bluuebunny/crossref_metadata_2025_split huggingface dataset:
Older age is associated with a shift from ventral to dorsal PCC in pathways connecting the DMN with visual and limbic areas and a directionality shift in pathways connecting the DMN with sensorimotor areas
Authors: Goelman Gadi , Dan Rotem , Bezdicek Ondrej , Jech Robert , Ekstein Dana 
Published: December 2022

AbstractAlterations in the default mode network (DMN) are known to associated with aging and with neurological and psychiatric diseases. We assessed age-dependent changes in interactions within the DMN and between the DMN with other brain areas, and correlations of these interactions with a battery of neuropsychological tests to formulate a macroscopic model of ageing.Using a novel multivariate analysis method, enabling determination of directed pathways, on resting-state functional MRI data from fifty young and thirty-one old healthy individuals, we identified directed intra- and inter-DMN directed pathways that differed between the groups and used their correlations with neuropsychological tests to infer their behavioral meaning.Pathways connecting the DMN with visual and limbic regions in old subjects engaged at BOLD low frequency and involved the dorsal PCC. In young subjects, they were at high frequency and involved the ventral PCC. Pathways combining the sensorimotor (SM) and the DMN, were efferent in young subjects (DMN<SM) and afferent in old subjects (DMN>SM). Most inter-DMN pathways in the old subjects, correlated with reduced speed and working memory and, were DMN efferent (DMN>).We suggest a macroscopic model of aging centered in the DMN. It suggests that the reduced sensorimotor efferent, probably brought about from reduced physical activity, and the increased need to control such activities by the mPFC, causes a higher dependency on external versus internal cues. This results in a shift from ventral to dorsal PCC of inter-DMN pathways. Consequently, the model combines physical activity with ageing.
Scaling behaviors of deep learning and linear algorithms for the prediction of stroke severity
Authors: Bourached Anthony , Bonkhoff Anna K. , Schirmer Markus D. , Regenhardt Robert W. , Bretzner Martin , Hong Sungmin , Dalca Adrian V. , Giese Anne-Katrin , Winzeck Stefan , Jern Christina , Lindgren Arne G. , Maguire Jane , Wu Ona , Rhee John , Kimchi Eyal Y. , Rost Natalia S. 
Published: December 2022

AbstractIntroductionDeep learning has allowed for remarkable progress in many medical scenarios. Since deep learning prediction models often require 105-107examples, it is currently unknown whether deep learning can also enhance predictions of symptoms post-stroke in real-world samples of stroke patients that are often several magnitudes smaller. Such stroke outcome predictions however could be particularly instrumental in guiding acute clinical and rehabilitation care decisions. We here compared the capacities of classically used linear and novel deep learning algorithms in their prediction of stroke severity.MethodsOur analyses relied on a total of 1,430 patients assembled from the MRI-GENIE collaboration and a Massachusetts General Hospital-based study. The outcome of interest was NIHSS-based stroke severity in the acute phase after ischemic stroke onset, which we predict by means of MRI-derived lesion location. We automatically derived lesion segmentations from diffusion-weighted clinical MRI scans, performed spatial normalization and included a principal component analysis (PCA) step, retaining 95% of the variance of the original data. We then repeatedly separated a train, validation, and test set to investigate the effects of sample size, we subsampled the train set to 100, 300, and 900 and trained the algorithms to predict the NIHSS score for each sample size with regularized linear regression and an 8-layered neural network. We selected hyperparameters on the validation set. We evaluated model performance based on the explained variance (R-squared) in the test set.ResultsWhile linear regression performed significantly better for a sample size of 100 patients, deep learning started to significantly outperform linear regression when trained on 900 patients. Average prediction performance improved by ∼20% when increasing the sample size 9x (maximum for 100 patients: 0.279 ± 0.005 (R2, 95% confidence interval), 900 patients: 0.337 ± 0.006).ConclusionsFor sample sizes of 900 patients, deep learning showed a higher prediction performance than typically employed linear methods. These findings suggest the existence of non-linear relationships between lesion location and stroke severity that can be utilized for an improved prediction performance for larger sample sizes.
Real-world evidence of mortality and survival rates in 256 individuals with APDS
Authors: Hanson Jennifer , Bonnen Penelope E. 
Published: December 2022

AbstractActivated Phosphoinositide 3-kinase Delta Syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants inPIK3CDandPIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function (GOF) variants in thePIK3CDgene while loss of function (LOF) variants inPIK3R1have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 was 87%, age 30 was 74%, age 40 and 50 were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The mortality data suggests that the standard of care treatment for APDS, immunoglobulin replacement therapy, appears to prevent most deaths due to severe infection, however, new treatments are needed to mitigate the risk of death from lymphoma and other cancers. This analysis based on real world evidence gathered from the medical literature is the largest study of survival for APDS to date.
Stakeholder perspectives on interventions to improve HIV Pre-Exposure Prophylaxis uptake and continuation in Lesotho: A participant-ranked preferences study
Authors: Geldsetzer Pascal , Chebet Joy J. , Chase Rachel P. , Tarumbiswa Tapiwa , Maponga Chivimbiso , Mandara Esther , Bärnighausen Till , McMahon Shannon A. 
Published: December 2022

AbstractBackgroundLow uptake and high discontinuation rates remain major obstacles to realizing the potential of Pre-Exposure Prophylaxis (PrEP) in changing the trajectory of the HIV epidemic in sub-Saharan Africa. Evidence on how PrEP could be successfully delivered has thus far mainly focused on key target groups rather than the general adult population. Set in the HIV-hyperendemic country of Lesotho, which is currently rolling out PrEP for the general adult population, this study aimed to determine stakeholders’ views on which are the most important barriers and most promising interventions to achieving high PrEP uptake and continuation.Methods and findingsWe conducted a card sorting and ranking exercise with 155 local stakeholders to identify key barriers and interventions. Stakeholders were a purposive sample of PrEP policy makers and implementing partners (n=7), healthcare providers (n=51), and end-users (n=97). End-users included adults who were currently using PrEP (n=55), formerly using PrEP (n=36), and were offered PrEP by a healthcare provider but declined (n=6). Participants sorted pre-selected interventions and barriers to PrEP coverage into three piles – most, somewhat, and least important. After sorting, participants ranked interventions and barriers in the “most important” piles in ascending order of significance. Ranked preferences were analyzed as voting data to identify the smallest set of candidates for which each candidate in the set would win a two-candidate election against any candidate outside the set. Participants viewed a lack of PrEP awareness as the most important barrier to PrEP uptake for women, and a fear of HIV testing for men. Community-based HIV testing was ranked as the most promising intervention to improve PrEP uptake for both men and women. Perceived or experienced stigma was seen as an important barrier for PrEP continuation for both men and women, with an additional important barrier for men being daily activities that compete with the time or mental bandwidth needed to take a daily pill. Adherence counseling and multi-month PrEP prescriptions were seen as the most promising interventions to improve PrEP continuation.ConclusionsOur findings suggest community-based activities that generate PrEP demand (community-based HIV testing and mass media campaigns), reinforced with facility-based follow-up (counseling and multi-month prescription) could be promising interventions to improve PrEP uptake and continuation in PrEP programs that are aimed at the general adult population. The views of the wide range of stakeholders that participated in this study could provide a useful starting point for design and implementation choices of PrEP delivery programs for the general adult population.
Utilization of Cycle Threshold Values of RTPCR SARS-Cov-2 Among Admitted Patients in a Public Hospital
Authors: Laurito Arbeen Acosta , Arengo Alyanna Mae Cuerquis 
Published: December 2022

ABSTRACTCoronavirus 2019 (COVID-19) was caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and not just affected the Philippines but also globally. Data on real-time PCR cycle threshold (Ct) values were accessible in the healthcare facility and previous studies did not support its direct clinical significance on patient’s management. The aim of this study was to investigate the RT-PCR Ct values of admitted COVID-19 confirmed patients in the epidemiologic context from April 2021 to November 2021.A total of 1,245 were tested and out of the 1,038 confirmed COVID-19 admitted patients, 579 (55.78%) were females and 459 were males (44.22%). There were 4 genes detected, namely: N, E, ORF1ab and RdRP genes, and the majority was N gene 925 (88.94%) while the least detected was 203 E gene of SARS-CoV-2. This study described the utilization of five (5) different COVID-19 test kits.Comparing the Ct values between the male and female groups, this study showed no significant differences. To compare between the different age groups and the three classifications of CT values was shown in Table 6. For the N gene, the current study showed a significant difference of CT value <25 among 0-17 years old vs 46-60 years old (p=0.00054), and among 0-17 years old vs >61 (senior citizens) years old group (p=0.00945). Moreover, a significant difference was observed for CT value >30 among 0-17 years vs 18-45 years old (p=0.00411) and among 0-17 years old vs >61 years old group (p=0.00025). CT values for the ORF gene showed significant differences. CT value <25 showed significant differences among 0-17 years versus 45-60 years old (p=0.00907) and 0-17 years versus >60 years old (p=0.04298). Moreover, CT value >30 showed significant differences among 0-17 years versus 46-60 years old (p=0.02344) and 0-17 years versus >60 years old (p=0.3411).Comparing the mean CT values of two consecutive months from April to Nov, this study showed a significant difference between April and May (p value= 0.0004), August and September (p value= 0.0212), and September and October (p value= 0.002). There was no significant difference with the following months: May and June, June and July, July and August, and October and November (Table 9).
Dynamic organization of cerebellar climbing fiber response and synchrony in multiple functional modules reduces dimensions for reinforcement learning
Authors: Hoang Huu , Tsutsumi Shinichiro , Matsuzaki Masanori , Kano Masanobu , Kawato Mitsuo , Kitamura Kazuo , Toyama Keisuke 
Published: December 2022

AbstractDaynamic functional organization by synchronization is theorized to be essential for dimension reduction of the cerebellar learning space. We analyzed a large amount of coordinate-localized, two-photon imaging data from cerebellar Crus II in mice undergoing “Go/No-go” reinforcement learning. Tensor component analysis revealed that a majority of climbing fiber inputs to Purkinje cells were reduced to only four functional components, corresponding to accurate timing control of motor initiation related to a Go cue, cognitive error-based learning, reward processing, and inhibition of erroneous behaviors after a No-go cue. Spatial distribution of these components coincided well with the boundaries of Aldolase-C/zebrin II expression in Purkinje cells, whereas several components are mixed in single neurons. Synchronization within individual components was bidirectionally regulated according to specific task contexts and learning stages. These findings suggest that the cerebellum, based on anatomical compartments, reduces dimensions by self-organization of components, a feature that may inspire new-generation AI designs.
Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors in the hippocampus
Authors: Zaytseva Anastasiya , Bouckova Evelina , Wiles McKennon J. , Wustrau Madison H. , Schmidt Isabella G. , Mendez-Vazquez Hadassah , Khatri Latika , Kim Seonil 
Published: December 2022

AbstractKetamine is shown to enhance excitatory synaptic drive in the hippocampus, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine’s therapeutic actions are likely mediated by enhancing neuronal Ca2+signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that inhibits excitatory synaptic transmission and postsynaptic Ca2+signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment for one hour in cultured mouse hippocampal neurons significantly reduces calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately induces the expression of Ca2+- Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). Such ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and synaptic plasticity in cultured hippocampal neurons. When a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within one hour after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine’s effects on animals’ behavior. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity in the hippocampus, which in turn enhances synaptic strength to induce rapid antidepressant actions.
The ratio of auxin to cytokinin controls leaf development and meristem initiation inPhyscomitrium patens
Authors: Cammarata Joseph , Roeder Adrienne H. K. , Scanlon Michael J. 
Published: December 2022

AbstractCrosstalk between auxin and cytokinin contributes to widespread developmental processes, including root and shoot meristem maintenance, phyllotaxy, and vascular patterning. Although auxin and cytokinin are potent regulators of plant development, our understanding of crosstalk between these hormones is limited to few model systems. The mossPhyscomitrium patens(formerlyPhyscomitrella patens) is a powerful system for studying plant hormone function. Auxin and cytokinin play similar roles in regulating moss gametophore (upright shoot) architecture, as they do in flowering plant shoots. However, auxin-cytokinin crosstalk is poorly understood in moss. Here we find that the ratio of auxin to cytokinin is an important determinant of development inP. patens, especially during leaf development and branch stem cell initiation. Addition of high levels of auxin toP. patensgametophores blocks leaf outgrowth. However, simultaneous addition of high levels of both auxin and cytokinin partially restores leaf outgrowth, suggesting that the ratio of these hormones is the overriding factor. Likewise, during branch initiation and outgrowth, chemical inhibition of auxin synthesis phenocopies cytokinin application. Finally, cytokinin insensitive mutants resemble plants with altered auxin signaling and are hypersensitive to auxin. In summary, our results suggest that the ratio between auxin and cytokinin signaling is the basis for developmental decisions in the moss gametophore.
Sex-specific microglial responses to glucocerebrosidase inhibition: relevance to GBA1-linked Parkinson disease
Authors: Brunialti Electra , Villa Alessandro , Toffoli Marco , Del Pozo Sara Lucas , Rizzi Nicoletta , Meda Clara , Maggi Adriana , Schapira Anthony H. V. , Ciana Paolo 
Published: December 2022

AbstractMicroglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we analysed the dynamic changes in shape and motility occurring in primary mouse microglia following pro-inflammatory or neurotoxic insults, thus finding sex-specific responses of microglial subpopulations. Male microglia exhibited a pro-inflammatory phenotype, whereas female microglia showed enhanced neuroprotective capabilities associated with the activation of Nrf2 detoxification pathway in neurons. The sex difference in neuroprotective functions is lost by inhibition of glucocerebrosidase, the product of the GBA1 gene, mutations of which are the major risk factor for Parkinson’s disease (PD). This finding is consistent with the increased risk of PD observed in female carriers of GBA1 mutation, when compared with wild type population, suggesting a role for microglial functionality in the etiopathogenesis of PD-GBA1.
Synergic homology directed recombination by PRDM9 meiotic factor
Authors: Sanvicente-García Marta , Gonzalez-Bermudez Lourdes , Turpín Isabel , Batlle Laura , Acosta Sandra , Güell Marc , Sanchez-Mejias Avencia 
Published: December 2022

ABSTRACTGenome editing requires precision to broadly move on to industrial and clinical applications. For this reason, homologous directed repair (HDR) is one of the preferred methods for small edits, other than knock-outs. However, HDR has low efficiency. Current investigations to enhance HDR have mainly gone in the direction of finding non-homologous end joining (NHEJ) inhibitors. NHEJ is crucial for cellular integrity, then the inhibition of this pathway is detrimental for the correct survival of living entities. In other studies, a second opportunity is given to HDR by targeting the byproducts of NHEJ, using an extra gRNA. In this study, we propose the use of a meiotic factor, PRDM9, to directly enhance homology recombination. Through the exploration of combinatorial factors and donor design, we have established an optimized protocol for HDR. PRDM9-Cas9 fusion combined with CtIP improves HDR/NHEJ ratio. In addition, we have validated this combinatorial approach for small edits through a traffic light reporter system, as well as for longer edits with a split-GFP reporter system.
Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism
Authors: Byrd Aaron , Marmorale Lucas , Addison Vanessa , Marcinowski Sophia , Buchan J. Ross 
Published: December 2022

AbstractA key pathological hallmark in >97% of all Amyotrophic Lateral Sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of a nuclear RNA binding protein, TDP-43. Driving clearance of cytoplasmic TDP-43 reduces toxicity in various ALS models, though how TDP-43 clearance is regulated remains controversial. To address this, we conducted an unbiased yeast genome-wide screen using high-throughput dot blots to identify genes that affect TDP-43 levels. Our screen identified ESCRT complex factors, which induce membrane invagination (particularly at multi-vesicular bodies; MVBs) and K63-linked ubiquitination as key facilitators of TDP-43 endolysosomal clearance. TDP-43 co-localized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation and accumulation. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation caused formation of “giant” MVBs which could reflect a pathological consequence of TDP-43 pertinent to ALS. Our studies shed light on endolysosomal-mediated cytoplasmic protein degradation, which likely impacts multiple substrates, and may be a target for novel ALS therapeutic strategies.
The unique structure and replication mode of the replication system ofKlebsiella pneumoniaeplasmid pIGMS31
Authors: Wawrzyniak Paweł , Barańska Sylwia , Hernández Pablo , Dylewski Maciej , Cecuda-Adamczewska Violetta , Stypiński Łukasz , Kabaj Paulina , Gościk Agata , Bartosik Dariusz 
Published: December 2022

AbstractDue to their relatively small size and the lack of housekeeping genes, bacterial plasmids are very convenient models for studying DNA replication. So, for a long time, they had been intensively studied in this regard. Unfortunately, only a limited number of model plasmid replication systems were analyzed in detail. In the era of high-throughput DNA sequencing, we are faced with an increasing gap in our knowledge of bacterial plasmid replication and a rapidly growing number of deposited new plasmid genome sequences. For this reason, we decided to investigate the replication system of the pIGMS31 plasmid, a representative of the newly described pHW126-like plasmids family. They are small replicons isolated from different clinical and environmental strains of Gamma proteobacteria. Whole shares unique replication modules with no significant similarities to known model plasmid replication systems. In this study, we identified and characterized the basic elements of the pIGMS31 replication module. Studies on regulatory mechanisms of replication initiation of this plasmid as well as on pIGMS31 replication mode were also performed. We revealed that the pIGMS31 replication module is composed of elements typical for boththetaand rolling circle replicons. This mosaic structure is reflected in the unique course of replication of this plasmid, with both modes of replication. What is more, our results led us to conclude that pHW126-like plasmids, despite DNA sequence similarity, are a highly diverse group of replicons.