Therapeutic resistance and tumor recurrence are two major hurdles in the treatment of pancreatic ductal adenocarcinoma. Recent findings suggest that both of these attributes are associated with a small subset of pancreatic tumor initiating cancer stem cells (CSCs). Here, we demonstrate that drozitumab, a human agonistic monoclonal antibody which binds the death receptor DR5, selectively eliminates CSCs, resulting in tumor growth inhibition and even regression of pancreatic tumors.

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4-/-) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4-/- mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4-/- and in piericidin A-treated Ndufs4+/+ mice than in respective controls. Impairment of HPV in Ndufs4-/- mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O2 restored HPV in response to LMBO. When compared with Ndufs4-/- mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.

Vitamin B12 (VitB12) deficiency rarely manifests with visual symptoms. Optic nerve damage in VitB12 deficiency is thought to be via degeneration. However, optic neuritis, though infrequent, has been reported secondary to VitB12 deficiency.

Emerging studies have shown that application of low concentration of bioactive phytomolecules can confer anti-proliferative effects on tumour cells by inducing senescence pathways. The alkaloid berberine is recognized for its anti-cancer attributes but its potential to induce senescence in tumour cells is least understood.

Nitric oxide (NO) exerts its biological effects primarily via activation of guanylate cyclase (GC) and production of cyclic guanosine monophosphate. Inhaled NO improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CPR). However, mechanisms of the protective effects of breathing NO after cardiac arrest are incompletely understood.

Herein, we report a bacteria-based strategy as an efficient, reasonable, benign, and promising methodology for remediating heavy metals fed waterbodies. The contemporary study deals with isolating, screening, and characterizing heavy metal resistive bacteria from metal-rich sites. The transcriptome analysis reveals the identity of the isolated species as Bacillus pumilus and Bacillus cereus. Batch studies put forth the bioremoval results in designed conditions of different pH, concentration, dose, and time. The mechanistic actions are drawn using complementary techniques such as Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR). The theory of surface adsorption of lead (Pb(II)) and nickel (Ni(II)) is further fostered by the application of adsorption isotherms. The conducted studies establish the bacterial morphological stratagems and multifarious biochemical approaches for countering metallic ions of Pb(II) and Ni(II). The exhibition of significant removal results by the isolated bacterial strains in simulated water samples with remarkable proliferation rates has opened up its favorability for industrial platforms.

Powassan virus (POWV; genus Flavivirus) is the sole North American member of the tick-borne encephalitis sero-complex and an increasing public health threat in the USA. Maintained in nature by Ixodes spp. ticks, POWV has also been isolated from species of other hard tick genera, yet it is unclear if these species can serve as vectors. Dermacentor variabilis and Amblyomma americanum share geographic and ecologic overlap with Ixodes spp. ticks and POWV transmission foci, raising the possibility that POWV could become established in these tick species and leading to range expansion and increased human risk. Therefore, we assessed the competency of Ixodes scapularis, D. variabilis and A. americanum for POWV lineage II (POWV II).

The current study aimed to develop a laboratory-scale biofilm photobioreactor system for biofuel production.

Computer-assisted diagnostic systems have been developed to aid doctors in diagnosing thyroid-related abnormalities. The aim of this research is to improve the diagnosis accuracy of thyroid abnormality detection models that can be utilized to alleviate undue pressure on healthcare professionals. In this research, we proposed deep learning, metaheuristics, and a MCDM algorithms-based framework to detect thyroid-related abnormalities from ultrasound and histopathological images. The proposed method uses three recently developed deep learning techniques (DeiT, Swin Transformer, and Mixer-MLP) to extract features from the thyroid image datasets. The feature extraction techniques are based on the Image Transformer and MLP models. There is a large number of redundant features that can overfit the classifiers and reduce the generalization capabilities of the classifiers. In order to avoid the overfitting problem, six feature transformation techniques (PCA, TSVD, FastICA, ISOMAP, LLE, and UMP) are analyzed to reduce the dimensionality of the data. There are five different classifiers (LR, NB, SVC, KNN, and RF) evaluated using the 5-fold stratified cross-validation technique on the transformed dataset. Both datasets exhibit large class imbalances and hence, the stratified cross-validation technique is used to evaluate the performance. The MEREC-TOPSIS MCDM technique is used for ranking the evaluated models at different analysis stages. In the first stage, the best feature extraction and classification techniques are chosen, whereas, in the second stage, the best dimensionality reduction method is evaluated in wrapper feature selection mode. Two best-ranked models are further selected for the weighted average ensemble learning and features selection using the recently proposed meta-heuristics FOX-optimization algorithm. The PCA+FOX optimization-based feature selection + random forest model achieved the highest TOPSIS score and performed exceptionally well with an accuracy of 99.13%, F2-score of 98.82%, and AUC-ROC score of 99.13% on the ultrasound dataset. Similarly, the model achieved an accuracy score of 90.65%, an F2-score of 92.01%, and an AUC-ROC score of 95.48% on the histopathological dataset. This study exploits the combination novelty of different algorithms in order to improve the thyroid cancer diagnosis capabilities. This proposed framework outperforms the current state-of-the-art diagnostic methods for thyroid-related abnormalities in ultrasound and histopathological datasets and can significantly aid medical professionals by reducing the excessive burden on the medical fraternity.

In the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox.

During a collecting trip exploring new habitats and locations for keratinophilic fungi, soil samples were collected from Bohani village in the central Indian state of Madhya Pradesh. Following isolation using a hair baiting technique, one sample yielded an interesting hyphomycetous fungus. The fungus, which could easily be observed under a dissecting microscope, formed prominently large, dark brown to opaque, fusoid conidia on horse hair after 2 mo of incubation. Single-conidial colonies were cultivated on Sabouraud dextrose agar medium by direct transfer, using a fine needle under a dissecting microscope. Morphologically the fungus resembles genera such as Bahugada, Hadrosporium, Manoharachariella, Pithomyces, and Septosporiopsis, but differs with regard to its conidia and conidiogenous cells. Based on its unique morphology, the present collection is described as a new genus, Matsushimamyces, with M. bohaniensis as type species. Phylogenetic analysis of the LSU region placed Matsushimamyces in Latoruaceae (Pleosporales, Dothideomycetes). Furthermore, based on the morphological and phylogenetic similarity (ITS and LSU rDNA), a second species, Polyschema venustum, is also referred to Matsushimamyces.

Studying expression of genes by direct sequencing and analysis of metatranscriptomes at a particular time and space can disclose structural and functional insights about microbial communities. The present study reports comparative analysis of metatranscriptome from two distinct soil ecosystems referred as M1 (agriculture soil) and O1 (organic soil).

The cellular NADH/NAD+ ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD+ ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD+ ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance2, insulin resistance3 and mitochondrial disease4, and are associated with a common genetic variant in GCKR5, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD+ ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of 'causal metabolism'.

Hydrogen sulfide (H2S) has long been known as a toxic environmental hazard. Discovery of physiological roles of H2S as a neurotransmitter by Kimura and colleagues triggered an intensive research in the biological roles of H2S in the past decades. Manipulation of H2S levels by inhibiting H2S synthesis or administration of H2S-releasing molecules revealed beneficial as well as harmful effects of H2S. As a result, it is now established that H2S levels are tightly controlled and too much or too little H2S levels cause harm. Nonetheless, translation of sulfide-based therapy to clinical practice has been stymied due to the very low therapeutic index of sulfide and the incomplete understanding of endogenous sulfide metabolism. One potential strategy to circumvent this problem is to use a safe and stable sulfide metabolite that may mediate effects of H2S. Alternatively, endogenous sulfide levels may be controlled using specific sulfide scavengers. In this review article, the role of endogenous H2S production and catabolism will be briefly reviewed followed by an introduction of thiosulfate and H2S scavengers as novel pharmacological tools to control H2S-dependent signaling.

In this study, we generated a transgenic strain of Leishmania braziliensis, an etiological agent associated with a diversity of clinical manifestations of leishmaniasis ranging from localized cutaneous to mucocutaneous to disseminated disease. Transgenic parasites expressing reporter proteins are valuable tools for studies of parasite biology, host-pathogen interactions, and anti-parasitic drug development. To this end, we constructed an L. braziliensis line stably expressing the reporters eGFP and luciferase (eGFP-LUC L. braziliensis). The integration cassette co-expressing the two reporters was targeted to the ribosomal locus (SSU) of the parasite genome. Transgenic parasites were characterized for their infectivity and stability both in vitro and in vivo. Parasite maintenance in axenic long-term culture in the absence of selective drugs did not alter expression of the two reporters or infection of BALB/c mice, indicating stability of the integrated cassette. Infectivity of eGFP-LUC, L. braziliensis, both in vivo and in vitro was similar to that obtained with the parental wild type strain. The possibility of L. braziliensis tracking and quantification using fluorescence and luminescence broadens the scope of research involving this neglected species, despite its importance in terms of public health concerning the leishmaniasis burden.

In the present investigation, a gene encoding extracellular lipase was cloned from a Bacillus licheniformis. The recombinant protein containing His-tag was expressed as inclusion bodies in Esherichia coli BL21DE3 cells, using pET-23a as expression vector. Expressed protein purified from the inclusion bodies demonstrated ~22 kDa protein band on 12 % SDS-PAGE. It exhibited specific activity of 0.49 U mg-1 and % yield of 8.58. Interestingly, the lipase displayed activity at wide range of pH and temperature, i.e., 9.0-14.0 pH and 30-80 °C, respectively. It further demonstrated ~100 % enzyme activity in presence of various organic solvents. Enzyme activity was strongly inhibited in the presence of β-ME. Additionally, the serine and histidine modifiers also inhibited the enzyme activities strongly at all concentrations that suggest their role in the catalytic center. Enzyme could retain its activity in presence of various detergents (Triton X-100, Tween 20, Tween 40, SDS). Sequence and structural analysis employing in silico tools revealed that the lipase contained two highly conserved sequences consisting of ITITGCGNDL and NLYNP, arranged as parallel β-sheet in the core of the 3D structure. The function of these conserve sequences have not fully understood.

The geometric and color features of agricultural material along with related physical properties are critical to characterize and express its physical quality. The experiments were conducted to classify the physical characteristics like size, shape, color and texture and then workout the relationship between manual observations and using image processing techniques for weight and volume of the four wheat refractions i.e. sound, damaged, shriveled and broken grains of wheat variety PBW 725. A flatbed scanner was used to acquire the images and digital image processing method was used to process the images and output of image analysis was compared with the actual measurements data using digital vernier caliper. A linear relationship was observed between the axial dimensions of refractions between manual measurement and image processing method with R2 in the range of 0.798-0.947. The individual kernel weight and thousand grain weight of the refractions were observed to be in the range of 0.021-0.045 and 12.56-46.32 g respectively. Another linear relationship was found between individual kernel weight and projected area estimated using image processing methodology with R2 in the range of 0.841-0.920. The sphericity of the refractions varied in the range of 0.52-0.71. Analyses of the captured images suggest ellipsoid shape with convex geometry while the same observation was recorded by physical measurements also. A linear relationship was observed between the volume of refractions derived from measured dimensions and calculated from image with R2 in the range of 0.845-0.945. Various color and grey level co-variance matrix texture features were extracted from acquired images using the open-source Python programming language and OpenCV library which can exploit different machine and deep learning algorithms to properly classify these refractions.

Friedreich's ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular, we showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. Here, we report the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical and effective regimen for clinical translation. We report three chief results. First, a daily, intermittent hypoxia regimen (16 h 11% O2/8 h 21% O2) conferred no benefit and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely owing to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths worldwide. Identification of gene biomarkers and their regulatory factors and signaling pathways is very essential to reveal the molecular mechanisms of NSCLC initiation and progression. Thus, the goal of this study is to identify gene biomarkers for NSCLC diagnosis and prognosis by using scRNA-seq data through bioinformatics techniques. scRNA-seq data were obtained from the GEO database to identify DEGs. A total of 158 DEGs (including 48 upregulated and 110 downregulated) were detected after gene integration. Gene Ontology enrichment and KEGG pathway analysis of DEGs were performed by FunRich software. A PPI network of DEGs was then constructed using the STRING database and visualized by Cytoscape software. We identified 12 key genes (KGs) including MS4A1, CCL5, and GZMB, by using two topological methods based on the PPI networking results. The diagnostic, expression, and prognostic potentials of the identified 12 key genes were assessed using the receiver operating characteristics (ROC) curve and a web-based tool, SurvExpress. From the regulatory network analysis, we extracted the 7 key transcription factors (TFs) (FOXC1, YY1, CEBPB, TFAP2A, SREBF2, RELA, and GATA2), and 8 key miRNAs (hsa-miR-124-3p, hsa-miR-34a-5p, hsa-miR-21-5p, hsa-miR-155-5p, hsa-miR-449a, hsa-miR-24-3p, hsa-let-7b-5p, and hsa-miR-7-5p) associated with the KGs were evaluated. Functional enrichment and pathway analysis, survival analysis, ROC analysis, and regulatory network analysis highlighted crucial roles of the key genes. Our findings might play a significant role as candidate biomarkers in NSCLC diagnosis and prognosis.

Trikatu Churna (TC) comprising Zingiber officinale rhizome, Piper longum, and Piper nigrum fruit, is effective in treating liver diseases and has high nutraceutical values. However, the efficacy of TC in treating alcoholic liver disease (ALD) and its mechanism remain largely unknown. This study evaluated the hepatoprotective effects of different doses of TC as well as to identify the bioactive components and determine their mechanism of action against ethanol-induced ALD. A compound-target network analysis model of TC was established to identify its potential bioactive compounds and pathways that might regulate its hepatoprotective effects. Further, in-vivo studies were performed to validate the potential of TC (200 mg/kg and 400 mg/kg b.w.) in the treatment and management of ALD. The study revealed that both the dosages of TC demonstrate significant (p > 0.0001) hepatoprotective effects by improving body weight, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphate (ALP), total cholesterol, total protein, globulin, albumin, and liver morphology. The High-performance thin-layer chromatography (HPTLC) fingerprinting of TC showed the presence of piperine. Network pharmacology identifies the role of TC in regulating various signaling processes including Advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE), Hypoxia-inducible factors (HIF-1), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Kappa B), and Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling to exert its anti-inflammatory, antioxidant and anti-apoptotic role in managing ALD. Based on the bioinformatics analysis, some of the key targets of TC were found to be Prostaglandin-Endoperoxide Synthase 2 (PTGS2) or Cyclooxygenase-2 (COX-2), Sirtuin 1 (SRT1), and caspase-3. These effects may serve as a novel therapeutic option for the treatment of ALD. These preclinical validation studies for the ethnopharmacological potential of TC in ALD treatment further paved the way for researchers to perform next-level translational and clinical studies. Further, in-depth experimental studies for the validation of these bioinformatics-based results will give a clearer picture of mechanisms.