A superporous and pH-sensitive hydrogel from Salvia hispanica (chia) seeds: stimuli responsiveness, on-off switching, and pharmaceutical applications.

The use of plant seed-based hydrogels to design drug delivery systems (DDSs) has increased due to their swellable, pH-responsive, biocompatible, biodegradable, and non-toxic nature. Herein, the chia seeds hydrogel (CSH) was extracted through an aqueous extraction method to explore its pH and salt-responsive swelling behavior and sustained release potential. The CSH was characterized using Fourier transform infrared (FT-IR) and solid-state cross-polarization magic angle spinning carbon-13 nuclear magnetic resonance (solid/state CP-MAS 13C/NMR) spectra. Thermal analysis indicated that the CSH is a thermally stable material and decomposes in two steps. The scanning electron microscope (SEM) images of CSH witnessed the existence of microscopic channeling and a superporous nature with average pore sizes of 18 ± 11 µm (transverse cross-sections) and 23 ± 15 µm (longitudinal cross-sections). The CSH is a haemocompatible material. The CSH revealed pH and saline-responsive swelling in powder and compressed form (tablet) in the following order; distilled water (DW) > pH 7.4 > pH 6.8 > pH 1.2. Moreover, the swelling of CSH followed second-order kinetics. The swelling of CSH powder and tablets was decreased with increasing salt concentration. The pH, solvent, and saline responsive on/off switching (swelling/deswelling) results of the CSH and tablets disclosed its stimuli-responsive nature. The CSH prolonged the release of valsartan for 5 h at pH 7.4, whereas, negligible release (19.3%) was noted at pH 1.2. The valsartan release followed first-order kinetics and the non-Fickian diffusion. In conclusion, the CSH is a stimuli-responsive smart material with great potential to develop pH-sensitive and targeted DDSs.

Preparation and characterization of a ciprofloxacin-loaded nanoparticles incorporated polymeric film dressing.

In an effort to prepare a modern polysaccharide-based dressing for sustained/prolonged delivery of the antibacterial agent to prevent and control skin wound infection, ciprofloxacin (CP)-loaded sodium alginate (SA)-chitosan (CS) nanoparticles (NPs) were incorporated into novel arabinoxylan (AX)-pectin (PC) blended polymeric films by solvent casting. The CP-NPs were prepared by a two-step ionic interaction method with < 300 nm size, about 25 mV zeta potential, 74% CP-loading efficiency, and approximately round shape. The CP-NPs were incorporated in optimized AX-PC polymeric film prepared by using 2% AX and 2% PC with a plasticizer (2% glycerol) and then these films were characterized for suitability as a film dressing. The transparency, improved mechanical strength, thermal stability, water transmission, and exudate uptake characteristics indicated that CP-NPs incorporated AX-PC polymeric films were suitable for dressing applications. The CP-NPs incorporated AX-PC films exhibited sustained CP release (90% release in 36 h) and better antibacterial susceptibility as compared to free CP-containing AX-PC films. Thus, CP-NPs incorporated AX-PC films are promising dressing materials to prevent and control wound infection with prolonged antibiotic release.

Concurrent Encounter of Superior Mesenteric Artery Syndrome and Nutcracker Syndrome in a Young Female Patient: A Case Report and Literature Review.

Superior mesenteric artery (SMA) syndrome causes duodenal obstruction between the SMA and aorta, which culminates into bowel obstruction. Meanwhile, nutcracker syndrome (NCS) involves left renal vein compression between the aorta and SMA, categorized by the compression site. We present a 15-year-old female with no prior medical or surgical history who displayed early signs of the rarely coexisting SMA and nutcracker phenomena, which were managed symptomatically along with nutritional support to reach her optimal body mass index.

PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics and Natural History.

PURPOSE: To analyze the genetics, clinical characteristics, and natural history of PDE6A-associated retinitis pigmentosa. DESIGN: Retrospective, longitudinal, observational cohort study. PARTICIPANTS: Patients with molecularly confirmed PDE6A-associated retinal dystrophy in a single tertiary referral center. METHODS: Review of medical records and retinal imaging, including fundus autofluorescence (FAF) imaging and spectral-domain optical coherence tomography (SD-OCT). Genetic results were reviewed, and the detected variants were assessed. RESULTS: Sixteen patients (32 eyes) were identified and evaluated longitudinally. Genetic analysis identified 14 variants in the PDE6A gene, including 8 novel variants. The mean age (±SD, range) was 34.8 years (± 17.4, 12 - 76) at baseline, with a mean follow-up time of 4.8 years. Best-corrected visual acuity (BCVA) was 0.45 ± 0.45 LogMAR (range 0.0 - 1.6) at baseline and 0.65 ± 0.7 LogMAR (range 0.0 - 2.3) at the last visit. BCVA was similar among eyes in 88% of patients. A hyperautofluorescent ring was observed on FAF in 50% and 44% of the eyes at baseline and follow up visit respectively, with a mean area of 9.7 ± 4.5mm2 at baseline and mean of 8.6 ± 4.8 mm2 at the follow-up visit. Mean horizontal ellipsoid zone width (EZW) at baseline was 1765 ± 1093 µm, which decreased to 1580 ± 1077 µm at follow up. Eighteen eyes exhibited cystoid macular oedema at baseline (56%), and 17 eyes (53%) at follow-up. There were statistically significant changes during the follow-up period in terms of BCVA, hyperautoflouroscent ring area and the EZW. CONCLUSIONS: This study highlights the natural history of PDE6A-retinopathy. The majority of the patients in this cohort had mild BCVA loss, and slowly progressive disease, based on FAF and OCT measurements.

Impact of different mating ratios of broiler breeder on reproductive performance during post moult phase.

Studies comparing mating ratio after forced molting are important for improving the efficiency of broiler breeder flocks. This study examined the effect of mating ratios on Egg production, chick weight, fertility, hatchability and embryonic mortality rate in Arbor Acres Plus broiler breeders post-moult phase. A total of 195 birds (62 weeks old), consisting of 15 cocks and 180 hens were randomly allocated with uniform body weight in a Completely Randomized Design into three groups based on the mating ratio (cock to hen). The groups included ratios of 1:10, 1:12, and 1:14, with each group replicated 5 times. Eggs were collected twice a day, and stored for 7 days at room temperature before placing them in the incubator. Results showed that mating ratios 1:10 and 1:12 had a positive effect on fertility rate and total hatchability compared to the 1:14 ratio. However, mating ratios did not affect laying rate, egg weight, egg mass, chick weight, hatchability of fertile eggs, and embryonic mortality rate. In conclusion, to reduce the cost of raising and caring cocks, a mating ratio of one cock to every twelve hens can be used for broiler breeders after forced molting to obtain the best fertility and hatching results.

Boosting the Electrochemical Oxygen Evolution with Nickel Oxide Nanoparticle-Modified Glassy Carbon Electrodes in Alkaline Solutions.

The present work investigates the electrocatalysis of oxygen evolution (OE) on a glassy carbon electrode modified with nickel oxide nanoparticles (NPs) (nano-Ni) in an alkaline solution. The nano-Ni is electrodeposited from an acidic sulfate electrolyte containing various additives, such as glucose, glycerol, and dimethyl glyoxime. The NPs are characterized morphologically and electrochemically using scanning electron microscopy and cyclic voltammetry. The elemental composition and electronic state of the modified electrodes were analyzed using X-ray photoelectron spectroscopy. A considerable enhancement in electrocatalytic activity, depending on the additives used, is observed. The study also explores the effect of nickel oxide loading to optimize the process. The highest cathodic shift in the onset potential of the oxygen evolution reaction is achieved with nickel oxide deposited in the presence of ethylene glycol.

Unveiling the nexus! Understanding knowledge issues, animal contact patterns and interaction of health care providers in the context of monkeypox and COVID-19 during monkeypox outbreak 2022.

BACKGROUND: A monkeypox (MPOX) outbreak occurred in May 2022. On June 3, 2022, the WHO Blueprint organized a consultation on MPOX research knowledge gaps and priority research questions because the engagement of health care providers (HCPs) in providing accurate information and the public's motivation to adapt protective behaviour were crucial. Thus, we conducted this study to explore the knowledge issues, animal patterns, and interactions of HCPs in the context of MPOX and COVID-19 during the MPOX outbreak. METHODS: We conducted a cross-sectional web-based survey among 816 HCPs working in governmental health facilities from many countries, mainly Syria, Egypt, Saudi Arabia, and Cameroon, in September 2022. RESULTS: Four hundred and sixty (56.37%) were aged between 18 and less than 35 years old. About 34.44% were physicians, while only 37.25% worked on the frontlines with patients. 37.99% and 5.88% received vaccinations against chickenpox and MPOX, respectively. In the meantime, 55.39% had taken courses or training programmes regarding COVID-19. Regarding knowledge-seeking behaviours (KSBs) about COVID-19, 38.73% were through passive attention, while only 28.8% got their information through active search. Most of the participants (56.86%) had a moderate level of knowledge regarding COVID-19. Only 8.82% had courses or training programmes regarding MPOX. Regarding KSB about MPOX, 50.86% were obtained through passive attention, while only 18.01% and 23.04% got their information through active and passive search, respectively. Most of the participants (57.60%) had a poor level of knowledge regarding MPOX. The regression analysis of the MPOX knowledge score revealed that individuals working on the frontlines with patients and those who had training programmes or courses were shown to have a higher score by 1.25 and 3.18 points, respectively. CONCLUSIONS: The studied HCPs had poorer knowledge about the MPOX virus than they did about the SARS-CoV-2 virus. Training programmes and education courses had an impact on their knowledge.

Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 µM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.

Clinical, Genetic and Histopathological Characteristics of CRX-associated Retinal Dystrophies.

PURPOSE: To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs). DESIGN: Retrospective multicenter cohort study including histopathology. SUBJECTS: Thirty-nine patients from 31 families with pathogenic variants in the CRX gene. METHODS: Clinical data of 152 visits were collected from medical records with a median follow-up time of 9.1 years (IQR, 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed. MAIN OUTCOME MEASURES: Visual acuity, retinal imaging, electroretinography (ERG), genotype-phenotype correlation, and histopathological examination were evaluated. RESULTS: The age at onset ranged from birth to the 8th decade of life. Median visual acuity was 1.00 logMAR (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Out of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis (LCA). In total, 21 different disease-associated heterozygous CRX variants were identified (10 missense, 8 frameshift, 2 deletion, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and two variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments. CONCLUSION: This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from LCA to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs.

Overview of online pharmacy regulations in Saudi Arabia and the Gulf cooperation council countries and their impact on online pharmacy service providers in Saudi Arabia: a qualitative analysis.

Background: Laws and regulations are needed to regulate the growing online pharmacy (OP) services. The main objective of this work was to provide an overview of the laws and regulations for OP services in the Gulf Cooperation Council (GCC) countries. In addition, the perception of how these laws and regulations in Saudi Arabia (SA) affect the online ordering of medications and health-related products from national and international OPs was explored. Methods: A secondary data collection through emails and a qualitative descriptive analysis was used to gain insight into the OP regulations in the GCC countries. Then, a qualitative study was carried out with semi-structured interviews to investigate the impact of these regulations on the practice and the market from the OP service providers' perspective. The interviews were carried out with a sample of major OP service providers in SA, to represent the GCC countries. During the interviews, multiple open-ended questions were used to explore opinions about the OP regulations and how these regulations affected the practice. The interviews were then transcribed and thematically analysed. Results: Responses were mainly received from regulators in SA, Bahrain, Oman and United Arab Emirates (UAE). SA and UAE allow for offering of OP services as add-on service for existing community pharmacy, while UAE also allows for standalone OP providers. SA, Bahrain, and Oman allow online ordering of both over-the-counter (OTC) and prescription-only medications (POM) from international OP; a prescription is required for POM and quantities allowed should be no more than 3 months' supply in case of SA and Oman while this was not specified in case of Bahrain. Invoice of purchase was also required for any POM to be released from customs in SA and Bahrain but not in Oman and UAE. Controlled medications were prohibited to be ordered online in SA, UAE, and Bahrain while it was allowed in Oman if the prescription was issued within 6-month, and the quantity dispensed was for 1 month only. Apart from online ordering of medications in these countries, no specific regulations existed to regulate ordering of other health-related products from local or international OPs. Whether Kwait and Qatar have regulations for OP could not be established due to lack of response. Two of the four interviewed representatives of OP service providers in SA were not aware of the existence of specific regulations for OP services. The representatives who were aware of these regulations were satisfied with them and found them beneficial for their business and for the patients at the same time. However, representatives raised concerns regarding the enforcement of regulations on international OP providers. Conclusion: The existing regulations for online ordering of medications are somewhat comparable between the GCC countries, with no specific regulations for ordering of other health-related products from local or international OPs. In SA, there is limited awareness of the existing regulations for OP services by providers. Nevertheless, the need for detailed regulations on certain aspects of OP services was highlighted, such as regulations for international OPs and importing medications for personal use.

Efficiency of using lactic acid and beefxide to reduce indicator microorganisms on beef in Mosul slaughterhouse.

Background: Meat contamination occurs in various ways, the most important of which are live animals before slaughter and the slaughter process (de-hiding and evisceration). For this, many substances were used that have an antimicrobial effect and can disinfect the surfaces of the carcass and extend its shelf life. Aim: This research aimed to study the efficiency of using some organic acids (lactic acid and beefxide) to reduce the microbial load (indicator microorganisms) on the surfaces of beef carcasses and some edible organs in the Mosul slaughterhouse. Methods: Two hundred sixty-four swabs (192 carcasses + 72 edible organ samples) were collected over the course of three months from the Mosul slaughterhouse in Nineveh Governorate between September 2023, and December 2023 (132 treated with organic acids and 132 not treated). The petrifilm method was used to detect indicator microorganisms in the samples. Results: Our results showed that the contamination rate in beef carcasses with generic Escherichia coli, coliforms, total coliform counts, and Enterobacteriaceae before treatment was 0.81, 1.22, 1.48, and 1.38 mean log colony forming unit (CFU/cm2), respectively. While the contamination rate in samples treated with organic acids for generic E. coli, coliforms, total coliform counts, and Enterobacteriaceae was -0.1, 0.31, 0.45, and 0.41 mean log CFU/cm2, respectively. Moreover, the level of contamination with indicator microorganisms in edible organs treated with organic acids was lower compared to untreated samples. Even though there was contamination with indicator microorganisms in the liver, heart, and kidney, there was no "significant" difference between them. Whereas there was no significant difference (p > 0.05) between lactic acid and beefxide solution in terms of reducing the rate of contamination of the indicator microorganisms in carcasses and the edible organs samples. Regarding the type of swabs used in the study, the results showed the effectiveness of sponge swabs, as the rate of microbial recovery (indicator microorganisms) was higher (p < 0.01) compared to cotton swabs. Conclusion: The study demonstrated the efficiency of using organic acids (lactic acid and beefxide solution) in reducing the microbial load to a level that does not cause diseases.

Coffee and Alzheimer's disease.

Coffee, a universally consumed beverage, is known to contain thousands of bioactive constituents that have garnered interest due to their potential neuroprotective effects against various neurodegenerative disorders, including Alzheimer's disease (AD). Extensive research has been conducted on coffee constituents such as Caffeine, Trigonelline, Chlorogenic acid, and Caffeic acid, focusing on their neuroprotective properties. These compounds have potential to impact key mechanisms in AD development, including amyloidopathy, tauopathy, and neuroinflammation. Furthermore, apart from its neuroprotective effects, coffee consumption has been associated with anticancerogenic and anti-inflammatory effects, thereby enhancing its therapeutic potential. Studies suggest that moderate coffee intake, typically around two to three cups daily, could potentially contribute to mitigating AD progression and lowering the risk of related neurological disorders. This literature underscores the potential neuroprotective properties of coffee compounds, which usually perform their neuronal protective effects via modulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nuclear factor erythroid-derived 2-like 2 (Nrf2), interleukins, tumor necrosis factor-alpha (TNF-α), and many other molecules.

Evaluating Compliance With the Ottawa Rules: A Retrospective Clinical Audit at a District General Hospital in the UK.

BACKGROUND: The Ottawa Rules are clinical decision tools designed to assist healthcare providers in determining the need for radiographs in patients with ankle or knee injuries. Compliance with these rules can lead to more efficient use of resources and reduced radiation exposure. OBJECTIVE: This retrospective clinical audit aimed to evaluate healthcare provider's compliance with the Ottawa Rules in an Emergency Department setting and assess the positivity rates of requested knee and ankle X-rays. METHODS: A two-cycle retrospective audit was conducted at Lincoln County Hospital's Emergency Department, involving 648 X-rays collected in two cycles. In between, multiple interventions were implemented to improve the outcomes. RESULTS: The study revealed varying levels of compliance with the Ottawa Rules, with higher compliance observed for knee X-rays than ankle X-rays. The compliance for knee X-rays improved from 74.6% to 89.9% and ankle X-rays improved from 33.1% to 75.8%. Positivity rates for ankle radiographs were higher than knee radiographs in both cycles. The interventions implemented between the cycles significantly improved compliance rates with the Ottawa Rules. CONCLUSION: The findings underscore the importance of adherence to the Ottawa Rules in optimizing patient care and resource utilization. The study suggests the need for continued education and periodic audits to maintain and further improve compliance rates. Additionally, the higher positivity rates for ankle radiographs highlight the importance of targeted imaging strategies based on clinical guidelines.

Development and validation of a virtual teaching method for minimally invasive surgery skills: a prospective cohort study.

INTRODUCTION: The COVID-19 pandemic led to a significant reduction in operative exposure for surgical trainees, necessitating alternative training methods to mitigate the impact on surgical education. This study sought to evaluate whether minimally invasive surgery (MIS) skills could be taught remotely using widely available technology with objective assessments of proficiency. METHODS: This was a pilot observational study with comparative assessment of face-to-face (F2F) and virtual training of novice learners in MIS skills. Performance and objective cognitive workload parameters (Surgical Task Load Index (SURG-TLX) score, heart rate and pupil metrics) were evaluated. The assessments were peg transfer (McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS)) and suturing (Suturing Training and Testing (SUTT)) tasks performed using box trainers. Virtual teaching was conducted by expert trainers using a web-based streaming platform. RESULTS: Technical challenges of delivering a virtual MIS skills course were addressed after a pilot course. Participants (n = 20) in the final course had similar baseline characteristics and were randomly allocated to F2F (n = 8) and virtual (n = 12) teaching groups. Participants in the online group completed the peg transfer task faster than the F2F group (11.25 minutes vs. 16.88 minutes; P = 0.015). There were no significant differences in all other MISTELS and SUTT performance measures between groups. Cognitive workload parameters (SURG-TLX score, heart rate and pupil metrics) were also similar between groups. CONCLUSION: This study has demonstrated that virtual teaching of MIS skills using a web-based streaming platform is feasible and effective, providing the foundation for low-cost, effective, and scalable MIS skills programs in the future.

Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration.

Combined sulforaphane and ß-sitosterol mitigate olanzapine-induced metabolic disorders in rats: Insights on FOXO, PI3K/AKT, JAK/STAT3, and MAPK signaling pathways.

One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of sulforaphane (SFN) and ß-sitosterol (ßSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, ßSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or ßSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and ßSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-ß signaling pathways. The administration of SFN and/or ßSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways.

Brain Targeting of Venlafaxine via Intranasal Transbilosomes Thermogel for Improved Management of Depressive Disorder.

The current research aimed to design and optimize hyaluronic acid-coated transbilosomes containing venlafaxine (VLF-HA-TBLs) for nose-to-brain delivery for improved management of depressive disorder. Venlafaxine-loaded transbilosomes (VLF-TBLs) were developed according to the film hydration procedure, optimized for maximum efficiency using the quality by design-based Box-Behnken design (BBD), and then coated with hyaluronic acid (HA). The optimized VLF-HA-TBLs were subjected to in vitro characterization, integrated into a thermolabile gel, and then exposed to in vivo evaluation studies. The results revealed that the VLF-HA-TBLs formulation exhibited acceptable size (185.6±4.9 nm), surface charge (-39.8±1.7 mV), and entrapment efficiency (69.6 ± 2.6%). The morphological study revealed that nanovesicles were spherical and displayed a consistent size distribution without particle aggregation. It also showed improved ex vivo nasal diffusion and a prolonged release profile. In addition, the formulated VLF-HA-TBLs were stable under the studied conditions and tolerable when applied intranasally. Compared to the intranasal administration of VLF solution (VLF-SOL), the biodistribution analysis showed that VLF-HA-TBLs delivered intranasally had a relative bioavailability of 441% in the brain and 288% in plasma. Moreover, the intranasal delivery of VLF-HA-TBLs demonstrated much higher bioavailability (512%) in the brain compared to VLF-SOL administered intravenously. Collectively, it could be possible to infer that HA-TBLs might be an effective nanocarrier to administer VLF to the brain via the nasal route.

INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.

Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.

The Caenorhabditis elegans protein SOC-3 permits an alternative mode of signal transduction by the EGL-15 FGF receptor.

Fibroblast Growth Factors and their receptors (FGFRs) comprise a cell signaling module that can stimulate signaling by Ras and the kinases Raf, MEK, and ERK to regulate animal development and homeostatic functions. In Caenorhabditis elegans, the sole FGFR ortholog EGL-15 acts with the GRB2 ortholog SEM-5 to promote chemoattraction and migration by the sex myoblasts (SMs) and fluid homeostasis by the hypodermis (Hyp7). Cell-specific differences in EGL-15 signaling were suggested by the phenotypes caused by egl-15(n1457), an allele that removes a region of its C-terminal domain (CTD) known to bind SEM-5. To determine how mutations altered EGL-15 activity in the SMs and Hyp7, we used the kinase reporter ERK-KTR to measure activation of the ERK ortholog MPK-1. Consequences of egl-15(n1457) were cell-specific, resulting in loss of MPK-1 activity in the SMs and elevated activity in Hyp7. Previous studies of Hyp7 showed that loss of the CLR-1 phosphatase causes a fluid homeostasis defect termed "Clear" that is suppressed by reduction of EGL-15 signaling, a phenotype termed "Suppressor of Clear" (Soc). To identify mechanisms that permit EGL-15 signaling in Hyp7, we conducted a genetic screen for Soc mutants in the clr-1; egl-15(n1457) genotype. We report the identification of SOC-3, a protein with putative SEM-5-binding motifs and PH and PTB domains similar to DOK and IRS proteins. In combination with the egl-15(n1457) mutation, loss of either soc-3, the GAB1 ortholog soc-1, or the SHP2 ortholog ptp-2, reduced MPK-1 activation. We generated alleles of soc-3 to test the requirement for the SEM-5-binding motifs, finding that residue Tyr356 is required for function. We propose that EGL-15-mediated SM chemoattraction relies solely on the direct interaction between SEM-5 and the EGL-15 CTD. In Hyp7, EGL-15 signaling uses two mechanisms: the direct SEM-5 binding mechanism; and an alternative, CTD-independent mechanism involving SOC-3, SOC-1, and PTP-2. This work demonstrates that FGF signaling uses distinct, tissue-specific mechanisms in development, and identifies SOC-3 as a potential adaptor that facilitates Ras pathway activation by FGFR.

Catalytic resonance theory: the catalytic mechanics of programmable ratchets.

Catalytic reaction networks of multiple elementary steps operating under dynamic conditions via a programmed input oscillation are difficult to interpret and optimize due to reaction system complexity. To understand these dynamic systems, individual elementary catalytic reactions oscillating between catalyst states were evaluated to identify their three fundamental characteristics that define their ability to promote reactions away from equilibrium. First, elementary catalytic reactions exhibit directionality to promote reactions forward or backward from equilibrium as determined by a ratchet directionality metric comprised of the input oscillation duty cycle and the reaction rate constants. Second, catalytic ratchets are defined by the catalyst state of strong or weak binding that permits reactants to proceed through the transition state. Third, elementary catalytic ratchets exhibit a cutoff frequency which defines the transition in applied frequency for which the catalytic ratchet functions to promote chemistry away from equilibrium. All three ratchet characteristics are calculated from chemical reaction parameters including rate constants derived from linear scaling parameters, reaction conditions, and catalyst electronic state. The characteristics of the reaction network's constituent elementary catalytic reactions provided an interpretation of complex reaction networks and a method of predicting the behavior of dynamic surface chemistry on oscillating catalysts.