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In recent days, the number of cancer cases is escalating promptly around the world. In general, conventional ablation methods, encompassing comprehensive drawbacks, are employed to cure cancer. At present, photo thermal therapy (PTT) is showing great promise to the treatment of cancer. However, the effective implementation of this technology is utmost challenging as several parameters affect the tumor surroundings. In this work, the effects of different parameters on the performance of PTT have been thoroughly investigated by considering a realistic model of human tissue underneath the skin using a finite element solver, COMSOL Multiphysics. Two different conditions, with and without considering gold nanoparticles at tumor site, are investigated where a laser beam is used as a source of energy. Fluence rate, temperature distribution, and thermal damage are highlighted in this work. It is observed that by utilizing a miniature needle with integrated waveguide and gold nanoparticles, a tumor can be effectively eradicated along with assuaging the conventional drawbacks of PTT. This study would also be useful for designing operative PTT for different parts of human tissue.

The ability to stack multiple genes in plants is of great importance in the development of crops with desirable traits but can be challenging due to limited selectable marker options. Here we establish split selectable marker systems using protein splicing elements called “inteins” for Agrobacterium-mediated co-transformation in plants. First, we show that such a split selectable marker system can be used effectively in plants to reconstitute a visible marker, RUBY, from two non-functional fragments through tobacco leaf infiltration. Next, to determine the general applicability of our split selectable marker systems, we demonstrate the utility of these systems in the model plants Arabidopsis and poplar by successfully stacking two reporters eYGFPuv and RUBY, using split Kanamycin or Hygromycin resistance markers. In conclusion, this method enables robust plant co-transformation, providing a valuable tool for the simultaneous insertion of multiple genes into both herbaceous and woody plants efficiently.

BackgroundMuch of what we know about insulin resistance is based on studies from metabolically active tissues such as liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance, however, the underlying mechanisms remain incompletely understood. ADP ribosylation factor 6 (Arf6) is a small GTPase that plays a critical role in endothelial cell (EC) function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance.MethodsWe used mouse models of constitutive EC-specific Arf6 deletion (Arf6f/-Tie2Cre) and tamoxifen inducible Arf6 knockout (Arf6f/fCdh5Cre). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose- and insulin-tolerance tests and hyperinsulinemic-euglycemic clamps. A fluorescence microsphere-based technique was used to measure tissue blood flow. Intravital microscopy was used to assess skeletal muscle capillary density.ResultsEndothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue (WAT) and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide (NO) bioavailability but independent of altered acetylcholine- or sodium nitroprusside-mediated vasodilation. In vitro Arf6 inhibition resulted in suppressed insulin stimulated phosphorylation of Akt and endothelial NO synthase. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow fed mice and glucose intolerance in high fat diet fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability.ConclusionResults from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

Aging results in an accumulation of cellular damage that activates tumor suppressor pathways leading to permanent cell cycle arrest known as cellular senescence. Damage to DNA is a robust inducer of cellular senescence. Furthermore, repeat DNA sequences at the ends of chromosomes known as telomeres are particularly susceptible to damage that leads to senescence. Senescent cells adopt a pro-oxidative, pro-inflammatory phenotype that often adversely impacts the local tissue milieu. Senolytics are drugs that specifically induce cell death in senescent cells. Senolytic drugs have been shown to delay or reduce a multitude of age-related diseases in pre-clinical studies and are currently under investigation for use in clinical trials in humans. Many senolytic drugs were originally discovered based on their ability to induce cell death in senescent endothelial cells in cell culture. However, a key unanswered question is whether this phenomenon occurs in vivo. This is critical to understand because endothelial cell senescence contributes to both cardiovascular and metabolic diseases. In the present study, we tested the hypothesis that chronic administration of a senolytic cocktail will reduce the burden of endothelial cell senescence, as well as other molecular hallmarks of aging, including DNA damage and telomere dysfunction. To test this hypothesis, we treated 21-month-old mice (N = 10 / group) with the senolytic drug cocktail dasatinib (D, 5 mg/kg body mass) and quercetin (Q, 50mg/kg body mass) on three consecutive days every two weeks for three months via oral gavage. Control mice were treated with vehicle control (10% polyethylene glycol 4000 solution). At 24 months of age, carotid artery endothelial cell mRNA was isolated and expression of the cyclin-dependent kinase inhibitor that enforces senescence known as p21 was reduced in D+Q treated compared to vehicle-treated mice (p < 0.05). Additionally, lungs from 10 mice per group were collected and pooled, CD31+ lung endothelial cells were isolated and cultured briefly, and ~267 cells per group were examined. Immunofluorescence for the DNA damage marker 53BP1 demonstrated that treatment with D+Q reduced the percentage of endothelial cells with DNA damage (p < 0.05). We also performed immunofluorescence-fluorescent in situ hybridization to detect the abundance of 53BP1 foci colocalized to telomeres, a measure of telomere-specific damage known as telomere dysfunction-induced foci (TIF). Treatment with D+Q reduced the percentage of endothelial cells containing TIF (p < 0.05). Taken together, these data demonstrate that treating aged mice with D+Q reduces endothelial cell senescence likely in part by clearing cells that have accumulated DNA damage and dysfunctional telomeres. National Institutes of Health Awards R01 AG048366 (LAL), R01 AG060395 (AJD), 5K08AG070281 (ET), 1F31AG076312 (SIB). Veteran's Affairs Merit Review Award I01 BX004492 (LAL) from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The contents do not represent the views of the U.S. Department of Veterans Affairs, the National Institutes of Health, or the United States Government. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Advanced age is accompanied by arterial dysfunction, as well as a diminished glycocalyx, which may be linked to reduced high molecular weight-hyaluronan (HMW-HA) synthesis. However, the impact of glycocalyx deterioration in age-related arterial dysfunction is unknown. We sought to determine if manipulations in glycocalyx properties would alter arterial function. Tamoxifen-induced hyaluronan synthase 2 (Has2) reduction was used to decrease glycocalyx properties. Three weeks post-tamoxifen treatment, glycocalyx thickness was lower in Has2 knockout compared to wild-type mice (P0.05). Has2 reduction phenocopies age-related arterial dysfunction, while 10 weeks of glycocalyx-targeted therapy that restores the glycocalyx also ameliorates age-related arterial dysfunction. These findings suggest that the glycocalyx may be a viable therapeutic target to ameliorate age-related arterial dysfunction.

Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab')2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-γ and tumor necrosis factor-α are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-γ. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.

Sustainable and resilient cropping intensity is now a global focus to address the food demand and nutrition security of the growing population. For sustainable intensification, maintaining soil fertility is a key concern. The nutrient management for the recently developed four crop-based cropping system in Bangladesh has not yet been studied. Hence, field experiments were conducted on the nutrient management of the four crop-based cropping system [Aus (pre-monsoon rice), Aman (monsoon rice), lentil, and mungbean] in calcareous soil in Bangladesh during the years of 2016/17 and 2017/18 to determine the appropriate fertilizer management package to improve crop productivity and sustain soil fertility. The experiment had six treatments assigned in a randomized complete block design with three replications. The treatments included T1 = control (without synthetic fertilizer), T2 = 50% recommended dose of fertilizer (RDF), T3 = 75% RDF, T4 = 100% RDF, T5 = 125% RDF, and T6 = farmers’ practice (FP). The results revealed that the 125% RDF significantly contributed to higher yields of all four crops. The rice equivalent yield (REY) was the highest for the fertilizer management of 125% RDF, which was 45.5%, 9.4%, and 12.2% higher than the control (T1), 100% RDF (T4), and FP, respectively. Considering the uptake of nutrients (N, P, K, S, Zn, and B) by the crops in the cropping system, the 125% RDF was superior to the other treatments. The nutrient management practices had a positive influence on the apparent nutrient recovery (ANR) efficiency of the cropping system. The fertilizer management of 125% RDF was also economically more profitable due to the increment in the cost–benefit ratio of 26.8%, 4.4%, and 4.9% over the control, 100% RDF, and FP, respectively. The results indicate that the current fertilizer recommendations and FP for aus, aman, lentil, and mungbean are not adequate for the change from the three crop to the four crop-based pattern, and an increased dose of fertilizer is required to increase the yield of each individual crop as well as the total system’s productivity. The fertilizer use efficiency is also higher for 125% RDF than the 100% RDF and FP indicating that to sustain the soil fertility in the four crop-based system, the current RDF and FP are not sufficient. This finding will help intensive cropping areas in preventing nutrient deficiencies that would lead to a reduction in the crop yield.

Silicon integrated Optical Phased Arrays (OPA) have been widely studied for wide and accurate beam steering applications, taking advantage of the high power handling capability, the stable and precise optical beam control, and the CMOS fabrication compatibility to realize low-cost devices. Both one-dimensional and two-dimensional silicon integrated OPAs have been demonstrated, and beam steering over a large angular range with versatile beam patterns have been achieved. However, existing silicon integrated OPAs are based on single mode operation, tuning the phase delay of the fundamental mode amongst phased array elements and generating a beam from each OPA. Whilst generating more beams for parallel steering are feasible by using multiple OPAs integrated on the same silicon circuit, the device size, complexity as well as power consumption increase substantially. To overcome these limitations, in this research, we propose and demonstrate the feasibility of designing and using multimode OPA to generate more than one beam from the same silicon integrated OPA. The overall architecture, multiple beam parallel steering operation principle, and key individual components are discussed. Results show that with the simplest two modes operation, the proposed multimode OPA design principle can realize parallel beam steering to reduce the number of beam steering required over the target angular range and the power consumption by almost 50%, whilst minimizing the device size by more than 30%. When the multimode OPA operates with a larger number of modes, the improvements on the number of beam steering, the power consumption and the size increase further.

Atherosclerosis is the root cause of major cardiovascular diseases (CVD) such as myocardial infarction and stroke. ADP-ribosylation factor 6 (Arf6) is a ubiquitously expressed GTPase known to be involved in inflammation, vascular permeability and is sensitive to changes in shear stress. Here, using atheroprone, ApoE-/- mice, with a single allele deletion of Arf6 (HET) or wildtype Arf6 (WT), we demonstrate that reduction in Arf6 attenuates atherosclerotic plaque burden and severity. We found that plaque burden in the descending aorta was lower in HET compared to WT mice (p˂0.001) after the consumption of an atherogenic Paigen diet for 5 weeks. Likewise, luminal occlusion, necrotic core size, plaque grade, elastic lamina breaks, and matrix deposition were lower in the aortic root atheromas of HET compared to WT mice (all p≤0.05). We also induced advanced human-like complex atherosclerotic plaque in the left carotid artery using partial carotid ligation surgery and found that atheroma area, plaque grade, intimal necrosis, intraplaque hemorrhage, thrombosis, and calcification were lower in HET compared to WT mice (all p≤0.04). Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p≤0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p≤0.001) but independent of changes in circulating lipids (all p≥0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.

Although cellular heterogeneity has been described for metabolic pathways, the upstream mechanisms, the downstream consequences, and the flexibility and transmission of these preferences to daughter cells remains largely unknown. Using live-cell imaging, Kosaisawe et al. demonstrate that cellular metabolism, determined by glycolysis and ATP, is spontaneously heterogeneous, plastic, and regulatory.

Background: Systemic inhibition of mammalian target of rapamycin (mTOR) improves age-related arterial and metabolic dysfunction. Although the mechanisms and tissues involved in this amelioration remain unknown, endothelial cells (ECs), key regulators of arterial and metabolic function, may be responsible for these effects. Hypothesis: The beneficial effects of systemic mTOR inhibition will be recapitulated after EC specific mTOR deletion in old mice. Methods: We studied 22-24 mo old wildtype (WT) and EC specific tamoxifen-inducible mTOR knockout (KO) mice. The arterial function was determined by assessing aortic stiffness by measuring pulse wave velocity (PWV) using Doppler ultrasound as well as endothelium-dependent dilation (EDD) and nitric oxide (NO) bioavailability using pressure myography. Carotid artery superoxide production was measured using electric paramagnetic resonance. Glucose (2g/kg, ip) and lipid (3mL/kg, oral) tolerance tests were performed to examine metabolic function. Results: Two weeks after tamoxifen administration (4mg/day, 4 days, oral), we found a ~ 60% reduction in EC mTOR protein (p=0.04). Aortic PWV was lower in KO compared to WT mice (Fig A), indicating lower aortic stiffness. EDD to acetylcholine (ACh) was higher in mesenteric arteries from KO compared to WT mice (Fig B) due to an increase in NO bioavailability (31.6 ± 8.6 vs 8.4 ± 2.3; p=0.01). Superoxide scavenger, TEMPOL, increased EDD in both WT and KO mice (Fig C), eliminating differences between groups. Superoxide was lower in carotid arteries of KO compared to WT (Fig D), suggesting that oxidative stress impairs EDD in WT mice and ablation of EC selective mTOR ameliorates this effect. Aged KO mice demonstrated greater glucose and lipid tolerance compared to WT (Fig E, F). Conclusions: Our findings demonstrate that EC specific deletion of mTOR provides beneficial effects on arterial function via reductions in oxidative stress and prevents metabolic dysfunction in old mice.

The demand for portability has speeded up the design of low-power electronic communication devices. Variable gain amplifier (VGA) is one of the most vulnerable elements of every modern receiver for the proper baseband processing of the signal. CMOS VGAs are generally suffered from low bandwidth and small gain range. In this research, a two-stage class AB VGA, each stage comprising of a direct transconductance amplifier and a linear transimpedance amplifier, is designed in Silterra 0.13-μm CMOS utilizing Mentor Graphics environment. The post-layout simulation results reveal that the VGA design achieves the widest bandwidth of 200 MHz and high gain range from -33 to 32 dB. The VGA dissipates only 2mW from a single 1.2 V DC supply. The core chip area of the VGA is also only 0.026 mm2 which is also the lowest compared to recent researches. Such a VGA will be a very useful module for all modern communication devices.

Introduction: Tuberculosis (TB) is one of the world’s deadliest disease. Presently, one fourth of the world’s population is thought to be infected with TB. Early diagnosis of tuberculosis is very important for therapeutic reasons and to control the spread of infection. The purpose of this study was to compare the efficacy of fluorescence (FL) microscopy in comparison to Ziehl- Neelsen (ZN) staining Methods: A cross-sectional study of 310 TB suspects attending Dhaka Medical College hospital subjected to four sputum examinations by ZN and FM. Löwenstein- Jensen culture was used as the gold standard. Of 310 suspects enrolled, 304 (98%) had a complete diagnostic work-up involving three sputum specimens for ZN and FM, culture and chest X-ray (CXR). Result: Out of 320 suspected case, 10 persons were out of our study. Among 310, 204 suspected case sputum culture was positive. Though we took sputum culture as gold standard, so there were 204 tuberculosis patient present in our study. Out of 204 TB patient 125 (61.2%) cases were positive in ZN staining. Negative ZN methods were also high 79 (39.7%) which indicate less sensitivity. On the other hand, FM methods showed 193 (94.6%) cases positive out of 204 sputum culture positive patient. It also presence of 11 cases which showed negative result in this methods. From this data we can assumed higher sensitivity of FL methods from ZN methods. Here 106 cases were culture negative. Out of these 106 people only 05 persons were positive in ZN staining whereas 10 persons were find to positive in FL methods. This message demonstrates us that specificity of ZN methods are slightly higher over FM methods. Overall sensitivity of ZN microscopic (61%)) methods are much lower than FL microscopic methods (95%). On the other hand, specificity was slightly reverse, which showed 95.5% in case ZN methods and 91% in FL methods. It also demonstrates that positive predictive value of ZN microscopy (96%) is slightly higher than FL microscopic (95%) methods but negative predictive value showed gross difference ZN microscopic (56%) and FL microscopic (89%) methods. Conclusions: The FL methods is more sensitive and shortens the diagnostic process of tuberculosis. Consequently, more patients can be put on a regimen for smear-positive TB, contributing to improved treatment and reducing transmission. For that Front-loaded (FL) microscopic approach may apply for early diagnosis and detection of tuberculosis. J MEDICINE JAN 2020; 21 (1) : 36-40

Zika virus (ZIKV) infection in pregnancy is associated with the development of microcephaly, intrauterine growth restriction, and ocular damage in the fetus. ZIKV infection of the placenta plays a crucial role in the vertical transmission from the maternal circulation to the fetus. Our previous study suggested that ZIKV induces endoplasmic reticulum (ER) stress and apoptosis of placental trophoblasts. Here, we showed that palmitoleate, an omega-7 monounsaturated fatty acid, prevents ZIKV-induced ER stress and apoptosis in placental trophoblasts. Human trophoblast cell lines (JEG-3 and JAR) and normal immortalized trophoblasts (HTR-8) were used. We observed that ZIKV infection of the trophoblasts resulted in apoptosis and treatment of palmitoleate to ZIKV-infected cells significantly prevented apoptosis. However, palmitate (saturated fatty acid) did not offer protection from ZIKV-induced ER stress and apoptosis. We also observed that the Zika viral RNA copies were decreased, and the cell viability improved in ZIKV-infected cells treated with palmitoleate as compared to the infected cells without palmitoleate treatment. Further, palmitoleate was shown to protect against ZIKV-induced upregulation of ER stress markers, C/EBP homologous protein and X-box binding protein-1 splicing in placental trophoblasts. In conclusion, our studies suggest that palmitoleate protects placental trophoblasts against ZIKV-induced ER stress and apoptosis.

Arabidopsis histone H3 lysine 4 (H3K4) demethylases play crucial roles in several developmental processes, but their involvement in seedling establishment remain unexplored. Here, we show that Arabidopsis JUMONJI DOMAIN-CONTAINING PROTEIN17 (JMJ17), an H3K4me3 demethylase, is involved in cotyledon greening during seedling establishment. Dark-grown seedlings of jmj17 accumulated a high concentration of protochlorophyllide, an intermediate metabolite in the tetrapyrrole biosynthesis (TPB) pathway that generates chlorophyll (Chl) during photomorphogenesis. Upon light irradiation, jmj17 mutants displayed decreased cotyledon greening and reduced Chl level compared with the wild-type; overexpression of JMJ17 completely rescued the jmj17-5 phenotype. Transcriptomics analysis uncovered that several genes encoding key enzymes involved in TPB were upregulated in etiolated jmj17 seedlings. Consistently, chromatin immunoprecipitation-quantitative PCR revealed elevated H3K4me3 level at the promoters of target genes. Chromatin association of JMJ17 was diminished upon light exposure. Furthermore, JMJ17 interacted with PHYTOCHROME INTERACTING FACTOR1 in the yeast two-hybrid assay. JMJ17 binds directly to gene promoters to demethylate H3K4me3 to suppress PROTOCHLOROPHYLLIDE OXIDOREDUCTASE C expression and TPB in the dark. Light results in de-repression of gene expression to modulate seedling greening during de-etiolation. Our study reveals a new role for histone demethylase JMJ17 in controlling cotyledon greening in etiolated seedlings during the dark-to-light transition.

We investigate the magnetization reversal of single-domain magnetic nanoparticle driven by the circularly polarized cosine chirp microwave pulse (CCMP). The numerical findings, based on the Landau–Lifshitz–Gilbert equation, reveal that the CCMP is by itself capable of driving fast and energy-efficient magnetization reversal. The microwave field amplitude and initial frequency required by a CCMP are much smaller than that of the linear down-chirp microwave pulse. This is achieved as the frequency change of the CCMP closely matches the frequency change of the magnetization precession which leads to an efficient stimulated microwave energy absorption (emission) by (from) the magnetic particle before (after) it crosses over the energy barrier. We further find that the enhancement of easy-plane shape anisotropy significantly reduces the required microwave amplitude and the initial frequency of CCMP. We also find that there is an optimal Gilbert damping for fast magnetization reversal. These findings may provide a pathway to realize the fast and low-cost memory device.

Introduction: Tragia involucrata L. have been utilized as traditional medicine in Indian subcontinent for the treatment of numerous illnesses such as inflammation, pain and skin infection. In this current study we sought to assess the anxiolytic, sedative and analgesic activity of Tragia involucrata L. leaves extract. Materials and methods: We first performed a phytochemical screening test of the leaves extracts following standard phytochemical screening protocols. We next examined the anxiolytic and sedative activity of crude methanol (TIME), ethyl acetate (TIEAE) and n-Hexane (TIHE) extract of Tragia involucrata L. leaves using mouse behavioral models such as elevated plus-maze test and pentobarbital-induced sleeping time test, respectively. Likewise, we evaluated the analgesic activity using acetic acid induced writhing test and formalin induced paw licking test. Additionally, we performed a quantitative analysis of heavy metals content of Tragia involucrata L. leaves by overnight digestion in concentrated nitric acid (HNO3). Results: Phytochemical screening demonstrated that TIME, TIEAE and TIHE contain flavonoids, alkaloids, tannins, phenols, terpenoids and sterols. Administration of these extracts resulted in higher number of open arm entry, lower number of close arm entry and higher time spent in open arm compared to control treatment (p < 0.05). Moreover, these treatments decreased the onset of sleep time and increased the duration of sleep compared to control treated mice (all p < 0.05). Likewise, extracts treated mice exhibited decreased number of writhing as well as lower acute phase and late phase duration compared to control treatment (all p < 0.05). The average level of As and Fe in Tragia involucrata L. leaves was 5.16 ± 0.012 ppm and 2.76 ± 0.015 ppm, respectively. Conclusion: Results from this study support that Tragia involucrata L. leaves extracts exhibit an anxiolytic, sedative and analgesic activity in mice.