Microenvironmental Determinants of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.

An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy.

Tetrahydrocannabinols (THCs) antagonize the CB1 and CB2 cannabinoid receptors, whose signaling to the endocannabinoid system is essential for controlling cell survival and proliferation as well as psychoactive effects. Most tumor cells express a much higher level of CB1 and CB2; THCs have been investigated as potential cancer therapeutic due to their cannabimimetic properties. To date, THCs have been prescribed as palliative medicine to cancer patients but not as an anticancer modality. Growing evidence of preclinical research demonstrates that THCs reduce tumor progression by stimulating apoptosis and autophagy and inhibiting two significant hallmarks of cancer pathogenesis: metastasis and angiogenesis. However, the degree of their anticancer effects depends on the origin of the tumor site, the expression of cannabinoid receptors on tumor cells, and the dosages and types of THC. This review summarizes the current state of knowledge on the molecular processes that THCs target for their anticancer effects. It also emphasizes the substantial knowledge gaps that should be of concern in future studies. We also discuss the therapeutic effects of THCs and the problems that will need to be addressed in the future. Clarifying unanswered queries is a prerequisite to translating the THCs into an effective anticancer regime.

Early asymptomatic prediction of potato soft rot disease using phytohormone-induced volatile biomarkers.

Potatoes (Solanum tuberosum L.) are one of the world's major staple crops. In stored potatoes, Pectobacterium carotovorum subsp carotovorum causes soft rot. As a result of the rapid spread of the disease during post-harvest storage, potato production suffers huge losses. By detecting disease early and controlling it promptly, losses can be minimized. The profile of volatiles of plants can be altered by phytopathogens. Identifying unique volatile organic compounds (VOCs) as biomarkers for early disease detection has attracted considerable research attention. This study compared the VOC profiles of healthy and soft rot inoculated potatoes (cv. "Kufri Pukhraj") over a time course using gas chromatography-mass spectrometry (GC-MS). It was found that there was a differential emission of 27 VOCs between healthy non-inoculated potatoes and soft rot inoculated potatoes. Among 27 VOCs, only five (1-octen-3-ol, 2-methylisoborneol, 3-octanone, 1,4-dimethyladamantane, and 2-methyl-2-bornene) were found exclusively in soft rot inoculated potatoes, suggesting them potential biomarker for non-destructive prediction of soft rot disease in potatoes. Reactive oxygen species (H2O2) and phytohormone methyl-jasmonate (MeJa) levels increased transiently on infection with soft rot. The analysis of the primary metabolism of soft rot infected tubers at three different stages suggests metabolic reprogramming that occurs at the early stage of infection, possibly leading to biomarker volatile emission. Based on these results, it appears that the initial potato-soft rot bacteria interaction initiates metabolic reprogramming mainly through H2O2 and the MeJa signalling pathway. In asymptomatic potatoes, these biomarkers may be promising candidates for non-destructive detection of soft rot at an early stage. These biomarkers can be used to develop an e-nose sensor to predict soft rot in the future.

Cost-effective chemiresistive biosensor with MWCNT-ZnO nanofibers for early detection of tuberculosis (TB) lipoarabinomannan (LAM) antigen.

The development of an affordable chemiresistive biosensor enhanced with a multi-walled carbon nanotube-zinc oxide (MWCNT-ZnO) nanofiber composite is presented. The sensor leverages the precise interaction between lipoarabinomannan (LAM) tuberculosis (TB) antigens and antibodies to achieve high sensitivity and specificity. The MWCNT-ZnO nanofibers have a larger surface area and better electrical conductivity, which makes it easier for TB antibodies to stick to them. The binding of LAM TB antigens to the fixed Monoclonal Antibody-MBS320597 induces significant resistance changes in the chemiresistive sensor, enabling accurate TB detection. Performance evaluation reveals a linear detection range from 1.0 to 100.0 pg/mL in the lower concentration range and up to 6.0 ng/mL in the higher concentration range, with a sensitivity of 79.750 mA pg mL-1 cm-2 and a lower limit of detection of 40.54 fg/mL. The sensor exhibits a response time of 102 s. Featuring rapid response time and high sensitivity, this biosensor is ideally suited for point-of-care (PoC) applications. The incorporation of MWCNT-ZnO nanofibers shows great potential for enhancing the development of sensitive and cost-effective TB diagnostic tools, which could play a crucial role in advancing global TB control and management efforts.

IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC. DESIGN: Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models. RESULTS: Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo. CONCLUSIONS: We identified Tc17 as a novel protumourigenic CD8+ T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.

Device-Physics Realization of ZnO-MWCNT Nanostructure-Based Field-Effect Biosensor for Ultrasensitive Simultaneous Genomic Detection of Foodborne Pathogens.

The complex and versatile interactions among the wide variety of the nanostructures and the target analytes have primarily limited the detailed investigation of the transduction mechanism of nanomaterial-assisted electrical signal-based biosensors despite their high sensitivity, low-cost, portability, and ease of deployment. Hence, no common ground is formed detailing the principle of operation, demanding a strong need for systematic examination instead of hit and trial. Therefore, a maiden mechanistic investigation has been carried out in this paper for a field-effect-based biosensor device relying on the energy band diagram and the surface potential profile. To demonstrate the experimental evidence and appreciate the importance of food safety, three hazardous foodborne pathogens (Proteus mirabilis, Escherichia coli, and Clostridium botulinum) have been detected herein. The biosensor device, built on a hydrothermally synthesized zinc oxide and MWCNT (ZnO-MWCNT) composite nanostructure, simultaneously incorporates three fairly specific ss-DNA probes. Furthermore, the unmet challenge of biosensor device variability is addressed through the optimum selection of operating voltage of the device via a unique "voltage-selection-algorithm". We believe that the rigorous experimentation and the insightful device-physics realization demonstrated in this work will pave the way for a future decisive biosensor platform.

2D vanadium disulfide nanosheets assisted ultrasensitive, rapid, and label-free electrochemical quantification of cancer biomarker (MMP-2).

Cancer is one of the most tormenting global health burdens reporting high mortality and morbidity worldwide. Matrix metalloproteinase 2 (MMP-2) protein has elevated expression for most types of cancers, including prostate and breast cancer. Therefore, accurate and specific detection of MMP-2 biomarker is crucial for screening, treatment, and prognosis of related cancer. In this work, we have proposed a label-free electrochemical biosensor for the detection of MMP-2 protein. This biosensor was fabricated using hydrothermally synthesized vanadium disulfide (VS2) nanosheets with monoclonal anti-MMP2 antibodies biofunctionalized using a suitable linker. The VS2nanomaterials were synthesized hydrothermally at different reaction temperatures (140 °C, 160 °C, 180 °C and 200 °C) generating different morphologies from a 3D bulk cubic structure at 140 °C to 2D nanosheets at 200 °C. Owing to the advantages of 2D VS2nanosheets with high surface-to-volume ratio, excellent electrochemical response and high antibody loading possibility, it was selected for fabricating an MMP-2 specific biosensor. The antibody-antigen binding event is analyzed by recording electrochemical impedance spectroscopy signals for different target MMP-2 protein concentrations. The sensitivity and lower limit of detection were 7.272 (ΔR/R)(ng ml)-1cm-2and 0.138 fg ml-1, respectively in 10 mM phosphate buffer saline for this proposed sensor. Further, interference studies were also performed which demonstrates the sensor to be highly selective against non-specific target proteins. This 2D VS2nanosheet-based electrochemical biosensor is a sensitive, cost-effective, accurate, and selective solution for cancer diagnosis.

Non-enzymatic glucose detection with screen-printed chemiresistive sensor using green synthesised silver nanoparticle and multi-walled carbon nanotubes-zinc oxide nanofibers.

Non-enzymatic screen-printed chemiresistive interdigitated electrodes (SPCIE) were designed and fabricated using a low-cost screen-printing method for detection of the glucose. The interdigitated electrodes (IDE) pattern was printed using conductive graphene ink on the glossy surface of the photo paper. The proposed glossy photo paper-based SPCIE are functionalized with multi-walled carbon nanotubes-zinc oxide (MWCNTs-ZnO) nanofibers to create the chemiresistive matrix. Further, to bind these nanofibers with the graphene electrode surface, we have used the green synthesized silver nanoparticles (AgNPs) with banana flower stem fluid (BFSF) as a binder solution. AgNPs with BFSF form the conductive porous natural binder layer (CPNBL). It does not allow to increase the resistivity of the deposited material on graphene electrodes and also keeps the nanofibers intact with paper-based SPCIE. The synthesized material of MWCNT-ZnO nanofibers and green synthesized AgNPs with BFSF as a binder were characterized by Ultraviolet-visible spectroscopy (UV-vis), scanning electron microscope (SEM), x-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). The amperometric measurements were performed on the proposed SPCIE sensor to detect the glucose sample directly. The innovative paper-based SPCIE glucose sensor exhibits a linear corelation between current measurements and glucose concentration in the range between 45.22µm and 20 mm, with a regression coefficient (R2) of 0.9902 and a lower limit of detection (LoD) of 45.22µm (n= 5). The sensitivity of the developed SPCIE sensor was 2178.57µAmM-1cm-2, and the sensor's response time determined was approximately equal to 18 s. The proposed sensor was also tested for real blood serum sample, and relative standard deviation (RSD) was found equal to 2.95%.

Electrochemical nano-biosensor based on electrospun indium zinc oxide nanofibers for the determination of complement component 3 protein.

Age-related macular degeneration (AMD) is a progressive chronic neurodegenerative retinal disease leading to vision loss, irreversible blindness, and visual impairment in older adults worldwide. Complement component 3 (C3) protein has been identified as the most predominant biomarker towards early diagnosis of AMD; therefore, there is an utmost requirement for non-invasive detection of C3 protein in the tear fluids of AMD patients. Considering this, we report an insightful electrochemical sensor capable of detecting clinically relevant concentrations ranging from 10 fg/mL to 1 µg/mL using electrospun indium-doped zinc oxide (InZnO) nanofibers as the transducing layer. The InZnO nanofibers have facilitated high anti-C3 antibody loading of 3.42 × 10-9 mol/cm2 and enhanced the overall charge transport mechanism at the sensor interface. The biofunctionalization process of the biosensor was investigated thoroughly using X-ray photoelectron spectroscopy (XPS) as well as different electrochemical techniques. The target C3 proteins were captured on the fabricated biosensor surface and determined through changes in charge transfer resistance (RCT) while executing electrochemical impedance spectroscopy (EIS) and peak current (Ip) in the case of cyclic voltammetry (CV) and differential pulse voltammetry (DPV), respectively. The InZnO nanofiber-based nano-biosensor demonstrated a very low limit of detections (LODs) of 5.214 fg/mL and 0.241 fg/mL with an excellent sensitivity of 4.6709 (ΔR/R) (g/mL)-1 cm-2 and 54.4939 (ΔIp/Ip)% (g/mL)-1 cm-2 for EIS and DPV techniques, respectively. By virtue of high antibody loading, ultrasensitive and ultra-selective capability, the indium-doped ZnO nanofibers show huge potential to be used as a high-performance diagnostic platform for AMD diagnosis.

NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease. DESIGN: NFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a . and NFATc1Δ/Δ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo. RESULTS: NFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration. CONCLUSION: NFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.

Simultaneous Detection of CO and NH3 Gases at Room Temperature with an Array of ZnS Chemiresistive Sensors and the Superposition Principle.

Simultaneous detection of multiple toxic gases in the air using room temperature gas sensors is significant in low-power environmental monitoring applications. However, the low-temperature resistive gas sensors are sensitive to more than one gas, and thus, an array of gas sensors and high energy-consuming machine learning algorithms are required to predict the concentrations of the individual gases in mixed target gas. Here, we report a computationally less intensive method to predict the composition of the target gases using linear gas sensors. A sensor array consisting of two ZnS resistive gas sensors biased at different voltages in conjunction with the superposition principle is used to predict the concentration of individual gases in the binary mixture of NH3 and CO present in the air. Further, the effect of humidity on response is mitigated by formulating the sensitivity of the sensors as a function of relative humidity. The proposed algorithm predicted the concentration of the individual gases in mixed gas with a maximum absolute error of ∼15% irrespective of humidity levels, which is practically allowed in most gas sensing applications. As the superposition principle is a low-power consuming technique, the proposed approach can be used in applications where trace levels of gases in mixed targets need to be detected with energy-efficient methods.

Overexpression of chrysanthemyl diphosphate synthase (CDS) gene in Tagetes erecta leads to the overproduction of pyrethrin.

Pyrethrins are widely accepted as natural insecticides and offers several advantages of synthetic compounds, i.e., rapidity of action, bioactivity against a wide range of insects, comparatively lesser costs and the like. A significant source of pyrethrin is Chrysanthemum cinerariaefolium; cultivated in restricted areas, as a result; natural pyrethrins are not produced in a large amount that would meet the ongoing global market demand. However, increasing its content and harnessing the desired molecule did not attract much attention. To enhance the production of pyrethrins in Tagetes erecta, the Chrysanthemyl diphosphate synthase (CDS) gene was overexpressed under the promoter CaMV35S. Hypocotyls were used as explant for transformation, and direct regeneration was achieved on MS medium with 1.5 mg L-1 BAP and 5.0 mg L-1 GA3. Putative transgenics were screened on 10 mgL-1 hygromycin. After successful regeneration, screening and rooting process, the transgenic plants were raised inside the glass house and PCR amplification of CDS and HYG-II was used to confirm the transformation. Biochemical analysis using HPLC demonstrated the expression levels of the pyrethrin, which was approx. twenty-six fold higher than the non-transformed Tagetes plant.

ZnO nanoparticles embedded silk fibroin-a piezoelectric composite for nanogenerator applications.

This paper demonstrates a flexible nanogenerator (NG) using Silk-Zinc Oxide (ZnO) composite by exploiting the inherent piezoelectric properties of silk and ZnO. A direct precipitation method was employed to synthesize Zinc Oxide nanoparticles (NPs). Silk-ZnO composite film was then prepared by spin-coating the homogenous silk-ZnO solution. The composition and morphology of silk-ZnO composite were analyzed using various standard characterization procedures. The biocompatibility study of the composite film was also performed through cell viability testing. The utility of as prepared composites was demonstrated through the fabrication of piezoelectric nanogenerator. This hybrid nanogenerator was capable to generate a maximum open circuit voltage of 25 V (peak to peak value) in the bending state for a specific ZnO concentration. The output response of the nanogenerator exhibited a good correlation with the bending angle of the device. A peak outputpower density of 6.67 mW cm-3was achieved from the nanogenerator. The fabricated prototype is efficient to light-up commercial red LEDs and to harvest energy from human body movement. The piezoelectric coefficient (d33) of silk-ZnO composite film was also experimentally figured out.

Microcapillary LAMP for rapid and sensitive detection of pathogen in bovine semen.

A microcapillary-based loop-mediated isothermal amplification (µcLAMP) has been described for specific detection of infectious reproductive pathogens in semen samples of cattle without sophisticated instrumentation. Brucella abortus, Leptospira interrogans serovar Pomona and bovine herpesvirus 1 (BoHV-1) cultures were mixed in bovine semen samples. The µcLAMP assay is portable, user-friendly, cost-effective, and suitable to be performed as a POC diagnostic test. We have demonstrated high sensitivity and specificity of µcLAMP for detection of Brucella, Leptospira, and BoHV-1 in bovine semen samples comparable to PCR and qPCR assays. Thus, µcLAMP would be a promising field-based test for monitoring various infectious pathogens in biological samples.HighlightsDetect infectious organism in bovines semenReduction in carryover contamination is an important attribute, which may reduce the false-positive reaction.µcLAMP is a miniaturized form, which could be performed with a minimum volume of reagents.The µcLAMP assay is portable, user-friendly, and suitable to be performed as a POC diagnostic test.

Protective efficacy of melatonin and insulin against LPS caused toxicity in diabetic mice.

Context: Deregulated glucose homeostasis leads to a life-threatening metabolic disorder known as diabetes. The insulin deficiency and hyperglycaemic condition related to diabetes cause dysregulation of the immune system.Objective: This study evaluated the combined efficacy of melatonin and insulin in attenuation of lipopolysaccharide (LPS) caused inflammation, macrophage functional impairment, and oxidative stress in the spleen of diabetic mice.Materials and Methods: Multiple low doses of streptozotocin (50mg/kg B. wt.) were administered intraperitoneally to induce diabetes. Diabetes mice were divided into two sets. Set-1 contained control, diabetes, diabetes insulin (2IU/100g B.wt.) treated, diabetes melatonin (100µg/100g. B.wt.) treated, and diabetes melatonin and insulin treated groups of mice. In set II, the same number of groups as those of set I were given a single dose of LPS (50µg/mice) 24 hours before euthanization.Results and Discussion: LPS caused a significant increase in oxidative stress, circulatory proinflammatory cytokines, significant suppression of antioxidant defense system, and phagocytic index in diabetic mice. Melatonin and insulin significantly improved the adverse effects caused by LPS treatment in diabetic mice. The present study noted that combined treatment of melatonin and insulin was more effective in attenuating LPS-induced devastating effects in laboratory mice.Conclusions: The present study may suggest a combinatorial approach in the therapeutic use of melatonin and insulin to improve such devastating conditions.

Chemical Element Profiling in the Sera and Brain of Bipolar Disorders Patients and Healthy Controls.

Bipolar Disorder (BD) is a severe recurrent affective mood disorder characterized by a wide range of lifelong mood swings, varying between depressive and manic states. BD affects more than 1% of the world's population irrespective of nationality, ethnic origin, or socioeconomic status and is one of the main causes of disability among young people, leading to cognitive and functional impairment and raised mortality, particularly death by suicide. Trace elements play a vital role in many biochemical and physiological processes. Compelling evidence shows that element toxicity might play a crucial role in the onset and progression of neurodegenerative disorders, but their involvement in mood disorders has been scarcely studied. In the present investigation, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of Al, B, Cu, K, Mg and V were significantly lower in the pre-frontal cortex of BD patients compared with those of the controls. A comparison of Spearman's rank correlation coefficients between the elements in the serum and brain of BD patients and control groups pointed to boron and aluminum as being involved in the disease. These results suggest that there is a disturbance in the elements' homeostasis and the inter-elements' relationship in the brain of BD patients and advocate a thorough examination of the possible involvement of chemical elements in different stages of the disease.

Synthesis and Biological Evaluation of Novel Bufalin Derivatives.

Bufalin and other cardiac steroids (CS) have been used for centuries for the treatment of congestive heart failure, arrhythmias, and other maladies. However, toxicity and the small therapeutic window of this family of steroids limit their use. Therefore, attempts to synthesize a potent, but less toxic, CS are of major importance. In the present study, two novel bufalin derivatives were synthesized and some of their pharmacological properties were characterized. The reaction of bufalin with Ishikawa's reagent resulted in the production of two novel bufalin derivatives: bufalin 2,3-ene and bufalin 3,4-ene. The compounds were purified with TLC and HPLC and their structure was verified with UV, NMR, and MS analyses. The biological activities of these compounds were evaluated by testing their ability to inhibit the Na+, K+-ATPase activity of the brain microsomal fraction to induce cytotoxic activity against the NCI-60 human tumor cell line panel and non-cancer human cells, and to increase the force of contraction of quail embryonic heart muscle cells in culture. The two steroids exhibited biological activities similar to those of other CS in the tested experimental systems, but with reduced cytotoxicity, advocating their development as drugs for the treatment of heart failure and arrhythmias.

Vanadium in Bipolar Disorders-Reviving an Old Hypothesis.

Bipolar disorder (BD) is a severe and common chronic mental illness. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Our previous studies supported the notion that alterations in Na+, K+-ATPase activity were involved in the etiology of BD. As various chemical elements inhibit Na+, K+-ATPase, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients, and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of V was significantly lower in the pre-frontal cortex of BD patients compared with that of the controls. Intracerebroventricular administration of V in mice elicited anxiolytic and depressive activities, concomitantly inhibited brain Na+, K+-ATPase activity, and increased extracellular signal-regulated kinase phosphorylation. A hypothesis associating V with BD was set forth decades ago but eventually faded out. Our results are in accord with the hypothesis and advocate for a thorough examination of the possible involvement of chemical elements, V in particular, in BD.

Artificial Intelligence-Based Portable Bioelectronics Platform for SARS-CoV-2 Diagnosis with Multi-nucleotide Probe Assay for Clinical Decisions.

In the context of the recent pandemic, the necessity of inexpensive and easily accessible rapid-test kits is well understood and need not be stressed further. In light of this, we report a multi-nucleotide probe-based diagnosis of SARS-CoV-2 using a bioelectronics platform, comprising low-cost chemiresistive biochips, a portable electronic readout, and an Android application for data acquisition with machine-learning-based decision making. The platform performs the desired diagnosis from standard nasopharyngeal and/or oral swabs (both on extracted and non-extracted RNA samples) without amplifying the viral load. Being a reverse transcription polymerase chain reaction-free hybridization assay, the proposed approach offers inexpensive, fast (time-to-result: ≤ 30 min), and early diagnosis, as opposed to most of the existing SARS-CoV-2 diagnosis protocols recommended by the WHO. For the extracted RNA samples, the assay accounts for 87 and 95.2% test accuracies, using a heuristic approach and a machine-learning-based classification method, respectively. In case of the non-extracted RNA samples, 95.6% decision accuracy is achieved using the heuristic approach, with the machine-learning-based best-fit model producing 100% accuracy. Furthermore, the availability of the handheld readout and the Android application-based simple user interface facilitates easy accessibility and portable applications. Besides, by eliminating viral RNA extraction from samples as a pre-requisite for specific detection, the proposed approach presents itself as an ideal candidate for point-of-care SARS-CoV-2 diagnosis.