Search

Francis J Zamora,1,2 Ellen Dowers,2 Faiza Yasin,3 Onyema Ogbuagu3 1Department of Pharmacy Services, Broward Health Medical Center, Fort Lauderdale, FL, USA; 2Department of Pharmacy Services, Yale-New Haven Hospital, New Haven, CT, USA; 3Section of Infectious Diseases, Yale AIDS Program, Yale University School of Medicine, New Haven, CT, USACorrespondence: Onyema OgbuaguSection of Infectious Diseases, Yale AIDS Program, Yale University School of Medicine, 135 College Street, Suite 323, New Haven, CT 06510, USATel +1 516-281-4557Fax 1 203 737 4051Email onyema.ogbuagu@yale.eduAbstract: There have been remarkable advances in drug development for the treatment of HIV-1 infection. From the co-formulation of combination antiretroviral therapy (cART) into single-tablet regimens to the development of long-acting antiretroviral (ARV) drug formulations, the treatment of HIV has and will become much more tolerable and less complicated for patients. In addition, and appropriately, there is a focus on reducing short- and long-term toxicities of treatment while maintaining robust efficacy. One of such approaches includes 2-drug regimen constructs that contain and retain effective ARV compounds while excluding components that have relatively unfavorable toxicity profiles. The first-ever 2-drug regimen approved for the treatment of HIV-1 infection for treatment-naive people living with HIV (PLWH), consisting of the integrase inhibitor dolutegravir (DTG) and the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (3TC), is reviewed in this paper. The chemical composition and properties, pharmacokinetic and pharmacodynamics profile, and clinical trial data on efficacy and safety of DTG/3TC are presented. An expert opinion aims to highlight important considerations for the use of DTG/3TC in the context of existing and emerging ARV options.Keywords: dolutegravir, lamivudine, combination antiretroviral therapy

Abstract Magnaporthe oryzae, the causal agent of blast disease, is one of the most destructive plant pathogens, causing significant yield losses on staple crops such as rice and wheat. The fungus infects plants with a specialized cell called an appressorium, whose development is tightly regulated by MAPK signaling pathways following the activation of upstream sensors in response to environmental stimuli. Here, we show the expression of the Glycogen synthase kinase 3 (GSK3) MoGSK1 in M. oryzae is regulated by Mps1 MAP kinase, particularly under the stressed conditions. Thus, MoGSK1 is functionally characterized in this study. MoGsk1 is functionally homologues to the Saccharomyces cerevisiae GSK3 homolog MCK1. Gene replacement of MoGSK1 caused significant delay in mycelial growth, complete loss of conidiation and inability to penetrate the host surface by mycelia-formed appressorium-like structures, consequently resulting in loss of pathogenicity. However, the developmental and pathogenic defects of Δmogsk1 are recovered via the heterologous expression of Fusarium graminearum GSK3 homolog gene FGK3, whose coding products also shows the similar cytoplasmic localization as MoGsk1 does in M. oryzae. By contrast, overexpression of MoGSK1 produced deformed appressoria in M. oryzae. In summary, our results suggest that MoGsk1, as a highly conservative signal modulator, dictates growth, conidiation and pathogenicity of M. oryzae.

Autophagy-related protein 8 (ATG8) is a highly conserved ubiquitin-like protein that modulates autophagy pathways by binding autophagic membranes and a number of proteins, including cargo receptors and core autophagy components. Throughout plant evolution, ATG8 has expanded from a single protein in algae to multiple isoforms in higher plants. However, the degree to which ATG8 isoforms have functionally specialized to bind distinct proteins remains unclear. Here, we describe a comprehensive protein-protein interaction resource, obtained using in planta immunoprecipitation (IP) followed by mass spectrometry (MS), to define the potato ATG8 interactome. We discovered that ATG8 isoforms bind distinct sets of plant proteins with varying degrees of overlap. This prompted us to define the biochemical basis of ATG8 specialization by comparing two potato ATG8 isoforms using both in vivo protein interaction assays and in vitro quantitative binding affinity analyses. These experiments revealed that the N-terminal β-strand-and, in particular, a single amino acid polymorphism-underpins binding specificity to the substrate PexRD54 by shaping the hydrophobic pocket that accommodates this protein's ATG8-interacting motif (AIM). Additional proteomics experiments indicated that the N-terminal β-strand shapes the broader ATG8 interactor profiles, defining interaction specificity with about 80 plant proteins. Our findings are consistent with the view that ATG8 isoforms comprise a layer of specificity in the regulation of selective autophagy pathways in plants.

The recent COVID-19 pandemic has prompted global governments to take several measures to limit and contain the spread of the novel virus. In the United States (US), most states have imposed a partial to complete lockdown that has led to decreased traffic volumes and reduced vehicle emissions. In this study, we investigate the impacts of the pandemic-related lockdown on air quality in the US using remote sensing products for nitrogen dioxide tropospheric column (NO2), carbon monoxide atmospheric column (CO), tropospheric ozone column (O3), and aerosol optical depth (AOD). We focus on states with distinctive anomalies and high traffic volume, New York (NY), Illinois (IL), Florida (FL), Texas (TX), and California (CA). We evaluate the effectiveness of reduced traffic volume to improve air quality by comparing the significant reductions during the pandemic to the interannual variability (IAV) of a respective reference period for each pollutant. We also investigate and address the potential factors that might have contributed to changes in air quality during the pandemic. As a result of the lockdown and the significant reduction in traffic volume, there have been reductions in CO and NO2. These reductions were, in many instances, compensated by local emissions and, or affected by meteorological conditions. Ozone was reduced by varying magnitude in all cases related to the decrease or increase of NO2 concentrations, depending on ozone photochemical sensitivity. Regarding the policy impacts of this large-scale experiment, our results indicate that reduction of traffic volume during the pandemic was effective in improving air quality in regions where traffic is the main pollution source, such as in New York City and FL, while was not effective in reducing pollution events where other pollution sources dominate, such as in IL, TX and CA. Therefore, policies to reduce other emissions sources (e.g., industrial emissions) should also be considered, especially in places where the reduction in traffic volume was not effective in improving air quality (AQ).

During plant cell invasion, the oomycete Phytophthora infestans remains enveloped by host-derived membranes whose functional properties are poorly understood. P. infestans secretes a myriad of effector proteins through these interfaces for plant colonization. Recently we showed that the effector protein PexRD54 reprograms host-selective autophagy by antagonising antimicrobial-autophagy receptor Joka2/NBR1 for ATG8CL binding (Dagdas et al., 2016). Here, we show that during infection, ATG8CL/Joka2 labelled defense-related autophagosomes are diverted toward the perimicrobial host membrane to restrict pathogen growth. PexRD54 also localizes to autophagosomes across the perimicrobial membrane, consistent with the view that the pathogen remodels host-microbe interface by co-opting the host autophagy machinery. Furthermore, we show that the host-pathogen interface is a hotspot for autophagosome biogenesis. Notably, overexpression of the early autophagosome biogenesis protein ATG9 enhances plant immunity. Our results implicate selective autophagy in polarized immune responses of plants and point to more complex functions for autophagy than the widely known degradative roles.

Plants use autophagy to safeguard against infectious diseases. However, how plant pathogens interfere with autophagy-related processes is unknown. Here, we show that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host autophagy protein ATG8CL to stimulate autophagosome formation. PexRD54 depletes the autophagy cargo receptor Joka2 out of ATG8CL complexes and interferes with Joka2's positive effect on pathogen defense. Thus, a plant pathogen effector has evolved to antagonize a host autophagy cargo receptor to counteract host defenses.

Necrotrophic fungi are unable to occupy living plant cells. How such pathogens survive first contact with living host tissue and initiate infection is therefore unclear. Here, we show that the necrotrophic grey mold fungus Botrytis cinerea undergoes massive apoptotic-like programmed cell death (PCD) following germination on the host plant. Manipulation of an anti-apoptotic gene BcBIR1 modified fungal response to PCD-inducing conditions. As a consequence, strains with reduced sensitivity to PCD were hyper virulent, while strains in which PCD was over-stimulated showed reduced pathogenicity. Similarly, reduced levels of PCD in the fungus were recorded following infection of Arabidopsis mutants that show enhanced susceptibility to B. cinerea. When considered together, these results suggest that Botrytis PCD machinery is targeted by plant defense molecules, and that the fungal anti-apoptotic machinery is essential for overcoming this host-induced PCD and hence, for establishment of infection. As such, fungal PCD machinery represents a novel target for fungicides and antifungal drugs.

Pathogens modulate plant cell structure and function by secreting effectors into host tissues. Effectors typically function by associating with host molecules and modulating their activities. This study aimed to identify the host processes targeted by the RXLR class of host-translocated effectors of the potato blight pathogen Phytophthora infestans. To this end, we performed an in planta protein-protein interaction screen by transiently expressing P. infestans RXLR effectors in Nicotiana benthamiana leaves followed by coimmunoprecipitation and liquid chromatography-tandem mass spectrometry. This screen generated an effector-host protein interactome matrix of 59 P. infestans RXLR effectors x 586 N. benthamiana proteins. Classification of the host interactors into putative functional categories revealed over 35 biological processes possibly targeted by P. infestans. We further characterized the PexRD12/31 family of RXLR-WY effectors, which associate and colocalize with components of the vesicle trafficking machinery. One member of this family, PexRD31, increased the number of FYVE positive vesicles in N. benthamiana cells. FYVE positive vesicles also accumulated in leaf cells near P. infestans hyphae, indicating that the pathogen may enhance endosomal trafficking during infection. This interactome dataset will serve as a useful resource for functional studies of P. infestans effectors and of effector-targeted host processes.

The blast fungus Magnaporthe oryzae gains entry to its host plant by means of a specialized pressure-generating infection cell called an appressorium, which physically ruptures the leaf cuticle.sup.1,2. Turgor is applied as an enormous invasive force by septin-mediated reorganization of the cytoskeleton and actin-dependent protrusion of a rigid penetration hypha.sup.3. However, the molecular mechanisms that regulate the generation of turgor pressure during appressorium-mediated infection of plants remain poorly understood. Here we show that a turgor-sensing histidine-aspartate kinase, Sln1, enables the appressorium to sense when a critical turgor threshold has been reached and thereby facilitates host penetration. We found that the Sln1 sensor localizes to the appressorium pore in a pressure-dependent manner, which is consistent with the predictions of a mathematical model for plant infection. A [DELTA]sln1 mutant generates excess intracellular appressorium turgor, produces hyper-melanized non-functional appressoria and does not organize the septins and polarity determinants that are required for leaf infection. Sln1 acts in parallel with the protein kinase C cell-integrity pathway as a regulator of cAMP-dependent signalling by protein kinase A. Pkc1 phosphorylates the NADPH oxidase regulator NoxR and, collectively, these signalling pathways modulate appressorium turgor and trigger the generation of invasive force to cause blast disease. The histidine-aspartate kinase Sln1 acts as a molecular sensor of turgor in appressoria of the rice blast fungus Magnaporthe oryzae, enabling penetration of the host leaf cuticle and plant infection., Author(s): Lauren S. Ryder [sup.1] [sup.2] , Yasin F. Dagdas [sup.1] [sup.2] [sup.3] , Michael J. Kershaw [sup.1] , Chandrasekhar Venkataraman [sup.4] , Anotida Madzvamuse [sup.4] , Xia Yan [sup.1] [...]

Mechanical properties of wood-inspired cell wall geometries were considered through compression testing and Finite Element Analysis (FEA) with ANSYS simulation. Six models, including earlywood, latewood, and various array configurations, were fabricated via 3D printing using acrylonitrile butadiene styrene (ABS) filament. Compression tests highlighted the annual ring model’s robustness, exhibiting a maximum load of 12707 MPa, while the 4x3 matrix displayed the lowest strength at 4247 MPa. Shifting rows led to reduced strength, which was particularly evident in vertical prints. An analysis of variance revealed significant differences in mechanical properties. Discrepancies between experimental tests and FEA results ranged from -45.9% to 35.2%. Earlywood exhibited a maximum deformation of 2.6 mm, whereas latewood showed lower deformation, indicating geometry’s influence on material behavior. Mesh quality remained consistent, ensuring dependable simulation outcomes. These findings underscore the pivotal role of geometry in compression resistance, laying the groundwork for future studies on wood densification mechanisms and the development of customized wood composites.

Copyright of Przegląd Elektrotechniczny is the property of Przeglad Elektrotechniczny and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fakhreldin Ali Yasin,1 Ismaeil Eldooma2 1Department of Family and Community Medicine, Faculty of Medicine University of Gezira, Wad-Medani, Sudan; 2Department of Planning, Research and Information, National Health Insurance Fund, Wad-Medani, Gezira State, SudanCorrespondence: Ismaeil Eldooma, National Health Insurance Fund, Department of Planning, Research, and Information, Wad-Medani, Gezira State, Sudan, Tel +249123162135, Email esmdooma@gmail.comIntroduction: Improving diabetic patients’ foot care behaviours is crucial in the incidence reduction of diabetic foot ulceration-associated complications.Objective: This study assessed the knowledge and practice of diabetic patients towards diabetic foot care and their general understanding of diabetes causes, complications, and treatment.Methods: A cross-sectional study was conducted at Aldaraga Clinic Centre, Sudan, with a sample size of 100 diabetic patients. A questionnaire and checklist were used to collect data for this study. The data was analyzed through SPSS Version 16 software.Results: The majority of respondents were females (62%), above 40 years old (66%), married, with a low educational level, and moderate-income (76%). The study revealed that most respondents did not attend any educational program about diabetes, indicating poor or no knowledge about diabetes mellitus. However, respondents had good knowledge of most signs and symptoms of diabetes, with the highest percentage (88%) for extreme thirst. Concerning the knowledge of respondents about complications of diabetes, it was generally poor, except for retinal diseases (70%). Participants’ knowledge of signs and symptoms of hypoglycemia was found to be poor at 25%. The study showed that most respondents did not know what diabetes gangrene is. Foot infections were the most dominant cause of hospitalization among diabetic patients, often leading to amputations.Conclusion: Enhancing foot care behaviours in diabetic patients is crucial to reduce diabetic foot ulceration risks. Patient-friendly educational interventions and regular physician reinforcement are urgently needed, including awareness programs, specialized diabetes centres, and health education through mass media to improve foot care practices and prevent complications like amputations.Keywords: diabetic foot care, diabetic knowledge, diabetic patients