MEDLINE, Scopus, and ScienceDirect) were searched for PW management (PWM)-related qualitative and quantitative articles published till December 31, 2022. Articles without details of waste disposal techniques and their health and environmental impacts were excluded. Based on the literature review, we determine that incineration can be considered a sustainable option for solid and semi-solid PWs, and WWTPs can be eco-friendly for liquid PWs, whereas encapsulation and landfilling are less sustainable. It is high time that objectively proven sustainable and eco-friendly techniques be implemented for PWM based on their dosage forms or nature of hazards. Medicine take-back, eco-pharmacovigilance, extended producer responsibility, co-payment, and life cycle analysis of pharmaceuticals focusing on reduction, reuse/re-dispensing can be integrated to make existing models sustainable, circular, and eco-friendly.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Solving the existing energy crisis, alleviating poverty, and mitigating the potential impacts of climate change have garnered significant attention of policy makers in Nepal. In this context, this ...paper examines the causal relationships among energy consumption, pollution emission, and economic growth for Nepal employing time series econometric methodology. Both Johansen cointegration and ARDL (Autoregressive Distributed Lag) bounds tests suggest presence of two cointegrating vectors, one when energy consumption and the other when carbon emissions are used as dependent variables. The Granger causality tests suggest presence of long-run bidirectional causality running from energy consumption to carbon emission and vice-versa and a unidirectional causality running from economic growth to both carbon emissions and energy consumption. These findings imply that policies that boost energy consumption may not spur economic growth, rather are more likely to exert adverse effects on the environment. On the other hand, energy conservation and carbon emission reduction policies would not impede the long-run economic growth. Policies that focus on alternative energy may be an approach in favor of mitigating climate change impacts while protecting environmental health and without a cost to the country's long-run economic growth.
•We examine causal relationships among energy, income, and pollution in Nepal.•Both Johansen test and ARDL bounds test suggest presence of two cointegrating vectors.•A feedback causal relationship exists between carbon emissions and energy consumption in the long run.•There is a unidirectional long-run causality running from economic growth to both pollution emissions and energy consumption.•Energy conservation and carbon emission reduction policies may not deter economic growth.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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