Enhanced Computational Study with Experimental Correlation on I-V Characteristics of Tantalum Oxide (TaOx) Memristor Devices in a 1T1R Configuration.

Memristors, non-volatile switching memory platform, has recently attracted significant interest, offering unique potential to enable the realization of human brain-like neuromorphic computing efficiency. Memristors also demonstrate excellent temperature tolerance, long-term durability, and high tunability with nanosecond pulses, making them highly attractive for neuromorphic computing applications. To better understand the material processing, microstructure, and property relationship of switching mechanisms in memristor devices, computational methodologies, and tools are developed to predict the I-V characteristics of memristor devices based on tantalum oxide (TaOx) resistive random-access memory (ReRAM) integrated with an n-channel metal-oxide-semiconductor (NMOS) transistor. A multiphysics model based on coupled partial differential equations for electrical and thermal transport phenomena is solved for the high- and low-resistance states during the formation, growth, and destruction of a conducting filament through SET and RESET stages. These stages effectively represent the migration of oxygen vacancies within an oxide exchange layer. A series of parametric studies and energy minimization calculations are conducted to determine probable ranges for key material and model parameters accounting for the experimental data. The computational model successfully predicted the measured I-V curves across various gate voltages applied to the NMOS transistor in the one transistor one resistance (1T1R) configuration.

Multicenter, open-label, prospective study shows safety and therapeutic benefits of a defined ginkgo biloba extract for adults with Major Neurocognitive Disorder.

INTRODUCTION: Safety and therapeutic effects of gingko biloba extract EGb 761® to treat cognitive decline have been demonstrated in numerous clinical trials. However, trials in Indian populations have been lacking. METHODS: This open-label, multicenter, single-arm, phase IV trial enrolled 150 patients aged ≥50 years with Major Neurocognitive Disorder due to Alzheimer's disease, major vascular neurocognitive disorder, or mixed forms of both according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria and a Mini-Mental State Examination (MMSE) score of 12-24. Patients took 120 mg EGb 761® twice daily for 18 weeks. Therapeutic effects were assessed by CERAD Constructional Praxis and Recall of Constructional Praxis (CERAD CP, CERAD Recall of CP), Trail-Making Test (TMT), Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD), Clinical Global Impressions (CGI) scale and 11-point box scales for tinnitus and vertigo. Safety assessment was based on the occurrence of adverse events as well as changes in clinical, laboratory and functional parameters. RESULTS: After 18 weeks, significant improvements compared to baseline were found in constructional praxis (CERAD CP, p<0.0001), memory (CERAD Recall of CP, p<0.0001), speed and executive functioning (TMT A, p<0.0001; TMT B, p<0.0001), and behavioral symptoms (BEHAVE-AD, p<0.0001). Forty-five adverse events were reported in 33 (22.0%) patients in total, including ten presumed adverse drug reactions in 9 (6.0%) patients. Headache and diarrhea of mild-to-moderate severity were the most frequent events. Two serious adverse events, both considered unrelated to the study drug, occurred in 2 (1.3%) patients. CONCLUSION: This study confirmed the favorable safety profile and suggested therapeutic benefits of EGb 761® in Indian patients with Major Neurocognitive Disorder.

Epitaxial growth of quasi-2D van der Waals ferromagnets on crystalline substrates.

Intrinsic magnetism in van der Waals materials has instigated interest in exploring magnetism in the 2D limit for potential applications in spintronics and also understanding of novel control of 2D magnetism by variation of layer thickness, gate tunability and magnetoelectric effects. The chromium telluride (CrxTey) family is an interesting subsection of ferromagnetic materials with high TC values, also presenting diverse stoichiometry arising from self-intercalation of Cr. Apart from the layered CrTe2 system, the other non-layered CrxTey compounds also offer exceptional magnetic properties and a novel growth technique to grow thin films of these non-layered compounds offer exciting possibilities for ultrathin spin-based electronics and magnetic sensors. In this work we have discussed the role of crystalline substrates in CVD growth of non-layered 2D ferromagnets, where the crystal symmetry of the substrate as well as the misfit and strain are the key players governing the growth mechanism of ultrathin Cr5Te8, a non-layered ferromagnet. The magnetic studies of the as-grown Cr5Te8 revealed signatures of co-existing soft and hard ferromagnetic phases which makes this system an intriguing system to search for emergent topological phases such as magnetic skyrmions.

Efficiency and Mechanism of Catalytic Siloxane Exchange in Vitrimer Polymers: Modeling and Density Functional Theory Investigations.

Of late, siloxane-containing vitrimers have gained significant interest due to their fast dynamic characteristics over a reasonable temperature range (180-220 °C), making them well-suited for diverse applications. The exchange reaction pathway in the siloxane vitrimers is accountable for the covalent adaptive network, with the reaction's effectiveness being regulated by either organic or organometallic catalysts. However, directly studying the exchange reaction pathway in the bulk phase using experimental approaches is challenging because of the intricate and interconnected structure of these vitrimers. Here, we perform comprehensive density functional theory (DFT) and experimental investigations to discover the detailed catalytic efficacy of siloxane exchange and provide direction for the reaction process using a 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) catalyst. The calculated transition barrier energy and catalytic efficiency of hexamethyldisiloxane and dihydroxy-dimethylsilane exchange derived from the nudged elastic band with transition-state calculations strongly agree with the experimental findings. In addition, Fukui indices, along with partial charges, are employed to evaluate the nucleophilic and electrophilic behaviors of silanol and siloxane molecules. Our analysis revealed that by utilizing the Fukui indices of both the acid and the base, we can make an approximate estimation of the respective kinetics of the SN2 process in the siloxane exchange reaction mechanism. These findings establish a foundation for comprehending a crucial aspect of the exchange mechanism in siloxane vitrimer systems and could aid in the development of novel catalysts.

Synthesis and Characterization of Biotene: A New 2D Natural Oxide From Biotite.

In this work, the synthesis and characterization of ultrathin metal oxide, called biotene, using liquid-phase exfoliation from naturally abundant biotite are demonstrated. The atomically thin biotene is used for energy harvesting using its flexoelectric response under multiple bending. The effective flexoelectric response increases due to the presence of surface charges, and the voltage increases up to ≈8 V, with a high mechano-sensitivity of 0.79 V N-1 for normal force. This flexoelectric response is further validated by density functional theory (DFT) simulations. The atomically thin biotene shows an increased response in the magnetic field and thermal heating. The synthesis of two-dimensional (2D) metal-oxide biotene suggests a wealth of future 2D-oxide material for energy generation and energy harvesting applications.

Shape memory polymer composites (SMPCs) using interconnected nanowire network foams as reinforcements.

Shape memory polymers (SMPs), although offer a suite of advantages such as ease of processability and lower density, lag behind their shape memory alloy counterparts, in terms of mechanical properties such as recovery stress and cyclability. Reinforcing SMPs with inorganic nanowires and carbon nanotubes (CNTs) is a sought-after pathway for tailoring their mechanical properties. Here, inorganic nanowires also offer the added advantage of covalently binding the fillers to the surrounding polymer matrices via organic molecules. The SMP composites (SMPCs) thus obtained have well-engineered nanowire-polymer interfaces, which could be used to tune their mechanical properties. A well-known method of fabricating SMPCs involving casting dispersions of nanowires (or CNTs) in mixtures of monomers and crosslinkers typically results in marginal improvements in the mechanical properties of the fabricated SMPCs. This is owed to the constraints imposed by the rule-of-mixture principles. To circumvent this limitation, a new method for SMPC fabrication is designed and presented. This involves infiltrating polymers into pre-fabricated nanowire foams. The pre-fabricated foams were fabricated by consolidating measured quantities of nanowires and a sacrificial material, such as (NH4)2CO3, followed by heating the consolidated mixtures for subliming the sacrificial material. Similar to the case of traditional composites, use of silanes to functionalize the nanowire surfaces allowed for the formation of bonds between both the nanowire-nanowire and the nanowire-polymer interfaces. SMPCs fabricated using TiO2nanowires and SMP composed of neopentyl glycol diglycidyl ether and poly(propylene glycol) bis(2-aminopropyl ether) (Jeffamine D230) in a 2:1 molar ratio exhibited a 300% improvement in the elastic modulus relative to that of the SMP. This increase was significantly higher than SMPC made using the traditional fabrication route. Well-known powder metallurgy techniques employed for the fabrication of these SMPCs make this strategy applicable for obtaining other SMPCs of any desired shape and chemical composition.

N/O→B dative bonds supplemented by N-HN/HC hydrogen bonds make BN-cages an attractive candidate for DNA-nucleobase adsorption - an MP2 prediction.

The response of B12N12-nanocages towards DNA-nucleobases (adenine, guanine, cytosine, and thymine) is investigated using MP2 and DFT (M06-2X) levels of theory with the 6-311+G** basis set. Multiple BN-cage-nucleobase structures for each nucleobase emerged depending on the number of Lewis base centers of nucleobases. The main source of stability of these complexes is the N/O→B dative bond, where the N or O atom of nucleobases donates the lone-pair electron to one of the boron atoms of the nanocage. Nitrogen atoms of the BN-cage, adjacent to the B-site forming dative bond, act as a proton acceptor to form multiple (N-HN and N-HC) hydrogen bonds, where proton-donors NH and CH are part of nucleobases. MP2/6-311+G** adsorption energies are -43.1, -43.4 and -45.3 kcal mol-1 (B12N12-adenine), -37.1, -41.9 and -43.3 kcal mol-1 (B12N12-guanine), -41.3 and -43.4 (B12N12-cytosine), and -29.3 and -31.3 (B12N12-thymine). Similar adsorption energies were recorded for larger BN-fullerenes-nucleobases, namely B16N16 and B24N24. Changes in adsorption energies and structures of these nano-bio-hybrid materials in aqueous media are also discussed. Computationally cost-effective MP2 single point calculations at the M06-2X optimized geometries were found to be reliable in predicting adsorption energies. The effect of the BN-network and H-bonds on the adsorption process is assessed by comparing the results with simple BH3-nucleobase models. BSSE correction to the adsorption energy is not recommended.

Photoabsorption Imaging at Nanometer Scales Using Secondary Electron Analysis.

Optical imaging with nanometer resolution offers fundamental insights into light-matter interactions. Traditional optical techniques are diffraction limited with a spatial resolution >100 nm. Optical super-resolution and cathodoluminescence techniques have higher spatial resolutions, but these approaches require the sample to fluoresce, which many materials lack. Here, we introduce photoabsorption microscopy using electron analysis, which involves spectrally specific photoabsorption that is locally probed using a scanning electron microscope, whereby a photoabsorption-induced surface photovoltage modulates the secondary electron emission. We demonstrate spectrally specific photoabsorption imaging with sub-20 nm spatial resolution using silicon, germanium, and gold nanoparticles. Theoretical analysis and Monte Carlo simulations are used to explain the basic trends of the photoabsorption-induced secondary electron signal. Based on our current experiments and this analysis, we expect that the spatial resolution can be further improved to a few nanometers, thereby offering a general approach for nanometer-scale optical spectroscopic imaging and material characterization.

Designing CdS-Based Ternary Heterostructures Consisting of Co-Metal and CoOx Cocatalysts for Photocatalytic H2 Evolution under Visible Light.

Heterostructure formation is an effective method used for designing photocatalysts that solve problems caused by photoexcited charge recombination phenomena associated with the photocatalytic water redox reaction. This work reports a new Co-metal-incorporated ternary heterostructured photocatalyst, CdS/CoOx/Co-metal, which enhanced charge separation to increase photocatalytic H2 evolution 30.5-fold in comparison to pure CdS under visible light. This work demonstrates for the first time the effect of the Co metal on photocatalytic H2 evolution using the CdS/CoOx/Co-metal ternary heterostructure. In the ternary heterostructure, Co metal and CoOx act as photogenerated electron- and hole-capturing cocatalysts, respectively. Results from photoelectrochemical studies along with photocatalytic H2 evolution data proved the enhancement of charge transfer and separation in the CdS/CoOx/Co-metal heterostructure due to the addition of Co metal and CoOx. Hence, the synergistic charge separation improvement achieved by the combination of CoOx and the Co metal with CdS produced a photocatalytic H2 evolution rate of 9.54 µmol/h, which is the highest reported H2 evolution rate for a CdS-based system under l sun solar irradiance (>420 nm) to the best of our knowledge.

Density functional tight binding study of ß-Ga2O3: Electronic structure, surface energy, and native point defects.

A new parameter set to model monoclinic gallium oxide, ß-Ga2O3, with the density functional tight binding (DFTB) method is developed. Using this new parameter set, DFTB calculations of bulk electronic band structure, surface energy of low-index surfaces, and formation energy of native point vacancy defects are performed and compared with the state-of-the-art density functional theory (DFT) calculations using the advanced hybrid exchange correlation functional. DFTB calculates the bandgap energy of 4.87 eV around the Fermi energy with the conduction band approximately following the DFT study by Peelaers and Van de Walle [Phys. Status Solidi B 252, 828 (2015)]. The surface energies calculated feature the correct order of stability among low index surfaces with surface energies in semiquantitative agreement with Bermudez' report [Chem. Phys. 323, 193 (2006)]. Oxygen and gallium vacancy defect formation energies and respective transition levels calculated using DFTB with a new parameter set are in semiquantitative agreement with the previous DFT reports by Varley et al. and Zacherle et al. [Appl. Phys. Lett. 97, 142106 (2010); Phys. Rev. B 87, 235206 (2013)]. This new semiempirical parameter set for ß-Ga2O3, validated in bulk, surface, and point properties, would be useful for large spatiotemporal quantum chemical calculations regarding ß-Ga2O3.

Disordered Nanostructure in Huntingtin Interacting Protein K Acts as a Stabilizing Switch To Prevent Protein Aggregation.

Protein misfolding due to mutation(s) and/or generation of unstable intermediate state(s) can be the cause of aberrant aggregations, leading to cellular degeneration. While molecular signatures like amyloidogenic regions cause aggregation, other features in proteins, like disorder and unique complexity regions, regulate and restrict such adhesive accumulation processes. Huntingtin interacting protein K (HYPK) is an aggregation-prone protein. Using various biophysical, microscopy, and computational techniques, we have deciphered how HYPK's N-terminal nanodisordered region plays a significant modulatory role in preventing its own aggregation and that of other proteins. HYPK's C-terminal hydrophobic regions lead to annular oligomerization and intermolecular charge interactions among the residues of low-complexity region (LCR) generate amorphous aggregates. The N-terminal disordered nanostructure loops toward the C-terminus, and a negative charge-rich patch in this region interacts with the LCR to shield LCR's positive charges. This interaction is required to prevent HYPK aggregation. Loss of this interaction causes partial unfolding of the structured C-terminus, resulting in HYPK's molten globule-like state and rapid annular oligomerization. The N-terminus also determines the specificity to mediate the differential bindings with aggregation-prone and wild type Huntingtin-exon1 proteins (Huntingtin97Q-exon1 and Huntingtin25Q-exon1). A sliding interaction of the specific N-terminal segment of HYPK along the extended polyglutamine region of Huntingtin-exon1 is responsible for HYPK's higher affinity for aggregation-prone Huntingtin than for its non-aggregating counterpart. Overall, our study provides evidence of the existence of disordered nanostructure in HYPK protein that mechanistically plays a decisive role in preventing both self and non-self protein aggregation.

Mce2R/Rv0586 of Mycobacterium tuberculosis is the functional homologue of FadRE. coli.

Lipid metabolism is critical to Mycobacterium tuberculosis survival and infection. Unlike Escherichia coli, which has a single FadR, the M. tuberculosis genome encodes five proteins of the FadR sub-family. While the role of E. coli FadR as a regulator of fatty acid metabolism is well known, the definitive functions of M. tuberculosis FadR proteins are still under investigation. An interesting question about the M. tuberculosis FadRs remains open: which one of these proteins is the functional homologue of E. coli FadR? To address this, we have applied two different approaches. The first one was the bioinformatics approach and the second one was the classical molecular genetic approach involving complementation studies. Surprisingly, the results of these two approaches did not agree. Among the five M. tuberculosis FadRs, Rv0494 shared the highest sequence similarity with FadRE. coli and Rv0586 was the second best match. However, only Rv0586, but not Rv0494, could complement E. coli ∆fadR, indicating that Rv0586 is the M. tuberculosis functional homologue of FadRE. coli. Further studies showed that both regulators, Rv0494 and Rv0586, show similar responsiveness to LCFA, and have conserved critical residues for DNA binding. However, analysis of the operator site indicated that the inter-palindromic distance required for DNA binding differs for the two regulators. The differences in the binding site selection helped in the success of Rv0586 binding to fadB upstream over Rv0494 and may have played a critical role in complementing E. coli ∆fadR. Further, for the first time, we report the lipid-responsive nature of Rv0586.

Hydrogenation of Penta-Graphene Leads to Unexpected Large Improvement in Thermal Conductivity.

Penta-graphene (PG) has been identified as a novel two-dimensional (2D) material with an intrinsic bandgap, which makes it especially promising for electronics applications. In this work, we use first-principles lattice dynamics and iterative solution of the phonon Boltzmann transport equation (BTE) to determine the thermal conductivity of PG and its more stable derivative, hydrogenated penta-graphene (HPG). As a comparison, we also studied the effect of hydrogenation on graphene thermal conductivity. In contrast to hydrogenation of graphene, which leads to a dramatic decrease in thermal conductivity, HPG shows a notable increase in thermal conductivity, which is much higher than that of PG. Considering the necessity of using the same thickness when comparing thermal conductivity values of different 2D materials, hydrogenation leads to a 63% reduction in thermal conductivity for graphene, while it results in a 76% increase for PG. The high thermal conductivity of HPG makes it more thermally conductive than most other semiconducting 2D materials, such as the transition metal chalcogenides. Our detailed analyses show that the primary reason for the counterintuitive hydrogenation-induced thermal conductivity enhancement is the weaker bond anharmonicity in HPG than PG. This leads to weaker phonon scattering after hydrogenation, despite the increase in the phonon scattering phase space. The high thermal conductivity of HPG may inspire intensive research around HPG and other derivatives of PG as potential materials for future nanoelectronic devices. The fundamental physics understood from this study may open up a new strategy to engineer thermal transport properties of other 2D materials by controlling bond anharmonicity via functionalization.

HosA, a MarR Family Transcriptional Regulator, Represses Nonoxidative Hydroxyarylic Acid Decarboxylase Operon and Is Modulated by 4-Hydroxybenzoic Acid.

Members of the Multiple antibiotic resistance Regulator (MarR) family of DNA binding proteins regulate transcription of a wide array of genes required for virulence and pathogenicity of bacteria. The present study reports the molecular characterization of HosA (Homologue of SlyA), a MarR protein, with respect to its target gene, DNA recognition motif, and nature of its ligand. Through a comparative genomics approach, we demonstrate that hosA is in synteny with nonoxidative hydroxyarylic acid decarboxylase (HAD) operon and is present exclusively within the mutS-rpoS polymorphic region in nine different genera of Enterobacteriaceae family. Using molecular biology and biochemical approach, we demonstrate that HosA binds to a palindromic sequence downstream to the transcription start site of divergently transcribed nonoxidative HAD operon and represses its expression. Furthermore, in silico analysis showed that the recognition motif for HosA is highly conserved in the upstream region of divergently transcribed operon in different genera of Enterobacteriaceae family. A systematic chemical search for the physiological ligand revealed that 4-hydroxybenzoic acid (4-HBA) interacts with HosA and derepresses HosA mediated repression of the nonoxidative HAD operon. Based on our study, we propose a model for molecular mechanism underlying the regulation of nonoxidative HAD operon by HosA in Enterobacteriaceae family.

Segmentation and additive approach: A reliable technique to study noncovalent interactions of large molecules at the surface of single-wall carbon nanotubes.

This investigation explores a new protocol, named Segmentation and Additive approach (SAA), to study exohedral noncovalent functionalization of single-walled carbon nanotubes with large molecules, such as polymers and biomolecules, by segmenting the entire system into smaller units to reduce computational cost. A key criterion of the segmentation process is the preservation of the molecular structure responsible for stabilization of the entire system in smaller segments. Noncovalent interaction of linoleic acid (LA, C18 H32 O2 ), a fatty acid, at the surface of a (10,0) zigzag nanotube is considered for test purposes. Three smaller segmented models have been created from the full (10,0)-LA system and interaction energies were calculated for these models and compared with the full system at different levels of theory, namely ωB97XD, LDA. The success of this SAA is confirmed as the sum of the interaction energies is in very good agreement with the total interaction energy. Besides reducing computational cost, another merit of SAA is an estimation of the contributions from different sections of the large system to the total interaction energy which can be studied in-depth using a higher level of theory to estimate several properties of each segment. On the negative side, bulk properties, such as HOMO-LUMO (highest occupied molecular orbital - lowest occupied molecular orbital) gap, of the entire system cannot be estimated by adding results from segment models. © 2016 Wiley Periodicals, Inc.

Site and chirality selective chemical modifications of boron nitride nanotubes (BNNTs) via Lewis acid-base interactions.

The pristine BNNTs contain both Lewis acid (boron) and Lewis base (nitrogen) centers at their surface. Interactions of ammonia and borane molecules, representatives of Lewis base and acid as adsorbates respectively, with matching sites at the surface of BNNTs, have been explored in the present DFT study. Adsorption energies suggest stronger chemisorption (about 15-20 kcal mol(-1)) of borane than ammonia (about 5-10 kcal mol(-1)) in both armchair (4,4) and zigzag (8,0) variants of the tube. NH3 favors (8,0) over the (4,4) tube, whereas BH3 exhibits the opposite preference, indicating some chirality dependence on acid-base interactions. A new feature of bonding is found in BH3/AlH3-BNNTs (at the edge site) complexes, where one hydrogen of the guest molecule is involved in three-center two-electron bonding, in addition to dative covalent bond (N: → B). This interaction causes a reversal of electron flow from borane/alane to BNNT, making the tube an electron acceptor, suggesting tailoring of electronic properties could be possible by varying strength of incoming Lewis acids. On the contrary, BNNTs always behave as electron acceptor in ammonia complexes. IR, XPS and NMR spectra show some characteristic features of complexes and can help experimentalists to identify not only structures of such complexes but also the location of the guest molecules and design second functionalizations. Interaction with several other neutral BF3, BCl3, BH2CH3 and ionic CH3(+) acids as well as amino group (CH3NH2 and NH2COOH) were also studied. The strongest interaction (>100 kcal mol(-1)) is found in BNNT-CH3(+) complexes and H-bonds are the only source of stability of NH2COOH-BNNT complexes.

Thermal anisotropy in nano-crystalline MoS2 thin films.

In this work, we grow thin MoS2 films (50-150 nm) uniformly over large areas (>1 cm(2)) with strong basal plane (002) or edge plane (100) orientations to characterize thermal anisotropy. Measurement results are correlated with molecular dynamics simulations of thermal transport for perfect and defective MoS2 crystals. The correlation between predicted (simulations) and measured (experimental) thermal conductivity are attributed to factors such as crystalline domain orientation and size, thereby demonstrating the importance of thermal boundary scattering in limiting thermal conductivity in nano-crystalline MoS2 thin films. Furthermore, we demonstrate that the cross-plane thermal conductivity of the films is strongly impacted by exposure to ambient humidity.

Selective Termination of Autophagy-Dependent Cancers.

The goal of cancer research is to identify characteristics of cancer cells that allow them to be selectively eliminated without harming the host. One such characteristic is autophagy dependence. Cancer cells survive, proliferate, and metastasize under conditions where normal cells do not. Thus, the requirement in cancer cells for more energy and macromolecular biosynthesis can evolve into a dependence on autophagy for recycling cellular components. Recent studies have revealed that autophagy, as well as different forms of cellular trafficking, is regulated by five phosphoinositides associated with eukaryotic cellular membranes and that the enzymes that synthesize them are prime targets for cancer therapy. For example, PIKFYVE inhibitors rapidly disrupt lysosome homeostasis and suppress proliferation in all cells. However, these inhibitors selectively terminate PIKFYVE-dependent cancer cells and cancer stem cells with not having adverse effect on normal cells. Here, we describe the biochemical distinctions between PIKFYVE-sensitive and -insensitive cells, categorize PIKFYVE inhibitors into four groups that differ in chemical structure, target specificity and efficacy on cancer cells and normal cells, identify the mechanisms by which they selectively terminate autophagy-dependent cancer cells, note their paradoxical effects in cancer immunotherapy, and describe their therapeutic applications against cancers.

PIKFYVE inhibitors trigger interleukin-24-dependent cell death of autophagy-dependent melanoma.

Inhibitors specifically targeting the 1-phosphatidylinositol 3-phosphate 5-kinase (PIKFYVE) disrupt lysosome homeostasis, thereby selectively terminating autophagy-dependent human cancer cells in vivo as well as in vitro without harming the viability of nonmalignant cells. To elucidate the mechanism by which PIKFYVE inhibition induces cell death, autophagy-dependent melanoma cells were compared with normal foreskin fibroblasts. RNA sequence profiling suggested that PIKFYVE inhibitors upregulated an endoplasmic reticulum (ER) stress response involving interleukin-24 (IL24; also known as MDA7) selectively in melanoma cells. Subsequent biochemical and genetic analyses confirmed these results and extended them to tumor xenografts in which tumor formation and expansion were inhibited. IL24 expression was upregulated by the DDIT3/CHOP/CEBPz transcription factor, a component of the PERK-dependent ER-stress response. Ectopic expression of IL24-induced cell death in melanoma cells, but not in foreskin fibroblasts, whereas ablation of the IL24 gene in melanoma cells prevented death. IL24 upregulation was triggered specifically by PIKFYVE inhibition. Thus, unlike thapsigargin and tunicamycin, which induce ER-stress indiscriminately, PIKFYVE inhibitors selectively terminated PIKFYVE-sensitive melanoma by inducing IL24-dependent ER-stress. Moreover, induction of cell death by a PIKFYVE inhibitor together with ectopic expression of IL24 protein was cumulative, thereby confirming the therapeutic potential of PIKFYVE inhibitors in the treatment of melanoma.

Analysis of posture and balance impairments in individuals with chronic nonspecific neck pain-an observational study.

Background: Neck pain is one of the most burdensome chronic musculoskeletal problems globally. Impaired proprioception is associated with Chronic Nonspecific neck pain as the structures of the cervical spine are crucial for proprioception and balance. There is a paucity of literature examining objective measures of balance and postural sway in patients with Nonspecific neck pain. Methods: This study was observational and consisted of 126 samples (63 cases and 63 controls who were recruited using convenience sampling. The demographics of the samples were collected and the postural and balance impairment was assessed using Biodex Balance SD. Mean, Median, and SD were obtained and the inferential analysis was done using the Whitney U Test and the level of significance was accepted at p < 0.05. Results: The subjects with neck pain showed had a lower static stability index, static sway index, static stability index- forward backward and static sway index lateral scores than the normal counterparts. There are significant differences in the overall static stability index, (p < 0.001). There was a significant difference in static sway index(p = 0.003), and static stability index lateral (p = 0.004). There was no significant difference for static sway index forward and backward (p = 0.550) and lateral sway index (p = 0.711). Conclusion: Subjects with neck pain showed had a lower static stability index, static sway index, static stability index- forward backward and static sway index lateral scores than the normal counterparts and there was a significant difference between the static sway and static stability index in forward and backward directions as well as in lateral direction. These findings may help to assess the specific balance parameters and address the underlying causes of balance issues in patients with neck pain and also provide a comprehensive care to the patients. Clinical Trial Registration: The trial was registered with CTRI India with registration number: CTRI/2022/07/044222.