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1.
ACS Appl Mater Interfaces ; 14(46): 52096-52107, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36346904

RESUMO

In this article, we report on high-performance deep ultraviolet photodetectors (DUV PDs) fabricated on metal-organic chemical vapor deposition (MOCVD)-grown ß-Ga2O3 heteroepitaxy that exhibit stable operation up to 125 °C. The fabricated DUV PDs exhibit self-powered behavior with an ultralow dark current of 1.75 fA and a very high photo-to-dark-current ratio (PDCR) of the order of 105 at zero bias and >105 at higher biases of 5 and 10 V, which remains almost constant up to 125 °C. The high responsivity of 6.62 A/W is obtained at 10 V at room temperature (RT) under the weak illumination of 42.86 µW/cm2 of 260 nm wavelength. The detector shows very low noise equivalent power (NEP) of 5.74 × 10-14 and 1.03 × 10-16 W/Hz1/2 and ultrahigh detectivity of 5.51 × 1011 and 3.10 × 1014 Jones at 0 and 5 V, respectively, which shows its high detection sensitivity. The RT UV-visible (260:500 nm) rejection ratios of the order of 103 at zero bias and 105 at 5 V are obtained. These results demonstrate the potential of Ga2O3-based DUV PDs for solar-blind detection applications that require high-temperature robustness.

2.
Biomaterials ; 292: 121914, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36436306

RESUMO

Critical limb ischemia (CLI) is a serious form of peripheral arterial disease that involves severe blockage of blood flow in lower extremities, often leading to foot necrosis and limb loss. Lack of blood flow and high pro-inflammation with overproduced reactive oxygen species (ROS) in CLI aggravate the degenerative events. Among other therapies, cell delivery is considered potential for restoring regenerative capacity, and preservation of cell survival under high oxidative stress has been challenging and prerequisite to harness cellular functions. Here, we introduce a multicellular delivery system that is intercalated with nanoceria-decorated graphene oxide (CeGO), which is considered to have high ROS scavenging ability while providing cell-matrix interaction signals. The CeGO nano-microsheets (8-nm-nanoceria/0.9-µm-GO) incorporated in HUVEC/MSC (7/3) could form cell-material hybrid spheroids mediated by cellular contraction. Under in vitro oxidative-stress-challenge with H2O2, the CeGO-intercalation enhanced the survival and anti-apoptotic capacity of cellular spheroids. Pro-angiogenic events of cellular spheroids, including cell sprouting and expression of angiogenic markers (HIF1α, VEGF, FGF2, eNOS) were significantly enhanced by the CeGO-intercalation. Proteomics analysis also confirmed substantial up-regulation of a series of angiogenesis-related secretome molecules. Such pro-angiogenic events with CeGO-intercalation were proven to be mediated by the APE/Ref-1 signaling pathway. When delivered to ischemic hindlimb in mice, the CeGO-cell spheroids could inhibit the accumulation of in vivo ROS rapidly, preserving high cell survival rate (cells were more proliferative and less apoptotic vs. those in cell-only spheroids), and up-regulated angiogenic molecular expressions. Monitoring over 28 days revealed significantly enhanced blood reperfusion and tissue recovery, and an ultimate limb salvage with the CeGO-cell delivery (∼60% salvaged vs. ∼29% in cell-only delivery vs. 0% in ischemia control). Together, the CeGO intercalated in HUVEC/MSC delivery is considered a potential nano-microplatform for CLI treatment, by scavenging excessive ROS and enhancing transplanted cell survival, while stimulating angiogenic events, which collectively help revascularization and tissue recovery, salvaging critical ischemic limbs.

3.
Nanomaterials (Basel) ; 12(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36296752

RESUMO

Although both the tendency of 2D materials to bend out of plane as well as its effect on materials' properties are well known, the factors influencing this phenomenon have not been extensively studied. Graphene, the one-atom-thick membrane of carbon atoms, is both arguably the best known 2D material, as well as the most prone to spontaneous corrugations. Here, we use electron diffraction to systematically study the factors influencing corrugations in graphene, including the size of the free-standing area, the preparation method, the amount of surface contamination, and electron-beam-induced structural disorder. We find that mechanically exfoliated graphene is less corrugated than graphene grown via chemical vapor deposition (corrugation amplitude of (0.83±0.10) Å compared to (1.33±0.20) Å for a free-standing area with a diameter of 1.7µm). Similarly, corrugation amplitude grows by more than a factor of two when the diameter of the free- standing area is increased from 1.7µm to ca. 3.0µm. Electron beam irradiation affects the corrugation in two ways, firstly by removing the hydrocarbon contamination, which decreases corrugation, and secondly by creating increasing amounts of disorder into the material, which again increases corrugation. Overall, our results show that control over the sample during both initial preparation and post-preparation treatment allows for a change in the amount of corrugation in free-standing 2D materials, which may lead to new advances in their use in applications.

4.
Mar Biotechnol (NY) ; 24(6): 1168-1175, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36220897

RESUMO

With the overuse and misuse of antibiotics amid COVID-19 pandemic, the antimicrobial resistance, which is already a global challenge, has accelerated its pace significantly. Finding novel and potential antibiotics seems one of the probable solutions. In this work, a novel Streptomyces sp. strain EMB24 was isolated and found to be an excellent source of antimicrobials as confirmed by agar-plug assay. It showed antibacterial activity against infection-causing bacteria, namely Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. In addition, Streptomyces sp. strain EMB24 inhibited the growth methicillin-resistant Staphylococcus aureus (MRSA), tetracycline-resistant Neisseria gonorrhoeae, and ampicillin-resistant Neisseria gonorrhoeae. Furthermore, to get deep insights about the genome and biosynthetic gene clusters producing antibiotics, whole genome sequencing was done. The strain EMB24 is closely related to the Streptomyces longispororuber as revealed by phylogenetic analysis which is a potential source of antibiotics and pigments as undecylprodigiosin and metacycloprodigiosin belonging to the class prodigiosin. Naphthyridinomycin, alkylresorcinols, desferrioxamine B and E, venezuelin, aborycin, MS-271, and siamycin are potent therapeutics that shared 100% similarity with the reference strain as revealed by the online antiSMASH tool.


Assuntos
COVID-19 , Staphylococcus aureus Resistente à Meticilina , Streptomyces , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Filogenia , Pandemias , Streptomyces/genética , Antibacterianos/farmacologia , Escherichia coli
5.
Water Res ; 225: 119175, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36191529

RESUMO

UV/chlor(am)ine are efficient for achieving multiple-barrier disinfection and maintaining residuals, while bromide (Br-) has notable impacts on the formation and toxicity of halonitromethanes (HNMs) during UV/chlor(am)ine disinfection. This study investigated the effects of Br- on HNMs formation and toxicity alteration during UV/chlor(am)ine disinfection of nitrate containing humic acid (HA) water. Results reveal that the maximum concentration of HNMs during UV/chlorine disinfection was 12.03 µg L-1 with 0.2 mg L-1 Br-, which was 22.5% higher than that without Br-, and the predominant species of HNMs were converted from trichloronitromethane (TCNM) to dibromonitromethane (DBNM) and tribromonitromethane (TBNM). However, the maximum concentration of HNMs during UV/chloramine disinfection was 3.69 µg L-1 with 0.2 mg L-1 Br-, which was increased by 26.0% than that without Br-, and the predominant species of HNMs were converted from dichloronitromethane (DCNM) to bromochloronitromethane (BCNM) and DBNM. Notably, the HNMs species and yields during UV/chloramine disinfection were less than those during UV/chlorine disinfection, primarily due to the higher concentrations of HO· and reactive chlorine/bromine species in UV/chlorine. Also, in the ranges of the Br-:Cl2 molar ratio from 0 to 0.32 and pH from 6.0 to 8.0, the Br-:Cl2 molar ratio of 0.16 and acidic pH contributed to the HNMs formation during UV/chlorine disinfection, and a high Br-:Cl2 molar ratio and neutral pH contributed to the HNMs formation during UV/chloramine disinfection. Note that the incorporation of Br- significantly improved the calculated cytotoxicity (CTI) and genotoxicity (GTI) of HNMs formed, and the calculated CTI and GTI of HNMs formed during UV/chloramine disinfection were 28.19 and 48.90% of those during UV/chlorine disinfection. Based on the diversity of nitrogen sources, the possible formation pathways of HNMs from nitrate containing HA water were proposed during UV/chlor(am)ine disinfection in the presence of Br-. Results of this study indicated that UV/chloramine can reduce the formation and toxicity of HNMs efficiently.


Assuntos
Desinfetantes , Poluentes Químicos da Água , Purificação da Água , Cloraminas , Desinfecção/métodos , Cloro , Substâncias Húmicas , Brometos , Nitratos , Purificação da Água/métodos , Bromo , Água , Halogenação , Poluentes Químicos da Água/análise , Nitrogênio
6.
Chemphyschem ; : e202200459, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36074347

RESUMO

The sodium superionic conductor (NASICON)-Na3 V2 (PO4 )3 (NVP) is an attractive cathode for sodium-ion batteries, which is still confronted with limited rate performance due to its low electronic conductivity. In this paper, a chemical strategy is adopted to partially replace V3+ of the NVP framework by low-valence Mn2+ and high-valence Mo6+ substitution. The crystal structure, sodium-ion diffusion coefficient and electrochemical performance of Mn-Mo-doped [Na3.94 V0.98 Mo0.02 Mn(PO4 )3 @C] cathode were investigated. X-ray diffraction confirmed the NASICON-type structure and XPS analysis confirmed the oxidation state of Mn and Mo in doped NVP cathode. The Na ion diffusion processes were inferred from Cyclic Voltammetry (CV), Galvanostatic intermittent titration technique (GITT) and Electrochemical Impedance Spectroscopy (EIS) measurement, which clearly show rapid Na-ion diffusion in NASICON-type cathode materials. The Mn-Mo-substituted NVP shows smoother charge-discharge profiles, improved rate performance (64.80 mAh/g at 1 C rate), better energy density (308.61 mWh/g) and superior Na-ion kinetics than that of unsubstituted NVP@C cathode. Their enhanced performance is attributed to large interstitial volume mainly created by high valence Mo6+ and enhanced capacity is attributed to the low valence Mn2+ doping. These results demonstrate that Mn-Mo-doped NVP cathode is strongly promising cathode material for sodium-ion batteries.

7.
Nanoscale Adv ; 4(2): 479-490, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36132701

RESUMO

We report on the fabrication of a vertical 2D/3D heterojunction diode between gallium selenide (GaSe) and silicon (Si), and describe its photoresponse properties. Kelvin probe force microscopy (KPFM) has been employed to investigate the surface potentials of the GaSe/Si heterostructure, leading to the evaluation of the value of the conduction band offset at the heterostructure interface. The current-voltage measurements on the heterojunction device display a diode-like nature. This diode-like nature is attributed to the type-II band alignment that exists at the p-n interface. The key parameters of a photodetector, such as photoresponsivity, detectivity, and external quantum efficiency, have been calculated for the fabricated device and compared with those of other similar devices. The photodetection measurements of the GaSe/Si heterojunction diode show excellent performance of the device, with high photoresponsivity, detectivity, and EQE values of ∼2.8 × 103 A W-1, 6.2 × 1012 Jones, and 6011, respectively, at a biasing of -5 V. Even at zero biasing, a high photoresponsivity of 6 A W-1 was obtained, making it a self-powered device. Therefore, the GaSe/Si self-driven heterojunction diode has promising potential in the field of efficient optoelectronic devices.

8.
Anim Biotechnol ; : 1-7, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36007588

RESUMO

To understand the pathology of natural cases of E. coli pathotypes infection in bovine calves, 45 cases of bovine calves, below one month of age, died due to enteritis were studied. Total seventeen cases (37.77%) turned positive for different pathotypes of E. coli by RT-PCR. Out of seventeen positive samples for E. coli, six cases (35.29%) were positive for eae gene, three cases (17.64%) for bfp gene and eight cases (47.05) for fimA gene of E. coli. Gross lesions in these cases showed pin-point to ecchymotic hemorrhages in the mucosa of jejunum, ileum and colon. The draining mesenteric lymph nodes were swollen, enlarged and showed cord -like structure. Histopathology of small intestine showed, villi lining cells were sloughed off, tips of villi capillary plexus were congested and hemorrhagic, and skipping lesions of microabscesses in the crypts of mucosa were observed. In the duodenum, necrosis of crypts and infiltration of mononuclear cells in the lamina propria and around Brunner's gland. In mesenteric lymph nodes the subscapular space were infiltrated with mononuclear cells with depletion of lymphoid follicles in cortical area. Peri-trabecular and medullary sinuses of mesenteric lymph nodes were necrosed.

9.
Microb Pathog ; 171: 105738, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36038085

RESUMO

Porcine circovirus type 2 (PCV-2) is of great economic significance to porcine industry worldwide. PCV-2 variants and genotypes, alternating world over, are the etiological agent of several clinical syndromes such as porcine dermatitis and nephropathy syndrome (PDNS), post-weaning multi-systemic wasting syndrome (PMWS) and others in pigs. This study is reporting an atypical manifestation of PDNS in twelve grower pigs, 3- to - 4.5 months age and either sex, died of the disease, with predominant lesions of nephropathy and no obvious clinical lesions in skin. Necropsy examination of pigs showed lesions of petechial -to- ecchymotic hemorrhages in the kidneys and in the right auricular musculature of the hearts. Microscopic lesions in H & E sections of the kidneys showed acute glomerulonephritis, interstitial nephritis, and vasculitis, but the skin morphology and architecture remained unaltered in contrast to the pathognomonic lesions of PDNS described in the literature. Other syndromic associations of PDNS in these cases included-perimyocarditis, interstitial pneumonia, depleted lymphoid tissues, tonsillitis, enteritis, and meningo-encephalitis. The lesional sites in duplicate paraffin tissue sections of kidneys, heart, lungs, spleen, lymph nodes, intestine, and brain demonstrated PCV-2 antigen in the cytoplasm of cells as highlighted by the intense immunolabeling on IHC staining. The PCV-2 positive organs reconfirmed by PCR, targeting ORF2 gene, which yielded 481bp size of products. The sequencing results of 481bp products on phylogenetic analysis showed 94% similarity with that of PCV-2 sequences in the database that grouped into PCV2d-2 genotype. The present report confirms, probably for the first time, the atypical PDNS cases due to PCV2d-2 genotype in naturally affected grower pigs of India.


Assuntos
Infecções por Circoviridae , Circovirus , Dermatite , Doenças dos Suínos , Animais , Dermatite/patologia , Parafina , Filogenia , Suínos , Doenças dos Suínos/patologia , Síndrome
10.
Biomaterials ; 288: 121732, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36031457

RESUMO

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-ß co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.


Assuntos
Regeneração Óssea , Diabetes Mellitus , Células-Tronco Mesenquimais , Tecidos Suporte , Animais , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular , Cério/farmacologia , Cério/uso terapêutico , Diabetes Mellitus/metabolismo , Integrinas/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Estresse Oxidativo , Ratos , Fator de Crescimento Transformador beta/metabolismo
11.
ACS Appl Bio Mater ; 5(8): 3753-3765, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35913850

RESUMO

The erosion of tooth enamel is a common oral disease. The erosion pattern and location and the effects of nanoscale chemical composition on the erosion susceptibility of enamel have been well documented. However, the enamel remineralization accompanied by erosion and its underlying physicochemical mechanisms still remain poorly understood. Here, using rat molars selected for its good relevancy to human teeth, we investigated the remineralization behavior of the outermost enamel surface at the nanoscale level during erosion in diluted hydrochloric acid solutions. While particles on the outermost enamel surface that represent the termination of crystallites protruding to the surface from the near-surface core eroded by acid-attack, the lateral-growth of the particles (i.e., the main remineralization picture of the surface enamel) occurred concurrently. Ionic analyses indicate that the particle growth is driven by the local increase in pH near the eroding enamel surface as a result of the combination of the PO43- and CO32- released from the enamel surface with H+. As the pH increases eventually to the equilibrium pH level (∼5.5), a local supersaturation of solute ions is induced, resulting in particle growth. A simple growth model based on the experimental results together with an assumption that the particle growth is a diffusional process suggests that the particle growth rate is controlled by the degree of supersaturation and accommodation site for solute ions, which are affected by the pH of solution eroding the enamel surface. The remineralization mechanism presented by our study can explain how the enamel on being acid-exposed or tooth decay progress by beverage or food can naturally remineralize in the oral cavity and how remineralization can foster different surface topology at the nanoscale, depending on the pH value of etchant before the dental filling material is applied.


Assuntos
Erosão Dentária , Animais , Bebidas , Esmalte Dentário , Humanos , Ratos , Erosão Dentária/induzido quimicamente , Remineralização Dentária/métodos
12.
Heliyon ; 8(7): e09941, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35874084

RESUMO

With lead-based light harvesters, perovskite solar cells (PSCs) have an efficiency of approximately 25.5%, making them a viable photovoltaic technology. The selection of the absorber materials for PSC in this work are (i) Cesium lead iodide (CsPbI3) with a 1.73eV bandgap as the first absorber layer, this halide imparts higher stability to perovskite solar cells (ii) CH3NH3PbI3 (MAPbI3) with a bandgap of 1.55eV is selected as the second absorber layer as this material provides better efficiency to the perovskite solar cells. SCAPS-1D simulation software is used to perform an efficiency analysis of perovskite-perovskite CsPbI3/MAPbI3 bilayer solar cell. For efficiency optimization of the perovskite-perovskite bilayer solar cell, we have tried to calibrate seven parameters of the cell. These parameters are (i & ii) selection of the electron and hole transport material (iii, iv & v) variation in the: defect density of bulk material, doping concentration and the thickness of absorber layers, (vi) variation in work function of front electrode (vii) varying interface defect density. After optimization, the efficiency (η) of bilayer PSC is estimated to be 33.54%. The other PV parameters observed in optimal efficiency condition are open-circuit voltage (VOC) = 1.34V, short-circuit current density (JSC) = 27.45 mA/cm2 and fill factor (FF) = 90.49%. The CsPbI3/MAPbI3 bilayer perovskite solar cell efficiency is roughly double the efficiency of single junction CsPbI3 or MAPbI3 PSC. Our analysis observed that the variation in the doping and defect density of narrow bandgap material profoundly impacts the efficiency of perovskite-perovskite bilayer solar cells compared to the wide bandgap material.

13.
Arch Pathol Lab Med ; 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35878400

RESUMO

CONTEXT.­: Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. OBJECTIVE.­: To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. DATA SOURCES.­: Sources were a literature review and the personal experience of authors and educators. CONCLUSIONS.­: High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

14.
Microb Pathog ; 169: 105650, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35764187

RESUMO

Foot-and-mouth disease (FMD) is an extremely contagious and economically devastating viral disease of cloven-hoofed domestic and wildlife animals. The disease is endemic in India and other developing countries of the world. The disease is mainly characterized by the presence of vesicular lesions and "tigroid heart" in calves. The current report describes the novel pathologic findings along with the distribution of FMDV antigens in brain of young calves naturally infected with FMDV. The carcasses of 37 calves suspected to have died from FMD were presented for postmortem investigation. Out of 37 dead calves, 10 calves showed the clinical signs of neurological abnormalities like opisthotonos, muscle twitching and tremor in hind limbs, stiffening of the neck followed by death. Microscopically, the meninges were congested, hemorrhagic, and infiltrated with mononuclear cells. The various sub anatomical sites of the brain showed the varying degrees of vascular changes, perivascular cuffing, focal to diffuse gliosis as well as degeneration and neuronal necrosis, indicating the nonsuppurative encephalitis. The immunolabeling of FMDV antigen was demonstrated in the neurons, inflammatory cells, and microglial cells besides its typical locations. The neurons of the brain also showed strong immunopositivity for caspase-3, caspase-9 and p53 and negative for Bcl-2 and apoptosis-inducing factor (AIF) by both immunohistochemistry and western blotting indicating the role of caspase mediated intrinsic, and p53 dependent apoptotic pathway. Further, the TUNEL assay also confirmed the apoptosis in the neurons and glial cells of the brain of naturally infected calves. This study in calves establishes a basis for resemblance to other members of Picornaviruses, such as Enterovirus 71 and Coxsackievirus of humans and showing the neuropathological alterations along with the distribution of FMDV antigens associated with apoptosis in younger calves.


Assuntos
Doenças dos Bovinos , Vírus da Febre Aftosa , Febre Aftosa , Animais , Encéfalo , Bovinos , Doenças dos Bovinos/diagnóstico , Humanos , Proteína Supressora de Tumor p53
15.
Br J Clin Pharmacol ; 88(12): 5238-5256, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35655123

RESUMO

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.


Assuntos
Esterases , Inibidores de Histona Desacetilases , Humanos , Animais , Camundongos , Inibidores de Histona Desacetilases/farmacologia , Fator Estimulador de Colônias de Macrófagos , Citocinas
16.
ACS Omega ; 7(14): 11731-11741, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35449938

RESUMO

Layer transfer offers enormous potential for the industrial implementation of two-dimensional (2D) material technology platforms. However, the transfer method used must retain the as-grown uniformity and cleanliness in the transferred films for the fabrication of 2D material-based devices. Additionally, the method used must be capable of large-area transfer to maintain wafer-scale fabrication standards. Here, a facile route to transfer centimeter-scale synthesized 2D transition metal dichalcogenides (TMDCs) (3L MoS2, 1L WS2) onto various substrates such as sapphire, SiO2/Si, and flexible substrates (mica, polyimide) has been developed using a water-soluble layer (Na2S/Na2SO4) underneath the as-grown film. The developed transfer process represents a fast, clean, generic, and scalable technique to transfer 2D atomic layers. The key strategy used in this process includes the dissolution of the Na2S/Na2SO4 layer due to the penetration of NaOH solution between the growth substrate and hydrophobic 2D TMDC film. As a proof-of-concept device, a broadband photodetector has been fabricated onto the transferred 3L MoS2, which shows photoresponse behavior for a wide range of wavelengths ranging from near-infrared (NIR) to UV. The enhancement in photocurrent was found to be 100 times and 10 times the dark current in the UV and visible regions, respectively. The fabricated photodetector shows a higher responsivity of 8.6 mA/W even at a low applied voltage (1.5 V) and low power density (0.6 µW/mm2). The detector enables a high detectivity of 2.9 × 1011 Jones. This work opens up the pathway toward flexible electronics and optoelectronics.

17.
Lancet HIV ; 9(5): e332-e340, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35489377

RESUMO

BACKGROUND: Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing. FINDINGS: We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir. INTERPRETATION: In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline.


Assuntos
Infecções por HIV , Inibidores de Integrase de HIV , Soropositividade para HIV , HIV-1 , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Pré-Escolar , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Soropositividade para HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Humanos , Lactente , Masculino , Oxazinas , Piperazinas , Piridonas , RNA/uso terapêutico , Comprimidos
18.
J Immunoassay Immunochem ; 43(5): 557-578, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-35354365

RESUMO

Streptococcus suis is an emerging bacterial pathogen of huge economic impact to the swine industry worldwide. The information regarding the carrier status of S. suis in the slaughtered pigs along with its genetic characterization is not available in Indian pig population, which needs to be addressed for the therapeutic and preventive measures. In the present study, 563 palatine tonsils of apparently healthy slaughtered pigs were probed for the prevalence, and genetic characterization of S. suis and prevalence were found to be 15.45% and 32.68% by bacteriological and molecular methods, respectively. In 87 isolates recovered, 6 cps-types were detected showing the predominance of serotype 7 (24.13%) and 5 (18.39%), whereas 11 cps-types were detected in tonsillar DNA involving cps-types 9 (28.26%) and 7 (14.13%) as the major serotypes with arcA+/sly+/epf+/mrp- being the prevalent genotype. The histopathological changes with the immunodetection of S. suis antigen confirmed its persistence in asymptomatic carriers. Of 87 bacterial isolates, 7 isolates (serotypes 7 & 2) were pathogenic to Swiss albino mice showing the classical lesions of meningitis and septicemia. The presence of virulent serotypes of S. suis in healthy slaughtered pigs suggests a great health risk to the people engaged in piggery operations and in-contact pigs.


Assuntos
Infecções Estreptocócicas , Streptococcus suis , Doenças dos Suínos , Animais , Genótipo , Humanos , Camundongos , Tonsila Palatina/microbiologia , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/epidemiologia , Infecções Estreptocócicas/veterinária , Streptococcus suis/genética , Suínos , Doenças dos Suínos/diagnóstico
19.
Evol Dev ; 24(1-2): 61-76, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35334153

RESUMO

Changing the shape of craniofacial bones can profoundly alter ecological function, and understanding how developmental conditions sculpt skeletal phenotypes can provide insight into evolutionary adaptations. Thyroid hormone (TH) stimulates metamorphosis and regulates skeletal morphogenesis across vertebrates. To assess the roles of this hormone in sculpting the craniofacial skeleton of a non-metamorphic vertebrate, we tested zebrafish for developmental periods of TH-induced craniofacial shape change. We analyzed shapes of specific bones that function in prey detection, capture and processing. We quantified these elements from late-larval through adult stages under three developmental TH profiles. Under wild-type conditions, each bone progressively grows allometrically into a mature morphology over the course of postembryonic development. In three of the four bones, TH was required to sculpt an adult shape: hypothyroidism inhibited aspects of shape change, and allowed some components of immature shape to be retained into adulthood. Excess developmental TH stimulated aspects of precocious shape change leading to abnormal morphologies in some bones. Skeletal features with functional importance showed high sensitivities to TH, including the transformator process of the tripus, the mandibular symphysis of the lower jaw, the scutiform lamina of the hyomandibula, and the anterior arm of the pharyngeal jaw. In all, we found that TH is necessary for shaping mature morphology of several essential skeletal elements; this requirement is particularly pronounced during larval development. Altered TH titer leads to abnormal morphologies with likely functional consequences, highlighting the potential of TH and downstream pathways as targets for evolutionary change.


Assuntos
Hormônios Tireóideos , Peixe-Zebra , Animais , Osso e Ossos , Arcada Osseodentária/fisiologia , Larva/metabolismo , Hormônios Tireóideos/metabolismo
20.
Microb Pathog ; 165: 105467, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35257804

RESUMO

Maedi is a lentiviral disease characterized by progressive interstitial pneumonia with humoural as well as cell mediated immune response. The present investigation was designed to detect the presence of MVV in different biological samples and to evaluate the immune response in naturally MVV infected sheep and goats. Total of 701 biological samples (289 lung tissues, 233 blood, 54 brain tissues, 74 mammary gland tissues and 51 joint tissues were screened for the MVV by nested PCR. MVV nucleic acid was detected in 10.41% of samples and it was observed that sheep samples showed positivity of 8.7% and goat samples 12.6%. Blood samples showed highest positivity (14.59%) followed by joint tissue (13.72), lungs (8.6%), mammary gland (8.1%) and brain (1.85%). MVV p28 antigen was detected in the cytoplasm of mononuclear cells, particularly in the macrophages of lungs and lymph nodes. Antibodies against SRLVs were detected by cELISA and seroprevalence of 19.58% was observed in both sheep and goats serum samples. The seropositivity was higher in sheep (22.9%) as compared to the goats (15.59%). IHC was done to identify the nature of the immune cells infiltrated in the MVV infected tissues and it was observed that B cells, CD8+ and macrophages were the predominant immune cells infiltrated in the lungs showing MVV infection. Expression of the cytokines was assessed by real time PCR and it was observed that expression of IL-10, IFN-γ, TNFα, IL-4, IL-2 and IL6 was down regulated in most of the cases but few samples showed upregulation. In conclusion, MVV is circulating in the sheep and goat population of the India and the disease causes altered immune response in the animal which may make the infected animals more prone to other infectious diseases.


Assuntos
Pneumonia Intersticial Progressiva dos Ovinos , Vírus Visna-Maedi , Animais , Cabras , Imunidade , Pneumonia Intersticial Progressiva dos Ovinos/patologia , Estudos Soroepidemiológicos , Ovinos
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