bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphological simulation tests the limits on phenotype discovery in 3D image analysis
Authors: Roston Rachel A. , Whikehart Sophie M. , Rolfe Sara M. , Maga Murat 
Published: July 2024

AbstractIn the past few decades, advances in 3D imaging have created new opportunities for reverse genetic screens. Rapidly growing datasets of 3D images of genetic knockouts require high-throughput, automated computational approaches for identifying and characterizing new phenotypes. However, exploratory, discovery-oriented image analysis pipelines used to discover these phenotypes can be difficult to validate because, by their nature, the expected outcome is not knowna priori. Introducingknownmorphological variation through simulation can help distinguish between real phenotypic differences and random variation; elucidate the effects of sample size; and test the sensitivity and reproducibility of morphometric analyses. Here we present a novel approach for 3D morphological simulation that uses open-source, open-access tools available in 3D Slicer, SlicerMorph, and Advanced Normalization Tools in R (ANTsR). While we focus on diffusible-iodine contrast-enhanced micro-CT (diceCT) images, this approach can be used on any volumetric image. We then use our simulated datasets to test whether tensor-based morphometry (TBM) can recover our introduced differences; to test how effect size and sample size affect detectability; and to determine the reproducibility of our results. In our approach to morphological simulation, we first generate a simulated deformation based on a reference image and then propagate this deformation to subjects using inverse transforms obtained from the registration of subjects to the reference. This produces a new dataset with a shifted population mean while retaining individual variability because each sample deforms more or less based on how different or similar it is from the reference. TBM is a widely-used technique that statistically compares local volume differences associated with local deformations. Our results showed that TBM recovered our introduced morphological differences, but that detectability was dependent on the effect size, the sample size, and the region of interest (ROI) included in the analysis. Detectability of subtle phenotypes can be improved both by increasing the sample size and by limiting analyses to specific body regions. However, it is not always feasible to increase sample sizes in screens of essential genes. Therefore, methodical use of ROIs is a promising way to increase the power of TBM to detect subtle phenotypes. Generating known morphological variation through simulation has broad applicability in developmental, evolutionary, and biomedical morphometrics and is a useful way to distinguish between a failure to detect morphological difference and a true lack of morphological difference. Morphological simulation can also be applied to AI-based supervised learning to augment datasets and overcome dataset limitations.
IgM plays a prominent role in naturally acquired immunity againstPlasmodium falciparumgametocytes
Authors: Chan Jo-Anne , Lisboa-Pinto Ashley , Lu Shirley , Harris Alexander , Dixon Matthew WA , Thomas Adam , Drew Damien R , Jayakrishnan Niva , Larcher Katrina , Naghizadeh Mohammad , Opi D Herbert , Reiling Linda , Theisen Michael , Chelimo Kiprotich , Ome-Kaius Maria , Mantila Daisy , Laman Moses , Robinson Leanne J , Mueller Ivo , King Christopher L , Dent Arlene , Kazura James W , Beeson James G 
Published: July 2024

ABSTRACTThe development of transmission-blocking vaccines againstPlasmodium falciparummalaria could facilitate malaria elimination. However, limitations in the knowledge of the human immune responses againstP. falciparumtransmission stages, known as gametocytes, represent a critical roadblock to vaccine development. We evaluated human antibodies acquired through natural malaria exposure to whole gametocytes and recombinant antigens expressed by transmission stages, including the major transmission-blocking vaccine candidates Pfs230 and Pfs48/45 and other transmission stages, Pf38, Pf12 and Pf41. Among individuals residing in Kenya and Papua New Guinea, we found substantial antibody responses to whole gametocytes and to all recombinant transmission stage antigens with high levels of IgG, IgG subclasses and IgM. Complement fixation by antibodies to gametocytes is key for effective transmission-blocking activity. We found that purified IgM was substantially more potent than IgG at mediating complement fixation and activation. Higher antibody levels were generally observed in individuals positive forP. falciparuminfection, including gametocyte positive individuals, and these antibodies generally increased with age. Our findings reveal that IgM is a prominent feature of antibody responses to gametocytes and that antibodies target multiple antigens. The further demonstration that IgM has high functional activity against gametocytes suggests IgM plays an important role in immunity to transmission stages. Our data provide new insights to inform the development of potent transmission-blocking vaccines.
The Cambridge Questionnaire for Apathy and Impulsivity Traits (CamQUAIT): a novel assessment tool for frontotemporal lobar degeneration-related syndromes
Authors: Lansdall CJ , Williams R , Coyle-Gilchrist I , Murley AG , Rouse MA , Bateman A , Rowe JB 
Published: July 2024

AbstractState of the ArtApathy and impulsivity are common in syndromes associated with frontotemporal lobar degeneration (FTLD). They are associated with high carer distress and poor patient outcomes. There are limited treatment options and progress has been hindered by a lack of appropriate outcome measures. This study aimed to develop a carer-rated questionnaire oriented to people with syndromes associated with FTLD.MethodologyPrincipal component and Rasch analysis were conducted on carer-, clinician- and patient-reported questionnaires and performance-based tests of behavioural change in the “Pick’s Disease and Progressive Supranuclear Palsy Prevalence and Incidence” (PiPPIN) study. We identified two key components which informed subsequent item development for a novel scale which we call the Cambridge Questionnaire for Apathy and Impulsivity Traits (CamQUAIT). The resulting scale comprised two subscales assessing “motivation and support” (CamQUAIT-M) and “impulsivity and challenging behaviours” (CamQUAIT-C). An independent sample of 132 carers for people with FTLD-associated syndromes completed the CamQUAIT, along with a battery of existing measures. The CamQUAIT was reduced to 15 items following Rasch analysis.ResultsBoth subscales showed good construct validity as assessed by high Person separation index (CamQUAIT-M=0.9; CamQUAIT-C=0.7) and Cronbach’s alpha (CamQUAIT-M=0.9; CamQUAIT-C=0.8). The subscales correlated moderately with each other (r=0.376, p<0.001), and with existing measures of behavioural change.ConclusionThe CamQUAIT is a targeted measurement tool to assess apathy, impulsivity, and related behavioural change in the context of FTLD-related syndromes. The scale demonstrates good measurement properties and is sensitive to group differences, providing a suitable outcome measure to evaluate novel symptomatic treatments.
The complex interplay between risk tolerance and the spread of infectious diseases
Authors: Nguyen Maximilian , Freedman Ari , Cheung Matthew , Saad-Roy Chadi , Espinoza Baltazar , Grenfell Bryan , Levin Simon 
Published: July 2024

AbstractRisk-driven behavior provides a feedback mechanism through which individuals both shape and are collectively affected by an epidemic. We introduce a general and flexible compartmental model to study the effect of heterogeneity in the population with regards to risk tolerance. The interplay between behavior and epidemiology leads to a rich set of possible epidemic dynamics. Depending on the behavioral composition of the population, we find that increasing heterogeneity in risk tolerance can either increase or decrease the epidemic size. We find that multiple waves of infection can arise due to the interplay between transmission and behavior, even without the replenishment of susceptibles. We find that increasing protective mechanisms such as the effectiveness of interventions, the number of risk-averse people in the population, and the duration of intervention usage reduces the epidemic overshoot. When the protection is pushed past a critical threshold, the epidemic dynamics enter an underdamped regime where the epidemic size exactly equals the herd immunity threshold and overshoot is eliminated. Lastly, we can find regimes where epidemic size does not monotonically decrease with a population that becomes increasingly risk-averse.
MAGNITUDE OF NEONATAL HYPOGLYCEMIA AND ITS ASSOCIATED FACTORS AMONG NEONATES ADMITTED TO NEONATAL INTENSIVE CARE UNIT AT HAWASSA CITY PUBLIC HOSPITALS, ETHIOPIA, 2023
Authors: Tadele Selam , Jembere Wegene , Aschale Mastewal , Mulugeta Tewodros , Jigso Samuel , Ayehu Mequanint , Sibhat Migbar 
Published: July 2024

AbstractBackgroundNeonatal hypoglycemia is one of the most common metabolic abnormalities seen in newborns. It is a major contributing factor to neonatal morbidity and mortality. Globally, it affects around 5–15% of all babies and approximately 50% of at-risk babies.. In Ethiopia, neonatal hypoglycemia is frequently diagnosed and one of the commonest causes of admission to the neonatal intensive care unit. Nevertheless, documented records regarding its magnitude and factors associated with hypoglycemia are scarce in the study area. Therefore we aimed to assess the magnitude of neonatal hypoglycemia and its associated factors among neonates admitted to the neonatal intensive care unit at Hawassa City Public Hospitals, Ethiopia.MethodInstitution-based cross-sectional study was conducted from April 20 – June 20, 2023among 293 neonates. A systematic random sampling technique was used to reach the study subjects. The data was collected through face-to-face interviews and card review by using structured pretested questionnaire and analyzed using SPSS software version 25. A multivariable logistic regression model was used to determine factors significantly associated with neonatal hypoglycemia with adjusted odds ratio, p-values <0.05 at 95% confidence interval (CI).ResultThe magnitude of neonatal hypoglycemia was found 16.6%. Variables significantly associated with the occurrence of neonatal hypoglycemia were: Diabetes mellitus [AOR=9.8, 95%CI (3.08-31.37)], perinatal asphyxia [AOR=2.87, 95%CI (1.07-7.72)], delayed initiation of breastfeeding [AOR=2.63, 95%CI (1.04-6.6)] and hypothermia [AOR=3.8, 95%CI (1.6-9.1)].ConclusionIn this study the magnitude of neonatal hypoglycemia among neonates was high. Neonates with hypothermia, perinatal asphyxia, and delayed initiation of breastfeeding and maternal history of diabetes mellitus have an increased risk of developing hypoglycemia. Hence, Health care providers who are working on delivery and neonatal care should focus on early identification and management of these identified factors.
DIFFERENT PHENOTYPES OF CHRONIC CONSTIPATION IN MALES AND FEMALES
Authors: Gardner Jerry D. , Triadafilopoulos George 
Published: July 2024

ABSTRACTINTRODUCTIONPatients with chronic constipation exhibit symptoms and motility abnormalities that occur in combinations, but the nature of these combinations has not been characterized.METHODSWe calculated prevalences of combinations of symptoms (abdominal pain, infrequent defecation, incomplete evacuation, straining), abnormal motility test results (prolonged colonic transit time, low anal basal pressure, low anal squeeze pressure, poor rectal sensation, absent balloon expulsion), or both using data from 75 females and 91 males with chronic constipation. We calculated the “Cluster Factor” as observed prevalence of a combination of symptoms, abnormal test results or both divided by the prevalence of the combination due to chance. We calculated the conditional probabilities of combinations of symptoms, abnormal motility test results or both given the prevalence of other members of the same combination.RESULTSCombinations of symptoms alone or abnormal motility test results alone in both males and females, and for combinations of symptoms plus abnormal motility test results in females, failed to cluster together beyond that attributable to chance alone. Males, however, showed significant clustering. Significant conditional probabilities with symptoms, and with symptoms plus abnormal motility test results was higher in males than females. Significant conditional probabilities with abnormal motility test results were not different between males and females.CONCLUSIONSGender-related differences in prevalences of combinations of symptoms and abnormal motility test results, of significant Cluster Factors, and of conditional probabilities indicate that chronic constipation in males reflects a fundamentally different disorder from that in females.
Coherent Raman microscopy detects nucleolar defects through amide I peak shifts originating from β-sheets: an application to visualizing ongoing cellular senescence
Authors: Ishibashi Shigeo , Inoko Akihito , Oka Yuki , Leproux Philippe , Kano Hideaki 
Published: July 2024

AbstractCellular senescence occurs through the accumulation of many kinds of stresses. Senescent cells in tissues also cause various age-related disorders. Therefore, detecting them without labeling is beneficial. However, existing biomarkers have limitations of requiring fixation and labeling, or their molecular backgrounds are uncertain. Coherent anti-Stokes Raman scattering (CARS) spectroscopic imaging is a novel option because it can assess and visualize molecular structures based on their molecular fingerprint. Here, we present a new label-free method to visualize cellular senescence by obtaining molecular fingerprint signals in nucleoli using a CARS microspectroscopic system. We found the peak of the nucleolar amide I band shifted to a higher wavenumber in binuclear senescent cells, which reflects changes in the protein secondary structure from predominant α-helices to β-sheets originating from amyloid-like aggregates. Following this, we developed a procedure that can visualize the senescent cells by providing the ratios and subtractions of these two components. We also confirmed that the procedure can visualize nucleolar aggregates due to unfolded/misfolded proteins produced by proteasome inhibition. Finally, we found that this method can help visualize the nucleolar defects in naïve cells even before binucleation. Thus, our method is beneficial to evaluate ongoing cellular senescence through label-free imaging of nucleolar defects.
Single-cell transcriptomic changes in oligodendroglial lineage cells derived from Parkinson’s disease patient-iPSCs with LRRK2-G2019S mutation
Authors: Dehestani Mohammad , Kessler Wiebke , Karmali Nasser , Sun Wenhua , Volos Polina , Tsitkov Stanislav , Dhingra Ashutosh , Rodriguez-Nieto Salvador , Tietz Julia , Schafflick David , Fernandes Noémia , Fitzgerald Julia , Fraenkel Ernest , Gasser Thomas , Rafiq Nisha Mohd , Kuhlmann Tanja , Bansal Vikas 
Published: July 2024

AbstractDespite extensive research, the contribution of the LRRK2 p.G2019S mutation to Parkinson’s disease (PD) remains unclear. Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression ofLRRK2. We induced PD patient-iPSCs with the LRRK2 p.G2019S mutation into oligodendroglial lineages and performed single-cell RNA sequencing. Cell type composition analysis revealed an increase in OPCs, proliferating OPCs and ciliated ependymal cells in LRRK2 lines, all of which are characterized byLRRK2expression. Differential expression analysis revealed transcriptomic changes in several pathways, including down-regulation of genes related to myelin assembly in ODCs, semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs. Cell-cell communication analysis identified significant alterations in several signaling pathways including a deactivation of PSAP signaling and an activation of MIF signaling in LRRK2 lines. Additionally, we observed an overall increase in SEMA6 signaling communication in LRRK2 cell lines; however, OPCs derived from these LRRK2 lines specifically lost SEMA6 signaling due to a down-regulation ofSEMA6AandPLXNA2. Pseudotemporal trajectory analysis revealed thatSHHhad significantly altered expression along the pseudotime, accompanied by higher expression levels in LRRK2 lines. We propose that dysfunctional semaphorin-plexin signaling, along with cilia movement and SHH signaling, might represent early events in PD pathology.
Orthogonalization of spontaneous and stimulus-driven activity by hierarchical neocortical areal network in primates
Authors: Matsui Teppei , Hashimoto Takayuki , Murakami Tomonari , Uemura Masato , Kikuta Kohei , Kato Toshiki , Ohki Kenichi 
Published: July 2024

AbstractUnderstanding how biological neural networks perform reliable information processing in the presence of intensive spontaneous activity (1-3) is an essential question in biological computation. Stimulus-evoked and spontaneous activities show orthogonal (dissimilar) patterns in the primary visual cortex (V1) of mice (4-6), which is likely to be beneficial for separating sensory signals from internally generated noise (5, 7-12); however, those in V1 of carnivores and primates show highly similar patterns (3, 13-17). Consequently, the mechanism of segregation of stimulus information and internally generated noise in carnivores and primates remain unclear. To address this question, we used primate-optimized functional imaging (18) to precisely compare spontaneous and stimulus-evoked activities in multiple areas of the marmoset visual cortical pathway (19). In marmoset V1, but not in mouse V1, spontaneous and stimulus-evoked activity shared similar activity patterns, suggesting a function of spontaneous activity specific to mammals with functional columns. However, in the higher-order visual areas of marmosets, spontaneous and stimulus-evoked activities exhibited dissimilar patterns. Analysis of neural activity geometry further revealed progressive orthogonalization of the two types of activities along the cortical hierarchy in marmosets, which reached a level comparable to that of mouse V1. Thus, orthogonalization of spontaneous and stimulus-evoked activity is a general principle of cortical computation, which, in primates, is implemented by the hierarchical areal network.
A broad cathepsin inhibitor blocks crystal-stimulated inflammasome-dependent and -independent inflammation, and gout arthritis
Authors: Orellano Laura Alejandra Ariza , Zeng Chunhui , Zhu Jiyun , Bogyo Matthew , Rock Kenneth L. , Lai Jiann-Jyh 
Published: July 2024

AbstractIn the disease gout, monosodium urate (MSU) crystals nucleate in joints and cause acute painful arthritis that can damage the affected joints. Similarly, the deposition of other crystals or irritant particles in tissues elicits an inflammatory response that can cause disease. These various particles stimulate macrophages to produce the proinflammatory cytokine interleukin 1β (IL-1β), which is a major driver of the ensuing inflammation. Here we show that in vivo and in vitro, broad spectrum cathepsin inhibitors, like VBY-825, blocked the activation of inflammasomes, which are known to be essential in generating bioactive IL-1β in response to crystals. In addition, the cathepsin inhibitors blocked an inflammasome-independent pathway that also generates mature IL-1β and which contributed substantially to crystal-stimulated inflammation in vivo. Through these effects, the cathepsin inhibitors markedly reduced gout arthritis and inflammation to the unrelated crystal silica, which is the etiologic agent in the disease silicosis. The cathepsin inhibitors didn’t affect any of the inflammatory processes after bioactive IL-1β was present in tissues. They also didn’t inhibit LPS-stimulated inflammationin mice, or TNF-⍺ production from macrophages. These findings provide proof of concept that cathepsin inhibitors are a novel class of anti-inflammatories that can inhibit crystal-stimulated disease with unique mechanisms of action.
Visual quality control withCytoMDS, a Bioconductor package for low dimensional representation of cytometry sample distances
Authors: Hauchamps Philippe , Delandre Simon , Temmerman Stéphane T. , Lin Dan , Gatto Laurent 
Published: July 2024

AbstractQuality Control (QC) of samples is an essential preliminary step in cytometry data analysis. Notably, identification of potential batch effects and outlying samples is paramount, to avoid mistaking these effects for true biological signal in downstream analyses. However, this task can prove to be delicate and tedious, especially for datasets with many samples.Here, we presentCytoMDS, a Bioconductor package implementing a dedicated method for low dimensional representation of cytometry samples composed of marker expressions for up to millions of single cells. This method allows a global representation of all samples of a study, with one single point per sample, in such a way that projected distances can be visually interpreted. It usesEarth Mover’s Distancefor assessing dissimilarities between multi-dimensional distributions of marker expression, andMulti Dimensional Scalingfor low dimensional projection of distances. Some additional visualization tools, both for projection quality diagnosis and for user interpretation of the projection coordinates, are also provided in the package.We demonstrate the strengths and advantages ofCytoMDSfor QC of cytometry data on three real biological datasets, revealing the presence of low quality samples, batch effects and biological signal between sample groups.
UNRAVELING THE LUNG VASCULAR REMODELING IN PULMONARY HYPERTENSION USING A QUANTITATIVE DIGITAL PATHOLOGY SOFTWARE
Authors: Serdjebi Cindy , Chandes Florine , Biernat Marzena , Lepoivre Bastien , Salvail Dany , Laurent Charles-E. 
Published: July 2024

ABSTRACTPulmonary arterial hypertension (PAH) is a rare chronic life-threatening disorder, characterized by the elevation of the mean pulmonary arterial pressure above 20 mmHg at rest. Histologically, PAH induces lung vascular remodeling, with the thickening of vessel wall. The conventional histological analysis commonly used in non-clinical models to assess lung vascular remodeling relies on manual measurements of representative lung vessels and is time-consuming. We have developed a fully automated reader-independent software (MorphoQuant-Lung) to both specifically detect vessels and measure vascular wall components from a-SMA rat lung sections. Analysis was performed on monocrotaline-and Sugen/hypoxia-induced PH rat models, treated or not with Sildenafil. The software requires 3-5 minutes to detect up to 1500 vessels per section, classify them per size, quantify intima, media and wall thicknesses, and calculate their level of occlusion. A comparison of our digital analysis results with those of the pathologist’s conventional visual analysis was performed for wall thickness and lumen radius showing a strong correlation between the two techniques (r: 0.80 and r: 0.88) regardless of the rat model. In addition, the occlusion estimated by automated analysis also strongly correlated with the mean pulmonary arterial pressure and the pulmonary vascular resistance (r ranging from 0.71 to 0.83) in both rat models. The added value of the present digital analysis paves the way for a more in-depth understanding of the PAH physiopathology in preclinical research and provides a robust and reliable tool for efficient therapeutic drug development.