bluuebunny/crossref_metadata_2025_split huggingface dataset:
History of incarceration and age-related cognitive impairment: Testing models of genetic and environmental risk in longitudinal panel study of older adults
Authors: Tanksley Peter T. , Logan Matthew W. , Barnes J.C. 
Published: June 2023

AbstractHistory of incarceration is associated with an excess of morbidity and mortality. While the incarceration experience itself comes with substantive health risks (e.g., injury, psychological stress, exposure to infectious disease), most inmates eventually return to the general population where they will be diagnosed with the same age-related conditions that drive mortality in the non-incarcerated population but at exaggerated rates. However, the interplay between history of incarceration as a risk factor and more traditional risk factors for age-related diseases (e.g., genetic risk factors) has not been studied. Here, we focus on cognitive impairment, a hallmark of neurodegenerative conditions like Alzheimer’s disease, as an age-related state that may be uniquely impacted by the confluence of environmental stressors (e.g., incarceration) and genetic risk factors. Using data from the Health and Retirement Study, we found that incarceration andAPOE-ε4genotype (i.e., the chief genetic risk factor for Alzheimer’s disease) both constituted substantive risk factors for cognitive impairment in terms of overall risk and earlier onset. The observed effects were mutually independent, however, suggesting that the risk conveyed by incarceration andAPOE-ε4genotype operate across different risk pathways. Our results have implications for the study of criminal justice contact as a public health risk factor for age-related, neurodegenerative conditions.
Generalizable and Automated Classification of TNM Stage from Pathology Reports with External Validation
Authors: Kefeli Jenna , Tatonetti Nicholas 
Published: June 2023

AbstractCancer staging is an essential clinical attribute informing patient prognosis and clinical trial eligibility. However, it is not routinely recorded in structured electronic health records. Here, we present a generalizable method for the automated classification of TNM stage directly from pathology report text. We train a BERT-based model using publicly available pathology reports across approximately 7,000 patients and 23 cancer types. We explore the use of different model types, with differing input sizes, parameters, and model architectures. Our final model goes beyond term-extraction, inferring TNM stage from context when it is not included in the report text explicitly. As external validation, we test our model on almost 8,000 pathology reports from Columbia University Medical Center, finding that our trained model achieved an AU-ROC of 0.815-0.942. This suggests that our model can be applied broadly to other institutions without additional institution-specific fine-tuning.
Prevalence and correlates of Metabolic Syndrome among adults in Freetown, Sierra Leone: A comparative analysis of NCEP ATP III, IDF and Harmonized ATP III criteria
Authors: Russell James Baligeh Walter , Koroma Theresa Ruba , Sesay Santigie , Samura Sallieu K , Lakoh Sulaiman , Bockarie Ansumana , Abiri Onomeh Thomas , Conteh Victor , Conteh Sorie , Smith Mohamed , Mahdi O Z , Lisk Durodami. R. 
Published: June 2023

AbstractBackgroundMetabolic syndrome (MS) is a global health concern, especially for low and middle-income countries with limited resources and information. The study’s objective was to assess the prevalence of MS in Freetown, Sierra Leone, using the Adult Treatment Panel III (ATP III), International Diabetes Federation (IDF) and Harmonize ATP III. Additionally, we aimed to establish the concordance between these three different criteria used.MethodsThis community-based health screening survey was conducted from October 2019 to October 2022. A multistage stratified random design was used to select adults aged 20 years and above. Mean, interquartile range (IQR), and logistic regression were used for statistical analysis. The kappa coefficient statistics resolved the agreement between these defined criteria.ResultsThe prevalence for NCEP ATP III, Harmonize ATP III and IDF criteria was 11.8% (95% CI: 9.0 - 15.15), 14.3% (95% CI: 11.3 - 18.0), and 8.5% (95% CI: 6.2 - 11.2), respectively for the 2,394 selected adults. The kappa coefficient (κ) agreement between the MS is: Harmonized ATP III and IDF criteria = [(208 (60.8%); (κ =0.62)]; Harmonized ATP III and NCEP ATP III = [(201 (58.7%); (κ =0.71)]; while IDF and NCEP ATP III was [(132 (38.6%); (κ =0.52)]. In the multivariable regression analysis, waist circumference correlated with all three MS criteria: ATP III [AOR = 0.85; C.I 95%: (0.40-1.78), p = 0.032], Harmonized ATP III [AOR = 1.14; C.I 95%: (0.62-2.11), p = 0.024], IDF [AOR = 1.06; C.I 95% (0.52-2.16), p = 0.018]ConclusionWe reported a high prevalence of MS in Freetown, Sierra Leone and identified waist circumference as a major risk factor for MS. This underscores the crucial role of health education and effective management of MS in Sierra Leone.
HD mutation results in a dominant negative effect on HTT function
Authors: Laundos Tiago L. , Li Shu , Cheang Eric , Santis Riccardo De , Piccolo Francesco M. , Brivanlou Ali H. 
Published: June 2023

AbstractHuntington’s disease (HD) remains an incurable and fatal neurodegenerative disease long after CAG-expansion mutation in the huntingtin gene (HTT) was identified as the cause. The underlying pathological mechanism, whether HTT loss of function or gain of toxicity results from mutation, remains a matter of debate. In this study, we genetically modulated wild-type or mutant HTT expression levels in isogenic human embryonic stem cells to systematically investigate their contribution to HD-specific phenotypes. Using highly reproducible and quantifiablein vitromicropattern-based assays, we observed comparable phenotypes with HD mutation and HTT depletion. However, halving endogenous wild-type HTT levels did not strongly recapitulate the HD phenotypes, arguing against a classical loss of function mechanism. Remarkably, expression of CAG-expanded HTT in non-HD cells induced HD-like phenotypes akin to HTT depletion. By corollary, these results indicate a dominant negative effect of mutated HTT on its wild-type counterpart. Complementation with additional copies of wild-type HTT ameliorated the HD-associated phenotypes, strongly supporting a classical dominant negative mechanism. Understanding the molecular basis of this dominant negative effect will guide the development of efficient clinical strategies to counteract the deleterious impact of mutant HTT on the wild-type protein.
Revisiting the role of cAMP in Drosophila aversive olfactory memory formation
Authors: Abe Takashi , Yamazaki Daisuke , Hiroi Makoto , Ueoka Yutaro , Maeyama Yuko , Tabata Tetsuya 
Published: June 2023

AbstractIn the olfactory aversive conditioning of Drosophila melanogaster, an odor, the conditioned stimulus (CS), is associated with electric shock, the unconditioned stimulus (US). The Rutabaga adenylyl cyclase in Kenyon cells (KCs) of the fly brain synthesizes cAMP, which is believed to serve as the coincidence detector synergistically stimulated by calcium/calmodulin evoked by the odor reception and GαS released in response to the dopamine signaling elicited by electric shock. However, live imaging analyses revealed that olfactory stimulation itself prompted the activation of dopaminergic neurons and resulted in the elevation of cAMP levels in KCs that received dopamine, regardless of calcium signaling. This finding raises questions about the longstanding and fundamental comprehension of conditioning mechanisms, as the cAMP levels in conditioned stimulus-positive (CS+) KCs could not be distinguished from those in the rest of the KCs. Our findings suggest that cAMP concentrations do not function as a mnemonic engram to CS+ neurons. Rather, the collective dynamics of cAMP are capable of integratively encoding the valence ascribed to odors being perceived at a given time. Furthermore, our investigation revealed that associative conditioning induces modifications in dopamine levels in response to both CS and US, resulting in alterations in cAMP levels. The increase in cAMP exerts a deleterious effect on the acetylcholine transmission from KCs. Accordingly, we postulate that, during conditioning, cAMP depresses KCs, thereby skewing the valence of the CS+ odor towards a more aversive state for the conditioned flies, and ultimately culminating in the formation of aversive memories.
“In vitro construction and long read sequencing analysis of a 24 kb long artificial DNA sequence encoding the Universal Declaration of the Rights of Man and of the Citizen ”
Authors: Leblanc Julien , Boulle Olivier , Roux Emeline , Nicolas Jacques , Lavenier Dominique , Audic Yann 
Published: June 2023

AbstractIn absence of DNA template, theab initioproduction of long double-stranded DNA molecules of predefined sequences is particularly challenging. The DNA synthesis step remains a bottleneck for many applications such as functional assessment of ancestral genes, analysis of alternative splicing or DNA-based data storage. We propose in this report a fullyin vitroprotocol to generate very long double-stranded DNA molecule starting from commercially available short DNA blocks in less than 3 days. This innovative application of Golden Gate assembly allowed us to streamline the assembly process to produce a 24 kb long DNA molecule storing part of the Universal Declaration of Human rights and citizens. The DNA molecule produced can be readily cloned into suitable host/vector system for amplification and selection.
The mechanism of Atg15-mediated membrane disruption in autophagy
Authors: Kagohashi Yoko , Sasaki Michiko , May Alexander I , Kawamata Tomoko , Ohsumi Yoshinori 
Published: June 2023

AbstractAutophagy is a lysosomal/vacuolar delivery system that isolates and degrades cytoplasmic material. Following delivery by autophagosomes, cytoplasmic components are released into the vacuole within an autophagic body (AB), which is a single-membrane structure derived from the inner membrane of the autophagosome. This membrane must be disrupted for degradation of the cytoplasmic cargo to occur. The vacuolar proteases Pep4 and Prb1, as well as the lipase Atg15, are known to be necessary for this process, but the mechanistic underpinnings remain unclear. In this study, we establish a system to detect lipase activity in the vacuole and use it to show that Atg15 is the sole vacuolar phospholipase and that Pep4 and Prb1 are required for the activation of Atg15 lipase function, which occurs following delivery of Atg15 to the vacuole by the MVB pathway. In vitro experiments also reveal that Atg15 is a B-type phospholipase of broad substrate specificity that is likely implicated in the disruption of a range of membranes delivered to the vacuole. Further, we use isolated ABs to demonstrate that Atg15 alone is able to disrupt AB membranes.
Genetic dissection of regulation by a repressing and novel activating corrinoid riboswitch enables engineering of synthetic riboswitches
Authors: Procknow Rebecca R. , Kennedy Kristopher J. , Kluba Maxwell , Rodriguez Lesley J. , Taga Michiko E. 
Published: June 2023

AbstractThe ability to sense and respond to intracellular metabolite levels enables cells to adapt to environmental conditions. Many prokaryotes use riboswitches – structured RNA elements usually located in the 5’ untranslated region of mRNAs – to sense intracellular metabolites and respond by modulating gene expression. The corrinoid riboswitch class, which responds to adenosylcobalamin (coenzyme B12) and related metabolites, is among the most widespread in bacteria. The structural elements for corrinoid binding and the requirement for a kissing loop interaction between the aptamer and expression platform domains have been established for several corrinoid riboswitches. However, the conformational changes in the expression platform that modulate gene expression in response to corrinoid binding remain unknown. Here, we employ anin vivoGFP reporter system inBacillus subtilisto define alternative secondary structures in the expression platform of a corrinoid riboswitch fromPriestia megateriumby disrupting and restoring base-pairing interactions. Moreover, we report the discovery and characterization of the first riboswitch known to activate gene expression in response to corrinoids. In both cases, mutually exclusive RNA secondary structures are responsible for promoting or preventing the formation of an intrinsic transcription terminator in response to the corrinoid binding state of the aptamer domain. Knowledge of these regulatory mechanisms allowed us to develop synthetic corrinoid riboswitches that convert repressing riboswitches to riboswitches that robustly induce gene expression in response to corrinoids. Due to their high expression levels, low background, and over 100-fold level of induction, these synthetic riboswitches have potential use as biosensors or genetic tools.
Rapid species discovery and identification with real-time barcoding facilitated by ONTbarcoder 2.0 and Oxford Nanopore R10.4
Authors: Srivathsan Amrita , Feng Vivian , Suárez Daniel , Emerson Brent , Meier Rudolf 
Published: June 2023

AbstractMost arthropod species are undescribed and hidden in biodiversity samples that are difficult to sort to species using morphological characters. Sorting specimens to putative species with DNA barcodes is an attractive alternative, but needs cost-effective techniques that are suitable for use in many laboratories around the world. Barcoding with Oxford Nanopore’s portable and inexpensive MinION sequencers could be a good presorting approach because it reduces the space and capital cost of a fully functional barcoding laboratory. Similarly important would be user-friendly and reliable software for analysis of the ONT data. It is here provided in the form of an updated ONTbarcoder that is available for all commonly used operating systems and includes a GUI. The new version of ONTbarcoder has three key improvements related to the higher read quality obtained with ONT’s latest basecallers and chemistry (R10.4 flow cells, Q20+ kits). Firstly, ONTbarcoder can now deliver real-time barcoding to complement ONT’s real-time sequencing. This means that the first barcodes are obtained within minutes of starting a sequencing run and a significant proportion of barcodes are available before sequencing completes. This real-time feature of ONTbarcoder can be configured to handle both Mk1B and Mk1C sequencers. The input is a demultiplexing sheet and sequencing data (raw or basecalled). Secondly, the improved read quality of ONT’s latest flow cells (R10.4) allows for the use of primers with shorter indices than those previously needed (9 bp vs. 12-13 bp). This decreases primer cost and improves PCR success rates. Thirdly, we demonstrate that the availability of R10.4 chemistry in the low-cost Flongle flow cell is an attractive option for users who require only 200-250 barcodes at a time.
Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6
Authors: Cook Anna A. , Leung Tsz Chui Sophia , Rice Max , Nachman Maya , Zadigue-Dubé Élyse , Watt Alanna J. 
Published: June 2023

AbstractSpinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-DHF, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6, and a promising therapeutic target.
Cortical over-representation of phonetic onsets of ignored speech in hearing impaired individuals
Authors: Carta Sara , Aličković Emina , Zaar Johannes , López Valdes Alejandro , Di Liberto Giovanni M. 
Published: June 2023

AbstractHearing impairment alters the sound input received by the human auditory system, reducing speech comprehension in noisy multi-talker auditory scenes. Despite such challenges, attentional modulation on the envelope tracking in multi-talker scenarios is comparable between normal hearing (NH) and hearing impaired (HI) participants, with previous research suggesting an over-representation of the speech envelopes in HI individuals (see, e.g., Fuglsang et al. 2020 and Presacco et al. 2019), even though HI participants reported difficulties in performing the task. This result raises an important question: What speech-processing stage could reflect the difficulty in attentional selection, if not envelope tracking? Here, we use scalp electroencephalography (EEG) to test the hypothesis that such difficulties are underpinned by an over-representation of phonological-level information of the ignored speech sounds. To do so, we carried out a re-analysis of an EEG dataset where EEG signals were recorded as HI participants fitted with hearing aids attended to one speaker (target) while ignoring a competing speaker (masker) and spatialised multi-talker background noise. Multivariate temporal response function analyses revealed that EEG signals reflect stronger phonetic-feature encoding for target than masker speech streams. Interestingly, robust EEG encoding of phoneme onsets emerged for both target and masker streams, in contrast with previous work on NH participants and in line with our hypothesis of an over-representation of the masker. Stronger phoneme-onset encoding emerged for the masker, pointing to a possible neural basis for the higher distractibility experienced by HI individuals.Significance StatementThis study investigated the neural underpinnings of attentional selection in multi-talker scenarios in hearing-impaired participants. The impact of attentional selection on phonological encoding was assessed with electroencephalography (EEG) in an immersive multi-talker scenario. EEG signals encoded the phonetic features of the target (attended) speech more strongly than those of the masker (ignored) speech; but interestingly, they encoded the phoneme onsets of both target and masker speech. This suggests that the cortex of hearing-impaired individuals may over-represent higher-level features of ignored speech sounds, which could contribute to their higher distractibility in noisy environments. These findings provide insight into the neural mechanisms underlying speech comprehension in hearing-impaired individuals and could inform the development of novel approaches to improve speech perception in noisy environments.
Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)
Authors: Kulminskaya Natalia , Rodriguez Gamez Carlos Francisco , Hofer Peter , Cerk Ines Kathrin , Dubey Noopur , Viertlmayr Roland , Sagmeister Theo , Pavkov-Keller Tea , Zechner Rudolf , Oberer Monika 
Published: June 2023

AbstractLipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein co-activation on a per-residue level. We identified the region from residues N209-N215 in mouse ATGL as essential for co-activation by mouse CGI-58. ATGL variants with amino-acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 co-activation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the co-activation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for co-activation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58 mediated co-activation of ATGL.