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Abstract Background The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. Methods We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. Results We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. Conclusion Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.

Abstract The prevalence of bacterial digestive diseases in plateau animals has caused considerable losses to the Tibetan livestock industry. Therefore, this study aimed to isolate safe lactic acid bacteria (LAB) with beneficial probiotic properties to protect yaks from intestinal diseases. After 16S rDNA matching, four strains of Lactobacillus fermentum (A4), Pediococcus pentosaceus (A3.4 and A1.2), and Pediococcus acidilactici (B1.9) were isolated from the intestinal tissues and content of healthy yaks. The results indicated that A4 was more tolerant to bile salt (0.3%), while A3.4 had better stability in an acidic (pH = 3.0) environment. The results of the antibacterial activity test suggested that the isolates inhibited most pathogenic bacteria by up to 20%, except for A3.4, which inhibited Pasteurella and Staphylococcus aureus by more than 20%. Moreover, the results of the antioxidant test demonstrated that A4 and A3.4 had potent antioxidant activity. In addition, the drug sensitivity test revealed that the isolates were susceptible to commonly used antibiotics. In terms of safety, the isolates promoted growth, enhanced intestinal development, and protected the intestinal barrier without causing any adverse effects. In conclusion, LAB isolated from yak intestinal contents are potential probiotics with excellent antibacterial properties.

The traditional cubic B-spline method offers limited local control over the curve solution. Adjusting the position of a control point affects the entire curve, making it challenging to make localized changes, e.g., smoothness. Moreover, the basis functions vanish on one side by the cubic B-spline method near the end conditions where the initial and boundary conditions are applied. To address these limitations, this research proposes a new basis by including a free parameter γ with the purpose of modifying the weights of nearby control points. This free parameter γ can influence the curve’s behavior in specific regions as well as the entire curve. This modification of the cubic B-spline method was used to approximate the second-order derivative at each collocation point. The convergence test showed that the proposed method was second-order convergent. Numerical examples of ordinary differential equations were used with different step values to evaluate the accuracy of the proposed method. The findings persistently indicated that the proposed technique provided better error estimates as compared to the other methods discussed in the literatures.

Infective Endocarditis (IE) is associated with severe complications including cardiac failure, septic embolisation to distant organs, and significant mortality, if not promptly diagnosed and treated. It is therefore pertinent to perform diagnostic echocardiography in patients who have clinical suspicion of IE as it can reveal size and location of vegetations along with the extent of infection in the surrounding tissue and aid in confirming a therapeutic response. Vegetations in IE usually involve the valves but rarely may be located in the ventricles. Left atrial mural vegetation is a very rare condition. The common pathogen causing IE is Staphylococcus Aureus seen in more than half of the cases. Streptococcus Viridans is a less virulent organism, found as a part of normal oral, respiratory, gastrointestinal and genital bacterial flora but has the potential to cause invasive bacteremia and infections. A 20-year-old female presented with fever, palpitations, and shortness of breath on exertion for last 4 months. She then had developed sudden onset left sided body weakness and facial weakness. She had an ill-sustained heaving apex beat with grade 4 pan-systolic murmur at mitral area. There was upper motor left-sided uncrossed hemiplegia. Transesophageal echocardiography revealed anterior mitral leaflet vegetation along with 2 vegetations attached to the posterior left atrial wall and the jet of mitral valve regurgitation was directed to the posterior wall of the left atrium towards the vegetations. Blood cultures revealed gram-positive Streptococcus Viridians sensitive to vancomycin which was continued. MRI Brain revealed hypodense T1WS and hyperdense T2WS/FLAIR area in the right lentiform nucleus. The final diagnosis was Infective Endocarditis with left atrial mural vegetations due to Streptococcus Viridians, complicated by septic embolisation causing stroke. At 6-week follow up, she was clinically asymptomatic and a repeat echocardiography demonstrated resolution of the vegetations.

People residing in arid and semi-arid regions face significant challenges because of water scarcity and floods. These challenges become more severe in downstream areas of hill torrents that experience highly unpredictable periods of droughts and floods due to highly variable rainfall. Constructing small dams in hill torrents to capture rainwater from watersheds, mitigate flash floods, and recharge artificial groundwater is one of the solutions to address these issues in South Punjab. However, the success of rainwater harvesting (RWH) systems depends on their technical design and suitable site selection. To identify appropriate sites for small dams for rainwater harvesting, a combination of Geographical Information Systems (GIS), Remote Sensing (RS), and Multi-Criteria Decision Analysis (MCDA) has been utilized in the catchment of the Vidore Hill Torrent, Punjab, Pakistan. The primary goal of this study was to evaluate the use of RS and MCDA in developing a suitability map, in a data-scarce region that can be useful for hydrologists, decision-makers, and planners in quickly identifying areas with the highest potential for RWH. The model incorporated several factors, including slope, runoff depth, land use, soil texture, drainage density, and lineament density. Implementing this method could also support policy changes toward widespread adoption of RWH. HIGHLIGHTS Management of water scarcity in dry period and floods in wet days.; Optimal solutions of Rainwater harvesting (RWH).; Application of GIS and remote sensing Approach.; Ranking of water conservation sites.; Guiding principles for the Policy implications.;

AbstractThe inconsistent pattern of precipitation, a shift in the seasonality of river flows, and the early onset of snow and glacier melt in recent decades across river basins of High Mountain Asia (HMA) has compelled us to further investigate future variations in sources of runoff under projected climate change scenarios. This will help in determining the timing and magnitude of runoff components and this will help in management of future water resources. The current study employed the University of British Columbia Watershed Model (UBC WM) to estimate the spatiotemporal variations in simulated runoff components (i.e. snowmelt, glacier melt, rainfall-runoff, and baseflow) and their relative contribution to total runoff of Gilgit River regarding the baseline period (1981–2010) in near (2021–2050) and far future (2071–2100) under low (SSP1), medium (SSP2) and high (SSP5) emission scenarios. A significant increase in the magnitude of mean annual temperature and precipitation is expected in the near future (2021–2050) than far future (2071–2100) under most SSPs. Moreover, high-altitude stations of the Gilgit River basin are expected to experience more warming in the near and far future than low altitudes under all SSPs. On average, regarding the baseline period, the simulated runoff is projected to increase in the near (27%, 30%, and 33%) and far future (30%, 53%, and 91%) under SSP1, SSP2, and SSP5, respectively. Moreover, an early onset of snow/glacier melting is predicted in the far future due to an increase in summer air temperature and a decline in winter (DJF) precipitation. Besides, the rise in high altitude temperature is expected to cause the melting of snow/glaciers even above 6000 m elevation in the far future.

Abstract In recent years, there have been an attempt to develop safe and environmental friendly solvents to replace conventional solvents, and use for extraction bioactive compounds from natural sources. A current investigation involved the preparation of green, methanolic, and ultrasonic extracts of S. sclarea, and compared their phenolic profiling using HPLC–DAD, antibacterial, antioxidant, and enzyme inhibition activities. The HPLC–DAD analysis revealed that Rosmarinic acid was the main content in all extracts, with Ellagic acid only present in the green extract. The green extract exhibited superior anti-biofilm activity against S. Aureus and E. Faecalis compared to the other extracts at MIC concentration. Furthermore, the green extract also displayed the highest inhibition of swarming motility in P. Aeruginosa with inhibition range 68.0 ± 2.1 (MIC) to 19.5 ± 0.6 (MIC/4). and better enzyme inhibitory activity against BChE (with IC50 = 131.6 ± 0.98 µg/mL) and AChE (with inhibition 47.00 ± 1.50%) compared to the other extracts; while, the ultrasonic extract showed strong inhibition of violacein production by C. Violaceum with a inhibition range 05.5 ± 0.1 (MIC/32) to 100 ± 0.00 (MIC), followed by the green extract with a inhibition range 15.0 ± 0.5 (MIC/8) to 100 ± 0.00 (MIC), additionally, the ultrasonic and methanoic extracts showed significant activity against urease enzyme with (IC50 = 171.6 ± 0.95 µg/mL and IC5 0 = 187.5 ± 1.32 µg/mL) respectively. Both the green and methanolic extracts showed considerable antioxidant activities, as β-carotene-linoleic acid (IC50 = 5.61 ± 0.47 µg/mL and 5.37 ± 0.27 µg/mL), DPPH · (IC50 = 19.20 ± 0.70 µg/mL and 16.31 ± 0.23 µg/mL), ABTS ·+(IC50 = 8.64 ± 0.63 µg/mL and 6.50 ± 0.45 µg/mL) and CUPRAC (A0.5 = 17.22 ± 0.36 µg/mL and 12.28 ± 0.12 µg/mL) respectively, likewise the green extract performing better in metal chelating compared to the other extracts. The green extraction is reported as a cost effective and solvent free method for extracting natural products that produces compounds free of toxic chemicals. This could be the method to be used in the industries as a renewable method.

Methotrexate (MTX) is the cornerstone of therapy in the treatment of rheumatoid arthritis (RA). However, its efficacy and toxicity are variable and remain unpredictable. Interindividual variation in the metabolism of MTX by the enzyme folyl polyglutamate synthetase (FPGS) has been associated with response variability in RA. In this work, we propose the development of a FPGS phenotyping assay that can be evaluated as a tool for the prediction of efficacy and toxicity in patients with RA prior to initiating MTX therapy. FPGS activity was measured in erythrocyte lysate by monitoring methotrexate polyglutamate (MTX + Glun) formation using ultra-performance liquid chromatography tandem–mass spectrometry (UPLC/MS/MS). Erythrocyte FPGS activity was measured in newly diagnosed RA (n = 35) and osteoarthritis (n = 7) patients. The enzymatic assay was optimized for measuring FPGS activity in 25 µL of packed erythrocytes over two hours. The coefficient of variation for intra- and inter-day analysis was found to be 5% and 12%, respectively. The method was used to measure FPGS enzyme kinetics, resulting in a mean (SD) Km of 30.3 (4.8) µM and a Vmax of 612 (193) pmol MTX + Glu2/h/mL of packed erythrocytes. Mean (SD) erythrocyte FPGS activity in patients with RA was found to be 445.93 (344.50) pmol MTX + Glu2/h/mL and with a 26-fold difference in the range (range: 83–2179 pmol MTX + Glu2/h/mL) whereas for patients with OA, it was found to be 409.80 (157.66) pmol MTX + Glu2/h/mL with a 3.5-fold difference in the range (range: 200.95–683.93 pmol MTX + Glu2/h/mL). Monitoring erythrocyte FPGS activity may be a feasible strategy of phenotyping for methotrexate efficacy and toxicity in patients with RA.

Objectives: Microbes inoculated with organic and inorganic amendments influence the nutrient pool in soil. Herein, this study aimed to investigate the potential of a harmonized tripartite approach to improve nutrient accessibility, uptake, and wheat productivity in nutrient-deficient soil. Methods: The tripartite components consisted of Trichoderma harzianum (TRI), compost (Comp), and inorganic phosphorus (P) sources, including rock phosphate (RP) and single super phosphate (SSP). Under field conditions, the experiment was conducted in a randomized complete block design with three replications. The main plot treatments consist of two compost application rates: 0 and 10 tons ha−1. Subplot treatments included the application of TRI and inorganic phosphorus sources at the rates of 5 and 90 kg ha−1 for RP and SSP, respectively. Results: The findings demonstrated that the harmonized tripartite treatments significantly regulated nutrient accessibility, uptake, and wheat productivity, with promising effects observed in combinations such as TRI + SSP + Comp and TRI + RP + Comp. TRI + RP + Comp positively influenced plant height, spike length, and biomass, while TRI + SSP + Comp led to increased grain yield (4325 ± 54 kg ha−1) compared to control (2765 ± 33 kg ha−1). Moreover, TRI + SSP + Comp significantly improved soil organic matter from 1.20 ± 0.03 % (control) to 2.28 ± 0.11 % and P concentration from 3.95 mg kg−1 to 13.60 ± 0.11 mg kg−1. Notably, TRI + Comp treatment maximized the accessibility of micronutrients, including copper (Cu), zinc (Zn), and manganese (Mn), and showed the higher availability of iron (Fe) with a sole TRI application. Furthermore, TRI + RP + Comp significantly increased the uptake of P, Cu, Fe, Zn, and Mn by 510 %, 106 %, 111 %, 63 %, and 137 %, respectively. Multivariate and cluster analyses further confirmed the strong positive relationship among most variables, highlighting the efficacy of the harmonized treatments without any negative associations. Conclusion: These findings accentuated the potential of a harmonized tripartite approach to significantly improve soil fertility, nutrient uptake, and productivity in wheat crops under nutrient-deficient soil.

Climatic variations cause droughts which badly affect the environment. The study focused on monitoring droughts to aid decision-making and mitigate their negative impacts on water availability for agriculture and livelihoods in the face of increasing water demand and climate change. To assess the agricultural droughts, a new agricultural Standardized Precipitation Index (aSPI) was calculated which is not used earlier in Balochistan. Widely recommended Standardized Precipitation Index (SPI) and Standardized Precipitation Evapotranspiration Index (SPEI) were used for meteorological drought assessment. Drought indices comparison was also conducted to check the applicability. Rainfall, maximum temperature, and minimum temperature data (1992 to 2021) were utilized to calculate SPI, aSPI, and SPEI at different timescales (3, 6, 9, and 12 months) using DrinC software and SPEI calculator. Indices results revealed the following severe to extreme drought years: 1998, 1999, 2000, 2001, 2002, 2004, 2008, 2011, 2014, 2016, and 2017. It was determined that Dalbandin, Quetta, Sibi, Kalat, Khuzdar, and Zhob experienced higher extreme drought frequencies. Both long- and short-term drought durations were observed. Indices comparison showed that SPI is the most efficient drought index compared to aSPI and SPEI. This study offers valuable insights for managing water resources in the face of climate-induced droughts. HIGHLIGHTS This study reviews the literature studies on different drought indices.; Indices of aSPI, SPI, and SPEI were used for the drought assessment.; A comparison was made between the indices to select the best index.;

Watershed management is necessary to conserve water resources because the watershed hydrological processes are more affected by climate and land use change, resulting in the problems of droughts, floods, soil erosion, etc. This study determined suitable alternatives that can ensure viable strategies for tackling the climate change impacts at the Soan River Basin (SRB). A framework was applied to assess the impacts of climate change and land use/cover change (LUCC) using the Soil and Water Assessment Tool (SWAT). A multi-criteria decision analysis (MCDA) was used to prioritize watershed management alternatives by comparing watershed management criteria and alternatives using the analytic hierarchy process (AHP). Framework findings showed a 69 and 31% decline in runoff, and a 58 and 42% increment in evapotranspiration (ET) due to climate change and LUCC, respectively. The top prioritized suitable alternatives were water harvesting structure (WHS) and vegetative cover (VC). Suitability analysis showed that 63.61 and 16.56% area of the SRB were moderately to highly suitable for WHS, respectively. For soil and water management, VC has been found suitable to moderately suitable for 72.68 and 26.75% of the basin area, respectively. So, there should be adoption of such measures which will assist in configuring the climate adaptive strategies. HIGHLIGHTS Climate change and LUCC were assessed through a framework using the SWAT model.; AHP was used for watershed management via suitable alternatives.; Water harvesting structures and vegetative cover were found to be the best alternatives for watershed management.; The selected alternatives can mitigate the climate change impacts on the watershed and may supplement to improve management practices.;

Abstract Antibiotics are widely used to treat various diseases. However, growing evidence indicates that antibiotic therapy in human life increases the incidence of inflammatory bowel disease (IBD). Therefore, we need appropriate methods to reduce the incidence or symptoms of IBD. In this study, we used lincomycin hydrochloride to construct a gut microbial dysbiosis model in mice, and then, constructed an ulcerative colitis (UC) model. Meanwhile, we used Lactobacillus plantarum A3 from equine to treat UC in mice with gut microbial dysbiosis. The results showed that lincomycin hydrochloride had little effect on the small gut microbiota in mice, but had a more destructive effect on the large intestin. Lactobacillus plantarum A3 alleviated the symptoms of UC in mice, which was reflected in its significantly reduced spleen index and disease activity index (DAI) (p

Avian tibial dyschondroplasia (TD) is a skeletal disease affecting fast growing chickens, resulting in non-mineralized avascular cartilage. This metabolic disorder is characterized by lameness and reduced growth performance causing economic losses. The aim of this study was to investigate the protective effects of baicalin against TD caused by thiram exposure. A total of two hundred and forty (n = 240) one day-old broiler chickens were uniformly and randomly allocated into three different groups (n = 80) viz. control, TD, and baicalin groups. All chickens received standard feed, however, to induce TD, the TD and baicalin groups received thiram (tetramethylthiuram disulfide) at a rate of 50 mg/kg feed from days 4–7. The thiram induction in TD and baicalin groups resulted in lameness, high mortality, and enlarged growth-plate, poor production performance, reduction in ALP, GSH-Px, SOD, and T-AOC levels, and increased AST and ALT, and MDA levels. Furthermore, histopathological results showed less vascularization, and mRNA and protein expression levels of Sox-9, Col-II, and Bcl-2 showed significant downward trend, while caspase-9 displayed significant up-regulation in TD-affected chickens. After the TD induction, the baicalin group was orally administered with baicalin at a rate of 200 mg/kg from days 8–18. Baicalin administration increased the vascularization, and chondrocytes with intact nuclei, alleviated lameness, decreased GP size, increased productive capacity, and restored the liver antioxidant enzymes and serum biochemical levels. Furthermore, baicalin significantly up-regulated the gene and protein expressions of Sox-9, Col-II, and Bcl-2, and significantly down-regulated the expression of caspase-9 (p

Groundwater plays a major role in addressing the worldwide problem of water scarcity and food security. With a growing population and increasing urbanization, there is a rising demand for groundwater to meet agricultural and domestic water needs. A variety of advanced approaches are necessary to sustain groundwater management. This study investigated the age and origin of groundwater, as well as its relationship with anthropogenic and climatic factors. Stable isotopes were used, namely oxygen-18 (18O) and deuterium (2H) for the estimation of groundwater origin and radioactive isotopes of Tritium (3H) for the estimation of its age. The investigation of stable isotopes revealed that the aquifer is predominantly influenced by river water, with a minor contribution from rainwater. Furthermore, the analysis of radioactive isotopes revealed that the groundwater age ranges from 5 to 50 years old in most areas. Older groundwater is predominantly found in urban areas, while younger groundwater is present in agricultural and woodland regions. However, the presence of “old” water in the upper groundwater layers in urban areas is attributed to over-abstraction and limited natural recharge. The primary climatic factor that governs the age and origin of groundwater is rainfall upstream of the study area, which directly contributes to the river flows. The rainfall is high in the east but, due to urbanization, recharge is decreased. Consequently, old and river recharge groundwater is found in this area. These observations underscore the unsustainable and alarming use of groundwater in urban areas.

Precise coupling of two fundamental mechanisms, chondrogenesis and osteogenesis via angiogenesis, plays a crucial role during rapid proliferation of growth plates, and alteration in their balance might lead to pathogenic conditions. Tibial dyschondroplasia (TD) is characterized by an avascular, non-mineralized, jade-white “cartilaginous wedge” with impaired endochondral ossification and chondrocyte proliferation at the proximal end of a tibial bone in rapidly growing poultry birds. Developing vascular structures are dynamic with cartilage growth and are regulated through homeostatic balance among pro and anti-angiogenic proteins and cytokines. Pro-angiogenic factors involves a wide spectrum of multifactorial mitogens, such as vascular endothelial growth factors (VEGF), platelet-derived growth factors (PDGF), basic fibroblast growth factor (bFGF), placental growth factors, transforming growth factor-β (TGF-β), and TNF-α. Considering their regulatory role via the sonic hedgehog, notch-gridlock, and ephrin-B2/EphB4 pathways and inhibition through anti-angiogenic proteins like angiostatin, endostatin, decoy receptors, vasoinhibin, thrombospondin, PEX, and troponin, their possible role in persisting inflammatory conditions like TD was studied in the current literature review. Balanced apoptosis and angiogenesis are vital for physiological bone growth. Any homeostatic imbalance among apoptotic, angiogenetic, pro-angiogenic, or anti-angiogenic proteins ultimately leads to pathological bone conditions like TD and osteoarthritis. The current review might substantiate solid grounds for developing innovative therapeutics for diseases governed by the disproportion of angiogenesis and anti-angiogenesis proteins.

Recent improvements in time series studies of hydro-climatological variables have led to the belief that the effects of nonstationarity are substantial enough to call the idea of traditional stationary approaches into doubt. The mean and variability of annual and seasonal rainfall in Pakistan are changing due to anthropogenic climate change. With the use of stationary and nonstationary frequency analysis techniques, this study set out to assess the impacts of nonstationarity in Southern Punjab, Pakistan, over the historical period of 1970–2015 and the future periods of 2020–2060 and 2060–2100. Four frequency distributions, namely Generalized Extreme Value (GEV), Gumbel, normal, and lognormal, were used. The findings of the nonstationarity impact across Southern Punjab showed different kinds of impacts, such as an increase or reduction in the return level of extreme precipitation. In comparison to other distributions, GEV provided the finest fit. In Bahawalnagar, Bahawalpur, Multan, Rahim Yar Khan and DG. Khan, the annual nonstationarity impacts for the 100-year return level were increased up to 15.2%, 8.7%, 58.3%, 18.7%, and 20%, respectively. Moreover, extreme precipitation was found to be increasing during the historical and projected periods, which may increase floods, while less water availability appeared at a seasonal scale (summer) during 2061–2100. The increased nonstationarity effects emphasized adapting these nonstationarities induced by climate change into the design of water resource structures.

The objective of this study was to assess the rate of effectiveness of cervical cancer awareness outreach among Vietnamese women in San Diego, USA. In collaboration with different community partners, educational seminars were hosted by student pharmacists in the Vietnamese community. We hypothesized that the seminars would increase cervical cancer awareness and encourage a positive outlook on obtaining annual Pap smears and HPV vaccines. The study design included pre- and post-intervention assessment surveys in either Vietnamese or English language. The surveys were administered to Vietnamese women who participated in the seminars. Eight seminars were hosted at local health fairs in San Diego. A total of 120 Vietnamese women participated in the seminars. Our study showed that educational seminars significantly improved the knowledge about cervical cancer, Pap smears and HPV vaccines. By comparing the pre- and post-intervention surveys, we observed an improvement in knowledge about cervical cancer (61% vs 93%, p < 0.001) and a positive change in the attitude towards obtaining a Pap smear within a year following the educational intervention (57% vs. 78%, p < 0.002). Therefore, we concluded that the educational health outreach seminars presented by student pharmacists are an effective educational model to help improve knowledge about cervical cancer and prevention among Vietnamese women.

Utilization of satellite precipitation products (SPPs) for reliable flood modeling has become a necessity due to the scarcity of conventional gauging systems. Three high-resolution SPPs, i.e., Integrated Multi-satellite Retrieval for GPM (IMERG), Global Satellite Mapping of Precipitation (GSMaP), and Climate Hazards Group InfraRed Precipitation with Station (CHIRPS), data were assessed statistically and hydrologically in the sparsely gauged Chenab River basin of Pakistan. The consistency of rain gauge data was assessed by the double mass curve (DMC). The statistical metrics applied were probability of detection (POD), critical success index (CSI), false alarm ratio (FAR), correlation coefficient (CC), root mean square error (RMSE), and bias (B). The hydrologic evaluation was conducted with calibration and validation scenarios for the monsoon flooding season using the Integrated Flood Analysis System (IFAS) and flow duration curve (FDC). Sensitivity analysis was conducted using ±20% calibrating parameters. The rain gauge data have been found to be consistent with the higher coefficient of determination (R2). The mean skill scores of GSMaP were superior to those of CHIRPS and IMERG. More bias was observed during the monsoon than during western disturbances. The most sensitive parameter was the base flow coefficient (AGD), with a high mean absolute sensitivity index value. During model calibration, good values of performance indicators, i.e., R2, Nash−Sutcliffe efficiency (NSE), and percentage bias (PBIAS), were found for the used SPPs. For validation, GSMaP performed better with comparatively higher values of R2 and NSE and a lower value of PBIAS. The FDC exhibited SPPs’ excellent performance during 20% to 40% exceedance time.

Accumulating evidence indicated that oxidative stress is closely related to inflammation and the progression of multiple chronic diseases, which seriously threaten the host health. Currently, multiple plant-derived polysaccharides have been demonstrated to ameliorate the negative effects of oxidative stress on the host, but the potential protective effect of radix paeoniae alba polysaccharide (RPAP) on host have not been well characterized. Here, we investigated whether different doses of RPAP administration could alleviate lipopolysaccharide (LPS)-induced intestinal injury and gut microbial dysbiosis in mice. Results indicated that RPAP administration effectively alleviated LPS-induced intestinal damage in dose dependent. Additionally, amplicon sequencing showed that RPAP administration reversed the significant decrease in gut microbial diversity caused by LPS exposure and restored the alpha-diversity indices to normal levels. Microbial taxonomic investigation also indicated that LPS exposure resulted in significant changes in the gut microbial composition, characterized by a decrease in the abundances of beneficial bacteria (Lactobacillus, Alistipes, Bacillus, Rikenellaceae_RC9_gut_group, etc.) and an increase in the contents of pathogenic bacteria (Klebsiella, Helicobacter, Enterococcus, etc.). However, RPAP administration, especially in high doses, could improve the composition of the gut microbiota by altering the abundance of some bacteria. Taken together, this study demonstrated that RPAP administration could ameliorate LPS-induced intestinal injury by regulating gut microbiota. Meanwhile, this also provides the basis for the popularization and application of RPAP and alleviating oxidative stress from the perspective of gut microbiota.

Aflatoxin B1 (AFB1), the most harmful aflatoxins, is a frequent contamination in feed and food items, raising global concerns in animal production and human public health. Also, AFB1 induces oxidative stress, cytotoxicity, mutations, and DNA lesions through its metabolic transformation into aflatoxin B1–8,9-epoxide (AFBO) by cytochrome P450 (CYP450). Hedyotis diffusa (HD) is a traditional Chinese herbal medicine known for its multiple pharmacological activities, including antioxidant, anti-inflammatory, and immunomodulatory. Yet, the influence of HD on AFB1-induced liver injury in ducks is still unknown. Here, we investigated whether HD positively affects AFB1-induced liver injury in ducks. Results revealed that I) AFB1 caused significant changes in serum biochemical indices and decreased growth performance of ducks (such as ALT, AST, ALP, TP, ALB, final body weight, and body weight gain), whereas HD supplementation at 200 mg/kg mitigated these alterations. II) HD alleviated hepatic histopathological changes and liver index induced by AFB1 in ducks. III) HD significantly attenuated AFB1-induced oxidative stress, as measured by increased antioxidant enzyme activities such as SOD, GPx, and T-AOC and decreased MDA levels. Furthermore, HD reduced the level of AFB1-DNA adduct in duck liver. IV) HD significantly promoted the transcriptional expression of NF-E2-related nuclear factor 2 (Nrf2) and associated genes, including heme oxygenase 1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1), glutamate-cysteine ligase catalytic (GCLC). In conclusion, these results demonstrated that HD could activate the Nrf2 pathway in ducks to reduce the hepatotoxicity driven by AFB1. This finding also provides theoretical and data support for a deeper understanding of the toxic mechanisms of AFB1 and its prevention.

Glioblastoma is a high-grade aggressive neoplasm characterised by significant intra-tumoral spatial heterogeneity. Personalising therapy for this tumour requires non-invasive tools to visualise its heterogeneity to monitor treatment response on a regional level. To date, efforts to characterise glioblastoma’s imaging features and heterogeneity have focussed on individual imaging biomarkers, or high-throughput radiomic approaches that consider a vast number of imaging variables across the tumour as a whole. Habitat imaging is a novel approach to cancer imaging that identifies tumour regions or ‘habitats’ based on shared imaging characteristics, usually defined using multiple imaging biomarkers. Habitat imaging reflects the evolution of imaging biomarkers and offers spatially preserved assessment of tumour physiological processes such perfusion and cellularity. This allows for regional assessment of treatment response to facilitate personalised therapy. In this review, we explore different methodologies to derive imaging habitats in glioblastoma, strategies to overcome its technical challenges, contrast experiences to other cancers, and describe potential clinical applications.

Objective: To find out the frequency of anemia, agranulocytosis and thrombocytopenia in hyperthyroid patients after the use of propylthiouracil. Study Design: Cross sectional study. Place and Duration of Study: Out Door Patients Department and Pathology Laboratory in Liaquat University Medical & Health Sciences, Hospital Hyderabad/Jamshoro, from May 2016 to Apr 2017. Methodology: Two hundred cases, comprising of adult patients were categorized into five groups, age group 15-30 years 79 (39.5%) patients presenting the highest out of total, age group 31-45 years 68 (34%) patients, age group 46-60 years 36 (18%), age group 61-75 years 14 (7%) patients, age group >75 years 3 (1.5) patients. Complete blood count was analyzed on Sysmex Kx21 and thyroid profiles were analyzed on Elecysis 2010 from the Pathology Department. SPSS version 22 was used for data analysis. Result: Out of total patients, 32 (16%) were males and 168 (84%) were females with mean age of 37.44 ± 14.82 years. Majority of patients 68 (34%) were anemic, while 4 (2%) had agranulocytosis and 11 (5.5%) had thrombocytopenia. Headache was reported in 111 (55.5%), exophthalmos in 106 (53%), sore throat in 172 (86%), fever in 136 (68%) and weight loss in 95 (47.5%) patients. Conclusion: Propylthiouracil causes defective hematopoiesis in hyperthyroid patients because propylthiouracil has adverse suppressive effects on bone marrow.

Abstract Background: To assess the contributing factors to adherence of pharmacotherapy and perception of elderly patients. Methods: This prospective cross-sectional study was conducted in the outpatient clinic of Civil Hospital Badin, Pakistan from January to June 2019. A total of 300 samples were selected to analyze the results. A self-designed proforma (prescribing indicator form) was used for collecting data including patient demographics, diagnosis, and the current medications prescribed for each patient. Results: Of the 300 selected participants, 221(73.7%) were male, while 79 (26.3%) were female. Majority of the subjects in the age group of 60–69 (52%) and 70–79 years (27%) followed by those aged > 79 (21%). Antibiotics were prescribed to 17.2% and vitamins to 14.7%. Patients' responses related to nonadherence factor were 92.7% for the cost, 32.7% for the long treatment duration, and 24% for the lack of knowledge. Out of the total patients, 28% were forgetful, 26.7% complained about complex therapy, 26.3% blamed financial problems, 19.7% patients had side effects, and 14.3% were negligent in taking the medication. Conclusion: Patient conformity can be enhanced by dropping polypharmacy and simplifying complex management, use of extended formulations, rate of medications, and by creating awareness among elderly patients.

Abstract Background: Lack of appropriate treatment for COVID-19 infection led the general population of Pakistan toward self-medication and symptomatic treatment; almost 80% of the population collected medications for future use during pandemic. Thus, the current study aimed to assess the use of medication as symptomatic treatment preventive strategy. Methods: This descriptive cross–sectional study was conducted on a local population of Hyderabad and Karachi, Sindh, Pakistan. The study duration was six months (April–September 2020). A total of 698 responders were selected via random sampling method. The number of participants were recruited based on 95% confidence interval with 5% margin error. Data were transferred into analysis sheet descriptively. Results: Most participants responded to the use of different over-the-counter (OTC) products for headache. The use of antibiotics with prescription due to allergic conditions, cough, respiratory tract infections including sore throat, and urinary tract infections was also found among the majority. Few respondents had self-medication practice with sedatives due to difficulty in falling asleep, and 9.5% had self-medication practice due to pain. About 20.8% of the population agreed that lockdown was a contributing factor in the self-medication practice. Conclusion: Pharmacists and healthcare professionals are advised to counsel the general public regarding the use of medication. A close collaboration is required at this stage to fight against COVID-19 and preventing the situation from worsening.

Thiram is a dithiocarbamate pesticide widely used in agriculture as a fungicide for storing grains to prevent fungal diseases. However, its residues have threatened the safety of human beings and the stability of the ecosystem by causing different disease conditions, e.g., tibial dyschondroplasia (TD), which results in a substantial economic loss for the poultry industry. So, the research on TD has a great concern for the industry and the overall GDP of a country. In current study, we investigated whether different concentrations (300, 500, and 700 mg/kg) of sodium butyrate alleviated TD induced under acute thiram exposure by regulating osteogenic gene expression, promoting chondrocyte differentiation, and altering the gut microbial community. According to the findings, sodium butyrate restored clinical symptoms in broilers, improved growth performance, bone density, angiogenesis, and chondrocyte morphology and arrangement. It could activate the signal transduction of the Wnt/β-catenin pathway, regulate the expression of GSK-3β and β-catenin, and further promote the production of osteogenic transcription factors Runx2 and OPN for restoration of lameness. In addition, the 16S rRNA sequencing revealed a significantly different community composition among the groups. The TD group increased the abundance of the harmful bacteria Proteobacteria, Subdoligranulum, and Erysipelatoclostridium. The sodium butyrate enriched many beneficial bacteria, such as Bacteroidetes, Verrucomicrobia, Faecalibacterium, Barnesiella, Rikenella, and Butyricicoccus, etc., especially at the concentration of 500 mg/kg. The mentioned concentration significantly limited the intestinal disorders under thiram exposure, and restored bone metabolism.

Change in seasonal snowfall and glaciers ablation control year-to-year variations in streamflows of the Upper Indus Basin (UIB) and hence ultimately impacts the water availability in downstream areas of UIB. This situation calls for an urgent response to study the long-term variations in runoff components in response to climate change. The current study investigates the spatiotemporal variations in runoff and runoff components in response to climate change to the streamflows of the Gilgit River from 1981 to 2020 by using the University of British Columbia Watershed Model (UBC WM). Three statistical indices such as the Nash–Sutcliffe efficiency (NSE), the coefficient of determination (R2), and the correlation coefficient (CC) were used to evaluate the performance of UBC WM in simulating the streamflows against observed streamflows. According to statistical indices, the UBC WM performed fairly well during both calibration (1981–2000: R2 = 0.90, NSE = 0.87, and CC = 0.95) and validation periods (2001–2015: R2 = 0.86, NSE = 0.83, and CC = 0.92). Trend analysis revealed a significant increase in all runoff components with large interannual variations in their relative contributions to streamflows from 1981 to 2020. From 1981 to 2020, the average relative contribution of snowmelt, glacier melt, rainfall-runoff, and baseflow was estimated to be 25%, 46%, 5%, and 24%, respectively to the streamflows of the Gilgit River. Seasonal analysis showed that about 86% of total runoff was contributed to the Gilgit River during the summer season (April–September) while only 14% in the winter season (October–March). Further analysis of runoff at a spatial scale revealed that approximately 76% of the total runoff of Gilgit River is generated between elevations from 3680 to 5348 m while 19% of total runoff is generated at an elevation 5348 m. Moreover, it was observed that groundwater contribution from soil lower zone (i.e., 76%) to streamflows was found greater than soil upper zone (i.e., 24%). The outcomes of this study will help the water resource managers and hydrologists to manage the water resources in downstream areas of the UIB for local consumption, industrial use, and agriculture.

Abstract Background Diarrhea is an important ailment limiting the production of the Tibetan pig industry. Dynamic balance of the intestinal microbiota is important for the physiology of the animal. The objective of this work was to study fungal diversity in the feces of early weaning Tibetan piglets in different health conditions. Results In the present study, we performed high-throughput sequencing to characterize the fungal microbial diversity in healthy, diarrheal and treated Tibetan piglets at the Tibet Autonomous Region of the People’s Republic of China. The four alpha diversity indices (Chao1, ACE, Shannon and Simpson) revealed no significant differences in the richness across the different groups (P > 0.05). In all samples, the predominant fungal phyla were Ascomycota, Basidiomycota and Rozellomycota. Moreover, the healthy piglets showed a higher abundance of Ascomycota than the treated ones with a decreased level of Basidiomycota. One phylum (Rozellomycota) showed higher abundance in the diarrheal piglets than in the treated. At genus level, compared with that to the healthy group, the proportion of Derxomyces and Lecanicillium decreased, whereas that of Cortinarius and Kazachstania increased in the diarrheal group. The relative abundances of Derxomyces, Phyllozyma and Hydnum were higher in treated piglets than in the diarrheal ones. Conclusions A decreased relative abundance of beneficial fungi (e.g. Derxomyces and Lecanicillium) may cause diarrhea in the early-weaned Tibetan piglets. Addition of probiotics into the feed may prevent diarrhea at this stage. This study presented the fungal diversity in healthy, diarrheal and treated early-weaned Tibetan piglets.

Abstract Background: Drug stores in Pakistan are run by dispensers with varied knowledge, qualification, and experience. The current study was sought to explore the knowledge, qualification, experience, and dispensing practices among dispensers working in drugstores in South Karachi, Pakistan. Methods: A cross-sectional survey was carried out using a structured questionnaire. Data were collected from medical stores in South Karachi which were then categorized, coded, and analyzed using SPSS version 23. Relationship among different study variables with pharmacist's availability and personal experience was assessed using statistical non-parametric Chi-square test. A total of 385 samples obtained using a simple random sampling method were included in the study. However, only 210 responses on questionnaire were complete which were then selected for study analysis between October and December 2018. Results: Of the 210 surveyed drugstores, 9% of their staff had studied only till primary school, 5.7% till the eighth grade, 25.2% up to secondary school level, 26.7% till higher secondary school level, 15.7% had non-professional education, and 8.1% were professional graduate. Only 9% of them had a degree in Pharm. D or B. Pharm, while 0.5% had a post-graduation qualification. Furthermore, 44.8% of pharmacies had a valid pharmacy license but the pharmacist was physically absent in 91% of the drugstores. Majority of pharmacies did not maintain appropriate temperature (refrigerator and/or room temperature). Majority of dispensers did not review prescription particulars before dispensing medications and also dispensed medications on older prescriptions as well as without prescription. Conclusion: In conclusion, the overall knowledge and practices of dispensers working in drugstores was poor. However, the presence of pharmacist was associated with good dispensing practices to a certain extent.

Abstract The studies of metal oxides in environmental remediation of chemical and biological pollutants are gaining colossal importance. Herein, we report the facile synthesis of multifunctional copper oxide nanosheets (CuO NS) using an aqueous extract of Rhazya stricta. The phytochemical investigation of R. stricta indicated the presence of saponins, tannins, and reducing sugars, responsible for the reduction and stabilization of CuO NS. A UV–Visible spectrophotometer initially confirmed the fabrication of CuO NS with specific Surface Plasmon Resonance at 294 nm. Field Emission Scanning Electron Microscopy (FE-SEM), Fourier-transform infrared spectroscopy FTIR, and XRD were further used to characterize the CuO NS. The obtained CuO NS were poly-dispersed with an average size of 20 nm. Interestingly these particles were aligned together in 3D cubical sheets layered above each other via self-assembly. The as-synthesized CuO NS showed enhanced antibacterial potential (17.63 mm, overall mean inhibition zone) in comparison to the known antibiotics (11.51 mm, overall mean inhibition zone) against both Solanaceous crop's wilt-causing bacteria (Ralstonia solanacearum and Clavibacter michiganensis). Furthermore, the appreciable photocatalytic potential of CuO NS has also been observed, causing 83% degradation of methylene blue (MB) upon solar irradiation. The synthesis methodology is devoid of any toxic waste or by-products. It could be used to produce eco-friendly CuO nanomaterial for industrial uses.

The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the human liver transcriptome but their role in hepatitis B virus infection is largely unknown. Here, Zhuang et al. show that REV-ERB regulates hepatitis B virus entry and BMAL1 directly binds HBV DNA and activates viral genome transcription.

Land cover change (LCC) and climate change (CC) impacts on streamflow in high elevated catchments are a great challenge to sustainable management and the development of water resources. This study evaluates the possible future impacts of both land cover and climate change on the streamflows in the Mohmand Dam catchment, Pakistan, by utilizing the semi-distributed hydrological model known as the Soil and Water Assessment Tool (SWAT), along with the latest Coupled Model Intercomparison Project phase 6 (CMIP6) dataset of different global climate models (GCMs). The downscaling of the precipitation and temperature data was performed by the CMhyd software. The downscaled precipitation and temperature projections from the best performing GCM, out of four GCMs, under two shared socioeconomic pathways (SSP2 and SSP5) and future land cover conditions were forced in a calibrated hydrological model (SWAT model). Compared to the baseline period (1990–2015), the outputs from the selected GCM indicated an increase in the average monthly precipitation, and the maximum and minimum temperature in the study area under both the SSP2 and SSP5 scenarios, by the end of the 21st century. It is expected that the increase in precipitation for the period 2016–2100 is 10.5% and 11.4% under the SSP2 and SSP5 scenarios, respectively. Simulated results from the SWAT model showed significant impacts from the projected climate and land cover changes on Mohmand Dam flows that include: (a) an increase in the overall mean annual flow ranging from 13.7% to 34.8%, whereas the mean monthly flows of June, July and August decreased, and (b) a shift in the peak flows in the Mohmand catchment from July to June. It is concluded that the projected climate changes can substantially influence the seasonality of flows at the Mohmand Dam site. Climate and land cover change impacts are significant, so project planners and managers must include CC and LCC impacts in the proposed operational strategy.

The current study was aimed to investigate the alleviative effect of Artemisia brevifolia (A. brevifolia) plant extract against CCl4-induced testicular damage in male albino rats. Forty-eight male albino rats were categorized into eight equal experimental groups i.e., control, vehicle control, CCl4 (1 ml/kg), CCl4 + silymarin, CCl4 + A. brevifolia (150 mg/kg), CCl4 + A. brevifolia (300 mg/kg), A. brevifolia (150 mg/kg) and A. brevifolia (300 mg/kg). After 56 days, blood and testicular samples were collected, and antioxidant enzyme activity, lipid peroxidation, hormonal concentration, daily sperm production (DSP), and histomorphometry were analyzed. The animals treated with the A. brevifolia extract exhibited a significant (p

Abstract Background The gut microbiota is a complex ecosystem, which is essential for the metabolism, health and immunity of host. Many diseases have been shown to be closely related to the alteration of intestinal flora. Aeromonas veronii as a conditioned pathogen can cause disease in Yangtze finless porpoise through intestinal infections. However, it is not clear whether the disease caused by Aeromonas veronii is related to changes of intestinal flora. In the current study, the diversity and composition of gut microbiota in the healthy and Aeromonas veronii-infected Yangtze finless porpoise were evaluated by high-throughput sequencing to further investigate the potential association between intestinal flora alteration and pathogen invasion. Results A total of 127,3276 high-quality sequences were achieved and 2465 operational taxonomic units (OTUs) were in common among all samples. The results of alpha diversity showed that there was no obvious difference in richness and diversity between healthy and Aeromonas veronii-infected Yangtze finless porpoise. Firmicutes, Bacteroidetes and Proteobacteria were the most dominant phyla in all samples. In addition, the healthy Yangtze finless porpoise exhibited higher abundance of Firmicutes and Fusobacteria than Aeromonas veronii-infected Yangtze finless porpoise, while, the level of Proteobacteria was decreased. At the genus level, Paeniclostridium and Paraclostridium were the predominant bacteria genera in the CK (healthy Yangtze finless porpoise) group. In the DIS (Aeromonas veronii-infected Yangtze finless porpoise) group, Lactobacillus and unidentified_Enterobacteriaceae were the dominant bacteria genera and the proportion of Paeniclostridium, Paraclostridium, Terrisporobacter, Cetobacterium, Candidatus Arthromitus, Terrabacter and Dechloromonas were reduced. Conclusions In conclusion, our results showed that Aeromonas veronii infection can alter the gut microbiota of the Yangtze finless porpoise by affecting the number of harmful bacteria and beneficial bacteria.

BACKGROUND: Although tyrosine kinase inhibitors (TKIs) are the gold standard in clinical management of chronic myeloid leukemia, it is not feasible to use these drugs in at least some cases when patients are resistance to all available TKIs due to compound BCR-ABL mutations, due to patient safety profile or due to the nonavailability of drugs in developing countries on account of cost or logistic issues. We reported earlier that interferon alpha can eradicate compound BCR-ABL mutations and induce stable responses. Here, we report a follow-up of this study. PATIENTS AND METHODS: Some chronic myeloid leukemia (CML) patients did not get TKIs directly because of very high cost of imatinib and were given interferon alpha (experimental group) until the provision of imatinib free of cost through GLIVEC® International Patient Assistance Program while the other groups of patients (control group) were directly given imatinib. A very sensitive allele-specific polymerase chain reaction was employed to detect BCR-ABL compound mutations before treatment and confirmation of mutations was carried out using reliable molecular assays. Mutations were reinvestigated at all important time points during the long-term follow-up studies. RESULTS: The use of interferon-alpha for 6 months prior to TKIs eradicated compound BCR-ABL mutations (Phe311Val/Met351Thr and Thr315Ile/Phe311Val/Met351Thr) and provided deep molecular responses without any progression or mortality in CML patients (experimental group) as compared with patients who did not use interferon and was directly given TKIs (control group). CONCLUSIONS: Interferon alpha can eradicate highly resistant BCR-ABL mutations and lead to durable deep molecular responses to TKIs in CML. Therefore, interferon-alpha is recommended for CML patients with compound mutations resistant to TKIs, specifically in those scenarios where some TKIs are not available or not safe to use for CML patients. Our long-term follow-up study is well supported by recently published literature.

Published in August 2021

Many biological studies of transcriptional control mechanisms produce lists of genes and non-coding genomic intervals from corresponding gene expression and epigenomic assays. In higher organisms, such as eukaryotes, genes may be regulated by distal elements, with these elements lying 10s–100s of kilobases away from a gene transcription start site. To gain insight into these distal regulatory mechanisms, it is important to determine comparative enrichment of genes of interest in relation to genomic regions of interest, and to be able to do so at a range of distances. Existing bioinformatics tools can annotate genomic regions to nearest known genes, or look for transcription factor binding sites in relation to gene transcription start sites. Here, we present PEGS (Peak set Enrichment in Gene Sets). This tool efficiently provides an exploratory analysis by calculating enrichment of multiple gene sets, associated with multiple non-coding elements (peak sets), at multiple genomic distances, and within topologically associated domains. We apply PEGS to gene sets derived from gene expression studies, and genomic intervals from corresponding ChIP-seq and ATAC-seq experiments to derive biologically meaningful results. We also demonstrate an extended application to tissue-specific gene sets and publicly available GWAS data, to find enrichment of sleep trait associated SNPs in relation to tissue-specific gene expression profiles.

A field experiment was conducted during the Rabi season 2017–2018 (October–March) at the University of Agriculture, Peshawar research farm to examine the influence of different nitrogen (N) and phosphorus (P) levels on two different oat varieties: Australian and Ukrainian. The treatments included control and three levels of nitrogen and phosphorus at 30, 60, and 90 kg ha−1. The treatments were arranged in randomized complete block design (RCBD) and replicated three times. The findings showed that the oat varieties were significantly different from one another in yield and yield parameters. The Australian variety recorded higher emergence (49 plants m−2), days to emergence (15 days), days to flowering (122 days), days to maturity (145 days), plant height (142.7 cm), number of leaves (6.03 leaves plant−1), number of tillers (92.2 tillers m−1), biological yield (8,179.2 kg ha−1), and grain yield (3,725.6 kg ha−1) than the Ukrainian variety. Similarly, different N and P levels, the maximum days to emergence, days to flowering, and days to maturity were recorded in a control plot. The application of 105 kg N + 90 kg P ha−1 was statistically similar to the application of 105 kg N + 60 kg P ha−1. Maximum emergence (60 plants m−2), number of leaves (7.0 leaves plant−1), plant height (118.6 cm), number of tillers m−1 (102.6), biological yield (9,687.5 kg ha−1), and grain yield (4,416.7 kg ha−1) were determined in Australian variety. Based on the findings of this study, the Australian variety performed better in terms of yield and yield components and the application of N and P fertilizers at the rate of 105 kg N + 60 kg P ha−1 produced the best results in both oat varieties.

Yaks (Bos grunniens) live primarily in high-altitude hypoxic conditions and have a unique intestinal micro-ecosystem, remarkable adaptability, and strong climatic resistance. Accumulating evidence revealed the importance of probiotics in host metabolism, gut microbiota, growth performance, and health. The goal of this study was to screen out probiotics with excellent probiotic potential for clinical application. In this study, four strains of Bacillus, i.e., Bacillus proteolyticus (named Z1 and Z2), Bacillus amyloliquefaciens (named J), and Bacillus subtilis (named K), were isolated and identified. Afterward, their probiotic potential was evaluated. Antioxidant activity tests revealed that Z1 had the highest DPPH and hydroxyl radical scavenging activity, whereas Z2 had higher reducing power and inhibited lipid peroxidation. Additionally, the antibacterial testing revealed that all strains were antagonistic to three indicator pathogens, Escherichia coli C83902, Staphylococcus aureus BNCC186335, and Salmonella enteritidis NTNC13349. These isolates also had a higher hydrophobicity, autoaggregation, and acid and bile tolerance, all of which helped to survive and keep dangerous bacteria out of the host intestine. Importantly, all strains could be considered safe in terms of antibiotic susceptibility and lack of hemolysis. In conclusion, this is the first study to show that B. proteolyticus and B. amyloliquefaciens isolated from yaks have probiotic potential, providing a better foundation for future clinical use.

The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.

Tibial dyschondroplasia debilities apoptotic and inflammasomal conditions that can further destroy chondrocytes. Inflammasomes are specialized protein complexes that process pro-inflammatory cytokines, e.g., interleukin-1β (IL-1β) and IL-18. Moreover, there is mounting evidence that many of the signaling molecules that govern programmed cell death also affect inflammasome activation in a cell-intrinsic way. During the last decade, apoptotic functions have been described for signaling molecules involving inflammatory responses and cell death pathways. Considering these exceptional developments in the knowledge of processes, this review gives a glimpse of the significance of these two pathways and their connected proteins in tibial dyschondroplasia. The current review deeply elaborates on the elevated level of signaling mediators of mitochondrial-mediated apoptosis and the inflammasome. Although investigating these pathways’ mechanisms has made significant progress, this review identifies areas where more study is especially required. It might lead to developing innovative therapeutics for tibial dyschondroplasia and other associated bone disorders, e.g., osteoporosis and osteoarthritis, where apoptosis and inflammasome are the significant pathways.

Brucellosis is a bacterial zoonotic disease that affects many animal species and can be transmitted to humans via direct contact or via contaminated food. Although brucellosis is a serious health hazard, its public health concern has been neglected in many countries. In some developing countries, such as Pakistan, where brucellosis is endemic, this disease continues to be of importance. A literature search for the past 11 years (2011–2021) provided a comprehensive insight into brucellosis in Pakistan. In this review, particular emphasis was placed on occurrence, diagnostic tests used, and prevention, treatment, and control in the context of the “One Health” approach.

Many biological studies of transcriptional control mechanisms produce lists of genes and non-coding genomic intervals from corresponding gene expression and epigenomic assays. In higher organisms, such as eukaryotes, genes may be regulated by distal elements, with these elements lying 10s–100s of kilobases away from a gene transcription start site. To gain insight into these distal regulatory mechanisms, it is important to determine comparative enrichment of genes of interest in relation to genomic regions of interest, and to be able to do so at a range of distances. Existing bioinformatics tools can annotate genomic regions to nearest known genes, or look for transcription factor binding sites in relation to gene transcription start sites. Here, we present PEGS (Peak set Enrichment in Gene Sets). This tool efficiently provides an exploratory analysis by calculating enrichment of multiple gene sets, associated with multiple non-coding elements (peak sets), at multiple genomic distances, and within topologically associated domains. We apply PEGS to gene sets derived from gene expression studies, and genomic intervals from corresponding ChIP-seq and ATAC-seq experiments to derive biologically meaningful results. We also demonstrate an extended application to tissue-specific gene sets and publicly available GWAS data, to find enrichment of sleep trait associated SNPs in relation to tissue-specific gene expression profiles.

Q fever remains a neglected zoonosis in many developing countries including Pakistan. The causing agent Coxiella (C.) burnetii is resistant to environmental factors (such as drying, heat and many disinfectants), resulting in a long-lasting infection risk for both human and animals. As the infection is usually asymptomatic, it mostly remains undiagnosed in animals until and unless adverse pregnancy outcomes occur in a herd. In humans, the infection leads to severe endocarditis and vascular infection in chronic cases. Limited data are available on molecular epidemiology and evolution of this pathogen, especially in ruminants. Genomic studies will help speculating outbreak relationships in this scenario. Likewise, pathogenesis of C. burnetii needs to be explored by molecular studies. Awareness programs and ensuring pasteurization of the dairy milk before human consumption would help preventing Q fever zoonosis.

In Pakistan, groundwater resources are depleting at an alarming rate due to intensive pumping, shifting of cropping patterns, and climate change vulnerability. The present study is aimed at investigating groundwater stress in the command area of Lower Chenab Canal (LCC) and associated branch canals. Groundwater stress is determined by considering the cropping patterns, surface water availability, groundwater levels, climatic variation, and crop water requirement (CWR) in the LCC command area. The climatic data is obtained from the Pakistan Meteorological Department (PMD) from 1990 to 2020. The records of temporal variation in cropping patterns are obtained from the Crop Reporting Service (CRS), Directorate of Agriculture, Lahore for the 1995–2020 period and classified according to Rabi season (November to April) and Kharif season (May to October). The LCC surface water flows data and groundwater levels are collected from the Punjab Irrigation Department (PID) Lahore from 2003 to 2018 and from 1995 to 2016, respectively. The CWR is estimated using the Cropwat 8.0 model and groundwater levels are estimated using the Inverse Distance Weighted (IDW) tool of ArcGIS software. It has been determined that Faisalabad, Sheikhupura, and Toba Tek Singh are highly groundwater stress cities having an average drawdown rate of 0.58 m/year. The surface water availability is also decreased from 7.75 to 4.81 billion cubic meters (Bm3) for the Kharif season whilst 4.17 to 2.63 Bm3 for the Rabi season. This study concluded that due to severe conditions in highly stressed areas, policy planners, decision-makers, and stakeholders should sincerely take some steps for maintaining groundwater levels either by capacity building workshops for the farmers or limiting the number of tubewells.

Domestic yaks (Bos grunniens) are indigenous to the Tibetan Plateau and display a high diarrhea rate due to poor habitat and husbandry conditions. Lactobacillus has been shown to exert beneficial effects as antimicrobial, growth promotion, and gut microbiota in humans and/or murine models, but the relevant data regarding Lactobacillus isolated from yaks was unavailable. Therefore, this study aimed to investigate the effects of Lactobacillus from yaks on the intestinal microbial community in a mouse model and determine whether Lactobacillus supplementation contributed in alleviating diarrhea by modulating gut microbiota. A total of 12 ileac samples from four groups were collected for 16S rRNA gene amplicon sequencing of V3-V4 region. Results revealed that although Lactobacillus supplementation did not change the diversity of gut microbiota in mice, the proportion of some intestinal microbiota significantly changed. Specifically, the proportion of Lactobacillus and Sphingomonas in the Lactobacillus treated-group (L-group) were increased as compared to control group (C-group), whereas Pantoea, Cutibacterium, Glutamicibacter, Turicibacter, Globicatella, Microbacterium, Facklamia, unidentified_Corynebacteriaceae, Brachybacterium, and Staphylococcus were significantly decreased in the L-group. In contrast, Escherichia coli (E. coli) infection significantly decreased the proportion of beneficial bacteria such as Globicatella, Acinetobacter, Aerococcus, and Comamonas, while loads of pathogenic bacteria significantly increased including Roseburia and Megasphaera. Interestingly, Lactobacillus administration could ameliorate the microbial community structure of E. coli-induced diarrheal mice by reducing the relative abundance of pathogenic bacteria such as Paenibacillus, Aerococcus, Comamonas, Acinetobacter, Corynebacterium, Facklamia, and Globicatella. Results in this study revealed that Lactobacillus supplementation not only improved the gut microbiota but also alleviated diarrhea in mice, which may be mediated by modulating the composition and function of gut microbiota. Moreover, this study is expected to provide a new theoretical basis for the establishment of a preventive and treatment system for diarrhea in yaks.

ObjectivesThe persistence pattern of anti-migraine drugs' use among migraineurs is very low in the United States and different European countries. However, the cost and persistence of antimigraine drugs in Asian countries have not been well-studied. Hence, the present study aimed to evaluate the treatment cost and persistence among migraineurs in Pakistan.MethodsData from prescriptions collected from migraineurs who visited the Outpatient Department (OPD) of different public and private sector tertiary-care hospitals of Karachi, Pakistan were used to conduct this retrospective cohort study from 2017 to 2019. The minimum follow up period for each migraineur was about 12 months for persistence analysis while dropped-out patients data were also included in survival analysis as right censored data. Pairwise comparisons from Cox regression/hazards ratio were used to assess the predictors of persistence with the reference category of non-binary variables i.e. hazard ratio = 1 for low frequency migraineurs and NSAIDs users. Persistence with anti-migraine drugs was estimated using the Kaplan-Meier curve along with the Log Rank test.ResultsA total of 1597 patients were included in this study, 729 (45.6%) were male and 868 (54.3%) were female. Non-steroidal anti-inflammatory drugs (NSAIDs) were the most prescribed class of drug initially for all classes of migraineurs (26.1%). Of them, 57.3% of migraineurs discontinued their treatment, 28.5% continued while 14.8% were switched to other treatment approaches. Persistence with initial treatment was more profound in female (58.8%) patients compared to males while the median age of continuers was 31 years. The total cost of migraine treatment in the entire study cohort was 297532.5 Pakistani Rupees ($1901.1). By estimating the hazard ratios (HR) using the Cox regression analysis, it can be observed that patients with high frequency (HR, 1.628; 95%CI, 1.221-2.179; pConclusionSimilar to western countries, the majority of migraineurs exhibited poor persistence to migraine treatments. Various factors of improved persistence were identified in this study.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).The authors retract the above paper due to: 1) conflict of interest among the authors; and 2) addition of co-author Dr. Muhammad Younus without his knowledge or permission. The authors apologize for these two grave mistakes.

No Abstract

Bacterial canker of tomato caused by the bacterial pathogen Clavibacter michiganensis subsp. michiganensis (Cmm) is a major limiting factor for tomato production worldwide. Currently there exists no resistant variety of tomato to bacterial canker; only cultural and chemical controls are available. This study synthesized AgNPs (silver nanoparticles) via a green chemistry route and investigated their bactericidal potential against bacterial canker of tomato (BCT). AgNPs were prepared using mycellial aqueous extract of agriculturally beneficial fungi Pythium oligandrum. The formation of AgNPs was confirmed by using UV–Vis spectroscopy for the absorbance pattern while their morphology was investigated by the transmission electron microscopy (TEM). The X-ray diffraction profile for the biogenic AgNPs confirmed a crystalline structure with an average particle size of 12 nm. AgNPs treated seeds showed a normal germination rate with normal seedling growth. An in-vitro study found that the prepared AgNPs caused the maximum inhibition of the bacterial pathogen. In the greenhouse the introduction of AgNPs significantly prevents and inhibits the bacterial pathogen Cmm on tomato plants. These results suggest that this process is a strong candidate for industrial scale production of AgNPs. These particles act as an inhibitor and broad spectrum antibacterial agent against cmm, and hence offer a new and eco-friendly alternative in BCT control.

Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of Bud23 in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5’UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5’UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function.