bluuebunny/crossref_metadata_2025_split huggingface dataset:
The performance of genome sequencing as a first-tier test for neurodevelopmental disorders
Authors: van der Sanden Bart P. G. H. , Schobers Gaby , Corominas Galbany Jordi , Koolen David A. , Sinnema Margje , van Reeuwijk Jeroen , Stumpel Connie T. R. M. , Kleefstra Tjitske , de Vries Bert B. A. , Ruiterkamp-Versteeg Martina , Leijsten Nico , Kwint Michael , Derks Ronny , Swinkels Hilde , den Ouden Amber , Pfundt Rolph , Rinne Tuula , de Leeuw Nicole , Stegmann Alexander P. , Stevens Servi J. , van den Wijngaard Arthur , Brunner Han G. , Yntema Helger G. , Gilissen Christian , Nelen Marcel R. , Vissers Lisenka E. L. M. 
Published: September 2022

AbstractGenome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%,n = 45) and SOC (28.7%,n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.
Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons
Authors: Fonseca-Ornelas Luis , Stricker Jonathan M. S. , Soriano-Cruz Stephanie , Weykopf Beatrice , Dettmer Ulf , Muratore Christina R. , Scherzer Clemens R. , Selkoe Dennis J. 
Published: September 2022

Abstractα-Synuclein (αSyn) aggregation in Lewy bodies and neurites defines both familial and ‘sporadic’ Parkinson’s disease. We previously identified α-helically folded αSyn tetramers, in addition to the long-known unfolded monomers, in normal cells. PD-causing αSyn mutations decrease the tetramer:monomer (T:M) ratio, associated with αSyn hyperphosphorylation and cytotoxicity in neurons and a motor syndrome of tremor and gait deficits in transgenic mice that responds in part to L-DOPA. Here, we asked whether LRRK2 mutations, the most common genetic cause of cases previously considered sporadic PD, also alter tetramer homeostasis. Patient neurons carrying G2019S, the most prevalent LRRK2 mutation, or R1441C each had decreased T:M ratios and pSer129 hyperphosphorylation of their endogenous αSyn along with increased phosphorylation of Rab10, a widely reported substrate of LRRK2 kinase activity. Two LRRK2 kinase inhibitors normalized the T:M ratio and the hyperphosphorylation in the G2019S and R1441C patient neurons. An inhibitor of stearoyl-CoA desaturase, the rate-limiting enzyme for monounsaturated fatty acid synthesis, also restored the αSyn T:M ratio and reversed pSer129 hyperphosphorylation in both mutants. Coupled with the recent discovery that PD-causing mutations of glucocerebrosidase in Gaucher’s neurons also decrease T:M ratios, our findings indicate that three dominant genetic forms of PD involve life-long destabilization of αSyn physiological tetramers as a common pathogenic mechanism that can occur upstream of progressive neuronal synucleinopathy. Based on αSyn’s finely-tuned interaction with certain vesicles, we hypothesize that the fatty acid composition and fluidity of membranes regulate αSyn’s correct binding to highly curved membranes and subsequent assembly into metastable tetramers.
Motion energy analysis during speech tasks in medication-naïve individuals with at-risk mental states for psychosis
Authors: Lopes-Rocha Ana Caroline , Corcoran Cheryl Mary , Andrade Julio Cesar , Peroni Leonardo , Haddad Natalia Mansur , Hortêncio Lucas , Serpa Mauricio Henriques , van de Bilt Martinus Theodorus , Gattaz Wagner Farid , Loch Alexandre Andrade 
Published: September 2022

AbstractMovement abnormalities are commonly observed in schizophrenia and at-risk mental states (ARMS) for psychosis. They are usually detected with clinical interviews, such that automated analysis would enhance assessment. Our aim was to use motion energy analysis (MEA) to assess movement during free-speech videos in ARMS and control individuals, and to investigate associations between movement metrics and negative and positive symptoms. Thirty-two medication-naïve ARMS and forty-six healthy control individuals were filmed during speech tasks. Footages were analyzed using MEA software, which assesses movement by differences in pixels frame-by-frame. Two regions of interest were defined—head and torso—and mean amplitude, frequency, and coefficient of variability of movements for them were obtained. These metrics were correlated with the Structured Interview for Prodromal Syndromes (SIPS) symptoms, and with the risk of conversion to psychosis—inferred with the SIPS risk calculator. ARMS individuals had significantly lower mean amplitude of head movement and higher coefficients of movement variability for both head and torso, compared to controls. Higher coefficient of variability was related to higher risk of conversion. Negative correlations were seen between frequency of movement and most SIPS negative symptoms. All positive symptoms were correlated with at least one movement variable. Movement abnormalities could be automatically detected in medication-naïve ARMS subjects by means of a motion energy analysis software. Significant associations of movement metrics with symptoms were found, supporting the importance of movement analysis in ARMS. This could be a potentially important tool for early diagnosis, intervention, and outcome prediction.
gDesigner: computational design of synthetic gRNAs for Cas12a-based transcriptional repression in mammalian cells
Authors: Crone Michael A. , MacDonald James T. , Freemont Paul S. , Siciliano Velia 
Published: September 2022

AbstractSynthetic networks require complex intertwined genetic regulation often relying on transcriptional activation or repression of target genes. CRISPRi-based transcription factors facilitate the programmable modulation of endogenous or synthetic promoter activity and the process can be optimised by using software to select appropriate gRNAs and limit non-specific gene modulation. Here, we develop a computational software pipeline, gDesigner, that enables the automated selection of orthogonal gRNAs with minimized off-target effects and promoter crosstalk. We next engineered aLachnospiraceaebacterium Cas12a (dLbCas12a)-based repression system that downregulates target gene expression by means of steric hindrance of the cognate promoter. Finally, we generated a library of orthogonal synthetic dCas12a-repressed promoters and experimentally demonstrated it in HEK293FT, U2OS and H1299 cells lines. Our system expands the toolkit of mammalian synthetic promoters with a new complementary and orthogonal CRISPRi-based system, ultimately enabling the design of synthetic promoter libraries for multiplex gene perturbation that facilitate the understanding of complex cellular phenotypes.
Neurophysiology of movement inhibition during full body reaching
Authors: Ho Rachel L. M. , Wang Wei-en , van der Veen Susanne M. , Antony Ajay , Thomas James S. , Coombes Stephen A. 
Published: September 2022

AbstractOur current understanding of response inhibition comes from go/no-go studies that draw conclusions based on the overt movement of single limbs (i.e., a single finger pushing a button). In general, go/no-go paradigms have found that an individual’s ability to correctly inhibit the motor system is indicative of a healthy central nervous system. However, measuring inhibition by an overt behavioral response may lack the sensitivity to conclude whether the motor system is completely inhibited. Therefore, our goal was to use behavioral and neurophysiological measures to investigate inhibition of the motor system during a full-body reaching task. When directly comparing neurophysiological and behavioral measures, we found that neurophysiological measures were associated with a greater number of errors during no-go trials and faster onset times during go trials. Further analyses revealed a negative correlation between errors and onset times, such that the muscles that activated the earliest during go trials also had the greatest number of errors during no-go trials. Together, our observations show that the absence of an overt behavioral response does not always translate to total inhibition of the motor system.
Predicting conversion to Alzheimer’s disease in individuals with Mild Cognitive Impairment using clinically transferable features
Authors: Rye Ingrid , Vik Alexandra , Kocinski Marek , Lundervold Alexander S. , Lundervold Astri J. 
Published: September 2022

AbstractPatients with Mild Cognitive Impairment (MCI) have an increased risk of Alzheimer’s disease (AD). Early identification of underlying neurodegenerative processes is essential to provide treatment before the disease is well established in the brain. Here we used longitudinal data from the ADNI database to investigate prediction of a trajectory towards AD in a group of patients defined as MCI at a baseline examination. One group remained stable over time (sMCI, n = 357) and one converted to AD (cAD, n = 321). By running two independent classification methods within a machine learning framework, with cognitive function, hippocampal volume and genetic APOE status as features, we obtained a cross-validation classification accuracy of about 70%. This level of accuracy was confirmed across different classification methods and validation procedures. Moreover, the sets of misclassified subjects had a large overlap between the two models. Impaired memory function was consistently found to be one of the core symptoms of MCI patients on a trajectory towards AD. The prediction above chance level shown in the present study should inspire further work to develop tools that can aid clinicians in making prognostic decisions.
The biocompatibility and antifungal effect of Rosmarinus officinalis against Candida albicans in Galleria mellonella model
Authors: Meccatti Vanessa Marques , Figueiredo-Godoi Lívia Mara Alves , Pereira Thaís Cristine , de Lima Patrícia Michelle Nagai , Abu Hasna Amjad , Senna Lavinia Barbosa , Marcucci Maria Cristina , Junqueira Juliana Campos , de Oliveira Luciane Dias 
Published: September 2022

AbstractThis study was performed to evaluate the biocompatibility and antifungal effect of Rosmarinus officinalis against Candida albicans in Galleria mellonella model. Five different concentrations of R. officinalis glycolic extract (50; 25; 12.5 e 6.25 mg/mL) were used to evaluate its biocompatibility in G. mellonella model, in which the nystatin suspension (100; 50; 25; 12.5 e 6.25%) was used as a control group. The antifungal action of R. officinalis glycolic extract was evaluated on C. albicans for 72, 48 and 12 h at two different phases: (1) using the extract as therapeutic agent; and (2) using the extract as prophylactic agent. PBS was used as a negative control group. G. mellonella survival curves were plotted using the Kaplan–Meier method and statistical analysis was performed using the log-rank test (Mantel–Cox) and the significance level was set at (α ≤ 0.05). There was no significant difference among the groups in which all were biocompatible except of a significant death rate of 26.6% with nystatin 100%. In phase 1, it was found that after 7 days, there was no statistically significant difference among the prophylactic treatment groups. In phase 2, the groups of R. officinalis 6.25 mg/mL for 72 h and R. officinalis of 12.5 mg/mL for 24 h promoted the survival rate of the larvae in comparison with the control group with a significant difference (p = 0.017) and (p = 0.032) respectively. Therefore, R. officinalis extract is biocompatible in different concentrations and can be used as a prophylactic agent against fungal infection.
Reconstituted TAD-size chromatin fibers feature heterogeneous nucleosome clusters
Authors: Korolev Nikolay , Zinchenko Anatoly , Soman Aghil , Chen Qinming , Wong Sook Yi , Berezhnoy Nikolay V. , Basak Rajib , van der Maarel Johan R. C. , van Noort John , Nordenskiöld Lars 
Published: September 2022

AbstractLarge topologically associated domains (TADs) contain irregularly spaced nucleosome clutches, and interactions between such clutches are thought to aid the compaction of these domains. Here, we reconstituted TAD-sized chromatin fibers containing hundreds of nucleosomes on native source human and lambda-phage DNA and compared their mechanical properties at the single-molecule level with shorter ‘601’ arrays with various nucleosome repeat lengths. Fluorescent imaging showed increased compaction upon saturation of the DNA with histones and increasing magnesium concentration. Nucleosome clusters and their structural fluctuations were visualized in confined nanochannels. Force spectroscopy revealed not only similar mechanical properties of the TAD-sized fibers as shorter fibers but also large rupture events, consistent with breaking the interactions between distant clutches of nucleosomes. Though the arrays of native human DNA, lambda-phage and ‘601’ DNA featured minor differences in reconstitution yield and nucleosome stability, the fibers’ global structural and mechanical properties were similar, including the interactions between nucleosome clutches. These single-molecule experiments quantify the mechanical forces that stabilize large TAD-sized chromatin domains consisting of disordered, dynamically interacting nucleosome clutches and their effect on the condensation of large chromatin domains.
Experimental validation of a multinomial processing tree model for analyzing eyewitness identification decisions
Authors: Winter Kristina , Menne Nicola M. , Bell Raoul , Buchner Axel 
Published: September 2022

AbstractTo improve police protocols for lineup procedures, it is helpful to understand the processes underlying eyewitness identification performance. The two-high threshold (2-HT) eyewitness identification model is a multinomial processing tree model that measures four latent cognitive processes on which eyewitness identification decisions are based: two detection-based processes (the detection of culprit presence and absence) and two non-detection-based processes (biased and guessing-based selection). The model takes into account the full 2 × 3 data structure of lineup procedures, that is, suspect identifications, filler identifications and rejections in both culprit-present and culprit-absent lineups. Here the model is introduced and the results of four large validation experiments are reported, one for each of the processes specified by the model. The validation experiments served to test whether the model’s parameters sensitively reflect manipulations of the processes they were designed to measure. The results show that manipulations of exposure duration of the culprit’s face at encoding, lineup fairness, pre-lineup instructions and ease of rejection of culprit-absent lineups were sensitively reflected in the parameters representing culprit-presence detection, biased suspect selection, guessing-based selection and culprit-absence detection, respectively. The results of the experiments thus validate the interpretations of the parameters of the 2-HT eyewitness identification model.
Imaging features of intraductal tubulopapillary neoplasm of the pancreas and its differentiation from conventional pancreatic ductal adenocarcinoma
Authors: Khristenko Ekaterina , Hank Thomas , Gaida Matthias M. , Kauczor Hans-Ulrich , Hackert Thilo , Klauß Miriam , Mayer Philipp 
Published: September 2022

AbstractIntraductal tubulopapillary neoplasms (ITPN) are rare pancreatic tumors (< 1% of exocrine neoplasms) and are considered to have better prognosis than classical pancreatic ductal adenocarcinoma (PDAC). The present study aimed to evaluate imaging features of ITPN in computed tomography (CT) and magnetic resonance (MR) imaging. We performed monocentric retrospective analysis of 14 patients with histopathologically verified ITPN, operated in 2003–2018. Images were available for 12 patients and were analysed independently by two radiologists, blinded to reports. Imaging features were compared to a matched control group consisting of 43 patients with PDAC, matched for sex and age. Histopathologic analysis showed invasive carcinoma component in all ITPN patients. CT-attenuation values of ITPN were higher in arterial and venous phases (62.3 ± 14.6 HU and 68 ± 15.6 HU) than in unenhanced phase (39.2 ± 7.9 HU), compatible with solid lesion enhancement. Compared to PDAC, ITPN lesions had significantly higher HU-values in both arterial and venous phases (arterial and venous phases, p < 0.001). ITPN were significantly larger than PDAC (4.1 ± 2.0 cm versus 2.6 ± 0.84 cm, p = 0.021). ITPN lesions were more often well-circumscribed (p < 0.002). Employing a multiple logistic regression analysis with forward stepwise method, higher HU density in the arterial phase (p = 0.012) and well-circumscribed lesion margins (p = 0.047) were found to be significant predictors of ITPN versus PDAC. Our study identified key imaging features for differentiation of ITPN and PDAC. Isodensity or moderate hypodensity and well-circumscribed margins favor the diagnosis of ITPN over PDAC. Being familiar with CT-features of these rare pancreatic tumors is essential for radiologists to accelerate the diagnosis and narrow the differentials.
Synthesis of natural product hybrids by the Ugi reaction in complex media containing plant extracts
Authors: Tomohara Keisuke , Ohashi Nao , Uchida Tatsuya , Nose Takeru 
Published: September 2022

AbstractPlant extracts are rich in a wide variety of molecules with diverse biological activities. Chemical engineering of plant extracts has provided a straightforward and simultaneous synthetic route for artificial molecules derived from plant products. This study achieved the synthesis of 13 natural product-like molecules by the Ugi multicomponent reaction using plant extracts as substrates. In particular, the engineering of a mixture of plant extracts demonstrated a unique synthetic route to a series of natural product hybrids, whereby otherwise unencountered naturally occurring molecules of different origins were chemically hybridized in complex media. Even though these reactions took place in complex media containing plant extracts, the well-designed process achieved a good conversion efficiency (~ 60%), chemoselectivity, and reproducibility. Additionally, some of the Ugi adducts exhibited promising inhibitory activity toward protease.
Evaluation of lung toxicity with bevacizumab using the spontaneous reporting database
Authors: Kanbayashi Yuko , Uchida Mayako , Kashiwagi Misui , Akiba Hitomi , Shimizu Tadashi 
Published: September 2022

AbstractThis study was undertaken to determine the risk of bevacizumab-induced lung toxicity, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analysed data for the period between April 2004 and March 2021. Data on lung toxicities were extracted, and relative risk of adverse events (AEs) was estimated using the reporting odds ratio. We analysed 5,273,115 reports and identified 20,399 reports of AEs caused by bevacizumab. Of these, 1679 lung toxicities were reportedly associated with bevacizumab. Signals were detected for nine lung toxicities. A histogram of times to onset showed occurrence from 35 to 238 days, but some cases occurred even more than one year after the start of administration. Approximately 20% of AEs were thromboembolic events. Among these, pulmonary embolism was the most frequently reported and fatal cases were also reported. The AEs showing the highest fatality rates were pulmonary haemorrhage, pulmonary infarction, and pulmonary thrombosis. In conclusion, we focused on lung toxicities caused by bevacizumab as post-marketing AEs. Some cases could potentially result in serious outcomes, patients should be monitored for signs of onset of AEs not only at the start of administration, but also over a longer period of time.
Socioeconomic inequalities in the continuum of care across women’s reproductive life cycle in Bangladesh
Authors: Parvin Nadira , Rahman Mosiur , Islam Md. Jahirul , Haque Syed Emdadul , Sarkar Prosannajid , Mondal Md. Nazrul Islam 
Published: September 2022

AbstractWe examined the association between socioeconomic status (SES) and continuum of care (CoC) completion rate in maternal, neonatal, and child health among mothers in Bangladesh. We used data from the Bangladesh Demographic Health Survey (BDHS) from 2017 to 2018. Our findings were based on the responses of 1527 married women who had at least one child aged 12 to 23 months at the time of the survey. As a measure of SES, we focused on the standard of living (hereinafter referred to as wealth). The CoC for maternal and child health (MNCH) services is the study's outcome variable. The CoC was calculated using seven MNCH interventions: four or more antenatal care (ANC) visits with a skilled practitioner, delivery by a skilled birth attendant, post-natal care for mothers (PNCM) within two days of giving birth, post-natal care for newborns (PNCM) within two days of birth, immunization, age-appropriate breastfeeding, and maternal current use of modern family planning (FP) methods. Only 18.1% of Bangladeshi women completed all seven MNCH care interventions during the reproductive life span. Participants in the high SES group were 2.30 times (95% confidence interval [CI] 1.61–3.28) more likely than those in the low SES group to have higher composite care index (CCI) scores. Women with secondary or higher secondary education, as well as women who were exposed to mass media at least once a week, women who lived in an urban setting, women who had an intended pregnancy, and women with one parity, are associated with high CCI scores when other sociodemographic variables are considered. The complete CoC for MNCH reveals an extremely low completion rate, which may suggest that Bangladeshi mothers, newborns, and children are not receiving the most out of their present health care. Participants in the high SES group displayed higher CCI values than those in the low SES group, indicating that SES is one of the primary drivers of completion of CoC for MNCH services.