Loss of Twist1 and balanced retinoic acid signaling from the meninges causes cortical folding in mice.

Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly are still poorly understood. We show that inactivating Twist1 in the primitive meninges causes cortical folding in mice. Cell proliferation in the meninges is reduced, causing loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Regionalized loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. The ventricular zone expands and the forebrain lengthens at this time due to expansion of apical radial glia. As the cortex expands, regionalized differences in the levels of neurogenesis are coupled with changes to the tangential distribution of neurons. Consequentially, cortical growth at and adjacent to the midline accelerates with respect to more dorsolateral regions, resulting in cortical buckling and folding. Maternal retinoic acid supplementation suppresses cortical folding by normalizing forebrain length, neurogenesis and the tangential distribution of neurons. These results suggest that Twist1 and balanced retinoic acid signaling from the meninges are required to maintain normal levels of neurogenesis and lissencephaly in mice.

Self-Powered Load Sensing Circuitry for Total Knee Replacement.

There has been a significant increase in the number of total knee replacement (TKR) surgeries over the past few years, particularly among active young and elderly people suffering from knee pain. Continuous and optimal monitoring of the load on the knee is highly desirable for designing more reliable knee implants. This paper focuses on designing a smart knee implant consisting of a triboelectric energy harvester and a frontend electronic system to process the harvested signal for monitoring the knee load. The harvester produces an AC signal with peak voltages ranging from 10 V to 150 V at different values of knee cyclic loads. This paper demonstrates the measurement results of a PCB prototype of the frontend electronic system fabricated to verify the functionality and feasibility of the proposed approach for a small range of cycling load. The frontend electronic system consists of a voltage processing unit to attenuate high peak voltages, a rectifier and a regulator to convert the input AC signal into a stabilized DC signal. The DC voltage signal provides biasing for the delta-sigma analog-to-digital converter (ADC). Thus, the output of the triboelectric harvester acts as both the power signal that is rectified/regulated and data signal that is digitized. The power consumption of the proposed PCB design is approximately 5.35 µW. Next, the frontend sensor circuitry is improved to accommodate a wider range of cyclic load. These results demonstrate that triboelectric energy harvesting is a promising technique for self-monitoring the load inside knee implants.

Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.

Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03912-5.

Probiotics and Their Bioproducts: A Promising Approach for Targeting Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus.

Antibiotic resistance is a serious global health problem that poses a threat to the successful treatment of various bacterial infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Conventional treatment of MRSA and VRE infections is challenging and often requires alternative or combination therapies that may have limited efficacy, higher costs, and/or more adverse effects. Therefore, there is an urgent need to find new strategies to combat antibiotic-resistant bacteria. Probiotics and antimicrobial peptides (AMPs) are two promising approaches that have shown potential benefits in various diseases. Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. AMPs, usually produced with probiotic bacteria, are short amino acid sequences that have broad-spectrum activity against bacteria, fungi, viruses, and parasites. Both probiotics and AMPs can modulate the host immune system, inhibit the growth and adhesion of pathogens, disrupt biofilms, and enhance intestinal barrier function. In this paper, we review the current knowledge on the role of probiotics and AMPs in targeting multi-drug-resistant bacteria, with a focus on MRSA and VRE. In addition, we discuss future directions for the clinical use of probiotics.

Polymeric nanoparticle gel for intracellular mRNA delivery and immunological reprogramming of tumors.

Immuno-oncology therapies have been of great interest with the goal of inducing sustained tumor regression, but clinical results have demonstrated the need for improved and widely applicable methods. An antigen-free method of cancer immunotherapy can stimulate the immune system to recruit lymphocytes and produce immunostimulatory factors without prior knowledge of neoantigens, while local delivery reduces the risk of systemic toxicity. To improve the interactions between tumor cells and cytotoxic lymphocytes, a gene delivery nanoparticle platform was engineered to reprogram the tumor microenvironment (TME) in situ to be more immunostimulatory by inducing tumor-associated antigen-presenting cells (tAPCs) to activate cytotoxic lymphocytes against the tumor. Biodegradable, lipophilic poly (beta-amino ester) (PBAE) nanoparticles were synthesized and used to co-deliver mRNA constructs encoding a signal 2 co-stimulatory molecule (4-1BBL) and a signal 3 immuno-stimulatory cytokine (IL-12), along with a nucleic acid-based immunomodulatory adjuvant. Nanoparticles are combined with a thermoresponsive block copolymer for gelation at the injection site for local NP retention at the tumor. The reprogramming nanoparticle gel synergizes with immune checkpoint blockade (ICB) to induce tumor regression and clearance in addition to resistance to tumor rechallenge at a distant site. In vitro and in vivo studies reveal increases in immunostimulatory cytokine production and recruitment of immune cells as a result of the nanoparticles. Intratumoral injection of nanoparticles encapsulating mRNA encoding immunostimulatory agents and adjuvants via an injectable thermoresponsive gel has great translational potential as an immuno-oncology therapy that can be accessible to a wide range of patients.

An Insilico evaluation of phytocompounds from Albizia amara and Phyla nodiflora as cyclooxygenase-2 enzyme inhibitors.

PURPOSE: The enzyme Cyclooxygenases (COX-1 and COX-2) catalyze the formation of prostaglandin, a mediator of the inflammatory pathway. Inflammation related pathological conditions may be alleviated by targeting the Cox enzymes.COX-2 inhibitors that are currently available in the market causes undesirable side effects. Our present study focuses on the in-silico inhibition of COX -2 enzyme by the phytocompounds from Albizia amara and Phyla nodiflora. METHODS: The phytochemicals present in Albizia amara and Phyla nodiflora were analyzed for their COX-2 inhibition potential. Eight compounds from Albizia amara and eleven compounds from Phyla nodiflora obtained from GC-MS analysis was used for the current study. Molecular docking was performed using AutoDock vina. The crystal structure of COX-2 (PDB ID: 5IKR) was obtained from Protein data bank. PyMol was used to remove any solvent, organic and inorganic molecules. Energy minimization of the protein was carried out using SPDBV software. Geometrical optimizations of the ligands were performed using Avogadro software. Celecoxib was used as the positive control. ADMET properties of the compounds were analyzed using SwissADME and ProtoxII online servers. Molecular mechanics/generalized born surface area (MM/GBSA) calculations were performed to evaluate the binding efficiency. Molecular dynamics of the protein and protein-ligand complex was studied for about 100 ns using Desmond package of Schrodinger suite. RESULTS: Among the eighteen compounds, Squalene present in both the plants showed a better binding energy of -7.7 kcal/mol, when compare to other phytocompounds present in the extract. The control celecoxib showed a binding energy of about - 9.4 kcal/mol. The toxicity and ADMET properties of squalene indicated that it is non-toxic and followed Lipinski's rule. Molecular Dynamics (MD) analysis showed that the binding of squalene to the enzyme was stable. CONCLUSION: Squalene could potentially inhibit COX2 and o wing to its properties, squalene can be formulated in gels/creams and could be possibly used for external edema and inflammation.

A Smart Knee Implant Using Triboelectric Energy Harvesters.

Although the number of total knee replacement (TKR) surgeries is growing rapidly, functionality and pain-reduction outcomes remain unsatisfactory for many patients. Continual monitoring of knee loads after surgery offers the potential to improve surgical procedures and implant designs. The goal of this study is to characterize a triboelectric energy harvester under body loads and to design compatible frontend electronics to digitize the load data. The harvester prototype would be placed between the tibial component and polyethylene bearing of a TKR implant. The harvester generates power from the compressive load. To examine the harvester output and the feasibility of powering a digitization circuitry, a triboelectric energy harvester prototype is fabricated and tested. An axial tibiofemoral load profile from normal walking (gait) is approximated as a 1 Hz sine wave signal and is applied to the harvester. Because the root mean square of voltages generated via this phenomenon is proportional to the applied load, the device can be simultaneously employed for energy harvesting and load sensing. With an approximated knee cyclic load of 2.3 kN at 1 Hz, the harvester generated output voltage of 18 V RMS, and an average power of 6 µW at the optimal resistance of 58MΩ. The harvested signal is rectified through a negative voltage converter rectifier and regulated through a linear-dropout regulator with a combined efficiency of 71%. The output of the regulator is used to charge a supercapacitor. The energy stored in the supercapacitor is used for low resolution sensing of the load through a peak detector and analog-to-digital converter. According to our analysis, sensing the load several times a day is feasible by relying only on harvested power. The results found from this work demonstrate that triboelectric energy harvesting is a promising technique for self-powering load sensors inside knee implants.

Novel therapeutic targets for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an untreatable and fatal neurodegenerative disease that is identified by the loss of motor neurons in the spinal cord, brain stem, and motor cortex which theatrically reduces life expectancy. Although the primary cause of ALS remains unclear, its heterogeneity put forward for consideration of association with various factors, including endogenous and/or environmental ones, which may be involved in progressive motor neuron stress that causes activation of different cell death pathways. It is hypothesized that this disease is triggered by factors related to genetic, environmental, and age-dependent risk. In spite of large neurobiological, molecular and genetic research, at the beginning of the 21st century, ALS still remains one of the most devastating neurodegenerative diseases because of the lack of effective therapeutic targets. It is a challenge for the clinical and scientific community. A better understanding of the etiology of ALS is necessary to develop specific targets of this progressive neurodegenerative disease. This review states about the current knowledge of targets in ALS research. This review provides an overview of the contribution of different targets like mitochondrial dysfunction, glutamate transport and excitotoxicity, protein accumulation, Oxidative stress, neuromuscular junction, microglia, and other molecular targets in the pathogenesis of ALS.

Fluroscopy in paediatric fractures--setting a local diagnostic reference level.

BACKGROUND: The ionizing radiations (Medical Exposure) Regulation 2000 has made it mandatory to establish diagnostic reference levels (DRLs) for all typical radiological examinations. OBJECTIVES: We attempt to provide dose data for some common fluoroscopic procedures used in orthopaedic trauma that may be used as the basis for setting DRLs for paediatric patients. MATERIALS AND METHODS: The dose area product (DAP) in 865 paediatric trauma examinations was analysed. Median DAP values and screening times for each procedure type along with quartile values for each range are presented. RESULTS: In the upper limb, elbow examinations had maximum exposure with a median DAP value of 1.21 cGy cm2. Median DAP values for forearm and wrist examinations were 0.708 and 0.538 cGy cm2, respectively. In lower limb, tibia and fibula examinations had a median DAP value of 3.23 cGy cm2 followed by ankle examinations with a median DAP of 3.10 cGy cm2. The rounded third quartile DAP value for each distribution can be used as a provisional DRL for the specific procedure type.

Management of clinical fractures of the scaphoid: results of an audit and literature review.

OBJECTIVES: Two to 5% of scaphoid fractures are missed on initial presentation. The failure of early recognition and treatment are considered to contribute to delayed union and non-union. Despite advances in diagnostic imaging, a dogmatic approach has persisted in the management of patients with clinical suspicion but no radiographic evidence of scaphoid fracture. A critical analysis of the current treatment protocol of indiscriminate cast immobilization and serial clinical and radiographic follow-up is presented. METHODS: A prospective study involving 90 patients with clinical signs suggestive of scaphoid injury, followed up until a definite boney injury was demonstrated or the patient was discharged. A review of the literature was conducted to question the need for immobilization in these patients and the potential use of other forms of diagnostic imaging in screening for occult scaphoid fractures. RESULTS: The incidence of true fractures of the scaphoid was 6.66% (5/75). Ten patients (13.33%) had other injuries around the wrist unrelated to the scaphoid. Eighty per cent of the patients had no definite boney injury and were needlessly immobilized, and followed up. A total of 128 scaphoid casts, 135 sets of scaphoid X-rays, 135 clinic appointments and a cumulative 148 weeks of cast immobilization involved patients with normal wrists. CONCLUSION: The incidence of radiologically inapparent fractures of the scaphoid is low. The use of a tender anatomical snuff box as the only clinical sign in the diagnosis of scaphoid injury is unsatisfactory. Other injuries around the wrist must be carefully excluded. There is insufficient evidence to support immobilizing all patients with clinical scaphoid fractures. For suspected fractures with no radiological evidence, symptomatic treatment is probably sufficient. Most occult fractures are visible at 2 weeks. Both magnetic resonance imaging and bone scintigraphy are accurate and cost effective and should be performed earlier rather than later.