bluuebunny/crossref_metadata_2025_split huggingface dataset:
RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation causing a distinct Mendelian Disorder
Authors: Paul Franziska , Ng Calista , Nafissi Shahriar , Nilipoor Yalda , Tavasoli Ali Reza , Mohamad Sahari Umar Bin , Bonnard Carine , Wong Pui-Mun , Nabavizadeh Nasrinsadat , Estiar Mehrdad A. , Majoie Charles B. , Lee Hane , Nelson Stanley F. , Gan-Or Ziv , Rouleau Guy A. , Van Veldhoven Paul P. , Massie Rami , Hennekam Raoul C. , Kariminejad Ariana , Reversade Bruno 
Published: October 2021

ABSTRACTRabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively-acting germline alleles p.Arg180Gly and p.Gly183Arg which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate PI3P and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts exhibit accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.
Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy
Authors: Brumme Zabrina L. , Mwimanzi Francis , Lapointe Hope R. , Cheung Peter , Sang Yurou , Duncan Maggie C. , Yaseen Fatima , Agafitei Olga , Ennis Siobhan , Ng Kurtis , Basra Simran , Lim Li Yi , Kalikawe Rebecca , Speckmaier Sarah , Moran-Garcia Nadia , Young Landon , Ali Hesham , Ganase Bruce , Umviligihozo Gisele , Omondi F. Harrison , Atkinson Kieran , Sudderuddin Hanwei , Toy Junine , Sereda Paul , Burns Laura , Costiniuk Cecilia T. , Cooper Curtis , Anis Aslam H. , Leung Victor , Holmes Daniel , DeMarco Mari L. , Simons Janet , Hedgcock Malcolm , Romney Marc G. , Barrios Rolando , Guillemi Silvia , Brumme Chanson J. , Pantophlet Ralph , Montaner Julio S.G. , Niikura Masahiro , Harris Marianne , Hull Mark , Brockman Mark A. 
Published: October 2021

ABSTRACTHumoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and ∼11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed.
A mechanistic mathematical model of initiation and malignant transformation in sporadic vestibular schwannoma
Authors: Paterson Chay , Bozic Ivana , Smith Miriam J. , Hoad Xanthe , Evans D. Gareth R. 
Published: October 2021

AbstractA vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have not attempted to account for alterations in specific genes, and could not distinguish between point mutations and loss of heterozygosity (LOH). Here, we present a mechanistic approach to modelling initiation and malignant transformation in Schwannoma. Each parameter is associated with a specific gene or mechanism operative in Schwann cells, and can be determined by combining incidence data with empirical frequencies of pathogenic variants and LOH. This results in new estimates for the base pair mutation rate u = 4.48 × 10−10 and the rate of LOH = 2.03 × 10−6/yr in Schwann cells. In addition to new parameter estimates, we extend the approach to estimate the risk of both spontaneous and radiation-induced malignant transformation. We conclude that radiotherapy is likely to have a negligible excess risk of malignancy for sporadic VS, with a possible exception of rapidly growing tumours.
New insights into the human 26S proteasome function and regulation
Authors: Kišonaitė Miglė , Afanasyev Pavel , Tafilaku Jonida , Rêgo Ana Toste , da Fonseca Paula C. A. 
Published: October 2021

SummaryThe 26S proteasome is a protease complex essential for proteostasis and strict regulation of diverse critical physiological processes, the mechanisms of which are still not fully described. The human 26S proteasome purification was optimized without exogenous nucleotides, to preserve the endogenous nucleotide occupancy and conformation of its AAA-ATPase subunits. This unveiled important effects on the proteasome function and structure resulting from exposure to Ca2+ or Mg2+, with important physiological implications. This sample, with an added model degron designed to mimic the minimum canonical ubiquitin signal for proteasomal recognition, was analysed by high-resolution cryo-EM. Two proteasome conformations were resolved, with only one capable of degron binding. The structural data show that this occurs without major conformation rearrangements and allows to infer into the allosteric communication between ubiquitin degron binding and the peptidase activities. These results revise existing concepts on the 26S proteasome function and regulation, opening important opportunities for further research.
Mesophyll conductance response to short-term changes in CO2 is related to leaf anatomy and biochemistry in diverse C4 grasses
Authors: Pathare Varsha S. , DiMario Robert J. , Koteyeva Nouria , Cousins Asaph B. 
Published: October 2021

SummaryMesophyll CO2 conductance (gm) in C3 species responds to short-term (minutes) changes in environment potentially due to changes in some leaf anatomical and biochemical properties and due to measurement artifacts. Compared to C3 species, there is less information about gm responses to short-term changes in environment conditions like pCO2 across diverse C4 species and the potential determinants of these responses.Using 16 diverse C4 grasses we investigated the response of gm to short-term changes in CO2 and how this response related to the leaf anatomical and biochemical traits.For all the measured C4-grasses gm increased as CO2 decreased; however, the percent change in gm varied (+13% to +250%) and significantly related to percent changes in leaf transpiration efficiency (TEi). The percent increase in gm was highest in grasses with thinner mesophyll cell walls and greater leaf nitrogen, activities of phosphoenolpyruvate carboxylase (PEPC), Rubisco and carbonic anhydrase, and a higher affinity of PEPC for bicarbonate.Our study demonstrates that CO2 response of gm varies greatly across diverse C4 grasses and identifies the key leaf anatomical and biochemical traits related to this variation. These findings have implications for improving C4 photosynthetic models, and in attempts to improve TEi through manipulation of gm.
Neural basis for adaptive motor behavior during car driving
Authors: Ohata Ryu , Ogawa Kenji , Imamizu Hiroshi 
Published: October 2021

AbstractCar driving is supported by motor skills trained through continuous daily practice. One of the skills unique to expert drivers is the ability to detect abrupt changes in the driving environment and then quickly adapt their operation mode to the changes. Previous functional neuroimaging studies on motor control investigated the mechanisms underlying behaviors adaptive to changes in control properties of simple experimental devices such as a computer mouse or a joystick. The switching of multiple internal models mainly engages adaptive behaviors and underlies the interplay between the cerebellum and frontoparietal network (FPN) regions as the neural process. However, it remains unclear whether the neural mechanisms identified through an experimental paradigm using such simple devices also underlie practical driving behaviors. In the current study, we measure functional magnetic resonance imaging (fMRI) activities while participants control a realistic driving simulator inside the MRI scanner. Here, the accelerator sensitivity of a virtual car is abruptly changed, requiring participants to respond to this change as quickly as possible. We first compare brain activities before and after the sensitivity change. As a result, sensorimotor areas, including the left cerebellum, increase their activities after the sensitivity change. Moreover, after the change, activity significantly increases in the inferior parietal lobe and dorsolateral prefrontal cortex, parts of the FPN regions. By contrast, the posterior cingulate cortex, a part of the default mode network, deactivates after the sensitivity change. Our results suggest that the neural bases found in previous experiments using the simpler devices can serve as the foundation of adaptive car driving. At the same time, this study also highlights the unique contribution of non-motor-related regions to addressing the high cognitive demands of driving.
Two-color super-resolution localization microscopy via joint encoding of emitter location and color
Authors: Wang Yujie , Kuang Weibing , Shang Mingtao , Huang Zhen-Li 
Published: October 2021

AbstractMulti-color super-resolution localization microscopy (SRLM) provides great opportunities for studying the structural and functional details of biological samples. However, current multi-color SRLM methods either suffer from medium to high crosstalk, or require a dedicated optical system and a complicated image analysis procedure. To address these problems, here we propose a completely different method to realize multi-color SRLM. This method is built upon a customized RGBW camera with a repeated pattern of filtered (Red, Green, Blue and Near-infrared) and unfiltered (White) pixels. With a new insight that RGBW camera is advantageous for color recognition instead of color reproduction, we developed a joint encoding scheme of emitter location and color. By combing this RGBW camera with the joint encoding scheme and a simple optical set-up, we demonstrated two-color SRLM with ∼20 nm resolution and < 2% crosstalk (which is comparable to the best reported values). This study significantly reduces the complexity of two-color SRLM (and potentially multi-color SRLM), and thus offers good opportunities for general biomedical research laboratories to use multi-color SRLM, which is currently mastered only by well-trained researchers.
Antibody-mediated depletion of human CLEC-2 in a novel humanised mouse model
Authors: Brown Helena C , Beck Sarah , Navarro Stefano , Di Ying , Soriano Jerez Eva M , Kaczmarzyk Jana , Thomas Steven G. , Mirakaj Valbona , Watson Steve P , Nieswandt Bernhard , Stegner David 
Published: October 2021

AbstractPlatelet C-type lectin-like receptor 2 (CLEC-2) has been proposed as a potential anti-thrombotic target as genetic or antibody-mediated receptor deficiency prevents occlusive thrombus formation in mice. This occurs through interaction with an unknown ligand as the endogenous ligand podoplanin is not present in the vasculature. However, the CLEC-2-podoplanin interaction does have an important role in tumour metastasis. There are currently no methods to test potential human therapeutics targeting CLEC-2, such as antibodies,in vivo. We have therefore generated and characterised a humanised CLEC-2 mouse (hCLEC-2KI) and developed a novel monoclonal anti-human CLEC-2 antibody, HEL1, forin vivotesting. hCLEC-2KImice were phenotypically normal and had comparable platelet glycoprotein receptor expression, activation and aggregation to wildtype platelets. hCLEC-2KImice had both comparable bleeding and vessel occlusion times to WT mice. Challenging hCLEC-2KImice with HEL1 or a second monoclonal anti-hCLEC-2 antibody, AYP1, resulted in transient thrombocytopenia as well as CLEC-2 depletion for more than 2 weeks but had no effect on haemostasis. This illustrates the power of the humanised CLEC-2 mouse model in evaluating novel therapeuticsin vivo, including antibodies that target CLEC-2, as well as the limited effect on haemostasis when targeting CLEC-2.
Natural influent bioaugmentation of activated sludge water resource recovery systems: implications for low temperature nitrification and heterotrophic population structures
Authors: Jauffur Shameem , Bakhshi Zeinab , Frigon Dominic 
Published: October 2021

AbstractThis work aimed at demonstrating the natural bioaugmentation of biological activated sludge systems with nitrifying biomass from influent wastewater in lab-scale reactors. Three sequencing batch reactors (SBR) were fed with sterile synthetic wastewater. While nitrification was complete at a temperature of 8 °C and a SRT of 20 days, it failed when the temperature was lowered to 5 °C, and the SRT decreased to 7 days. In the test period, the sterile synthetic wastewater fed to the Test Reactor was supplemented by influent solids harvested at a full-scale treatment facility at a total suspended solids concentration of 100 mg/L, which corresponded to approximately 5 mg-COD/L of nitrifying biomass. Upon this addition, nitrification was restores. Subsequent halting the supply of influent solids to the Test Reactor led a rapid failure of nitrification and washout of nitrifiers from the SBR. Reproducibility was demonstrated by switching the feed composition between the Test and Negative control reactors. PCR-based amplicon sequencing analyses targeting the amoA, and nxrB genes of the Nitrospira genus have shown that the influent wastewater governed the structure and composition of the activated sludge nitrifying populations. The most abundant ammonia-oxidizing bacteria (AOB) and Nitrospira-related nitrite-oxidizing bacteria (NOB) in the influent seeds occurred as the most dominant ones in the activated sludge. This pattern was observed even when the influent seeds varied over time. The heterotrophic populations were less affected by the influent seeds with the activated sludge and raw sewage showing distinct microbial populations based on principal coordinate analysis (PCoA). However, the immigrant populations appeared to modulate the structure of the activated sludge heterotrophic communities to some extent. These findings provide concrete evidence of the presence of active nitrifiers in raw wastewater capable of supporting nitrification in an otherwise non-conducive environment. This may have important implications on process design, operation and optimization of wastewater treatment systems.HighlightsLab-scale reactors fed sterile synthetic wastewater at low temperatures and SRTs.Nitrification failed when conditions were adjusted to 5 °C and a SRT of 7 days.Nitrification restored by addition of real wastewater influent solids.Nitrifiers in solids from sewers naturally bioaugment activated sludge systems.Activated sludge models should consider the immigration of nitrifiers with influent.Graphical abstract
A sensitized genetic screen to identify regulators ofC. elegansgermline stem cells
Authors: Robinson-Thiewes Sarah , Kershner Aaron M. , Shin Heaji , Haupt Kimberly A. , Kroll-Connor Peggy , Kimble Judith 
Published: October 2021

AbstractGermline stem cells (GSCs) inCaenorhabditis elegansare maintained by GLP-1/Notch signaling from the niche and by a downstream RNA regulatory network. Loss of the GLP-1 receptor causes GSCs to precociously undergo meiotic differentiation, the “Glp” phenotype, due to a failure to self-renew.lst-1andsygl-1are functionally redundant direct targets of GLP-1 signaling whose gene products work with PUF RNA binding proteins to promote GSC self-renewal. Whereas single loss-of-function mutants are fertile,lst-1 sygl-1double mutants are sterile and Glp. We set out to identify genes that function redundantly with eitherlst-1orsygl-1to maintain GSCs. To this end, we conducted forward genetic screens for Glp mutants in genetic backgrounds lacking functional copies of eitherlst-1orsygl-1. The screens generated nineglp-1alleles, twolst-1alleles, and one allele ofpole-1, which encodes the catalytic subunit of DNA polymerase ε. Threeglp-1alleles reside in Ankyrin (ANK) repeats not previously mutated.pole-1single mutants have a low penetrance Glp that is enhanced by loss of eitherlst-1orsygl-1. Thus, the screen uncovered one locus that interacts genetically with bothlst-1andsygl-1and generated useful mutations for further studies of GSC regulation.
Real-time imaging of optic nerve head collagen microstructure and biomechanics using instant polarized light microscopy
Authors: Lee Po-Yi , Yang Bin , Hua Yi , Waxman Susannah , Zhu Ziyi , Ji Fengting , Sigal Ian A 
Published: October 2021

AbstractCurrent tools lack the temporal or spatial resolution necessary to image many important aspects of the architecture and dynamics of the optic nerve head (ONH). We evaluated the potential of instant polarized light microscopy (IPOL) to overcome these limitations by leveraging the ability to capture collagen fiber orientation and density in a single image. Coronal sections through the ONH of fresh normal sheep eyes were imaged using IPOL while they were stretched using custom uniaxial or biaxial micro-stretch devices. IPOL allows identifying ONH collagen architectural details, such as fiber interweaving and crimp, and has high temporal resolution, limited only by the frame rate of the camera. Local collagen fiber orientations and deformations were quantified using color analysis and image tracking techniques. We quantified stretch-induced collagen uncrimping of lamina cribrosa (LC) and peripapillary sclera (PPS), and changes in LC pore size (area) and shape (convexity and aspect ratio). The simultaneous high spatial and temporal resolutions of IPOL revealed complex ONH biomechanics: i) stretch-induced local deformation of the PPS was nonlinear and nonaffine. ii) under load the crimped collagen fibers in the PPS and LC straightened, without torsion and with only small rotations. iii) stretch-induced LC pore deformation was anisotropic and heterogeneous among pores. Overall, with stretch the pores were became larger, more convex, and more circular. We have demonstrated that IPOL reveals details of collagen morphology and mechanics under dynamic loading previously out of reach. IPOL can detect stretch-induced collagen uncrimping and other elements of the tissue nonlinear mechanical behavior. IPOL showed changes in pore morphology and collagen architecture that will help improve understanding of how LC tissue responds to load.HighlightsWe demonstrate that instant polarized light microscopy allows visualization and quantification of changes in optic nerve head collagen morphology and architecture under dynamic loadingWe show crimped collagen fibers in the peripapillary sclera and lamina cribrosa straightening under load, without torsion and with only small rotations.We show that stretch-induced local deformation of the peripapillary sclera was nonlinear and nonaffine.We show that stretch-induced lamina cribrosa pore deformation was anisotropic and heterogeneous among pores.Our results show this novel imaging technique could help understand the role of collagen microstructure in eye physiology, aging, and in biomechanics-related diseases, such as glaucoma and myopia.
Adverse events of special interest for COVID-19 vaccines - background incidences vary by sex, age and time period and are affected by the pandemic
Authors: Nyberg Fredrik , Lindh Magnus , Vanfleteren Lowie E.G.W. , Hammar Niklas , Wettermark Björn , Sundström Johan , Santosa Ailiana , Kirui Brian K. , Gisslén Magnus 
Published: October 2021

AbstractBackgroundWith large-scale COVID-19 vaccination implemented world-wide, safety signals needing rapid evaluation will emerge. We report population-based, age- and-sex-specific background incidence rates of conditions representing potential vaccine adverse events of special interest (AESI) for the Swedish general population using register data.MethodsWe studied an age/sex-stratified random 10% sample of the Swedish population on 1 Jan 2020, followed for AESI outcomes during 1 year, as the COVID-19 pandemic emerged and developed, before the start of vaccinations. We selected and defined the following outcomes based on information from regulatory authorities, large-scale adverse events initiatives and previous studies: aseptic meningitis, febrile seizure, Kawasaki syndrome, MISC, post-infectious arthritis, arthritis, myocarditis, ARDS, myocardial infarction, stroke, ischemic stroke, hemorrhagic stroke, venous thromboembolism, pulmonary embolism, kidney failure, liver failure, erythema multiforme, disseminated intravascular coagulation, autoimmune thyroiditis, and appendicitis. We calculated incidence rates stratified by age, sex and time period (quarters of 2020), and classified them using Council of International Organizations of Medical Sciences (CIOMS) categories: very common, common, uncommon, rare, or very rare.ResultsWe included 972,723 study subjects, representing the Swedish national population on 1 Jan 2020. We found that AESI incidence rates vary greatly by age and in some cases sex. Several common AESIs showed expected increase with age, while some (e.g. appendicitis, aseptic meningitis, autoimmune thyroiditis, Kawasaki syndrome and MISC) were more common in young people, and others exhibited a flatter age pattern (e.g. myocarditis, DIC and erythema multiforme). Consequently, the CIOMS classification for AESIs varied widely according to age. Considerable variability was suggested for some AESI rates across the 4 quarters of 2020, potentially related to pandemic waves, seasonal variation, healthcare system overload or other healthcare delivery effects.ConclusionAge, sex, and timing of rates are important to consider when background AESI rates are compared to corresponding rates observed with COVID-19 vaccines.