Prebiotics Mitigate the Detrimental Effects of High-Fat Diet on memory, anxiety and microglia functionality in Ageing Mice.

Ageing is characterised by a progressive increase in systemic inflammation and especially neuroinflammation. Neuroinflammation is associated with altered brain states that affect behaviour, such as an increased level of anxiety with a concomitant decline in cognitive abilities. Although multiple factors play a role in the development of neuroinflammation, microglia have emerged as a crucial target. Microglia are the only macrophage population in the CNS parenchyma that plays a crucial role in maintaining homeostasis and in the immune response, which depends on the activation and subsequent deactivation of microglia. Therefore, microglial dysfunction has a major impact on neuroinflammation. The gut microbiota has been shown to significantly influence microglia from birth to adulthood in terms of development, proliferation, and function. Diet is a key modulating factor that influences the composition of the gut microbiota, along with prebiotics that support the growth of beneficial gut bacteria. Although the role of diet in neuroinflammation and behaviour has been well established, its relationship with microglia functionality is less explored. This article establishes a link between diet, animal behaviour and the functionality of microglia. The results of this research stem from experiments on mouse behaviour, i.e., memory, anxiety, and studies on microglia functionality, i.e., cytochemistry (phagocytosis, cellular senescence, and ROS assays), gene expression and protein quantification. In addition, shotgun sequencing was performed to identify specific bacterial families that may play a crucial role in the brain function. The results showed negative effects of long-term consumption of a high fat diet on ageing mice, epitomised by increased body weight, glucose intolerance, anxiety, cognitive impairment and microglia dysfunction compared to ageing mice on a control diet. These effects were a consequence of the changes in gut microbiota modulated by the diet. However, by adding the prebiotics fructo- and galacto-oligosaccharides, we were able to mitigate the deleterious effects of a long-term high-fat diet.

Real Time Tracking of Nanoconfined Water-Assisted Ion Transfer in Functionalized Graphene Derivatives Supercapacitor Electrodes.

Water molecules confined in nanoscale spaces of 2D graphene layers have fascinated researchers worldwide for the past several years, especially in the context of energy storage applications. The water molecules exchanged along with ions during the electrochemical process can aid in wetting and stabilizing the layered materials resulting in an anomalous enhancement in the performance of supercapacitor electrodes. Engineering of 2D carbon electrode materials with various functionalities (oxygen (─O), fluorine (─F), nitrile (─C≡N), carboxylic (─COOH), carbonyl (─C═O), nitrogen (─N)) can alter the ion/water organization in graphene derivatives, and eventually their inherent ion storage ability. Thus, in the current study, a comparative set of functionalized graphene derivatives-fluorine-doped cyanographene (G-F-CN), cyanographene (G-CN), graphene acid (G-COOH), oxidized graphene acid (G-COOH (O)) and nitrogen superdoped graphene (G-N) is systematically evaluated toward charge storage in various aqueous-based electrolyte systems. Differences in functionalization on graphene derivatives influence the electrochemical properties, and the real-time mass exchange during the electrochemical process is monitored by electrochemical quartz crystal microbalance (EQCM). Electrogravimetric assessment revealed that oxidized 2D acid derivatives (G-COOH (O)) are shown to exhibit high ion storage performance along with maximum water transfer during the electrochemical process. The complex understanding of the processes gained during supercapacitor electrode charging in aqueous electrolytes paves the way toward the rational utilization of graphene derivatives in forefront energy storage applications.

Effect of Statin Lipophilicity on the Proliferation of Hepatocellular Carcinoma Cells.

The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects.

Manganese matere bonds in biological systems: PDB inspection and DFT calculations.

A Protein Data Bank (PDB) survey has revealed noncovalent contacts involving Mn centres and protein residues. Their geometrical features are in line with the interaction between low electron density sites located along the Mn-O/N coordination bonds (σ-holes) and the lone pairs belonging to TYR, SER or HIS residues, known as a matere bond (MaB). Calculations at the PBE0-D3/def2-TZVP level of theory were used to investigate the strength and shed light on the physical nature of the interaction. We expect the results presented herein will be useful for those scientists working in the fields of bioinorganic chemistry, particulary in protein-metal docking, by providing new insights into transition metal⋯Lewis base interactions as well as a retrospective point of view to further understand the structural and functional implications of this key transition metal ion.

Targeting HIF-1α in sickle cell disease and cancer: unraveling therapeutic opportunities and risks.

INTRODUCTION: HIF-1α, a key player in medical science, holds immense significance in therapeutic approaches. This review delves into its complex dynamics, emphasizing the delicate balance required for its modulation. HIF-1α stands as a cornerstone in medical research, its role extending to therapeutic strategies. This review explores the intricate interplay surrounding HIF-1α, highlighting its critical involvement and the necessity for cautious modulation. AREAS COVERED: In sickle cell disease (SCD), HIF-1α's potential to augment fetal hemoglobin (HbF) production and mitigate symptoms is underscored. Furthermore, its role in cancer is examined, particularly its influence on survival in hypoxic tumor microenvironments, angiogenesis, and metastasis. The discussion extends to the intricate relationship between HIF-1α modulation and cancer risks in SCD patients, emphasizing the importance of balancing therapeutic benefits and potential hazards. EXPERT OPINION: Managing HIF-1α modulation in SCD patients requires a nuanced approach, considering therapeutic potential alongside associated risks, especially in exacerbating cancer risks. An evolutionary perspective adds depth, highlighting adaptations in populations adapted to low-oxygen environments and aligning cancer cell metabolism with primitive cells. The role of HIF-1α as a therapeutic target is discussed within the context of complex cancer biology and metabolism, acknowledging varied responses across diverse cancers influenced by intricate evolutionary adaptations.

Asiatic Black Bear-Human Conflict: A Case Study from Guthichaur Rural Municipality, Jumla, Nepal.

Our study assessed patterns of Asiatic black bear (Ursus thibetanus)-human conflicts within the Guthichaur rural municipality, Jumla, Nepal. Through semi-structured interviews with villagers, focus group discussions (FGDs), and key informant interviews (KIIs), we gathered black bear-human conflict information from 2009 to 2019. We identified three primary types of black bear-human interactions: crop damage, livestock depredation, and human injuries. Of these, crop damage (77.03%) emerged as the most prevalent issue. Notably, peak occurrences were observed during autumn (September-October) typically between 9 PM and 3 AM. Livestock depredations were more frequent during nighttime in April-August, with cows/ox (70.12%) being the most depredated animal. Our data also revealed five recorded cases of black bear attacks on humans, which transpired from September to October, primarily in farmland areas in varying years. Despite a prevailing negative perception of bears, a notable level of support exists for their conservation efforts among local communities. Furthermore, these conflicts could be mitigated by reinforcing indigenous crop protection methods and implementing targeted mitigation strategies, as observed in other regions with successful black bear-human interaction management.

ROP GTPases with a geranylgeranylation motif modulate alkaloid biosynthesis in Catharanthus roseus.

Rho of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in specialized metabolism is poorly understood. Previously, we demonstrated that inhibition of protein geranylgeranyl transferase (PGGT-I) negatively impacts the biosynthesis of monoterpene indole alkaloids (MIA) in Madagascar periwinkle (Catharanthus roseus), indicating the involvement of prenylated proteins in signaling. Here, we show through biochemical, molecular, and in planta approaches that specific geranylgeranylated ROPs modulate C. roseus MIA biosynthesis. Among the six C. roseus ROP GTPases (CrROPs), only CrROP3 and CrROP5, having a C-terminal CSIL motif, were specifically prenylated by PGGT-I. Additionally, their transcripts showed higher expression in most parts than other CrROPs. Protein-protein interaction studies revealed that CrROP3 and CrROP5, but not ΔCrROP3, ΔCrROP5, and CrROP2 lacking the CSIL motif, interacted with CrPGGT-I. Further, CrROP3 and CrROP5 exhibited nuclear localization, whereas CrROP2 was localized to the plasma membrane. In planta functional studies revealed that silencing of CrROP3 and CrROP5 negatively affected MIA biosynthesis, while their overexpression upregulated MIA formation. In contrast, silencing and overexpression of CrROP2 had no effect on MIA biosynthesis. Moreover, overexpression of ΔCrROP3 and ΔCrROP5 mutants devoid of sequence coding for the CSIL motif failed to enhance MIA biosynthesis. These results implicate that CrROP3 and CrROP5 have a positive regulatory role on MIA biosynthesis and thus shed light on how geranylgeranylated ROP GTPases mediate the modulation of specialized metabolism in C. roseus.

Recent Trends in Nanocarrier-Based Drug Delivery System for Prostate Cancer.

Prostate cancer remains a significant global health concern, requiring innovative approaches for improved therapeutic outcomes. In recent years, nanoparticle-based drug delivery systems have emerged as promising strategies to address the limitations of conventional cancer chemotherapy. The key trends include utilizing nanoparticles for enhancing drug delivery to prostate cancer cells. Nanoparticles have some advantages such as improved drug solubility, prolonged circulation time, and targeted delivery of drugs. Encapsulation of chemotherapeutic agents within nanoparticles allows for controlled release kinetics, reducing systemic toxicity while maintaining therapeutic efficacy. Additionally, site-specific accumulation within the prostate tumor microenvironment is made possible by the functionalization of nanocarrier with targeted ligands, improving therapeutic effectiveness. This article highlights the basics of prostate cancer, statistics of prostate cancer, mechanism of multidrug resistance, targeting approach, and different types of nanocarrier used for the treatment of prostate cancer. It also includes the applications of nanocarriers for the treatment of prostate cancer and clinical trial studies to validate the safety and efficacy of the innovative drug delivery systems. The article focused on developing nanocarrier-based drug delivery systems, with the goal of translating these advancements into clinical applications in the future.

South African flag sign to a giant coronary artery aneurysm.

Background: Coronary arteritis leading to aneurysm is one of the unusual presentations of IgG4-related disease. Acute myocardial infarction as a complication of IgG4-related giant coronary artery aneurysm is even rarer. Case summary: We describe the case of a 56-year-old gentleman who presented to our institute with Canadian Cardiovascular Society (CCS) class III angina. His symptoms were persistent even with high-dose antianginal medications. He had an acute coronary syndrome two weeks back for which he was treated conservatively in a peripheral health centre. His 12-lead electrocardiogram at the time of the event was suggestive of high lateral ST-segment elevation myocardial infarction (South African flag sign). His transthoracic echocardiography showed mild left ventricular dysfunction and a large echogenic mass lateral to the left ventricle. Coronary angiography followed by cardiac computed tomography revealed a giant pseudoaneurysm of the proximal and mid-left anterior descending coronary artery. FDG-PET scan showed significant metabolic activity in the aneurysm wall and mediastinal lymph nodes suggesting active inflammation. IgG4-related coronary arteritis was suspected, and the patient underwent aneurysmectomy and coronary artery bypass (CABG) surgery. The histopathology of the resected segment showed diffuse IgG4-secreting plasma cells confirming the diagnosis. Discussion: Atherosclerosis is the most common cause of coronary aneurysms in adults. However, cardiologists should be aware of atypical causes like IgG4-related disease that can even present with acute coronary syndrome. Although multimodality imaging is beneficial during early evaluation, histopathological analysis is the cornerstone for the diagnosis of IgG4-related disease. The management involves both immunosuppressive medication and endovascular or surgical repair.

IADVL SIG Recalcitrant Dermatophytosis Position Statement on Super Bioavailable Itraconazole.

Itraconazole (ITZ) has been the mainstay of oral antifungal treatment for the current epidemic of recalcitrant dermatophytosis (RD) in India. Recently, a newer formulation of ITZ, super bioavailable itraconazole (SUBA-ITZ), is made available in the market by many pharmaceutical companies. It is important for dermatologists to understand the pharmacokinetic properties of SUBA-ITZ vis-a-vis conventional pellet formulation to use it effectively and safely. Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) has established a special interest group for recalcitrant dermatophytosis (SIG-RD) to strengthen research, continuing medical education, and industry collaboration on the subject. This position statement on SUBA-ITZ by SIG-RD is an attempt to address current pieces of evidence and the position of this new formulation in the management of RD.

Sensory deficits of the paretic and non-paretic upper limbs relate with the motor recovery of the poststroke subjects.

BACKGROUND: Post stroke, motor paresis has usually been considered to be a crucial factor responsible for the disability; other impairments such as somatosensory deficits may also play a role. OBJECTIVE: To determine the relation between the sensory deficits (paretic and non-paretic upper limbs) and the motor recovery of the paretic upper limb and to predict the potential of motor recovery based on the sensory deficits among stroke subjects. METHODS: The study was a cross-sectional study conducted in a rehabilitation institute. Ninety-five poststroke hemiparetic subjects having sensory impairment in any of the modalities were considered for this study. Sensory deficits were assessed on both the upper limbs (paretic and non-paretic) primarily using Erasmus MC modification of the revised version of Nottingham Sensory Assessment (Em-NSA) and Nottingham Sensory Assessment (Stereognosis) (NSA-S). The motor recovery was assessed using the Fugl-Meyer assessment (FMA). RESULTS: The measures of sensory deficits exhibited weak but significant correlation [the paretic (Em-NSA and NSA; r = .38 to .58; p < .001) and the non-paretic (Em-NSA and NSA; r = .24 to .38; p = .03 to .001)] with the motor recovery of the paretic upper limb as measured by FMA. The potential of favorable recovery of the paretic upper limb may be predicted using the cutoff scores of Em-NSA (30, 21, and 24) and NSA-S (5, 8, and 5) of the paretic side. CONCLUSION: In stroke, sensory deficits relate weakly with the recovery of the paretic upper limb and can predict recovery potential of the paretic upper limb.

Serum apolipoproteins (apoA-1, apoB, and apoB/apoA-1 ratio) for early identification of dyslipidemia in children with CKD.

BACKGROUND: Dyslipidemia in children with chronic kidney disease (CKD) is identified based on lipid profile parameters; however, changes in lipoprotein quality precede quantitative changes. METHODS: A cross-sectional study was done from January to October 2021; overweight, obese children, known cases of diabetes mellitus, hypothyroidism or on steroid therapy, or lipid lowering drugs were excluded. Clinical details were elicited and examinations done. Besides hemogram, kidney function tests, liver function tests, total cholesterol, low density lipoproteins (LDL), triglycerides, high density lipoproteins (HDL), and apolipoproteins A-1 and B were estimated to identify dyslipidemia. Relevant tests of significance were applied, and ROC curves were drawn for apoA-1, apoB, and apoB/apoA-1 ratios. RESULTS: A total of 76 (61 M:15 F) children with median (IQR) age 7 (3.25-11) years were enrolled; cause of CKD was CAKUT in 82.3% patients. Dyslipidemia (alteration of 1 or more lipid parameters) was seen in 78.9% with a prevalence of 71.7% in early and 95.7% in later stages of CKD (P = 0.02); most had elevated serum triglyceride levels. The median (IQR) values of apoB, apoA-1, and apoB/apoA-1 ratio were 78 (58-110) mg/dl, 80 (63-96.75) mg/dl, and 0.88 (0.68-1.41), respectively; apoB, apoA-1, and apoB/apoA-1 ratio had a sensitivity of 26.67%, 86.67%, and 70%, respectively, and specificity of 87.5%, 62.5%, and 62.5%, respectively, for diagnosis of dyslipidemia. The ROC for apoB, apoA-1, and apoB/apoA-1 ratio showed AUC of 0.66, 0.68, and 0.74 (P = 0.4, 0.02, < 0.01), respectively. CONCLUSIONS: The prevalence (78.9%) of dyslipidemia was high in patients with CKD especially in those with later stages. The ratio of apoB/apoA-1 was altered early and appears to be promising for early detection.

Canal of nuck hernia with uterus and ovary presenting as inguinal swelling in a female infant.

Canal of nuck hernia is rarely reported in pediatric population. We report one such case of a canal of nuck hernia in a 2-month-old girl containing uterus, ovary and small bowel diagnosed on ultrasonography, and which was later confirmed and treated surgically.

Pneumatic Insufflation to Confirm Distal Stoma When in Doubt.

Background Distal colostogram and ileostogram are commonly performed radiological procedures in the pediatric population. It is sometimes difficult to identify the distal stoma while performing these procedures. Aim The aim of this study was to describe a technique for the confident identification of distal stoma. Methods Injection of a small quantity of air through the catheterized stoma and following it can help to identify the stoma, as proximal or distal, based on anatomy of the delineated bowel. Conclusion Pneumatic insufflation is a simple, quick procedure to confidently identify the distal stoma whenever in doubt.

Shear wave elastography of kidneys in children: utility in distinguishing steroid-resistant and steroid-sensitive nephrotic syndrome.

PURPOSE: To assess the renal elasticity values using (SWE) and correlate the values with steroid sensitivity to distinguish between steroid-resistant nephrotic syndrome (SRNS) and steroid-sensitive nephrotic syndrome (SSNS) in children. METHODS: In this IRB-approved cross-sectional study, 83 children (4-14 years) diagnosed with nephrotic syndrome were included from July 2021 to December 2022. SWE measurements were done for each kidney's upper pole, interpolar region, and lower pole. Mean as well as median SWE were calculated. Correlation of the renal stiffness values was done with different laboratory findings (blood urea, serum creatinine, 24 h urine protein, serum albumin, and serum cholesterol), the grayscale findings (cortical echogenicity, and corticomedullary differentiation), and the final diagnosis of SRNS and SSNS. The statistical tests were done at a significance level of α = 0.05. RESULTS: The median (IQR) overall SWE of kidneys was higher in SRNS group 12.64 (8.4-19.68) kPa than SSNS group 9.87 (8.20-12.56) kPa. The difference was significant (p = 0.004). At a cut-off of ≥ 10.694 kPa (AUROC- 0.641), the overall SWE predicted SRNS group with a sensitivity of 70% and a specificity of 63%. A significant correlation (p < 0.05) was found between the SWE and 24-h urine protein, cortical echogenicity, and corticomedullary differentiation in SSNS, while only between SWE and corticomedullary differentiation in SRNS. CONCLUSION: The mean SWE was higher in children with SRNS. While SWE has potential to differentiate SSNS from SRNS, a different study design where SWE is performed at presentation is needed for confirmation.

Critical assessment of selenourea as an efficient small molecule fluorescence quenching probe to monitor protein dynamics.

Organoselenium compounds have recently been the experimentalists' delight due to their broad applications in organic synthesis, medicinal chemistry, and materials science. Selenium atom replacement of the carbonyl oxygen of the urea moiety dramatically reduces the HOMO-LUMO gap and oxidation potential, which completely changes the physicochemical properties of selenocarbonyl compounds. To our surprise, the photophysics and utility of a simple molecule such as selenourea (SeU) have not been explored in detail, which persuaded us to investigate its role in excited state processes. The steady-state emission, temperature-dependent time-correlated single photon counting, and femtosecond fluorescence upconversion experimental results confirmed that SeU significantly enhances the fluorescence quenching through a photoinduced electron transfer (PET) mechanism with an ∼10 ps ultrafast intrinsic PET lifetime component which is mostly absent in thiourea (TU). A wide range of fluorophores, based on their different redox abilities and fluorescence lifetimes covering a broad spectral window (λex: 390-590 nm and λem: 490-690 nm), were chosen to validate the proof of the concept. It was extended to tetramethylrhodamine (TMR)-5-maleimide labeled lysozyme protein, where we observed significant fluorescence quenching in the presence of SeU. The present work emphasizes that the high quenching efficiency with an ultrafast PET process, reduced orbital energy gap, and higher negative free energy change of the electron transfer reaction are the representative characteristics of selenourea or selenoamides to enable them as potential surrogates of thioamides or oxoamides quenching probes to monitor protein conformational changes and dynamics.

Fe-MOF Catalytic Nanoarchitectonic toward Electrochemical Ammonia Production.

Electrochemical reduction of nitrate into ammonia has lately been identified as one among the promising solutions to address the challenges triggered by the growing global energy demand. Exploring newer electrocatalyst materials is vital to make this process effective and feasible. Recently, metal-organic framework (MOF)-based catalysts are being well investigated for electrocatalytic ammonia synthesis, accounting for their enhanced structural and compositional integrity during catalytic reduction reactions. In this study, we investigate the ability of the PCN-250-Fe3 MOF toward ammonia production in its pristine and activated forms. The activated MOF catalyst delivered a faradaic efficiency of about 90% at -1 V vs RHE and a yield rate of 2.5 × 10-4 mol cm-2 h-1, while the pristine catalyst delivered a 60% faradaic efficiency at the same potential. Theoretical studies further provide insights into the nitrate reduction reaction mechanism catalyzed by the PCN-250-Fe3 MOF catalyst. In short, simpler and cost-effective strategies such as pretreatment of electrocatalysts have an upper hand in aggravating the intrinsic material properties, for catalytic applications, when compared to conventional material modification approaches.