bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coronavirus disease 2019, hypertension, and renin–angiotensin–aldosterone system inhibitors
Authors: Rizk John G. , Sanchis-Gomar Fabian , Henry Brandon M. , Lippi Giuseppe , Lavie Carl J. 
Published: August 2022

Purpose of review
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mostly uses the angiotensin-converting enzyme 2 (ACE-2) as cellular receptor for entering the host cells. Some, but not all, animal studies have shown that renin–angiotensin–aldosterone system (RAAS) inhibitors can increase ACE-2 expression. On that premise, it was hypothesized that these agents could make it more likely to develop coronavirus disease 2019 (COVID-19). On the other hand, there was also evidence that being on these agents could lessen the severity of the lung injury in patients with severe SARS-CoV-2 infection. Herein, we review the available evidence on the role of RAAS inhibitors on SARS-CoV-2 and COVID-19 development.

Recent findings
Recent randomized controlled trials demonstrate that RAAS blockade or withdrawal does not influence the severity of COVID-19 in patients who are already on these medications. Currently, there is no evidence to support stopping RAAS inhibitors in patients hospitalized for COVID-19. Several questions still need to be addressed. Ongoing studies are currently evaluating the de novo use of RAAS inhibitors in patients with COVID-19. Another area that needs to be investigated is whether or not using these medications increase the risk of infection.

Summary
The wealth of evidence indicates that ACE inhibitors and angiotensin-receptor blocker administration has no harmful effects on hospitalizations and severity of COVID-19 in patients already on these medications and might even reduce mortality among hypertensive patients diagnosed with COVID-19. More evidence and data need to be collected, and at this time, these agents should not be discontinued.
Comparing 2D-shear wave to transient elastography for the evaluation of liver fibrosis in nonalcoholic fatty liver disease
Authors: Karagiannakis Dimitrios S , Markakis George , Lakiotaki Dimitra , Cholongitas Evangelos , Vlachogiannakos Jiannis , Papatheodoridis George 
Published: August 2022

Background and aim
The aim of this study is to evaluate the performance of 2D-shear wave elastography (2D-SWE) in patients with nonalcoholic fatty liver disease (NAFLD) and compare it to transient elastography.

Methods
Over 6 months, 552 patients with NAFLD underwent liver stiffness measurement (LSM) by both 2D-SWE and transient elastography with controlled attenuation parameter (CAP) at the same visit.

Results
LSM was not feasible by transient elastography (M/XL probe) in 18 (3.3%) and by 2D-SWE in 26 (4.7%) patients. The median LSM of transient elastography was 5.5 (2.8–75) kPa and of 2D-SWE 6.2 (3.7–46.2) kPa. LSMs by transient elastography and 2D-SWE were correlated regardless of the obesity status (r, 0.774; P < 0.001; r, 0.774; P < 0.001; r, 0.75; P < 0.001 in BMI <25, 25–30 and ≥30 kg/m2 respectively), or the degree of liver steatosis (r = 0.63; P < 0.001 and r = 0.743; P < 0.001 in mild and moderate/severe steatosis, respectively). According to transient elastography, 88 (15.9%) patients were classified with at least severe fibrosis (≥F3) and 55 (10%) with cirrhosis. By using the 2D-SWE, 85 (15.4%) patients had at least severe fibrosis and 52 (9.4%) cirrhosis. The correlation between the two methods was strong in patients with at least severe fibrosis (r, 0.84; P < 0.001) or cirrhosis (r, 0.658; P < 0.001). When transient elastography was used as reference, 2D-SWE showed an excellent accuracy of 98.8 and 99.8% in diagnosing severe fibrosis and cirrhosis, respectively.

Conclusions
In NAFLD, 2D-SWE and transient elastography have comparable feasibility and clinical applicability providing LSMs with strong correlation, even in overweight/obese patients, independently of the severity of liver steatosis and fibrosis. Thus, either of the two methods can be effectively used for the assessment of fibrosis in this setting.
Preoperative Cognitive Impairment and Postoperative Delirium in Elderly Surgical Patients
Authors: Weiss Yotam , Zac Lilach , Refaeli Einat , Ben-Yishai Shimon , Zegerman Alexander , Cohen Barak , Matot Idit 
Published: August 2022

Objective:
To test the hypothesis that in surgical patients ≥70 years, preoperative cognitive impairment is independently associated with postoperative delirium.

Background:
Postoperative delirium is common among elderly surgical patients and is associated with longer hospitalization and significant morbidity. Some evidence suggest that baseline cognitive impairment is an important risk factor. Routine screening for both preoperative cognitive impairment and postoperative delirium is recommended for older surgical patients. As of 2019, we implemented such routine perioperative screening in all elective surgical patients ≥70 years.

Methods:
Retrospective single-center analysis of prospectively collected data between January and December 2020. All elective noncardiac surgical patients ≥70 years without pre-existing dementia were included. Postoperative delirium, defined as 4A’s test score ≥4, was evaluated in the postanesthesia care unit and during the initial 2 postoperative days. Patients’ electronic records were also reviewed for delirium symptoms and other adverse outcomes.

Results:
Of 1518 eligible patients, 1338 (88%) were screened preoperatively [mean (SD) age 77 (6) years], of whom 21% (n=279) had cognitive impairment (Mini-Cog score ≤2). Postoperative delirium occurred in 15% (199/1338). Patients with cognitive impairment had more postoperative delirium [30% vs. 11%, adjusted odds ratio (95% confidence interval) 3.3 (2.3–4.7)]. They also had a higher incidence of a composite of postoperative complications [20% vs. 12%, adjusted odds ratio: 1.8 (1.2–2.5)], and median 1-day longer hospital stay [median (interquartile range): 6 (3,12) vs. 5 (3,9) days].

Conclusions:
One-fifth of elective surgical patients ≥70 years present to surgery with preoperative cognitive impairment. These patients are at increased risk of postoperative delirium and major adverse outcomes.
Ultraliser: a framework for creating multiscale, high-fidelity and geometrically realistic 3D models for in silico neuroscience
Authors: Abdellah Marwan , García Cantero Juan José , Román Guerrero Nadir , Foni Alessandro , Coggan Jay S. , Calì Corrado , Agus Marco , Zisis Eleftherios , Keller Daniel , Hadwiger Markus , Magistretti Pierre J. , Markram Henry , Schürmann Felix 
Published: August 2022

AbstractUltraliser is a neuroscience-specific software framework capable of creating accurate and biologically realistic 3D models of complex neuroscientific structures at intracellular (e.g. mitochondria and endoplasmic reticula), cellular (e.g. neurons and glia) and even multicellular scales of resolution (e.g. cerebral vasculature and minicolumns). Resulting models are exported as triangulated surface meshes and annotated volumes for multiple applications in in silico neuroscience, allowing scalable supercomputer simulations that can unravel intricate cellular structure-function relationships. Ultraliser implements a high performance and unconditionally robust voxelization engine adapted to create optimized watertight surface meshes and annotated voxel grids from arbitrary non-watertight triangular soups, digitized morphological skeletons or binary volumetric masks. The framework represents a major leap forward in simulation-based neuroscience, making it possible to employ high-resolution 3D structural models for quantification of surface areas and volumes, which are of the utmost importance for cellular and system simulations. The power of Ultraliser is demonstrated with several use cases in which hundreds of models are created for potential application in diverse types of simulations. Ultraliser is publicly released under the GNU GPL3 license on GitHub (BlueBrain/Ultraliser).SignificanceThere is crystal clear evidence on the impact of cell shape on its signaling mechanisms. Structural models can therefore be insightful to realize the function; the more realistic the structure can be, the further we get insights into the function. Creating realistic structural models from existing ones is challenging, particularly when needed for detailed subcellular simulations. We present Ultraliser, a neuroscience-dedicated framework capable of building these structural models with realistic and detailed cellular geometries that can be used for simulations.Key pointsUltraliser creates spatial models of neuro-glia-vascular (NGV) structures with realistic geometries.Ultraliser creates high fidelity watertight manifolds and large scale volumes from centerline descriptions, non-watertight surfaces, and binary masks.Resulting models enable scalable in silico experiments that can probe intricate structure-function relationships.The framework is unrivalled both in ease-of-use and in the accuracy of resulting geometry representing a major leap forward in simulation-based neuroscience.
Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue
Authors: Kumar Saumya , Basto Afonso P. , Ribeiro Filipa , Almeida Silvia C. P. , Campos Patricia , Peres Carina , Al-Khalidi Sarwah , Kilbey Anna , Tosello Jimena , Piaggio Eliane , Russo Momtchilo , Gama-Carvalho Margarida , Coffelt Seth B. , Roberts Ed W. , Florindo Helena , Graca Luis 
Published: August 2022

AbstractEffective antibody responses are essential to generate protective humoral immunity. Different inflammatory signals polarize T cells towards an appropriate effector phenotype during an infection or immunization. Th1 and Th2 cells have been associated with the polarization of humoral responses for several decades. However, it is now established that T follicular helper cells (Tfh) have a unique ability to access the B cell follicle and support the Germinal Centre (GCs) responses by providing help to B cells. We investigated the specialization of Tfh cells induced under type-1 and type-2 conditions. We first studied homogenous Tfh cell populations generated by adoptively transferred TCR-transgenic T cells in mice immunized with type-1 and type-2 adjuvants. Using a machine learning approach, we established a gene expression signature that discriminates Tfh cells polarized towards type-1 and type-2 response, defined as Tfh1 and Tfh2 cells. The Tfh1 and Tfh2 distinct signature was validated against datasets of Tfh cells induced following LCMV or helminth infection. Using single-cell transcriptomics, we also dissected the heterogeneity of Tfh cells from the two immunizing conditions. Our results show that Tfh cells acquire a specialized function under distinct types of immune responses, but with the coexistence of a small population of Tfh cells of the alternative type. Furthermore, the specific molecular hallmarks of Tfh1 and Tfh2 cells identified herein offer putative new targets for tuning humoral responses.
Assessment of mosquito longevity, fecundity, and dengue virus titer following exposure to plasma from a host with Type 2 diabetes mellitus – a pilot study
Authors: Smartt Chelsea T. , Kendziorski Natalie , Chen Tse-Yu , Farless Sara 
Published: August 2022

AbstractThe mosquito Aedes aegypti (Linnaeus) prefers feeding on humans and will encounter many blood components that might influence mosquito physiology and vectorial capacity. The effects of dengue virus infection in patients with type-2 diabetes mellitus revealed an influence on platelet numbers in blood and diabetic persons are more likely to develop severe dengue. Infection with dengue virus (DENV) is known to impact diabetic patients but the impact of diabetic blood on mosquito vectorial capacity is not known. This pilot study investigated the effects of ingesting blood plasma from a patient with diabetes on mosquito fecundity, longevity, and vector competence for DENV-2 in the mosquito, Ae. aegypti. Female mosquitoes fed on plasma from a diabetic individual laid significantly more eggs. Diabetic plasma shortened overall mosquito life span. Vector competence was significantly different between extrinsic incubation periods at 7 (3.44±2.5 log PFUe DENV) and 14 days post-infection (4.28±2.4 log PFUe DENV) in mosquitoes fed DENV-2 in plasma from a diabetic individual. As this study is an initial investigation into the influence of diabetes plasma on mosquito life history traits, a more comprehensive study with more samples of diabetes plasma is underway and should yield more details about the impact of diabetes on mosquito biology.
Optogenetic Targeting of AII Amacrine Cells restores Retinal Computations performed by the Inner Retina
Authors: Khabou Hanen , Orendorff Elaine , Trapani Francesco , Rucli Marco , Desrosiers Melissa , Yger Pierre , Dalkara Deniz , Marre Olivier 
Published: August 2022

AbstractMost inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of inner retinal neurons is a promising avenue to restore vision in retinas having lost their photoreceptors. Expression of optogenetic proteins in surviving ganglion cells, the retinal output, allows them to take on the lost photoreceptive function. Nonetheless, this creates an exclusively ON retina by expression of depolarizing optogenetic proteins in all classes of ganglion cells, whereas a normal retina extracts several features from the visual scene, with different ganglion cells detecting light increase (ON) and light decrease (OFF). Refinement of this therapeutic strategy should thus aim at restoring these computations. In an attempt to do so, we used a promoter that targets gene expression to a specific interneuron of the retina called the AII amacrine cell. The AII amacrine cell simultaneously activates the ON pathway and inhibits the OFF pathway. We show that the optogenetic stimulation of AII amacrine cells allows restoration of both ON and OFF responses in the retina, but also mediates other types of retinal processing such as sustained and transient responses. Targeting amacrine cells with optogenetics is thus a promising avenue to restore better retinal function and visual perception in patients suffering from retinal degeneration.
Evolution to increased positive charge on the viral spike protein may be part of the adaptation of SARS-CoV-2 to human transmission
Authors: Cotten Matthew , Phan My V.T. 
Published: August 2022

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, continues to evolve and infect individuals. The exterior surface of the SARS-CoV-2 virion is dominated by the spike protein and the current work examined spike protein biochemical features that have changed during the 2 years that SARS-CoV-2 has infected humans. These biochemical properties may influence virion survival and promote movement through the environment and within the human airway to reach target cells to bind, enter and establish the next round of infection. In addition to selective pressure to avoid immune recognition of viral proteins, we hypothesised that SARS-CoV-2 emerged from an animal reservoir capable of human infection and transmission but in a sub-optimum state and a second level of selective pressure is acting on these biochemical features. Our analysis identified a striking change in spike protein charge, from −8.3 in the original Lineage A and B viruses to −1.26 in the current Omicron viruses. In summary, we conclude that in addition to immune selection pressure, the evolution of SARS-CoV-2 has also altered viral spike protein biochemical properties. Future vaccine and therapeutic development should also exploit and target these biochemical properties.
Light-dependent Control of Bacterial Expression at the mRNA Level
Authors: Ranzani Américo T. , Wehrmann Markus , Kaiser Jennifer , Juraschitz Marc , Weber Anna M. , Pietruschka Georg , Mayer Günter , Möglich Andreas 
Published: August 2022

AbstractSensory photoreceptors mediate numerous light-dependent adaptations across organisms. In optogenetics, photoreceptors achieve the reversible, non-invasive, and spatiotemporally precise control by light of gene expression and other cellular processes. The light-oxygen-voltage receptor PAL binds to small RNA aptamers with sequence specificity upon blue-light illumination. By embedding the responsive aptamer in the ribosome-binding sequence of genes of interest, their expression can be downregulated by light. We developed the pCrepusculo and pAurora optogenetic systems that are based on PAL and allow to down- and upregulate, respectively, bacterial gene expression using blue light. Both systems are realized as compact, single plasmids that exhibit stringent blue-light responses with low basal activity and up to several ten-fold dynamic range. As PAL exerts light-dependent control at the RNA level, it can be combined with other optogenetic circuits that generally control transcription initiation. By integrating regulatory mechanisms operating at the DNA and mRNA levels, optogenetic circuits with emergent properties can thus be devised. As a case in point, the pEnumbra setup permits to upregulate gene expression under moderate blue light whereas strong blue light shuts off expression again. Beyond providing novel signal-responsive expression systems for diverse applications in biotechnology and synthetic biology, our work also illustrates how the light-dependent PAL-aptamer interaction can be harnessed for the control and interrogation of RNA-based processes.
ROP16-mediated activation of STAT6 facilitates encystment of type IIIToxoplasma gondiiin neurons
Authors: Kochanowsky Joshua A. , Chandrasekaran Sambamurthy , Sanchez Jacqueline R. , Thomas Kaitlin K. , Koshy Anita A. 
Published: August 2022

AbstractToxoplasma gondiiestablishes a long-lived latent infection in the central nervous system (CNS) of its hosts. Reactivation in immunocompromised individuals can lead to life threatening disease. Latent infection is driven by the ability of the parasite to convert from the acute-stage tachyzoite to the latent-stage bradyzoite which resides in long-lived intracellular cysts. While much work has focused on the parasitic factors that drive cyst development, the host factors that influence encystment are not well defined. Here we show that a polymorphic secreted parasite kinase (ROP16), that phosphorylates host cell proteins, mediates efficient encystment ofT. gondiiin stress-induced models of encystment and primary neuronal cell cultures (PNCs) in a strain-specific manner. Using short-hairpin RNA (shRNA) knockdowns in human foreskin fibroblasts (HFFs) and PNCs from transgenic mice, we determined that ROP16’s cyst enhancing abilities are mediated by phosphorylation of the host cell transcription factor STAT6. To test the role of STAT6in vivo, we infected STAT6KO mice, finding that, compared to infected wild-type mice, infected STAT6KO mice have a decrease in cyst burden, but not overall parasite burden or dissemination to the CNS. Finally, we found a similar ROP16-dependent encystment defect in human pluripotent stem cell-derived neurons. Together, these findings identify a host cell factor (STAT6) thatT. gondiimanipulates in a strain-specific manner to generate a favorable encystment environment.
Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure
Authors: Weihl Conrad C. , Töpf Ana , Bengoechea Rocio , Duff Jennifer , Charlton Richard , Garcia Solange Kapetanovic , Domínguez-González Cristina , Alsaman Abdulaziz , Hernández-Laín Aurelio , Franco Luis Varona , Sanchez Monica Elizabeth Ponce , Beecroft Sarah J , Goulee Hayley , Daw Jil , Bhadra Ankan , True Heather , Inoue Michio , Findlay Andrew , Laing Nigel , Olivé Montse , Ravenscroft Gianina , Straub Volker 
Published: August 2022

AbstractDNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A>T; p.Lys286Ter), or homozygous missense variants (c.74G>A; p.Arg25Gln and c.785T>C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.
Grapevine leaf MALDI-MS imaging reveals the localisation of a putatively identified sucrose metabolite associated to Plasmopara viticola development
Authors: Maia Marisa , McCann Andréa , Malherbe Cédric , Far Johann , Cunha Jorge , Eiras-Dias José , Cordeiro Carlos , Eppe Gauthier , Quinton Loïc , Figueiredo Andreia , De Pauw Edwin , Silva Marta Sousa 
Published: August 2022

AbstractDespite well-established pathways and metabolites involved in grapevine-Plasmopara viticola interaction, information on the molecules involved in the first moments of pathogen contact with the leaf surface and their specific location is still missing. To understand and localise these molecules, we analysed grapevine leaf discs infected with P. viticola with MSI. Plant material preparation was optimised, and different matrices and solvents were tested. Our data shows that trichomes hamper matrix deposition and the ion signal. Results show that putatively identified sucrose presents a higher accumulation and a non-homogeneous distribution in the infected leaf discs in comparison with the controls. This accumulation was mainly on the veins, leading to the hypothesis that sucrose metabolism is being manipulated by the development structures of P. viticola. Up to our knowledge this is the first time that the localisation of a putatively identified sucrose metabolite was shown to be associated to P. viticola infection sites.