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Abstract Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.

Abstract Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.

BackgroundHepatocellular cancer (HCC) is associated with high mortality, and early diagnosis leads to better survival. Patients with cirrhosis, especially due to nonalcoholic fatty liver disease and viral hepatitis, are at higher risk of developing HCC and form the main screening group. The current screening methods for HCC (6-monthly screening with serum alpha fetoprotein and ultrasound liver) have low sensitivity; hence, there is a need for better screening markers for HCC. ObjectiveOur study, TENDENCY, aims to validate the novel screening markers (methylated septin 9, urinary volatile organic compounds, and urinary peptides) for HCC diagnosis and study these noninvasive biomarkers in liver disease. MethodsThis is a multicenter, nested case-control study, which involves comparing the plasma levels of methylated septin 9 between confirmed HCC cases and patients with cirrhosis (control group). It also includes the comparison of urine samples for the detection of HCC-specific volatile organic compounds and peptides. Based on the findings of a pilot study carried out at University Hospital Coventry & Warwickshire, we estimated our sample size to be 308 (n=88, 29% patients with HCC; n=220, 71% patients with cirrhosis). Urine and plasma samples will be collected from all participants and will be frozen at –80 °C until the end of recruitment. Gas chromatography–mass spectrometry will be used for urinary volatile organic compounds detection, and capillary electrophoresis–mass spectrometry will be used for urinary peptide identification. Real-time polymerase chain reaction will be used for the qualitative detection of plasma methylated septin 9. The study will be monitored by the Research and Development department at University Hospital Coventry & Warwickshire. ResultsThe recruitment stage was completed in March 2023. The TENDENCY study is currently in the analysis stage, which is expected to finish by November 2023. ConclusionsThere is lack of effective screening tests for hepatocellular cancer despite higher mortality rates. The application of more sensitive plasma and urinary biomarkers for hepatocellular cancer screening in clinical practice will allow us to detect the disease at earlier stages and hence, overall, improve HCC outcomes. International Registered Report Identifier (IRRID)DERR1-10.2196/44264

Malignancies have been associated with paraneoplastic syndromes, such as dermatomyositis. Subacute cutaneous lupus erythematosus (SCLE) can occur due to a wide array of cancers. Paraneoplastic SCLE obeys McLean’s criteria and often regresses after the underlying malignancy has been treated appropriately. Anti-Ro/SSA antibodies are often present in patients with paraneoplastic SCLE; however, there have been many instances where anti-Ro may not be present. We report a case of non-Hodgkin lymphoma causing SCLE, a malignancy not previously known to be associated with paraneoplastic SCLE. We also highlight the importance of perhaps prompt chemotherapy to treat the underlying malignancy, as a failure to do so may lead to worse patient outcomes.

Abstract Older adults are the most vulnerable group in the labor market, given their physical and functional health risks. Moreover, they are also at a greater risk of psychological factors like work stress due to risk of age, ageism and social well-being. Given these challenges and the growing proportion of older adults in the developing world, this paper studies the theoretical connotation between work stress and health related wellbeing outcomes among working elderly in India. Using BKPAI survey this study adopts multiple modeling approach (descriptive analysis, one-way analysis of variance, and a logit regression model) to test the association between work stress and wellbeing and understand this theoretical connotation in elderly labor market. Our results confirm that work stress is found to be significantly associated with socio-economic and health risks like income, gender, education, morbidity, disability, and socio-psychological barriers among working older adults. Females are likely to have more risk for work stress [OR, 1.72; (95% CI 2.89–2.91)] than males. Similarly, more affluent groups (wealthiest) are less likely to have any work stress [OR, 0.38; (95% CI-0.25–0.58)]. Older adults with multi-morbidity are at greater odds of having work stress [OR 2.26; (95% CI-1.74–2.94)]. Work stress is a common issue that enhances at higher ages due to the work, health, and socio-economic vulnerability of older adults. The study finds a significant impact of these factors on work stress and therefore argues for a comprehensive policy approach to address the psychological health risk of the working older adults in the labor market.

Background: About 270 million cases have been confirmed, and 5.3 million fatalities Worldwide due to SARS-CoV-2. Several vaccine candidates have entered phase 3 of the clinical trial and are being investigated to provide immunity to the maximum percentage of people. A safe and effective vaccine is required to tackle the current COVID-19 waves. There have been reports that clinical endpoints and psychological parameters are necessary to consider vaccine efficacy. This review examines the clinical endpoints required for a successful SARS-CoV-2 vaccine and the influences of psychological parameters on its efficacy. Methods: The main research question was to find out the clinical endpoints that determine the vaccine efficacy? And what kind of psychological parameters affect the vaccine efficacy? The information was taken from several journals, databases, and scientific search engines like Googe scholar, Pubmed, Scopus, Web of Science, Science direct, WHO website, and other various sites. The research studies were searched using keywords; SAR-CoV-2 vaccine efficacy, psychological effect on SARS-CoV-2 vaccine, SARS-CoV-2 vaccine endpoints. Results: This review has highlighted various clinical endpoints that are the main determinants of clinical vaccine efficacy. Currently, vaccinations are being carried out throughout the world; it is important to investigate the main determinants affecting vaccine efficacy. We have focused on the clinical endpoints and the influence of psychological parameters that affect the vaccine efficacy in clinical settings. The primary endpoints include the risk of infection, symptoms, and severity of COVID-19, while hospitalization length, supplemental oxygen requirement, and mechanical ventilation are secondary endpoints in the clinical endpoints. Some tangential endpoints were also considered, including organ dysfunction, stroke, and MI. Many psychological associated things have influenced the vaccine efficacy, like the lower antibody titers in the vaccinated people. In addition to that, Short- and long-term stress and sleep deprivation were also found to affect the vaccine efficacy. Conclusion: The review summarizes the important clinical endpoints required for a successful vaccine candidate. In addition to primary and secondary endpoints, auxiliary endpoints and the disease burden also play an important role in modulating vaccine efficacy. Moreover, the psychological perspective also influences vaccine efficacy. Effective follow-up of participants should follow to examine the clinical endpoints to reach any conclusion about vaccine efficacy.

Previously, several characterization of local Pre-Hausdorffness and $ D $-connectedness have been examined in distinct topological categories. In this paper, we give the characterization of local $ T_{0} $ (resp. local $ T_{1} $) $ \mathcal{L} $-valued closure spaces, examine how their mutual relationship. Furthermore, we give the characterization of a closed point and $ D $-connectedness in $ \mathcal{L} $-valued closure spaces and examine their relations with local $ T_{0} $ and local $ T_{1} $ objects. Finally, we examine the characterization of local Pre-Hausdorff and local Hausdorff $ \mathcal{L} $-valued closure spaces and study their relationship with generic Hausdorff objects and $ D $-connectedness.

The crystal structure of Michaelis complex of the bovine trypsin with N‐α‐benzoyl‐l‐arginine ethyl ester (BAEE) was determined at 2.30 Å resolution. The structure of enzyme‐substrate complex was solved in space group H32. The active site of trypsin was found to be occupied with the N‐α‐benzoyl‐l‐arginine ethyl ester. The hydrolyzed product of substrate molecules was also crystallized with trypsin. The substrate was embedded within the S1 binding site of the enzyme, and showed contacts with Gly‐195, Ser‐216, and Ser‐192. Some water molecules were also found within the vicinity of catalytic residues of enzyme. Interestingly, the hydrolyzed product present within the crystal lattice was found to be with inverted configuration. The crystal structure of trypsin in‐complex with N‐α‐benzoyl‐l‐arginine ethyl ester has never been reported previously. [ABSTRACT FROM AUTHOR]

Peroxidase is a biotechnologically important enzyme. The purification of peroxidase from the root of Citrullus colocynthis was carried out in a simple two-step process with maximum purity level. The sample was extracted in a high salt buffer, and the enzyme was partially purified with a Q-Sepharose anion exchange column. Final purification was carried out with HighLoad 16/600 Superdex G-75 column. The purified protein was analysed with SDS gel electrophoresis, which suggested a single band of approximately 35 kDa. Further, the enzyme was identified with the help of Mass spectrometric analysis using an ESI-QTOF Mass spectrometer. The study will be helpful for the isolation and its commercial uses in biotechnology. [ABSTRACT FROM AUTHOR]

The core of this paper is to employ the Matrix Language Frame (MLF) model on Urdu-English clausal-internal switching to identify whether the Matrix Language Frame model potentially accounts for the bilingual linguistic competence efficiently. For this, a qualitative methodology has been adopted for this study. For empirical evidence, data has been taken from eighty Urdu- English bilinguals within a naturalistic setting after categorizing them into four groups, and each group has 20 participants. After conducting audio-recording through non-participant interviews in an informal setting, the collected data was transcribed. The MLF model posited that two languages are fused in a single Intra-CP of a mixed string. The linearly dominant language is Matrix language (ML) that incorporates only late outsider system morphemes. Odd is Embedded language (EL) that supplies content morphemes satisfying the system morpheme principle (SMP) uniformly and morpheme order principle (MOP). The present study ubiquitously scrutinizes that naturalistic data of Urdu-English bilinguals highlights the innovative results: it predicts that Matrix language (ML) is unidentified in intra-CP, no late outsider system morphemes linearize a code-switched sentence, unparalleled constituent and clausal structure, System Morpheme Principle (SMP) and Morpheme Order Principle (SMP) provides the illegitimate output and computes ungrammatical sentences hence; the Matrix Language Frame model redundantly and inconsistently accounts for Urdu-English naturalistic data and its principles have failed to compute Urdu-English naturalistic data.

Superior Mesenteric Artery (SMA) during renal surgery is rarely reported but potentially devastating complication. It can rarely occur in patients with distorted vascular anatomy like in large left renal tumors with vascular infiltration and bulky lymphadenopathy, or in the setting of re-do surgery with extensive scarring. Failure to recognize and repair an SMA injury may result in ischemic bowel and consequently high mortality. Herein, we present a case scenario of injury to the SMA during radical nephrectomy missed intraoperatively and managed conservatively in the post-operative period in view of collateral circulation to the gut.

Candida glabrata is the most frequently isolated non-albicans Candida species in clinical samples and is known to develop resistance to commonly used antifungal drugs. Human β defensins (hBDs) are antimicrobial peptides of immune systems and are active against a broad range of pathogens including Candida species. Herein, the antifungal effect of hBD-1 and its mechanism of action in C. glabrata was studied. The antifungal susceptibility of hBD-1 against C. glabrata was calculated by broth microdilution assay. To study the mechanism of antifungal action, the impact of hBD-1 on cell cycle, expression of oxidative stress enzymes, and membrane disintegration were assessed. The susceptibility results confirmed that hBD-1 possessed the minimum inhibitory concentration of 3.12 µg/mL and prevented the growth and caused yeast cell death to various extents. The peptide at subinhibitory and inhibitory concentrations blocked the cell cycle in C. glabrata in G0/G1 phase and disturbed the activity of primary and secondary antioxidant enzymes. Furthermore, at higher concentrations disruption of membrane integrity was observed. Altogether, hBD-1 showed candidicidal activity against C. glabrata and was able to induce oxidative stress and arrested cell cycle in C. auris and therefore has a potential to be developed as an antifungal drug against C. glabrata.

Plants with medicinal properties have the ability to provide a variety of herbal medications with fewer adverse effects. From the literature survey, it has been revealed that Berberis pachyacantha (BP) is being traditionally used for liver diseases. The cytoprotective effect of dichloromethane (DCM), ethyl acetate, and n-butanol extracts of BP were investigated against ethanol-induced cytotoxicity in HepG2 cells. The results revealed that the cytotoxicity of ethanol was substantially decreased by DCM, ethyl acetate, and n-butanol extracts of BP in a dose-dependent manner. The ethyl acetate extract(BPE), which showed the highest hepatoprotective potential, was further investigated to assess its ability to quench the reactive oxygen species (ROS) generated by ethanol using fluorescence microscopy. We further confirmed in vivo activity against ethanol-induced liver damage in wistar rats. Finally, isolation and characterization of active components from bioactive extracts of B. pachyacantha were carried out. DCM extract (BPD) of B. pachyacantha yielded quercetin, oxy-berberine, β-sitosterol, and berberine. The berberine and quercetin have been isolated first time from this species of Berberis. Based on the in vitro hepatoprotective and in vivo screening tests, B. pachyacantha has manifested hepatoprotective action in the experimented models.

After having reached the stage where Islamic civilization delivered optimum, it started declining. Nevertheless, in different epochs of Islamic history, some remarkable personalities emerged reclaiming the functionality of iḥyā; i.e., the renaissance principle. In the contemporary times, Mālek Bennabī and Syed Mawdūdī have phenomenally contributed to the Muslim renaissance discourse. Both of them have critically examined the pathology of jumūd; i.e., the tendency of stagnation in the Muslim world. Although, they identified similar causes and symptoms, nevertheless, having lived in different socio-political contexts, they came up with certain methodological differences in their approach. Both the scholars developed a systematic response suggesting a way forward--the method of renaissance. In Bennabī’s discourse, the pathology is fundamentally civilizational, i.e., crisis in the civilizational equation between man, soil and time. While in Mawdūdī’s discourse, the pathology is fundamentally political; i.e., crisis in the nature of political relation between state, society and religion. Against this backdrop, the paper aims to present following points. First, the paper presents a brief analysis of Bennabī’s civilizational approach and Mawdūdī’s political approach in order to understand their scheme of thought while engaging with the question of jumūd and iḥyā. Second, the paper juxtaposes the three key concepts namely civilization, religion, and revival used by both Bennabī and Mawdūdī in their theoretical elaborations to outline the differences and similarities in their method of analysis. Keywords: Islam, Decline, Renaissance, Civilizational Approach, Political Approach

A facile, eco-friendly and cost-efficient method has been used for the biofabrication of silver nanoparticles. The aqueous extract of Salvia officinalis was used as a bioreducing agent and as a capping/stabilizing agent in the single-step biosynthesis of silver nanoparticles. Biosynthesized silver nanoparticles were characterized by various instrumental techniques, which included UV–vis spectroscopy, transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR) energy-dispersive X-ray spectroscopy (EDS) and thermogravimetric analysis (TGA)-differential thermal analysis (DTA). The colour of the reaction mixture of silver nitrate solution and an aqueous extract of S. officinalis turned dark brown after 10 min of mixing; hence, the reduction of Ag+ to Ag° occurred. UV–vis spectroscopy demonstrated the formation of stable silver nanoparticles with a surface plasmon resonance (SPR) band at λmax of 446 nm. TEM analysis demonstrated that the biosynthesized silver nanoparticles are spherical in shape and approximately 40 nm in size. Based on the observed results, a possible mechanism has been proposed for the formation of the silver nanoparticles. These biosynthesized silver nanoparticles were analysed, and the enhancement of their catalytic properties against toxic dye under various experimental conditions was demonstrated. According to the observed results, the catalytic activity for the degradation of azo dye Congo red (CR) was efficient under optimal experimental conditions. The phytochemical-based synthesis of nanoparticles provides a suitable, inexpensive and ecofriendly alternative for the degradation of highly toxic organic compounds and harmful azo dyes.

Wild plants have always held economic, nutritional and medicinal value for human beings. Present work is the study of local information of some wild plants being used for remedial purposes in District Muzaffarabad, Azad Jammu and Kashmir, Pakistan. The indigenous knowledge of local conventional uses was collected through survey and personal interviews during field trips. A total of 50 plant species were identified by taxonomic description using field guides and locally by medicinal knowledge of people living in the area. About 150 informers were interviewed randomly to record local names and ethno-medicinal uses of different plant species.

The concept of measures of noncompactness is applied to prove the existence of a solution for a boundary value problem for an infinite system of second order differential equations in $\ell_p$ space. We change the boundary value problem into an equivalent system of infinite integral equations and result is obtained by using Darbo's type fixed point theorem. The result is illustrated with help of an example.

Abstract Background Peripheral nerve injury is a debilitating condition that may lead to partial or complete motor, sensory and autonomic function loss and lacks effective therapy until date. Therefore, it is quite imperative to explore impending remedies for rapid and accurate functional retrieval following such conditions. Natural product-based intervention can prove effective to facilitate the process of functions regain. Methods Here, we investigated the effect of processed Strychnos nux-vomica seeds at a dose of 250 mg/kg body weight in a mouse model of induced Sciatic nerve lesion in promoting the recovery of the functions. A compression injury was induced in the Sciatic nerve of the right leg in the mice. Sensory function recovery was evaluated by hot-plate and formalin tests, whereas the motor function retrieval was assessed by measuring muscle grip strength, sciatic functional index, and muscle mass restoration. Oxidative stress and blood cell count were measured by biochemistry and haematological analyses. Results This study indicates that Strychnos nux-vomica seeds enhance the rate of recovery of both sensory and motor functions. It helps restore the muscle mass, attenuates total oxidant status and enhances the total anti-oxidant capacity of the biological system. Moreover, the treated animals manifested an enhanced glucose tolerance aptitude and augmented granulocyte and platelet counts. Improved oxidant control, enhanced glucose sensitivity and amended granulocyte and platelet counts are likely to contribute to the advantageous effects of Strychnos nux-vomica, and warrant further in-depth studies for deciphering possible mechanisms and identification of active constituent(s) responsible for these effects. Conclusion Strychnos nux-vomica seed offers functional recovery promoting effects following a mechanical injury to the Sciatic nerve and the possible reasons behind this effect can be reduced oxidative stress and improved glycaemic control. Further and detailed investigations can unravel this mystery.

Phosphorus stands as a vital nutrient crucial for plant growth, demanding efficient utilization for sustainable agricultural practices. Phosphate-solubilizing microorganisms (PSMs) have surfaced as promising allies in enhancing phosphorus use efficiency (PUE) within cropping systems. This review encapsulates recent insights into the essential role of PSMs in bolstering PUE and their influence on cropping systems. We discuss the mechanisms through which PSMs facilitate the solubilization of insoluble phosphates in the soil, rendering them accessible for plant uptake. PSMs exhibit the capacity to produce organic acids, enzymes, and siderophores, which aid in releasing phosphorus from soil minerals, thus amplifying their availability to plants. Additionally, we explore the symbiotic relationships between PSMs and plants, elucidating how PSMs foster plant growth and development by generating plant growth-promoting hormones, countering pathogens through antibiosis, and enhancing stress tolerance. Harnessing the potential of PSMs emerges as a promising avenue to combat phosphorus deficiency and foster sustainable agricultural practices. [ABSTRACT FROM AUTHOR]

Density, ρ, viscosity, η, and refractive index, nD of glucose, sucrose, and raffinose have been measured in 0.015 m aqueous glycine at 298.15, 303.15, 308.15, and 313.15 K. From these experimental data, apparent molar volumes, Vϕ, apparent specific volumes, Vϕ,sp as a function of the concentration of solutes, the standard partial molar volume, Vϕ0, transfer volume from water to aqueous glycine solutions, ΔVϕ(tr)0, and partial molar expansibility of solute, Eϕ0 have been calculated for glucose, sucrose and raffinose in aqueous glycine solutions. Falkenhagen coefficient A and Jones–Dole coefficient B, free energies of activation of viscous flow per mole of solvent, Δμ10#, and solute, Δμ20#, enthalpy, ΔH0#, and entropy, ΔS0# of activation of viscous flow have been evaluated by using viscosity data. The molar refraction has been calculated by using measured refractive index data. Results have been explained in terms of solute–solute and solute–solvent interactions. Keywords: Glucose, Sucrose, Raffinose, Aqueous glycine, Solute–solvent interaction

Background: Nephrolithiasis is a common complication of primary hyperparathyroidism (PHPT), and in a subgroup of patients stones are clinically silent. Patients with silent and symptomatic stones may differ biochemically. There is a scarcity of data available comparing patients with silent and symptomatic renal stones in PHPT. Aims: To characterize patients with PHPT with nephrolithiais and to compare patients with silent and symptomatic stones. Materials and Methods: We reviewed clinical data of 186 patients with PHPT managed at our center from January 1996 to December 2017. Silent renal stones were defined as ultrasonography finding of renal stones without symptoms. Symptomatic renal stones were defined as those with symptoms or a history of graveluria or any procedure for nephrolithiasis. A 5-mm diameter was set as the cut-off between micro- and macrolithiasis. We compared those with (n = 95) and without (n = 91) stones, and, among stone formers, those with symptoms (n = 66) and silent (n = 29) were compared. Results: There was no significant difference between stone formers and nonstone formers with respect to biochemical parameters. Patients with silent renal stones had significantly lower serum calcium and higher phosphate, than those with symptomatic stones. Most (75%) patients with silent renal stones had microlithiais, while only a fifth (22%) with symptomatic renal stones had microlithiasis. Conclusion: Nephrolithiasis is a common complication of PHPT. Most patients with silent renal stones had microlithiasis and biochemical features of less severe disease. Patients with silent renal stones may represent early mild stage of PHPT.

Background and Aims: Foreign-body ingestion is a common phenomenon, especially in children. In normal adults, foreign-body ingestion is usually accidental and mostly ingestion occurs with food and impaction is a result of structural abnormalities of the upper gastrointestinal tract (UGIT). However, accidental ingestion of nonfood products is unusual; especially ingestion of pins (scarf or safety pins) and needles is unknown. We come across ingestion of these unusual/sharp foreign bodies routinely from the past few years. The aim of this study was to observe, over a period of 1 year, the spectrum of nonfood or true foreign-body ingestion in our community and to see the impact of an early endoscopy on outcome or retrieval of the ingested objects. Materials and Methods: In a prospective observational study, we studied the profile of foreign-body ingestion in normal individuals of all ages and both sexes, excluding the individuals with any structural abnormalities of the gut and the people with psychiatric ailment. Results: Of total 51 patients with foreign-body ingestion, 42 (82%) were 20 or