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Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adeno-associated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.

Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits. Significance Sensory experience exerts profound control over the structure and function of developing cortical circuits during an early postnatal critical period. Abnormalities in this process contribute to perceptual and cognitive deficits, but molecular mechanisms generating excitatory and inhibitory cortical networks during this period remain poorly understood. We show here that Semaphorin 7A (Sema7A) is highly expressed in mouse somatosensory cortex when tactile information conveyed by the thalamus shapes development of somatosensory cortical networks. In mice lacking Sema7A, the anatomical layout of the somatosensory cortex is disrupted, dendritic arbors are misoriented, inhibitory connections develop abnormally, and thalamocortical activity fails to elicit a normal balance of excitation and inhibition. Taken together, our data indicate that maturation of thalamocortical and local circuits in cortex requires Sema7A.

Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adeno-associated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI. Author SummaryFig. 1.BMP/Smad1 signaling pathway mediates the axon growth potential. As DRG neurons mature, there is an age-dependent decline of the axon growth potential and a concurrent down-regulation of the BMP/Smad1 signaling. A peripheral lesion of adult DRG neurons rekindles the innate growth potential, whereas a central branch lesion in SCI does not lead to regeneration. Reactivating Smad1 selectively in adult DRG neurons either before or after SCI enhances the growth potential, thereby promoting axonal regeneration. y axis: relative neuronal regeneration capacity.Taken together, we have found an essential role of the BMP/Smad1 pathway in axon outgrowth during development and in rekindling the innate growth potential in adult sensory neurons. Importantly, we discovered a promoting effect of AAV-BMP4 in the regeneration of long-projection sensory fibers in a rodent model of SCI (Fig. 1). Modulating the BMP/Smad1 pathway thus represents a therapeutic strategy for axonal regeneration. We then performed injection of AAV encoding BMP4 (AAV-BMP4) into the lumbar CSF space in adult mice. The DRG neurons isolated from AAV-BMP4–injected mice extended much longer axons in dissociated cultures compared with controls. Next, we tested AAV-BMP4 in a mouse SCI model of complete dorsal column transection. Mice were first injected with AAV vector and 2 wk later received a T8 dorsal column transection of the spinal cord, thus allowing sufficient time for BMP4 overexpression to prime the DRG neurons. Regenerating axons were visualized by labeling with Dextran-Texas Red. In the control groups—sham, saline, or AAV-GFP injection—at 2 wk after SCI, virtually all ascending fibers in the fasciculus gracilis had retracted from the proximal end of the lesion border. In contrast, in the AAV-BMP4 group, regenerative responses were observed. Significantly more injured fibers penetrated the proximal lesion border, traversed the lesion center, and even emerged from the distal border. Most regenerating fibers tended to remain in bundles, ascending to the superficial portions of the scar, and then renegotiated their passage back to deeper portions of the posterior column. Thus, the regenerating axons have characteristic circuitous trajectories along the anterior–posterior axis, as opposed to the straight trajectories of uninjured axons. Next, we delivered AAV-BMP4 shortly after SCI, a more clinically relevant scenario. Notably, we observed similar axonal regrowth in these animals. Therefore, AAV-BMP4 delivered shortly after SCI is sufficient to activate the growth of DRG neurons.We then set out to test whether in vivo activation of Smad1 in adult DRG neurons could promote sensory axon regeneration in a rodent SCI model. We designed a viral vector strategy for transgene delivery based on recombinant adeno-associated virus (AAV) technology, coupled with a clinically applicable and minimally invasive delivery method. We reasoned that because DRGs reside at the end of nerve root sleeves surrounded by cerebrospinal fluid (CSF), delivering the AAV viral vector directly into the lumbar CSF space would lead to widespread distribution of the AAV to target multilevel DRGs. Injection of AAV encoding GFP (AAV-GFP) into the lumbar CSF space surrounding the spinal cord led to high, selective transduction of DRG neurons.We first examined Smad1 expression patterns and found that Smad1 transcripts are strongly expressed in embryonic DRG neurons. Immunostaining revealed a dynamic expression pattern of phosphorylated Smad1 (pSmad1): high in embryonic DRGs, low in adult DRGs, and reappearing after a conditioning lesion. This parallels the different intrinsic axon growth potentials of embryonic, naïve adult, and conditioned adult DRG neurons. We then took advantage of a selective small-molecule inhibitor of type I BMP receptor kinases, dorsomorphin (DM). Blocking BMP/Smad1 signaling via DM inhibited axon growth in a dose-dependent fashion in DRG cultures. Growth-associated protein 43, a protein marker for active axon growth, was significantly decreased, and growth cones appeared dystrophic. To further confirm that it is the Smad1-dependent BMP pathway that is critical for axon growth, we knocked down Smad1 by RNAi in embryonic DRG neurons and found that the axonal growth was severely inhibited, an effect that could be rescued by an RNAi-resistant Smad1 construct. In contrast, stimulation by exogenous BMP led to a further increase in the nuclear accumulation of pSmad1 and concurrent enhancement of axon growth potential. Similarly, in adult DRG cultures, blocking the BMP signaling by pharmacological inhibition, genetic ablation of Smad1, or acute Smad1 knockdown by RNAi led to a failure of initiation of axonal outgrowth or to an arrest of axonal elongation. These results support a model in which reactivation of the Smad1-dependent BMP pathway is critical for rekindling the innate growth potential in adult sensory neurons.DRG neurons have an axon with two branches—a peripheral branch that innervates sensory organs and a central branch that relays information to the CNS. The central branches of adult DRG neurons in the spinal cord are refractory to regeneration unless their peripheral branches are severed first (Fig. 1). This so-called “conditioning lesion” paradigm activates a transcription program that enhances the intrinsic axonal growth potential (4). Previously, we have demonstrated that Smad1 is induced after peripheral axotomy and that intraganglionic delivery of BMP2 or -4, members of the BMP family, activates Smad1 and enhances the axon growth potential of adult DRG neurons in cultures. In contrast, severing the central branches of DRGs fails to activate Smad1, which correlates with the absence of regeneration after SCI (5). These results suggested a possible involvement of Smad1 in regulating the axon growth of DRG neurons. It is not known, however, whether Smad1 governs the axon growth program in young neurons and whether down-regulation of this pathway underlies the age-related decline of the intrinsic axon growth potential after birth. Furthermore, it remains to be determined whether failure to reactivate Smad1 contributes to a lack of growth after SCI and whether empowering older neurons with increased Smad1 signaling can promote axon regeneration after SCI in vivo.Adult neurons fail to regenerate axons because of a growth-inhibiting environment at the injury site (1) and because of an age-dependent decline in the intrinsic axon growth potential (2). Nevertheless, blocking extracellular growth-inhibitory molecules or alleviating the intracellular negative regulators of axonal growth enable only limited axonal regeneration (3). Thus, additional, unidentified molecular pathways that can rekindle innate growth capability must exist.Spinal cord injury (SCI) disrupts axons of nerve cells, with devastating neurological outcomes; yet no effective clinical treatment exists. One major obstacle to axonal regeneration after injury is the age-related decline of the ability of axons to regrow. The mechanisms underlying this decline are incompletely understood. Here we show that a developmentally regulated signaling pathway—the bone morphogenetic protein (BMP) pathway—governs axonal growth in embryonic dorsal root ganglion (DRG) neurons. Down-regulation of the pathway after birth contributes to the age-related decline of the axon growth potential. Selectively reactivating Smad1, an intracellular mediator of BMP signaling in adult DRG neurons, results in sensory axon regeneration in a mouse model of SCI. Smad1 signaling can be effectively manipulated by a viral vector encoding BMP that is delivered by using a clinically applicable and minimally invasive technique, an approach that does not lead to abnormalities in sensation or pain perception. Importantly, transected axons are able to regenerate when the treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.The authors declare no conflict of interest.This article is a PNAS Direct Submission. M.H.T. is a guest editor invited by the Editorial Board.See full research article on page E99 of www.pnas.org.Cite this Author Summary as: PNAS 10.1073/pnas.1100426108.1ME Schwab, D Bartholdi, Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 76, 319–370 (1996).2F Sun, Z He, Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr Opin Neurobiol 20, 510–518 (2010).3MT Fitch, J Silver, CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol 209, 294–301 (2008).4PM Richardson, VM Issa, Peripheral injury enhance

Fall armyworm (FAW; Spodoptera frugiperda (J. E. Smith)) is emerging as the most destructive pest of maize in India since its report in May 2018. Its rapid spread to more than 90% of maize-growing areas of diverse agro-ecologies of India within a span of 16 months presents a major challenge to smallholder maize farmers, maize-based industry, as well as food and nutritional security. FAW has been reported from other crops as well like sorghum and millets with varied proportion of economic damage. In this review, the transboundary movement of FAW, role of ecology, its spread and damage are discussed. Management of FAW by developing and deploying various pest management tools is elaborated. The role of agroecological measures for reducing FAW damage with African experiences has also been highlighted.

Over the years, many clinical and engineering methods have been adapted for testing and screening for the presence of diseases. The most commonly used methods for diagnosis and analysis are computed tomography (CT) and X-ray imaging. Manual interpretation of these images is the current gold standard but can be subject to human error, is tedious, and is time-consuming. To improve efficiency and productivity, incorporating machine learning (ML) and deep learning (DL) algorithms could expedite the process. This article aims to review the role of artificial intelligence (AI) and its contribution to data science as well as various learning algorithms in radiology. We will analyze and explore the potential applications in image interpretation and radiological advances for AI. Furthermore, we will discuss the usage, methodology implemented, future of these concepts in radiology, and their limitations and challenges.

In today’s world, efficiency and margin of safety are prime considerations for any applications. To address such parameters in aerospace or high-tech consumer products, there are still limitations in terms of capabilities from a material perspective. Aluminium 7075 is predominantly used as a combination material in these applications, but it has many drawbacks such as early wear/friction, low fatigue life cycle, high weight ratios, high deformation and stresses. To overcome these key issues, many reinforcements have been used to date. However, the results are not so convincing with respect to tribological applications, and the aforementioned issues still persist. In the current work, a novel hybrid composite comprising Aluminium 7075 as substrate and the reinforcement of silicon carbide and aluminium oxide at varying combinations of 3 to 9% in steps of 3% and a constant percentage of 5% were added, respectively. The exhaustive work focuses on extracting the mechanical, tribological and physical properties of a hybrid composite. Furthermore, a microcharacterisation study of these combinations was carried out using FE-SEM and EDX. In a continuation to this simulation, a study was performed using ANSYS Workbench to identify a suitable gear application with real-time loading conditions. The observed results show a tensile strength of 366 MPa for 6%SiC, hardness of 93 VHN and wear rate of 0.00025 mm3/Nm for the 9%SiC combination.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab -paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m 2 [ n  = 64] and 295 mg/m 2 [ n  = 58] every 3 weeks) compared with nab -paclitaxel (260 mg/m 2 every 3 weeks [ n  = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m 2 , PICN 295 mg/m 2 , and nab -paclitaxel 260 mg/m 2 arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m 2 , PICN 295 mg/m 2 , and nab -paclitaxel 260 mg/m 2 arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m 2 every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab -paclitaxel 260 mg/m 2 every 3 weeks. Statistically, significant differences were not observed in the PICN and nab -paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

Studies have shown that distress and accompanying neuroendocrine stress responses as important predictor of survival in advanced breast cancer patients. Some psychotherapeutic intervention studies have shown have modulation of neuroendocrine-immune responses in advanced breast cancer patients. In this study, we evaluate the effects of yoga on perceived stress, sleep, diurnal cortisol, and natural killer (NK) cell counts in patients with metastatic cancer. In this study, 91 patients with metastatic breast cancer who satisfied selection criteria and consented to participate were recruited and randomized to receive \"integrated yoga based stress reduction program\" ( = 45) or standard \"education and supportive therapy sessions\" ( = 46) over a 3 month period. Psychometric assessments for sleep quality were done before and after intervention. Blood draws for NK cell counts were collected before and after the intervention. Saliva samples were collected for three consecutive days before and after intervention. Data were analyzed using the analysis of covariance on postmeasures using respective baseline measure as a covariate. There was a significant decrease in scales of symptom distress ( < 0.001), sleep parameters ( = 0.02), and improvement in quality of sleep ( = 0.001) and Insomnia Rating Scale sleep score ( = 0.001) following intervention. There was a decrease in morning waking cortisol in yoga group ( = 0.003) alone following intervention. There was a significant improvement in NK cell percent ( = 0.03) following intervention in yoga group compared to control group. The results suggest modulation of neuroendocrine responses and improvement in sleep in patients with advanced breast cancer following yoga intervention.

Bacterium Pseudomonas aeruginosa BCH was able to degrade naphthylaminesulfonic azo dye Amaranth in plain distilled water within 6 h at 50 mg l −1 dye concentration. Studies were carried out to find the optimum physical conditions and which came out to be pH 7 and temperature 30 °C. Amaranth could also be decolorized at concentration 500 mg l −1 . Presence of Zn and Hg ions could strongly slow down the decolorization process, whereas decolorization progressed rapidly in presence of Mn. Decolorization rate was increased with increasing cell mass. Induction in intracellular and extracellular activities of tyrosinase and NADH-DCIP reductase along with intracellular laccase and veratryl alcohol oxidase indicated their co-ordinate action during dye biodegradation. Up-flow bioreactor studies with alginate immobilized cells proved the capability of strain to degrade Amaranth in continuous process at 20 ml h −1 flow rate. Various analytical studies viz.—HPLC, HPTLC, and FTIR gave the confirmation that decolorization was due to biodegradation. From GC-MS analysis, various metabolites were detected, and possible degradation pathway was predicted. Toxicity studies carried out with Allium cepa L. through the assessment of various antioxidant enzymes viz. sulphur oxide dismutase, guaiacol peroxidase, and catalase along with estimation of lipid peroxidation and protein oxidation levels conclusively demonstrated that oxidative stress was generated by Amaranth.

Abstract Background Stenotrophomonas sepilia, identified in 2021, is part of the Stenotrophomonas maltophilia complex (Smc) and shares high genomic identity with S. maltophilia. Resistance to levofloxacin, the recommended fluoroquinolone for S. maltophilia, is being increasingly reported. Recent studies indicate that levonadifloxacin, a novel benzoquinolizine, may be more effective. This study evaluates the antimicrobial efficacy of levofloxacin and levonadifloxacin against clinical isolates of S. sepilia. Objectives To assess the antibacterial effectiveness of levofloxacin and levonadifloxacin against novel pathogen S. sepilia. Methods A total of 116 S. maltophilia isolates, identified by MALDI-TOF MS, were collected from five centres across India. S. sepilia was confirmed by PCR using primers targeting a unique genomic sequence (NCBI accession number LXXZ00000000.1). Minimum inhibitory concentrations (MICs) of levonadifloxacin and levofloxacin were determined by using the microbroth-dilution method and Etest as per CLSI guidelines. The levofloxacin breakpoint was used to interpret MICs of levonadifloxacin. Results Among a total of 116 circulating S. maltophilia isolates collected, 46 were identified as S. sepilia, representing a prevalence rate of (∼40%), thus highlighting its significance as an important pathogen within the Smc. Both levofloxacin and levonadifloxacin demonstrated a 98% inhibition rate against the 46 S. sepilia tested. Only one S. sepilia isolate resistant to levofloxacin showed intermediate susceptibility to levonadifloxacin, which consistently had lower MICs. Conclusions Levofloxacin and levonadifloxacin show similar susceptibility rates against S. sepilia, with levonadifloxacin exhibiting lower MICs. Further studies are required to establish clinical utility of levonadifloxacin in managing these infections.