Production of buns, the bakery-based snack food, with reduced refined wheat flour content: Recent developments.

Buns are very soft puffed bakery snack items, popular in many countries, especially low- and middle-income nations. Buns are either eaten directly or used in the preparation of culinary items. Buns are mainly prepared using refined wheat flour rich in gluten protein and devoid of husk. Consuming gluten-containing foods is leading to several health complications among consumers worldwide. Hence, several researchers have tried to reduce the gluten content in the dough by incorporating cereals flours, protein-rich sources like soy, cheese whey, etc., hydrocolloids, millets, pomace, and seed flour of vegetables and fruits, etc. These additives not only reduce gluten content in the buns to a certain extent but also enhance the fibre content and nutritional profile of the buns. This mini-review summarizes the recent developments in the production of buns using these additives to improve their nutritional quality.

Longitudinal QTc stability and impact of baseline cardiac rhythm on discharge dose in dofetilide-treated patients.

INTRODUCTION: Dofetilide suppresses atrial fibrillation (AF) in a dose-dependent fashion. The protective effect of AF against QTc prolongation induced torsades de pointe and transient post-cardioversion QTc prolongation may result in dofetilide under-dosing during initiation. Thus, the optimal timing of cardioversion for AF patients undergoing dofetilide initiation to optimize discharge dose remains unknown as does the longitudinal stability of QTc . The purpose of this study was to evaluate the impact of baseline rhythm on dofetilide dosing during initiation and assess the longitudinal stability of QTc-all (Bazzett, Fridericia, Framingham, and Hodges) over time. METHODS: Medical records of patients who underwent preplanned dofetilide loading at a tertiary care center between January 2016 and 2019 were reviewed. RESULTS: A total of 198 patients (66 ± 10 years, 32% female, CHADS2 -Vasc 3 [2-4]) presented for dofetilide loading in either AF (59%) or sinus rhythm (SR) (41%). Neither presenting rhythm, nor spontaneous conversion to SR impacted discharge dose. The cumulative dofetilide dose before cardioversion moderately correlated (r = .36; p = .0001) with discharge dose. Postcardioversion QTc-all prolongation (p < .0001) prompted discharge dose reduction (890 ± 224 mcg vs. 552 ± 199 mcg; p < .0001) in 30% patients. QTc-all in SR prolonged significantly during loading (p < .0001). All patients displayed QTc-all reduction (p < .0001) from discharge to short-term (46 [34-65] days) that continued at long-term (360 [296-414] days) follow-ups. The extent of QTc-all reduction over time moderately correlated with discharge QTc-all (r = .54-0.65; p < .0001). CONCLUSION: Dofetilide initiation before cardioversion is equivalent to initiation during SR. Significant QTc reduction proportional to discharge QTc is seen over time in all dofetilide-treated patients. QTc returns to preloading baseline during follow-up in patients initiated in SR.

Relationship between Surpoint Tag Index, a Radiofrequency Ablation lesion quality indicator, and Atrial wall thickness in Cavotricuspid isthmus Ablations exhibiting bidirectional block.

BACKGROUND: An RFA lesion quality indicator, Surpoint Tag Index® (TI) incorporates key factors: power, time, and contact force, impacting lesion quality. TI accurately estimates lesion depth in animal studies. However, the relationship between TI and in-vivo atrial wall thickness in patients exhibiting bidirectional block remains unknown. OBJECTIVE: To describe the relationship between atrial wall thickness and TI in CTI exhibiting bidirectional block. METHODS: Data from 492 RFA lesions from 25 patients undergoing PVI and CTI ablations in SR with point-by-point RF lesions (<45 W) utilizing a Thermocool Smarttouch® SF ablation catheter and CARTO-3 mapping were retrospectively analyzed. Operators were blinded to TI data and CTI thickness. CTI thickness was obtained using ICE images on Cartosound pre-ablation. Durable lesions were defined as part of a lesion set exhibiting bidirectional block of >30 min. RESULTS: In lesions exhibiting bidirectional block, the thinnest (1-2 mm; 5% lesions) and thickest (8-10 mm; 6% lesions) portions of the CTI correlated with the lowest (429 ± 75) and highest (516 ± 64) TI. The bulk of thickness (2-6 mm; 80%) correlated with a TI of 455 ± 72 (p = 0.001). There was a weak but positive correlation between TI and CTI thickness (r = 0.2; p ≤ 0.01). Examined in sectors, the anterior 1/3rd CTI was the thickest (4.8 ± 1.9 mm) but correlated with a similar TI value (479 ± 75 vs. 471 ± 70; p = 0.34) as the thinner middle 1/3rd (3.8 ± 1.7 mm; p ≤ 0.0001). CONCLUSION: A mean TI value of 455 correlates with bidirectional block across the bulk of CTI with lower and higher values needed for the thinner and thicker portions, respectively. Tissue composition, aside from wall thickness, influences TI values for the creation of the bidirectional block.

Impact of a dedicated atrial fibrillation clinic on diagnosis-to-ablation time.

Background: Outcomes following catheter ablation (CA) for atrial fibrillation (AF) improve as the diagnosis-to-ablation time (DAT) shortens. Use of a protocol-based integrated care model through a dedicated atrial fibrillation clinic (AFC) may serve to standardize treatment pathways and decrease DAT. Objective: To evaluate the DAT and clinical characteristics of patients with AF referred from an AFC vs a conventional electrophysiology clinic (EC). Methods: Retrospective analysis was completed in consecutive patients undergoing index AF ablation at Riverside Methodist Hospital in 2019 with minimum 1 year follow-up. Patients were categorized based off their CA referral source (AFC vs EC) and where the initial visit following index diagnosis of AF occurred (AFC vs EC). Results: A total of 182 patients (mean age 65 years, 64% male) were reviewed. Patients referred from an AFC (21%) had a median DAT of 342 days (interquartile range [IQR], 125-855 days) compared to patients referred from EC (79%) with a median DAT of 813 days (IQR, 241-1444 days; P = .01). Patients with their index visit following AF diagnosis occurring in the AFC (9%) had significantly shorter median DAT (127 days [IQR, 95-188 days]) compared to EC (91%) (789 days [IQR, 253-1503 days]; P = .002). Patients with DAT <1 year had lower AF recurrence than patients with DAT >1 year (P = .04, hazard ratio = 0.58, 95% confidence interval 0.3418-1.000). Conclusion: DAT is a modifiable factor that may affect CA outcomes. Significant reductions in DAT were observed in patients evaluated through a dedicated AF clinic.

The Role of Patiromer in Delaying the Onset of Renal Replacement Therapy in Patients with Advanced Renal Failure.

Patients with chronic kidney disease (CKD) are at an increased risk of developing hyperkalemia, which can be potentially life threatening. Hyperkalemia is frequently encountered with renin-angiotensin-aldosterone system inhibitor (RAASi) therapy use in patients with CKD and often results in the underdosing or discontinuation of these drugs. RAASi therapy has been proven to delay the progression of CKD, ameliorate proteinuria, and reduce the overall risk of cardiovascular morbidity and mortality. Patiromer is a sodium-free, potassium-binding polymer used for the treatment of hyperkalemia. We present a case series of four patients with Stage 4 or 5 CKD in whom the initiation of dialysis was delayed with the use of patiromer. For one patient, dialysis was delayed by 18 months, whereas the remaining three patients, in whom hyperkalemia was one of the main complications, remain dialysis independent to date.

HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron.

Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1α (HIF-1α) and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α-dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α-expressing tumor enteroids. Our work demonstrated that HIF-2α integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2α that can be leveraged for CRC treatment.

Plant-based stearidonic acid as sustainable source of omega-3 fatty acid with functional outcomes on human health.

Dietary omega-3 long chain polyunsaturated fatty acids (n-3 LC-PUFA) like eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are known to be potent biological regulators with therapeutic and preventive effects on human health. Many global health organizations have recommended consuming marine based omega-3 sources for neonatal brain development and reducing the risk of various chronic diseases. However, due to concerns regarding the origin, sustainable supply and safety of the marine sources, alternative n-3 PUFA sources are being explored. Recently, plant-based omega-3 sources are gaining much importance because of their sustainable supply and dietary acceptance. α-linolenic acid (ALA, 18:3n-3) rich seed oils are the major omega-3 fatty acid source available for human consumption. But, efficiency of conversion of ALA to n-3 LC-PUFAs in humans is limited due to a rate-limiting step in the n-3 pathway catalyzed by Δ6-desaturase. Botanical stearidonic acid (SDA, 18:4n-3) rich oils are emerging as a sustainable omega-3 source with efficient conversion rate to n-3 LC-PUFA especially to EPA, as it bypasses the Δ6-desaturase rate limiting step. Several recent studies have identified the major plant sources of SDA and explored its potential health benefits and preventive roles in inflammation, cardiovascular disease (CVD) and cancer. This systematic review summarizes the current state of knowledge on the sources, nutraceutical roles, food-based applications and the future perspectives of botanical SDA.

Discovery of isoxazolyl-based inhibitors of Plasmodium falciparum cGMP-dependent protein kinase.

The cGMP-dependent protein kinase in Plasmodium falciparum (PfPKG) plays multiple roles in the life cycle of the parasite. As a result, this enzyme is a potential target for new antimalarial agents. Existing inhbitors, while potent and active in malaria models are not optimal. This communication describes initial optimization of a structurally distinct class of PfPKG inhibitors.

Relationship between right ventricular pacing and non-sustained ventricular arrhythmias in patients with dual-chamber pacemaker and normal range left ventricular ejection fraction

Background@#Right ventricular pacing (RVP) increases heart failure, AF, and death rates in pacemaker patients and ventricular arrhythmias (VAs) in defibrillator patients. However, the impact of RVP on VAs burden and its clinical significance in pacemaker patients with normal range LVEF of > 50–55% remains unknown. We sought to evaluate the relationship of RVP and VAs and its clinical impact in a pacemaker patient population. @*Methods@#Records of 105 patients who underwent de novo dual-chamber pacemaker implant or a generator change (Medtronic™ or Boston Scientific™) for AV block and sinus node disease at a tertiary care center between September 1, 2015, and September 1, 2016, were retrospectively reviewed. @*Results@#Data from 105 patients (51% females, mean age 76 ± 1 years, mean LVEF 61 ± 0.7%) without history of VAs (98.2%) were reviewed over 1044 ± 23 days. Dependent patients (100% RVP) exhibited the lowest VAs burden when compared to  1/h of PVC runs and increasing PVC runs/h were significantly associated with hospitalization (p = 0.04) and all-cause mortality (p = 0.03), respectively. @*Conclusions@#In pacemaker patients with normal range LVEF (> 50–55%), 100% RVP is associated with the lowest burden of NSVT. Furthermore, patients with < 1% RVP also exhibit low VA burden; however, intermittent RVP seems to significantly correlate with non-sustained VAs.

Physico-chemical Characterization, Profiling of Total Lipids and Triacylglycerol Molecular Species of Omega-3 Fatty Acid Rich B. arvensis Seed Oil from India.

Buglossoides arvensis is indigenous to India and its seed oil is rich in unique and nutritionally important omega-3 fatty acid namely, stearidonic acid (SDA). It is a non-conventional oil seed plant and needs to be agronomically adapt for commercial utilization. In the present study, oil extracted from the agronomically adapted high yielding cultivar of B. arvensis seeds was analyzed for its oil content, fatty acid (FA) composition, physico-chemical characteristics, total lipids and triacylglycerol molecular species. The oil content, peroxide, acid, iodine, p-anisidine values and tocopherol content of the oil were 18.53% (w/w), 2.06 meq of active oxygen / kg of oil, 2.55 mg KOH/g oil, 217.2 g I2/100g oil, 10.7 and 774.8 mg/kg oil respectively. Oxidative stability as determined by the induction period was found to be 3.1 h. Polyunsaturated fatty acid (PUFA) content of the oil was 81.3% (of total FA), comprising of α-linolenic acid (ALA; 48.5%), SDA (18.6%), linoleic acid (LA; 10.3%) and γ-linolenic acid (GLA; 3.9%). Profiling of lipid classes showed neutral lipids (89.3%, w/w) as most abundant lipid class followed by glycolipids (7.4%, w/w) and phospholipids (3.3%, w/w). High resolution mass spectrometric analysis of triacylglycerol (TAG) molecular species showed TAGs with C54 carbons in the acyl chain as most abundant. Positional distribution analysis showed GLA and SDA predominantly at the sn-2 position of triacylglycerol. FTIR analysis revealed common characteristics molecular features similar to PUFA rich oils. Overall, the results suggest that B. arvensis seed oil is an excellent ω3-ω6-ω3 or ALA-SDA-GLA source for food and nutraceutical industries.

Discovery of a Stress-Activated Protein Kinase Inhibitor for Lymphatic Filariasis.

Lymphatic filariasis infects over 120 million people worldwide and can lead to significant disfigurement and disease. Resistance is emerging with current treatments, and these therapies have dose limiting adverse events; consequently new targets are needed. One approach to achieve this goal is inhibition of parasitic protein kinases involved in circumventing host defense mechanisms. This report describes structure-activity relationships leading to the identification of a potent, orally bioavailable stress activated protein kinase inhibitor that may be used to investigate this hypothesis.

Clinical Impact of Saline Volume Infused Through Irrigated-Tip Ablation Catheter in Low Acuity Paroxysmal Atrial Fibrillation Ablation Patients.

BACKGROUND: Radio-Frequency ablation (RFA) to achieve pulmonary vein isolation (PVI) remains mainstay therapy for symptomatic paroxysmal atrial fibrillation (PAF). The clinical consequences of large saline infusions during AF ablation have not been systematically studied. We utilized the differential flow-rates of the two commercially available ablation catheters (AC): 'ThermoCool' (TCAC) and 'Surround Flow' (SFAC) from Biosense-Webster to evaluate the clinical impact of the saline infused in the immediate post-ablation period. METHODS: Consecutive charts of PAF patients between 18 and 81 years who underwent RFA procedure at a tertiary care hospital were reviewed. RESULTS: Forty-seven patients were included in the study (33Males, 65±11years, LVEF 58±7% and left atrial diameter 44±7.5mm, 23TCAC-use). The saline volume infused through the AC was significantly higher with TCAC vs SFAC use (1277±316vs697±299 ml; p<0.001), with no difference in volume infused from other sources, total procedure or RFA times (p>0.05). This led to significant increase in post-ablation weight gain (96±23 vs 97.5±24kg; p=0.002), furosemide usage (39% vs 0%; p=0.0006), urine production (120±79 vs 63±31ml/hr; p=0.003) and post-RFA potassium reduction (4.4±0.42 vs 4±0.32mmol/l; p<0.001) with TCAC use. Significant post-RFA reduction in magnesium, calcium and creatinine, associated hyperchloremic metabolic acidosis and a modest QTc prolongation were also observed with use of both ACs albeit only moderate to weakly correlated with saline volume infused through the AC. No clinical adverse outcomes were encountered. CONCLUSIONS: Higher saline-volume infusing AC use in PAF ablation causes significant post-ablation weight gain despite higher furosemide use, larger urine production and associated post-RFA potassium reduction without increasing morbidity in lower acuity patients. Furthermore, an array of post-ablation electrolyte disturbances causes a modest and clinically insignificant QTc prolongation.

Unravelling a stearidonic acid-rich triacylglycerol biosynthetic pathway in the developing seeds of Buglossoides arvensis: A transcriptomic landscape.

Buglossoides arvensis is an emerging oilseed crop that is rich in stearidonic acid (SDA) and has several potential applications in human health and nutrition. The molecular basis of SDA biosynthesis in this plant remains unknown due to lack of genomic information. To unravel key genes involved in SDA-rich triacylglycerol (TAG) biosynthesis, we performed transcriptome sequencing of pooled mRNA from five different developmental stages of B. arvensis seeds using Illumina NextSeq platform. De novo transcriptome assembly generated 102,888 clustered transcripts from 39.83 million high-quality reads. Of these, 62.1% and 55.54% of transcripts were functionally annotated using Uniprot-Viridiplantae and KOG databases, respectively. A total of 10,021 SSR-containing sequences were identified using the MISA tool. Deep mining of transcriptome assembly using in silico tools led to the identification of genes involved in fatty acid and TAG biosynthesis. Expression profiling of 17 key transcripts involved in fatty acid desaturation and TAG biosynthesis showed expression patterns specific to the development stage that positively correlated with polyunsaturated fatty acid accumulation in the developing seeds. This first comprehensive transcriptome analysis provides the basis for future research on understanding molecular mechanisms of SDA-rich TAG accumulation in B. arvensis and aids in biotechnological production of SDA in other oilseed crops.

Mechanism of inhibition of botulinum neurotoxin type A light chain by two quinolinol compounds.

Quinolinol-based compounds are a promising starting point for discovery of effective inhibitors of the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism of inhibition by quinolinol compounds facilitate interpretation of docking data and inhibitor optimization. In this study, a fluorogenic substrate of BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 µM and 5.8 µM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors of BoNT/A LC with inhibition constants (KI) 3.2 µM and 6.2 µM for MSU58 and MSU84, respectively. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding of the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis.

Curcumin ameliorates streptozotocin-induced liver damage through modulation of endoplasmic reticulum stress-mediated apoptosis in diabetic rats.

We investigated the effect of curcumin on liver injury in diabetic rats induced by streptozotocin (STZ) through modulation of endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). Experimental diabetes was induced by a single intraperitoneal injection of STZ (55 mg/kg), and curcumin was given at 100 mg/kg by gavage for 56 days. We observed that curcumin improved the morphological and histopathological changes, significantly decreased hepatic ERS marker protein: glucose-regulated protein 78, and improved liver function in diabetic rats. Moreover, treatment with curcumin markedly decreased the sub-arm of the UPR signaling protein such as phospho-double-stranded RNA-dependent protein kinase-like ER kinase, CCAAT/enhancer-binding protein homologous protein, tumor necrosis factor receptor-associated factor 2, and inositol-requiring enzyme1α; and inhibited tumor necrosis factor α, interleukin 1ß, phospho-p38 mitogen-activated protein kinase, and apoptosis signal-regulating kinase 1 in liver tissues of diabetic rats. Apoptotic and anti-apoptotic signaling proteins, such as cleaved caspase-3 and B-cell lymphoma 2, were significantly increased and decreased, respectively in diabetic rats; curcumin treatment prevented all of these alterations. In summary, our results indicate that curcumin has the potential to protect the diabetic liver by modulating hepatic ERS-mediated apoptosis, and provides a novel therapeutic strategy for the diabetic liver damage.

Progress in the discovery and development of heat shock protein 90 (Hsp90) inhibitors.

The discovery and clinical development of heat shock protein 90 (Hsp90) inhibitors continue to progress. A number of Hsp90 inhibitors are in clinical trials, and preclinical discoveries of new chemotypes that bind to distinct regions in the protein as well as isoform selective compounds are active areas of research. This review will highlight progress in the field since 2010.

Influence of isolate origin and presence of various genes on biofilm formation by Enterococcus faecium.

Enterococcus faecium, a major cause of nosocomial infections, is often isolated from conditions where biofilm is considered to be important in the establishment of infections. We investigated biofilm formation among E. faecium isolates from diverse sources and found that the occurrence and amount of biofilm formation were significantly greater in clinical isolates than fecal isolates from community volunteers. We also found that the presence of the empfm (E. faecium pilus) operon was associated with the amount of biofilm formation. Furthermore, we analyzed the possible association between the distribution of 16 putative virulence genes and the occurrence of biofilm production. Even though the prevalence of these virulence genes was significantly higher in clinical isolates, we did not observe any correlation with the occurrence of biofilm formation.

The majority of a collection of U.S. endocarditis Enterococcus faecalis isolates obtained from 1974 to 2004 lack capsular genes and belong to diverse, non-hospital-associated lineages.

Eighty-one endocarditis-derived Enterococcus faecalis isolates that were collected from individual patients in the United States between 1974 and 2004 were sequence typed and analyzed for the presence of various genes, including some previously associated with virulence. Overall, using our previously described trilocus sequence typing (TLST), 44 different sequence types (STs) were found within this collection; 26 isolates were singletons (a unique TLST sequence type [ST(T)]), some ST(T)s contained multiple isolates (up to 6 isolates), and 16% of the isolates (13 isolates) could be grouped by additional sequence typing into clonal cluster 21 (CC21). Of note, only four isolates (7%) of the 56 whose multilocus sequence types were determined were found to belong to one of the previously described hospital-associated clonal clusters CC2 and CC9, and only 15% and 37% of all isolates had high-level resistance to gentamicin and streptomycin, respectively, including 10% that were resistant to both. We also found that 64% of the isolates lacked the genes for production of capsule polysaccharide, which has been proposed to enhance the pathogenic potential of the hospital-associated clonal clusters. In summary, while our collection is not a random sample of cases of E. faecalis endocarditis, these results indicate that nonencapsulated strains belonging to non-hospital-associated lineages were predominant among endocarditis E. faecalis isolates recovered during this time period.

Contribution of individual Ebp Pilus subunits of Enterococcus faecalis OG1RF to pilus biogenesis, biofilm formation and urinary tract infection.

The endocarditis and biofilm-associated pilus (Ebp) operon is a component of the core genome of Enterococcus faecalis that has been shown to be important for biofilm formation, adherence to host fibrinogen, collagen and platelets, and in experimental endocarditis and urinary tract infection models. Here, we created single and double deletion mutants of the pilus subunits and sortases; next, by combining western blotting, immunoelectron microscopy, and using ebpR in trans to increase pilus production, we identified EbpA as the tip pilin and EbpB as anchor at the pilus base, the latter attached to cell wall by the housekeeping sortase, SrtA. We also confirmed EbpC and Bps as the major pilin and pilin-specific sortase, respectively, both required for pilus polymerization. Interestingly, pilus length was increased and the number of pili decreased by deleting ebpA, while control overexpression of ebpA in trans restored wild-type levels, suggesting a dual role for EbpA in both initiation and termination of pilus polymerization. We next investigated the contribution of each pilin subunit to biofilm formation and UTI. Significant reduction in biofilm formation was observed with deletion of ebpA or ebpC (P<0.001) while ebpB was found to be dispensable; a similar result was seen in kidney CFUs in experimental UTI (ΔebpA, ΔebpC, P≤0.0093; ΔebpB, non-significant, each vs. OG1RF). Hence, our data provide important structural and functional information about these ubiquitous E. faecalis pili and, based on their demonstrated importance in biofilm and infection, suggest EbpA and EbpC as potential targets for antibody-based therapeutic approaches.