bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic analysis of a malaria outbreak in Laos driven by a selective sweep for Plasmodium falciparum kelch13 R539T mutants
Authors: Wasakul Varanya , Disratthakit Areeya , Mayxay Mayfong , Chindavongsa Keobouphaphone , Sengsavath Viengphone , Thuy-Nhien Nguyen , Pearson Richard D , Phalivong Sonexay , Xayvanghang Saiamphone , Gonçalves Sonia , Day Nicholas P , Newton Paul N , Ashley Elizabeth A , Kwiatkowski Dominic P , Dondorp Arjen M , Miotto Olivo 
Published: August 2022

AbstractMalaria outbreaks are an important public health concern in endemic regions approaching elimination. Genetic surveillance of malaria parasites can elucidate the population dynamics of an outbreak, and help identify its causes. We investigated the epidemiology of a Plasmodium falciparum outbreak in Attapeu Province, Laos, during the 2020-2021 season. An analysis of 249 samples, collected by routine genetic surveillance during the outbreak, revealed a massive loss of genetic diversity in the parasite population, primarily caused by the rapid expansion of a multidrug resistant strain, named LAA1. This strain carried the kelch13 R539T mutation and expanded clonally, replacing the previously dominant kelch13 C580Y mutants (KEL1/PLA1) resistant to dihydroartemisinin-piperaquine. Identity by descent (IBD) patterns showed that LAA1 was a recombinant that inherited 60% of its genome from a strain first sampled in Cambodia over a decade ago. A less common outbreak strain (LAA2) carried the kelch13 C580Y allele, but was distinct from KEL1/PLA1, its genome essentially identical to that of a Cambodian parasite from 2009. A third, low-frequency strain (LAA7) was a recombinant of KEL1/PLA1 with a R539T mutant, the latter providing the kelch13 variant. These results strongly suggest that the outbreak was driven by a selective sweep, possibly associated with drug-resistant phenotypes of the outbreak strains. The observation that new variants of established multidrug resistant populations can overwhelm previously dominant strains so rapidly has implications for elimination of malaria. Genetic surveillance provides the tools for characterizing outbreaks, and for monitoring the evolution and spread of the populations involved.
Predicting work disability among people with chronic conditions: a large prospective cohort study
Authors: Nyberg Solja T. , Airaksinen Jaakko , Pentti Jaana , Ervasti Jenni , Jokela Markus , Vahtera Jussi , Virtanen Marianna , Elovainio Marko , Batty G. David , Kivimäki Mika 
Published: August 2022

AbstractFew risk prediction scores are available to identify people at increased risk of work disability, particularly for those with an existing morbidity. We examined the predictive performance of disability risk scores for employees with chronic disease. We used prospective data from 88,521 employed participants (mean age 43.1) in the Finnish Public Sector Study which included people with chronic disorders: musculoskeletal disorder, depression, migraine, respiratory disease, hypertension, cancer, coronary heart disease, diabetes and comorbid depression and cardiometabolic disease. 105 predictors were assessed at baseline and participants were linked to a national disability pension register. During a mean follow-up of 8.6 years, 6836 (7.7%) participants got a disability pension, the incidence varying between 9.9% among participants with migraine and 27.7% in those with comorbid depression and cardiometabolic disease. C-statistics for an 8-item risk score, comprising age, self-rated health, number of sickness absences, socioeconomic position, number of chronic illnesses, sleep problems, BMI, and smoking at baseline, was 0.80 (95%CI: 0.80-0.81) for musculoskeletal disorders (N=33,601), 0.83 (0.82-0.84) for migraine (N=22,065), 0.82 (0.81-0.83) for respiratory disease (N=15,372) and exceeded 0.72 for other disease groups. With 30% estimated risk as a threshold, a positive test detection rate and false positive rate ranged from 42.2% and 18.8% (cancer) to 79.8% and 45.2% (comorbid depression and cardiometabolic disease). Predictive performance was not improved in models with a new set of predictors or re-estimated coefficients. In conclusion, the 8-item work disability risk score may serve as a scalable screening tool in identifying individuals with increased risk for work disability.
Detection of Monkeypox virus DNA in the wastewater of an airport in Rome, Italy: expanding environmental surveillance to emerging threats
Authors: La Rosa G , Mancini P , Veneri C , Bonanno Ferraro G , Lucentini L , Iaconelli M , Suffredini E. 
Published: August 2022

AbstractSince May 2022, monkeypox cases have been reported in non-endemic countries, and the disease was declared a Public Health Emergency of International Concern. Rapid identification of new cases is critical for outbreak control. Environmental surveillance can be used as a complementary tool for detecting pathogens circulating in communities. This study aimed to investigate whether Monkeypox DNA can be detected in wastewater from a transportation hub.Twenty samples were collected in Italy’s first airport in Rome and tested using published and modified real-time PCR assays targeting the G2R region (TFN gene), F3L, and N3R genes. Nested PCR assays were also used for confirmation by sequencing. Three samples tested positive by real-time PCR and/or by nested PCR, confirming the occurrence of the virus in the airport’s wastewater.Wastewater surveillance can be quickly adapted to investigate emerging threats and can be used to track the introduction and/or the diffusion of the Monkeypox virus in communities.
Associations of the Triglyceride and Glucose Index with Hypertension Stages, Phenotypes, and Progressions among Middle-aged and Older Chinese
Authors: Shan Shiyi , Li Shuting , Lu Keyao , Cao Jin , Sun Weidi , Zhou Jiali , Ren Ziyang , Zhu Siyu , Hou Leying , Chen Dingwan , Song Peige 
Published: August 2022

AbstractBackgroundThe triglyceride and glucose (TyG) index has been proposed as a surrogate indicator of insulin resistance. By far, the associations of the TyG index with hypertension stages, phenotypes, and progressions remain unclear.MethodsThe data originated from two waves (2011 and 2015) of the China Health and Retirement Longitudinal Study (CHARLS). Participants with systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg and/or using antihypertensive medications were considered hypertensive. After excluding those under antihypertensive medications, hypertension stages were classified as stage 1 and stage 2, and phenotypes were classified as isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic diastolic hypertension (SDH). Multinomial logistic regression was used to investigate the associations of the TyG index with hypertension stages and phenotypes, together with their progressions from 2011 to 2015.ResultsAt baseline in CHARLS 2011, a total of 8,209 participants were recruited, among whom 3,169 (38.6%) were hypertension. Compared with individuals with the lowest quartile (Q1) of TyG index, those with the highest quartile (Q4) were significantly associated with increased risks of stage 1 hypertension (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.38-2.13), stage 2 hypertension (1.74, 1.27-2.38), ISH (1.66, 1.31-2.11), IDH (2.52, 1.26-5.05), and SDH (1.65, 1.23-2.23). Similar results were found when the TyG index was used as a continuous variable. From 2011 to 2015, a higher baseline TyG index was revealed to be significantly associated with the progressions from normotension to stage 1 (for Q4 vs Q1: 1.45, 1.05-2.00; for per-unit: 1.39, 1.16-1.65), normotension to ISH (for per-unit: 1.28, 1.04-1.56), and normotension to IDH (for Q4 vs Q1: 3.46, 1.42-8.44; for per-unit: 1.94, 1.27-2.97).ConclusionsThe TyG index was significantly associated with different hypertension stages, phenotypes and their progressions. Our findings highlight the importance of the TyG index as a potential surrogate indicator for early hypertension screening and management.
Aiding Oral Squamous Cell Carcinoma diagnosis using Deep learning ConvMixer network
Authors: Toan Nguyen Quoc 
Published: August 2022

ABSTRACTIn recent years, Oral squamous cell carcinoma (OSCC) has become one of the world’s most prevalent cancers, and it is becoming more prevalent in many populations. The high incidence rate, late diagnosis, and inadequate treatment planning continue to be major concerns. Despite the enhancement in the applications of deep learning algorithms for the medical field, late diagnosis, and approaches toward precision medicine for OSCC patients remain a challenge. Due to a lack of datasets and trained models with low computational costs, the diagnosis, an important cornerstone, is still done manually by oncologists. Although Convolutional neural networks (CNNs) have become the dominant architecture for vision tasks for plenty of years, recent experiments show that Transformer-based models, most noticeably the Vision Transformer (ViT), may out-compete them in some settings. Therefore, in this research, a method called ConvMixer, which combines great features from CNNs and patches based on ViT was applied to an original very small dataset of only 1224 images in total for 2 classes, Normal epithelium of the oral cavity (Normal) and OSCC, 696 slides for 400x magnification and 528 slides for 100x magnification. However, the proposed models with small parameters and data augmentation performed magnificently, with 400x magnification (Accuracy: 99.81% - F1score: 99.87%) and 100x magnification (Accuracy: 99.62% - F1score: 99.77%).
Quantifying decision-making in dynamic, continuously evolving environments
Authors: Ruesseler Maria , Weber Lilian AE , Marshall Tom R , O’Reilly Jill X , Hunt Laurence T 
Published: August 2022

AbstractDuring perceptual decision-making tasks, centroparietal EEG potentials report an evidence accumulation-to-bound process that is time locked to trial onset. However, decisions in real-world environments are rarely confined to discrete trials; they instead unfold continuously, with accumulation of time-varying evidence being recency-weighted towards its immediate past. The neural mechanisms supporting recency-weighted continuous decision making remain unclear. Here, we use a novel continuous task design to study how the Centroparietal Positivity (CPP) adapts to different environments that place different constraints on evidence accumulation. We show that adaptations in evidence weighting to these different environments are reflected in changes in the CPP. The CPP becomes more sensitive to fluctuations in sensory evidence when large shifts in evidence are less frequent, and the potential is primarily sensitive to fluctuations in decision-relevant (not decision-irrelevant) sensory input. A complementary triphasic component over occipito-parietal cortex encodes the sum of recently accumulated sensory evidence, and its magnitude covaries with parameters describing how different individuals integrate sensory evidence over time. A computational model based on leaky evidence accumulation suggests these findings can be accounted for by a shift in decision threshold between different environments, which is also reflected in the magnitude of pre-decision EEG activity. Our findings reveal how adaptations in EEG responses reflect flexibility in evidence accumulation to the statistics of dynamic sensory environments.
DNA capture and loop extrusion dynamics by cohesin-NIPBL
Authors: Kaur Parminder , Shi Zhubing , Lu Xiaotong , Zhang Hongshan , Finkelstein Ilya J. , Tao Yizhi Jane , Yu Hongtao , Wang Hong 
Published: August 2022

ABSTRACT3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains (TADs) and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. Using high-speed AFM (HS-AFM) imaging, we show that cohesin-NIPBL captures DNA through arm extension, followed by transfer of DNA to its globular domain and DNA loop initiation independent of ATPase hydrolysis. Additional shorter protrusions (feet) from cohesin-NIPBL transiently bind to DNA, facilitating its loading onto DNA. Furthermore, HS-AFM imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results provide critical missing links in our understanding of DNA binding and loop extrusion by cohesin-NIPBL.
A spatial map of human macrophage niches links tissue location with function
Authors: Matusiak Magdalena , Hickey John W. , Luca Bogdan , Lu Guolan , Kidzinski Lukasz , Shu Shirley , Colburg Deana Rae Crystal , Phillips Darci J. , Brubaker Sky W. , Charville Gregory W. , Shen Jeanne , Nolan Garry P. , Newman Aaron M. , West Robert B. , van de Rijn Matt 
Published: August 2022

SummaryMacrophages are the most abundant immune cell type in the tumor microenvironment (TME). Yet the spatial distribution and cell interactions that shape macrophage function are incompletely understood. Here we use single-cell RNA sequencing data and multiplex imaging to discriminate and spatially resolve macrophage niches within benign and malignant breast and colon tissue. We discover four distinct tissue-resident macrophage (TRM) layers within benign bowel, two TRM niches within benign breast, and three tumor-associated macrophage (TAM) populations within breast and colon cancer. We demonstrate that IL4I1 marks phagocytosing macrophages, SPP1 TAMs are enriched in hypoxic and necrotic tumor regions, and a novel subset of FOLR2 TRMs localizes within the plasma cell niche. Furthermore, NLRP3 TAMs that colocalize with neutrophils activate an inflammasome in the TME and in Crohn’s disease and are associated with poor outcomes in breast cancer patients. This work suggests novel macrophage therapy targets and provides a framework to study human macrophage function in clinical samples.
NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells
Authors: Maskalenka Katsiaryna , Alagöz Gökberk , Krueger Felix , Wright Joshua , Rostovskaya Maria , Nakhuda Asif , Bendall Adam , Krueger Christel , Walker Simon , Scally Aylwyn , Rugg-Gunn Peter J. 
Published: August 2022

ABSTRACTGene duplication events are important drivers of evolution by providing genetic material for new gene functions. They also create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the key transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naïve-state pluripotent stem cells. Sequence analysis and epitope-tagging of the endogenous locus revealed that NANOGP1 is protein-coding with an intact homeobox domain. NANOGP1 has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways including point mutations in the homeodomain. NANOGP1 is a strong inducer of naïve pluripotency; however, unlike NANOG, it is not required to maintain the undifferentiated status of human naïve pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development.Summary statementEstablishing that NANOGP1 has retained partial functional conservation with its ancestral copy NANOG sheds light on the role of gene duplication and subfunctionalisation in human pluripotency and development.
Beat encoding at mistuned octaves within single sensory neurons
Authors: Barayeu Alexandra , Schäfer Ramona , Grewe Jan , Benda Jan 
Published: August 2022

AbstractBeats are periodic amplitude modulations resulting from the superposition of two spectrally close periodic signals, where the difference between the two signal frequencies defines the frequency of the beat. Such amplitude modulations are known to be well encoded in corresponding firing rate modulations in auditory fibers as well as in electrosensory afferents. In a field study we showed the behavioral relevance of beat-like amplitude modulations exceeding spectrally close interactions in electric fish. Thus, we here study the encoding of beat-like waveforms over a wide range of difference frequencies in the electrosensory system ofApteronotus leptorhynchus. Contrary to expectations from the previously measured beat tuning, the activity of p-type electroreceptor afferents follows a repetitive pattern with slow modulations of their firing rate reoccurring around multiples of the frequency of the carrier signal. Mathematical reasoning supported by simulations of modified integrate-and-fire models reveals that neither Hilbert transform, squaring, harmonics of the carrier, half-wave rectification, nor the threshold-non-linearity of a spike generator are sufficient to extract slow beating signal envelopes around the octave of the carrier. Rather, a threshold operation smoothed out by exponentiation with a power of three is needed prior to spike generation to explain the repetitive occurrence of slow signal envelopes and electroreceptor responses. Our insights suggest the synapses of inner hair cells as candidate mechanisms underlying the perception of beats at mistuned octaves that has been described by Georg Simon Ohm, Hermann Helmholtz, and others already in the 19th century.
The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells
Authors: Hourfar Hamdam , Aliakbari Farhang , Aqdam Shabboo Rahimi , Nayeri Zahra , Bardania Hassan , Otzen Daniel E. , Morshedi Dina 
Published: August 2022

AbstractThe role of the blood-brain barrier (BBB) is to control trafficking of biomolecules and protect the brain. This function can be compromised by pathological conditions. Parkinson’s disease (PD) is characterized by the accumulation of α-synuclein aggregates (αSN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how αSN-AGs affect the BBB in in vitro co-culturing models consisting of human brain endothelial hCMEC/D3 cells alone and co-cultured with astrocytes and neurons/glial cells. When cultivated on their own, hCMEC/D3 cells were compromised by αSN-AGs, which decreased cellular viability, mitochondrial membrane potential, wound healing activity, TEER and permeability parameters, as well as increased the levels of ROS and NO. Co-culturing of these cells with activated microglia also increased BBB impairment according to TEER and systemic immune cell transmigration assays. In contrast, hCMEC/D3 cells co-cultured with astrocytes or dopaminergic neurons or simultaneously treated with their conditioned media showed increased resistance against αSN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), αSN-AGs and BBB.Graphical Abstract
Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM
Authors: Saotome Kei , Dudgeon Drew , Colotti Kiersten , Moore Michael J. , Jones Jennifer , Zhou Yi , Rafique Ashique , Yancopoulos George D. , Murphy Andrew J. , Lin John C. , Olson William C. , Franklin Matthew C. 
Published: August 2022

AbstractThe recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response. Structural characterization is key for understanding the specificity of TCR-pMHC interactions and informing the development of therapeutics. Despite the rapid rise of single particle cryoelectron microscopy (cryoEM), x-ray crystallography has remained the preferred method for structure determination of TCR-pMHC complexes. Here, we report cryoEM structures of two distinct full-length α/β TCR-CD3 complexes bound to their pMHC ligand, the cancer-testis antigen HLA-A2/MAGEA4 (230-239). We also determined cryoEM structures of pMHCs containing MAGEA4 (230-239) peptide and the closely related MAGEA8 (232-241) peptide in the absence of TCR, which provided a structural explanation for the MAGEA4 preference displayed by the TCRs. These findings provide insights into the TCR recognition of a clinically relevant cancer antigen and demonstrate the utility of cryoEM for high-resolution structural analysis of TCR-pMHC interactions.
Locating cellular contents during cryoFIB milling by cellular secondary-electron imaging
Authors: Lin Chao , Zhang Li , Zhang Ziying , Jiang Yifeng , Li Xueming 
Published: August 2022

AbstractCryo-electron tomography (cryoET) is a powerful technique that enables the direct study of the molecular structure of tissues and cells. Cryo-focused ion beam (cryoFIB) milling plays an important role in preparation of high-quality thin lamellar samples for cryoET studies, promoting the rapid development of cryoET in recent years. However, locating the regions of interest in a large cell or tissue during cryoFIB milling remains a major challenge limiting cryoET applications on arbitrary biological samples. Here, we report an on-the-fly location method based on cellular secondary electron imaging (CSEI). CSEI is derived from a basic imaging function of the cryoFIB instruments and enables high-contrast imaging of the cellular contents of frozen hydrated biological samples, highlighted by that both fluorescent labels and additional devices are not required. The present work discusses the imaging principles and settings for optimizing CSEI. Tests on several commercially available cryoFIB instruments demonstrated that CSEI was feasible on mainstream instruments to observe all types of cellular contents and was reliable under different milling conditions. Assisted by CSEI, we established a simple milling-location workflow and tested it using the basal body ofChlamydomonas reinhardtii.
Cryo-EM reveals the structure and dynamics of a 723-residue malate synthase G
Authors: Ho Meng-Ru , Wu Yi-Ming , Lu Yen-Chen , Ko Tzu-Ping , Wu Kuen-Phon 
Published: August 2022

AbstractDetermination of sub-100 kilodalton (kDa) structures by cryo-electron microscopy (EM) is a longstanding but not straightforward goal. Here, we present a 2.9-Å cryo-EM structure of a 723-amino acid apo-form malate synthase G (MSG) from Escherichia coli. The cryo-EM structure of the 82-kDa MSG exhibits the same global folding as structures resolved by crystallography and nuclear magnetic resonance (NMR) spectroscopy, and the crystal and cryo-EM structures are indistinguishable. Analyses of MSG dynamics reveal consistent conformational flexibilities among the three structural approaches, most notably that the α/β domain exhibits heterogeneity. We observed that sidechains of F453, L454, M629, and E630 residues involved in hosting the cofactor acetyl-CoA and substrate rotate differently between the cryo-EM apo-form and complex crystal structures. Our work demonstrates that the cryo-EM technique can be used to determine structures and conformational heterogeneity of sub-100 kDa biomolecules to a quality as high as that obtained from crystallography and NMR spectroscopy.