Optically pumped magnetometers disclose magnetic field components of the muscular action potential

AimAiming at analysing the signal conduction in muscular fibres, the spatio-temporal dynamics of the magnetic field generated by the propagating muscle action potential (MAP) is studied.MethodIn this prospective, proof of principle study, the magnetic activity of the intrinsic foot muscle after electric stimulation of the tibial nerve was measured using optically pumped magnetometers (OPMs). A classical biophysical electric dipole model of the propagating MAP was implemented to model the source of the data. In order to account for radial currents of the muscular tubules system, a magnetic dipole oriented along the direction of the muscle was added.ResultsThe signal profile generated by the activity of the intrinsic foot muscles was measured by four OPM devices. Three OPM sensors captured the spatio-temporal magnetic field pattern of the longitudinal intrinsic foot muscles. Changes of the activation pattern reflected the propagating muscular action potential along the muscle. A combined electric and magnetic dipole model could explain the recorded magnetic activity.InterpretationOPM devices allow for a new, non-invasive way to study MAP patterns. Since magnetic fields are less altered by the tissue surrounding the dipole source compared to electric activity, a precise analysis of the spatial characteristics and temporal dynamics of the MAP is possible. The classic electric dipole model explains major but not all aspects of the magnetic field. The field has longitudinal components generated by intrinsic structures of the muscle fibre. By understanding these magnetic components, new methods could be developed to analyse the muscular signal transduction pathway in greater detail. The approach has the potential to become a promising diagnostic tool in peripheral neurological motor impairments.     

Sex differences in the detection of motor unit action potentials identified using high-density surface electromyography

Sex-related disparities in force production of humans have been widely observed. Previous literature has attributed differences in peripheral traits, such as muscle size, to explain these disparities. However, less is known about potential sex-related differences in central neuromuscular traits and many comparable studies, not exploring sex-related differences, exhibit a selection-bias in the recruitment of subjects making the generalization of their findings difficult. Utilizing high-density electromyography arrays and motor unit (MU) decomposition, the aim of the current study is to compare MU yield and discharge properties of the tibialis anterior between male and female humans. Twenty-four subjects (10 females) performed two submaximal (20%) isometric dorsiflexion contractions. On average, males yielded nearly twice the amount of MUs as females. Further, females had significantly higher MU discharge rate, lower MU action potential amplitude, and lower MU action potential frequency content than males despite similar levels of torque and MU discharge variability. These findings suggest differences in central neuromuscular control of force production between sexes; however, it is unclear how lower yield counts affect the accuracy of these results.     

Conformational analysis by NMR and molecular dynamics of adamantane-doxorubicin prodrugs and their assemblies with β-cyclodextrin: A focus on the design of platforms for controlled drug delivery

Nanoscale design and construction of affinity-based drug delivery systems (ADDS) is an active research area with enormous potential for the improvement of cancer treatment. For the therapeutic load of these ADDS, a promising strategy is the design of pH-sensitive prodrugs based on the construction of conjugates between adamantane and doxorubicin (Ad-Dox), which stands out as an excellent model system to obtain novel supramolecular materials. Construction of these prodrugs involves a modification of three zones of doxorubicin which in principle does not affect the action mechanism: the carbonyl group C13 (hydrazone linker), the primary alcohol neighboring the carbonyl (ester linker) and the 3′ amino group of daunosamine sugar (amide linker). These modifications are aimed to improve the efficacy and reduce the systemic toxicity of the drug chemotherapy by controlling its release in cancer cells. In this work, we performed 2D NMR experiments and molecular dynamics simulations to characterize the conformational changes of three constructed prodrugs. Our results demonstrated that ring A and the daunsamine sugar of the hydrazone and amide linkers conserve the half-chair state ⁹H₈, while the ester linker disrupts this conformation. Our study also showed that the hydrazone-linked compound (Ad-h-Dox) does not modify the conformation of the original drug and maintains cytotoxic activity. Moreover, the inclusion complex (IC) of Ad-h-Dox with β-cyclodextrin (βCD) generated a highly soluble platform in water, whereas the ester-linked compound (Ad-e-Dox) causes the loss of biological activity. This study proves that Ad-h-Dox prodrug can be an optimum prodrug and act as a building block for a more complex drug transport system.     

Sorting through the extensive and confusing roles of sortilin in metabolic disease

Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding more than 50 proteins, covering a wide range of biological functions including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, where it functions as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer’s disease, prion diseases, Parkinson’s disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies. However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic diseases and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL-C levels.     

Phytochemical profiling and antioxidant potential of Daphne mucronata Royle and action against paracetamol-induced hepatotoxicity and nephrotoxicity in rabbits

The paracetamol-induced injuries of liver and kidneys in animals are mostly used to screen out the hepato and nephroprotective effect of extract or other therapeutic agents. In the present study total phenolic and flavonoid contents, in vitro antioxidant, and in vivo hepato/nephroprotective (on paracetamol-induced intoxication in experimental rabbits) potentials of the Daphne mucronata leaves methanolic extract were determined. For the identification of possible phytochemicals, HPLC (high performance liquid chromatography) analysis was carried out and a total of eight phenolic compounds; malic acid, gallic acid, chlorogenic acid, epigallocatechin gallate, quercetin, morin, ellagic acid, and rutin were identified. D. mucronata extract at doses of 250 and 500 mg/kg body weight were given for eight days to paracetamol intoxicated rabbits and the observed results were compared with standard Silymarin. The level of liver enzymes like aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum triglyceride, serum cholesterol, serum bilirubin, and kidneys biomarkers like serum urea, uric acid, and creatinine, as well as lipid peroxidation malondialdehyde contents were increased while the antioxidant enzymes like reduced glutathione and total antioxidant capacity were decreased. Furthermore, histopathological analysis of the liver and kidney tissues of control and treated groups also confirmed the hepatoprotective and nephroprotective effect of the D. mucronata which was most probably due to its high antioxidant phenolic and flavonoid phytoconstituents.     

Thunbergia laurifolia leaf extract partially recovers lead-induced renotoxicity through modulating the cell signaling pathways

This research investigated the reno-protective effect of Thunbergia laurifolia Linn. (TL) in a lead-induced toxicity test through the modulation of cell signaling pathways. The study carried out to evaluate the effect of TL leaf extracts in Swiss Albino mice exposed to lead acetate (PbAc). Prior to in vivo study, a probable kidney-protective effect of the plant leaf extract was presumed through an activity-specific (PASS) molecular docking analysis. In animal model study, albino mice were divided in seven groups and co-treated with PbAc and TL (100, 200 mg/kgBW) or vitamin E (100 mg/kgBW) for 38 days, whereas the untreated control, TL control, and vehicle control groups received sodium acetate, PbAc, sodium acetate plus mineral oil, respectively. At the end of treatment, blood and kidney tissue were collected for investigating Pb concentration, estimating biochemical profile, evaluating oxidative stress and inflammatory parameters. The histopathological change of kidney along with apoptosis was assessed from kidney sections using H & E staining and TUNEL assay. Pb-exposed mice were found to be increased concentration of Pb in the blood and kidney sample, which further led to increased MDA levels in the plasma, blood, and tissue. Followed by kidney damage, increased expression of TNF-α, iNOS, and COX-2 in kidney tissues were noticed, which were related to elevated TNF-α in the systemic circulation of Pb-treated mice. Co-treatment with TL or vitamin E significantly reduced altered structure and apoptosis of kidney tissues. Downregulation of inflammatory markers especially TNF-α, iNOS, and COX-2 with simultaneous improvement of renal function through reduced plasma BUN and creatinine levels demonstrate that TL act as a potential dietary supplement to detoxify Pb in kidney showing an antioxidant and anti-inflammatory effect.     

Novel insights into ATP-Stimulated Cleavage of branched DNA and RNA Substrates through Structure-Guided Studies of the Holliday Junction Resolvase RuvX

Much of our understanding of the homologous recombination (HR) machinery hinges on studies using Escherichia coli as a model organism. Interestingly enough, studies on the HR machinery in different bacterial species casts doubt on the universality of the E. coli paradigm. The human pathogen Mycobacterium tuberculosis encodes two Holliday junction (HJ)‐resolvase paralogues, namely RuvC and RuvX; however, insights into their structural features and functional relevance is still limited. Here, we report on structure-guided functional studies of the M. tuberculosis RuvX HJ resolvase (MtRuvX). The crystalline MtRuvX is a dimer in the asymmetric unit, and each monomer has a RNAse H fold vis-à-vis RuvC-like nucleases. Interestingly, MtRuvX also contains some unique features, including the residues essential for ATP binding/coordination of Mg²⁺ ions. Indeed, MtRuvX exhibited an intrinsic, robust ATPase activity, which was further accentuated by DNA cofactors. Structure-guided substitutions of single residues at the ATP binding/Mg²⁺coordination sites while markedly attenuating the ATPase activity completely abrogated HJ cleavage, indicating an unanticipated relationship between ATP hydrolysis and DNA cleavage. However, the affinity of ATPase-deficient mutants for the HJ was not impaired. Contrary to RuvC, MtRuvX exhibits relaxed substrate specificity, cleaving a variety of branched DNA/RNA substrates. Notably, ATP hydrolysis plays a regulatory role, rendering MtRuvX from a canonical HJ resolvase to a DNA/RNA non-sequence specific endonuclease, indicating a link between HJ resolvase and nucleic acid metabolism. These findings provide novel insights into the structure and dual-functional activities of MtRuvX, and suggest that it may play an important role in DNA/RNA metabolism.     

Molecular dynamics and simulation analysis against superoxide dismutase (SOD) target of Micrococcus luteus with secondary metabolites from Bacillus licheniformis recognized by genome mining approach

Micrococcus luteus, also known as M. luteus, is a bacterium that inhabits mucous membranes, human skin, and various environmental sources. It is commonly linked to infections, especially among individuals who have compromised immune systems. M. luteus is capable of synthesizing the enzyme superoxide dismutase (SOD) as a component of its protective response to reactive oxygen species (ROS). This enzyme serves as a promising target for drug development in various diseases. The current study utilized a subtractive genomics approach to identify potential therapeutic targets from M. luteus. Additionally, genome mining was employed to identify and characterize the biosynthetic gene clusters (BGCs) responsible for the production of secondary metabolites in Bacillus licheniformis (B. licheniformis), a bacterium known for its production of therapeutically relevant secondary metabolites. Subtractive genomics resulted in identification of important extracellular protein SOD as a drug target that plays a crucial role in shielding cells from damage caused by ROS. Genome mining resulted in identification of five potential ligands (secondary metabolites) from B. licheniformis such as, Bacillibactin (BAC), Paenibactin (PAE), Fengycin (FEN), Surfactin (SUR) and Lichenysin (LIC). Molecular docking was used to predict and analyze the binding interactions between these five ligands and target protein SOD. The resulting protein–ligand complexes were further analyzed for their motions and interactions of atoms and molecules over 250 ns using molecular dynamics (MD) simulation analysis. The analysis of MD simulations suggests, Bacillibactin as the probable candidate to arrest the activities of SOD. All the five compounds reported in this study were found to act by directly/indirectly interacting with ROS molecules, such as superoxide radicals (O₂–) and hydrogen peroxide (H₂O₂), and transforming them into less reactive species. This antioxidant activity contributes to its protective effects against oxidative stress-induced damage in cells making them likely candidate for various applications, including in the development of antioxidant-based therapies, nutraceuticals, and functional foods.     

Ergonomics for surgeons – prototype of an external surgeon support system reduces muscular activity and fatigue

BackgroundSince the unergonomic postures cannot be changed during a surgery, it seems reasonable to externally support the surgeon's posture in order to relieve the musculature. To evaluate this matter, we conducted a pilot study to investigate if a prototype of an external surgeon support system (S3) relieves the musculature in an objectively measurable manner.MethodsSimultaneous surface electromyography (EMG) was used alongside a combination of a laser Doppler flowmeter and a tissue spectrometer to record back and leg muscles during a simulated surgical situation.FindingsWith S3, muscle activity was significantly lower (p < 0.05) and also fatigue decreased when compared to without S3. Muscle blood flow and oxygenation were relatively close to baseline with S3, but increased without S3.InterpretationAn ergonomic S3 is a possible approach to reduce muscle activity and fatigue and may therefore prevent chronic back pain amongst surgeons in the long term.     

Structure-based analyses of gut microbiome-related proteins by neural networks and molecular dynamics simulations

An imbalance in the gut microbiome is linked to immune disorders, such as autoimmune, allergic, and chronic inflammatory disorders. Elucidation of disease mechanisms is a matter of urgency. It requires precise elucidation of the structure-based mechanisms of protein interactions involved in disease onset. In addition, an understanding of the protein dynamics is vital because these fluctuations affect the function and interaction of disease-associated proteins. Experimental evaluation of not only protein interactions, functions, and structures but also the dynamics are time-consuming; therefore, computational predictions are necessary to elucidate disease mechanisms. Here, we introduce recent studies on structure-based analyses of proteins using computational approaches, particularly artificial intelligence (AI) and molecular dynamics (MD) simulations.     

Efficacy of choline and DHA supplements or enriched environment exposure during early adult obesity in mitigating its adverse impact through aging in rats

IntroductionThe aim of this study was to assess the efficacy of choline and DHA or exposure to environmental enrichment in obese adult and aging rats on alterations in body mass index, serum lipid profile and arterial wall changes, despite stopping high fat diet consumption and interventions during adulthood.Methods21 day old male Sprague Dawley rats were assigned as Experiment-1 & 2 - PND rats were divided into 4 groups with interventions for 7 months (n = 8/group). NC– Normal control fed normal chow diet; OB- Obese group, fed high fat diet; OB + CHO + DHA- fed high fat diet and oral supplementation of choline, DHA. OB + EE- fed high fat diet along with exposure to enriched environment .Experiment-2 had similar groups and interventions as experiment 1 but for next 5 months were fed normal chow diet without any interventions. Body mass index was assessed and blood was analyzed for serum lipid profile. Common Carotid Artery (CCA) was processed for Haematoxylin and eosin, Verhoff Vangeison stains. Images of tissue sections were analyzed and quantified using image J and tissue quant software.ResultsIn experiment.1, mean body mass index (p < 0.001), serum lipid profile (p < 0.01), thickness of tunica intima (p < 0.05), tunica media (p < 0.01) and percentage of collagen fibers (p < 0.01) of CCA were significantly increased in OB compared to NC. These were significantly attenuated in OB + CHO + DHA and OB + EE compared to OB. In experiment.2, mean body mass index (p < 0.01), serum lipid profile (p < 0.05) and thickness of tunica media of CCA (p < 0.01) were significantly increased in OB compared to NC. In OB + CHO + DHA and OB + EE, significant attenuation was observed in mean body mass index and mean thickness of tunica media compared to same in OB.ConclusionAdult obesity has negative impact on body mass index, serum lipid profile and arterial wall structure that persists through aging. Supplementation of choline and DHA or exposure to enriched environment during obesity attenuates these negative impacts through aging.     

Prioritizing conservation areas and vulnerability analyses of the genus Pinus L. (Pinaceae) in Mexico

Mexico hosts the highest species richness of pines (Pinus, Pinaceae) worldwide; however, the priority areas for their conservation in the country are unknown. In this study, the ecological niche of the 50 native pine species was modeled. Then, through a multi-criteria analysis, the priority areas for the conservation of the genus Pinus were identified according to the spatial patterns of richness, geographic rareness, irreplaceability, the level of vulnerability of their habitat and the status of legal protection. The results revealed that the regions with high species richness differed from those with high endemism. Also, most pine species have undergone processes of habitat degradation, having been the endemic species the most affected. The priority areas covered regions with high species richness, high endemism, and highly degraded forests, located at mountainous portions of the Baja California Peninsula, the Sierra Madre Occidental, the Sierra Madre Oriental, the Trans-Mexican Volcanic Belt, and the Sierra Madre del Sur. A low proportion of priority areas overlapped with protected areas or terrestrial regions considered priorities for biological conservation. These results suggest that conservation efforts for this genus should be focused beyond regions with high species richness and current protected areas. Besides, the priority areas identified in this study can be the basis to create biological corridors and new protected areas, which could contribute significantly to the conservation of this genus in Mexico.     

Impact on S. aureus and E. coli Membranes of Treatment with Chlorhexidine and Alcohol Solutions: Insights from Molecular Simulations and Nuclear Magnetic Resonance

Membranes form the first line of defence of bacteria against potentially harmful molecules in the surrounding environment. Understanding the protective properties of these membranes represents an important step towards development of targeted anti-bacterial agents such as sanitizers. Use of propanol, isopropanol and chlorhexidine can significantly decrease the threat imposed by bacteria in the face of growing anti-bacterial resistance via mechanisms that include membrane disruption. Here we have employed molecular dynamics simulations and nuclear magnetic resonance to explore the impact of chlorhexidine and alcohol on the S. aureus cell membrane, as well as the E. coli inner and outer membranes. We identify how sanitizer components partition into these bacterial membranes, and show that chlorhexidine is instrumental in this process.     

Antitumor immunity enhancement through Newcastle viral oncolysate in mice model: A promising method to treat tumors

A Newcastle disease virus (NDV) oncolysate has been established as a unique and effective immune-stimulatory root for tumor treatment. Thus, the aim of the current study was to investigate the effects of intratumoral administration of NDV oncolysate on immune response and tumor regression of C57BL/6 mouse model of human papillomavirus (HPV) related transplanted with TC-1 syngeneic cancer cells. To further investigate the mechanism underlying the antitumor response, cytolytic and lymphocyte proliferation responses in splenocytes were measured using lactate dehydrogenase (LDH) release and MTT assays, respectively. In this regard, levels of IL-10, IFN-γ, and IL-4 were measured using ELISA after re-stimulation. The immune responses efficacy was evaluated by in vivo tumor regression assay. The results showed that immunization with the different titers of NDV lysate significantly reduced tumor volume in comparison with a combination of virus lysate and tumor cell lysate. Also, virus lysate could significantly enhance cytotoxic T lymphocyte production and lymphocyte proliferation rates versus tumor cell lysate. Also, our major findings are that the peritumorally injection of NDV oncolysate effectively induces antitumor immune responses through increased levels of IL-4, IFN-γ, and reduction of IL-10. These results indicate that this treatment is a specific, active immune mechanism stimulator, and may prove to be a useful therapeutic for a treatment against cervical cancers and merits further investigation.     

Passive Diffusion of Ciprofloxacin and its Metalloantibiotic: A Computational and Experimental study

Fluoroquinolones (FQ) are antibiotics widely used in clinical practise, but the development of bacterial resistance to these drugs is currently a critical public health problem. In this context, ternary copper complexes of FQ (CuFQPhen) have been studied as a potential alternative. In this study, we compared the passive diffusion across the lipid bilayer of one of the most used FQ, ciprofloxacin (Cpx), and its ternary copper complex, CuCpxPhen, that has shown previous promising results regarding antibacterial activity and membrane partition. A combination of spectroscopic studies and molecular dynamics simulations were used and two different model membranes tested: one composed of anionic phospholipids, and the other composed of zwitterionic phospholipids. The obtained results showed a significantly higher membrane permeabilization activity, larger partition, and a more favourable free energy landscape for the permeation of CuCpxPhen across the membrane, when compared to Cpx. Furthermore, the computational results indicated a more favourable translocation of CuCpxPhen across the anionic membrane, when compared to the zwitterionic one, suggesting a higher specificity towards the former. These findings are important to decipher the influx mechanism of CuFQPhen in bacterial cells, which is crucial for the ultimate use of CuFQPhen complexes as an alternative to FQ to tackle multidrug-resistant bacteria.     

l-carnitine: Nutrition,pathology, and health benefits

Carnitine is a medically needful nutrient that contributes in the production of energy and the metabolism of fatty acids. Bioavailability is higher in vegetarians than in people who eat meat. Deficits in carnitine transporters occur as a result of genetic mutations or in combination with other illnesses such like hepatic or renal disease. Carnitine deficit can arise in diseases such endocrine maladies, cardiomyopathy, diabetes, malnutrition, aging, sepsis, and cirrhosis due to abnormalities in carnitine regulation. The exogenously provided molecule is obviously useful in people with primary carnitine deficits, which can be life-threatening, and also some secondary deficiencies, including such organic acidurias: by eradicating hypotonia, muscle weakness, motor skills, and wasting are all improved l-carnitine (LC) have reported to improve myocardial functionality and metabolism in ischemic heart disease patients, as well as athletic performance in individuals with angina pectoris. Furthermore, although some intriguing data indicates that LC could be useful in a variety of conditions, including carnitine deficiency caused by long-term total parenteral supplementation or chronic hemodialysis, hyperlipidemias, and the prevention of anthracyclines and valproate-induced toxicity, such findings must be viewed with caution.     

Growth performance,haematological assessment and chemical composition of Nile tilapia,Oreochromis niloticus (Linnaeus, 1758) fed different levels of Aloe vera extract as feed additives in a closed aquaculture system

A 105-day experimental trial was conducted to assess different levels of dietary Aleo vera extract supplementation on water quality parameters, proximate composition, growth performance and haematological parameters of fry Oreochromis niloticus. Four different percentages of dietary leaf extract powder of Aleo vera (ALE) with a basal feed, designated as, i.e., T0 (Control group; without ALE), T1 (1% ALE), T2 (2% ALE), and T3 (3% ALE). Fish fry was reared in concrete tanks (7.0 m, 1.6 m, 1.0: L, W, H; water volume 11.2 m3/tank), with an average initial weight 4.04 ± 0.03 g/ fry, and each treatment was triplicated. Fry was randomly distributed at a stocking rate of 450 individuals/ tanks. The water quality parameters revealed that temperature, pH, salinity, dissolved oxygen (DO) and nitrates were found in a promising range as given by FAO/WHO limits. However, the record values obtained for Electric Conductivity (EC), Total dissolved solids (TDS), and alkalinities were not found in all tanks' suitable range according to FAO/WHO limits. The results revealed a significant impact of different percentages of dietary ALE supplementation on fry's body composition and haematological parameters. Moreover, the final body weight, final body length, average daily weight gain (g), net weight gain (g) and specific growth rate (%) were significantly higher (p < 0.05) in T1 and T2 compared with T0 and T3 treatments. The poorest feed conversion ratio was recorded in the T2 group compared with other treatments. Thus, the current study provides information about the nutritional quality of Nile tilapia culturing in Pakistan.