bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of psychiatric disease and aging onFKBP5expression converge on cortical supragranular neurons
Authors: Matosin Natalie , Arloth Janine , Czamara Darina , Edmond Katrina Z. , Maitra Malosree , Fröhlich Anna Sophie , Martinelli Silvia , Kaul Dominic , Bartlett Rachael , Curry Amber R. , Gassen Nils C. , Hafner Kathrin , Müller Nikola S , Worf Karolina , Rehawi Ghalia , Nagy Corina , Halldorsdottir Thorhildur , Cruceanu Cristiana , Gagliardi Miriam , Gerstner Nathalie , Ködel Maik , Murek Vanessa , Ziller Michael J , Scarr Elizabeth , Tao Ran , Jaffe Andrew E. , Arzberger Thomas , Falkai Peter , Kleinmann Joel E. , Weinberger Daniel R. , Mechawar Naguib , Schmitt Andrea , Dean Brian , Turecki Gustavo , Hyde Thomas M. , Binder Elisabeth B. 
Published: January 2021

ABSTRACTIdentification and characterisation of novel targets for treatment is a priority in the field of psychiatry.FKBP5is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported thatFKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell-types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propelFKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n=1024) ofFKBP5/1 examining prefrontal cortex (BA9, BA11, BA24) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease-state, aging and genotype on corticalFKBP5/1 expression including in a cell-type specific manner. We identified consistently heightenedFKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq) and targeted histology, we established that these disease- and aging-effects onFKBP5/1 expression were most pronounced in excitatory supragranular neurons. We then found that this increase inFKBP5levels likely impacts on synaptic plasticity, asFKBP5gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in supragranular neurons. These findings pinpoint a novel cellular and molecular mechanism that has significant potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.
Exploring a local genetic interaction network using evolutionary replay experiments
Authors: Vignogna Ryan C. , Buskirk Sean W. , Lang Gregory I. 
Published: January 2021

ABSTRACTUnderstanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations inKEL1(P344T) andHSL7(A695fs) that arose in an experimentally-evolvedSaccharomyces cerevisiaepopulation. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using “evolutionary replay” experiments we identified additional mutations that have positive genetic interactions with thekel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where thekel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in thekel1-P344T background. We reconstructed mutations in the ancestral andkel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors withKEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, and sheds light on a previously under-explored region of the yeast genetic interaction network.
Bidirectional, unlike unidirectional transport, allows transporting axonal cargos against their concentration gradient
Authors: Kuznetsov Ivan A. , Kuznetsov Andrey V. 
Published: January 2021

AbstractEven though most axonal cargos are synthesized in the soma, the concentration of many of these cargos is larger at the presynaptic terminal than in the soma. This requires transport of these cargos from the soma to the presynaptic terminal or other active sites in the axon. Axons utilize both bidirectional (for example, slow axonal transport) and unidirectional (for example, fast anterograde axonal transport) modes of cargo transport. Bidirectional transport seems to be less efficient because it requires more time and takes more energy to deliver cargos. In this paper, we studied a family of models which differ by the modes of axonal cargo transport (such as anterograde and retrograde motor-driven transport and passive diffusion) as well as by the presence or absence of pausing states. The models are studied to investigate their ability to describe axonal transport against the cargo concentration gradient. We argue that bidirectional axonal transport is described by a higher-order mathematical model, which allows imposing cargo concentration not only at the axon hillock but also at the axon terminal. The unidirectional transport model allows only for the imposition of cargo concentration at the axon hillock. Due to the great lengths of the axons, anterograde transport mostly relies on molecular motors, such as kinesins, to deliver cargos synthesized in the soma to the terminal and other active sites in the axon. Retrograde transport can be also motor-driven, in which case cargos are transported by dynein motors. If cargo concentration at the axon tip is higher than at the axon hillock, retrograde transport can also occur by cargo diffusion. However, because many axonal cargos are large or they assemble in multiprotein complexes for axonal transport, the diffusivity of such cargos is very small. We investigated the case of a small cargo diffusivity using a perturbation technique and found that for this case the effect of diffusion is limited to a very thin diffusion boundary layer near the axon tip. If cargo diffusivity is decreased in the model, we show that without motor-driven retrograde transport the model is unable to describe a high cargo concentration at the axon tip. To the best of our knowledge, our paper presents the first explanation for the utilization of seemingly inefficient bidirectional transport in neurons.
Mechanism of activation and regulation of Deubiquitinase activity in MINDY1 and MINDY2
Authors: Rehman Syed Arif Abdul , Armstrong Lee A. , Lange Sven M. , Kristariyanto Yosua Adi , Grawert Tobias W. , Knebel Axel , Svergun Dmitri I. , Kulathu Yogesh 
Published: January 2021

ABSTRACTOf the eight distinct polyubiquitin chains that can be assembled, K48-linked ubiquitin is the most well-understood linkage and modification of proteins with K48 chains targets the modified protein for degradation. By removing ubiquitin from substrates or trimming ubiquitin chains, deubiquitinases (DUBs) can modulate the outcome of ubiquitylation. MINDY1 and MINDY2 are members of the MINDY family of DUBs that have exquisite specificity for cleaving K48-linked polyubiquitin. Being recently discovered DUBs, we have a poor understanding of their catalytic mechanism. By analysing crystal structures of MINDY1 alone and in complex with monoubiquitin or K48-linked ubiquitin chains, we here reveal how substrate interaction relieves autoinhibition and activates the DUB. Further, our analyses reveal a non-canonical catalytic triad composed of Cys-His-Thr and explain how these DUBs sense both ubiquitin chain length and linkage type to trim K48-linked ubiquitin chains. Our findings highlight the multiple layers of regulation modulating DUB activity in MINDY1 and MINDY2.SynopsisStructure of MINDY1 in complex with K48-linked diUb reveals how K48-linked polyUb is recognized and cleavedThe Cys loop mediates autoinhibition of the DUB and substrate binding at the S1 and S1’ sites relieves autoinhibition and activates the enzyme for catalysisMINDY1 uses a non-canonical catalytic triad composed of Cys-His-ThrMINDY1 has five ubiquitin binding sites within its catalytic domain and switches from exo to endo cleavage in a ubiquitin chain length-dependent manner
Activation of the vagal anti-inflammatory reflex by remote ischaemic conditioning in humans: experimental cross-over study
Authors: May Shaun M. , Chiang Eric , Reyes Anna , Martir Gladys , Patel Amour , Karmali Shamir , Patel Sanjiv , West Simeon , del Arroyo Ana Gutierrez , Gourine Alexander V. , Ackland Gareth L. 
Published: January 2021

AbstractBACKGROUNDNon-invasive approaches in humans that may activate the vagal anti-inflammatory reflex are lacking. Neurons within the dorsal motor vagal nucleus (DMVN) activate both the vagal anti-inflammatory reflex (which regulates leukocyte trafficking by controlling neutrophil surface CD11b expression) and cardioprotection afforded by remote ischemic conditioning (RIC). We tested the hypothesis that RIC recruits vagal activity and activates the anti-inflammatory reflex in humans by reducing neutrophil (CD16+)CD11b expression.METHODSParticipants (age:50±19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 37×8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate variability) before, and 10 minutes after, the last RIC cycle. The primary outcome was RR-interval, compared between RICblock and RIC. Secondary outcomes were time-domain, frequency-domain, and flow cytometric quantification of CD16+CD11b expression in whole blood (incubated with lipopolysaccharide (LPS) or saline) compared between RICblock and RIC.RESULTSRIC increased RR-interval (lowered heart rate) by 40ms (95% confidence intervals (95%CI):13-66; n=17; P=0.003). RR-interval did not change after RICblock (mean difference:20ms (95%CI:-11 to 50); P=0.19). High-frequency (vagal) modulation of heart rate was reduced after RICblock, but preserved after RIC (P<0.001). indicating RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression was lower after RIC (3615 median fluorescence units (95%CI:475-6754); P=0.026), compared with 2331 units (95%CI:-3921 to 8582); P=0.726) after RICblock.CONCLUSIONRIC recruits the vagal anti-inflammatory reflex, which requires intact afferent signalling from the peripheral tissue undergoing ischaemia/reperfusion to increase vagal tone and reduce neutrophil activation.TRIAL REGISTRATIONresearchregistry6482.
Oscillations support short latency co-firing of neurons during human episodic memory formation
Authors: Roux Frédéric , Parish George , Chelvarajah Ramesh , Rollings David T. , Sawlani Vijay , Hamer Hajo , Gollwitzer Stephanie , Kreiselmeyer Gernot , Wal Marije Ter , Kolibius Luca , Staresina Bernhard , Wimber Maria , Self Matthew W. , Hanslmayr Simon 
Published: January 2021

AbstractTheta and gamma oscillations in the medial temporal lobe are suggested to play a critical role for human memory formation via establishing synchrony in neural assemblies. Arguably, such synchrony facilitates efficient information transfer between neurons and enhances synaptic plasticity, both of which benefit episodic memory formation. However, to date little evidence exists from humans that would provide direct evidence for such a specific role of theta and gamma oscillations for episodic memory formation. Here we investigate how oscillations shape the temporal structure of neural firing during memory formation in the medial temporal lobe. We measured neural firing and local field potentials in human epilepsy patients via micro-wire electrode recordings to analyze how brain oscillations promote co-incidences of firing between neurons during successful and unsuccessful encoding of episodic memories. The results show that phase-coupling of neurons to faster theta and gamma oscillations correlates with co-firing at short latencies (∼20-30 ms) and occurs during successful memory formation. Phase-coupling at slower oscillations in these same frequency bands, in contrast, correlates with longer co-firing latencies and occurs during memory failure. Thus, our findings provide evidence which implicate neural oscillations into the synchronization of neural firing in the medial temporal lobe during the encoding of episodic memories.
DeepSVP: Integration of genotype and phenotype for structural variant prioritization using deep learning
Authors: Althagafi Azza , Alsubaie Lamia , Kathiresan Nagarajan , Mineta Katsuhiko , Aloraini Taghrid , Almutairi Fuad , Alfadhel Majid , Gojobori Takashi , Alfares Ahmad , Hoehndorf Robert 
Published: January 2021

AbstractMotivationStructural genomic variants account for much of human variability and are involved in several diseases. Structural variants are complex and may affect coding regions of multiple genes, or affect the functions of genomic regions in different ways from single nucleotide variants. Interpreting the phenotypic consequences of structural variants relies on information about gene functions, haploinsufficiency or triplosensitivity, and other genomic features. Phenotype-based methods to identifying variants that are involved in genetic diseases combine molecular features with prior knowledge about the phenotypic consequences of altering gene functions. While phenotype-based methods have been applied successfully to single nucleotide variants as well as short insertions and deletions, the complexity of structural variants makes it more challenging to link them to phenotypes. Furthermore, structural variants can affect a large number of coding regions, and phenotype information may not be available for all of them.ResultsWe developed DeepSVP, a computational method to prioritize structural variants involved in genetic diseases by combining genomic and gene functions information. We incorporate phenotypes linked to genes, functions of gene products, gene expression in individual celltypes, and anatomical sites of expression, and systematically relate them to their phenotypic consequences through ontologies and machine learning. DeepSVP significantly improves the success rate of finding causative variants in several benchmarks and can identify novel pathogenic structural variants in consanguineous families.Availabilityhttps://github.com/bio-ontology-research-group/DeepSVPContactrobert.hoehndorf@kaust.edu.sa
In-frame deletion of SPECC1L microtubule binding domain results in embryonic tissue movement and fusion defects
Authors: Goering Jeremy P. , Wenger Luke W. , Stetsiv Marta , Moedritzer Michael , Hall Everett G. , Isai Dona Greta , Jack Brittany , Umar Zaid , Rickabaugh Madison K. , Czirok Andras , Saadi Irfan 
Published: January 2021

AbstractEmbryonic morphogenesis of the neural tube, palate, ventral body wall and optic fissure require precise sequence of tissue movement and fusion, which if incomplete, leads to anencephaly/exencephaly, cleft palate, omphalocele and coloboma, respectively. These are genetically heterogeneous birth defects, so there is a continued need to identify etiologic genes. Patients with autosomal dominantSPECC1Lmutations show syndromic malformations, including hypertelorism, cleft palate and omphalocele. TheseSPECC1Lmutations cluster in the second coiled-coil domain (CCD2), which facilitates association with microtubules. To study SPECC1L function in mice, we first generated a null allele (Specc1lΔEx4) lacking the entire SPECC1L protein. Homozygous mutants for these truncations died perinatally without cleft palate or exencephaly. Given the clustering of human mutations in CCD2, we hypothesized that targeted perturbation of CCD2 may be required. Indeed, homozygotes for in-frame deletions involving CCD2 (Specc1lΔCCD2) resulted in ~50% exencephaly and ~50% cleft palate. Interestingly, these two phenotypes are never observed in the same embryo. Examination of embryos with and without exencephaly revealed that the oral cavity was narrower in exencephalic embryos, which allowed palatal shelves to elevate despite their defect. In contrast to an evenly distributed subcellular expression pattern, mutant SPECC1L-ΔCCD2 protein showed abnormal subcellular localization, decreased overlap with microtubules, increased actin bundles, and dislocated non-muscle myosin II to the cell cortex. Thus, we show that perturbations of CCD2 in the context of full SPECC1L protein affects tissue fusion dynamics, indicating that humanSPECC1LCCD2 mutations are gain-of-function. Improper SPECC1L subcellular localization appears to disrupt connections between actomyosin and microtubule networks, which in turn may affect cell alignment and coordinate movement during tissue morphogenesis.
Use of continuous sample translation to reduce radiation damage for XPCS studies of protein diffusion
Authors: Lurio Laurence B. , Thurston George M. , Zhang Qingteng , Narayanan Suresh , Dufresne Eric M. 
Published: January 2021

An experimental setup to measure X-ray photon correlation spectroscopy during continuous sample translation is presented and its effectiveness as a means to avoid sample damage in dynamics studies of protein diffusion is evaluated. X-ray damage from focused coherent synchrotron radiation remains below tolerable levels as long as the sample is translated through the beam sufficiently quickly. Here it is shown that it is possible to separate sample dynamics from the effects associated with the transit of the sample through the beam. By varying the sample translation rate, the damage threshold level, D
thresh = 1.8 kGy, for when beam damage begins to modify the dynamics under the conditions used, is also determined. Signal-to-noise ratios, R
sn ≥ 20, are obtained down to the shortest delay times of 20 µs. The applicability of this method of data collection to the next generation of multi-bend achromat synchrotron sources is discussed and it is shown that sub-microsecond dynamics should be obtainable on protein samples.
NMR spectroscopy in wine authentication: An official control perspective
Authors: Solovyev Pavel A. , Fauhl‐Hassek Carsten , Riedl Janet , Esslinger Susanne , Bontempo Luana , Camin Federica 
Published: January 2021

AbstractWine authentication is vital in identifying malpractice and fraud, and various physical and chemical analytical techniques have been employed for this purpose. Besides wet chemistry, these include chromatography, isotopic ratio mass spectrometry, optical spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy, which have been applied in recent years in combination with chemometric approaches. For many years, 2H NMR spectroscopy was the method of choice and achieved official recognition in the detection of sugar addition to grape products. Recently, 1H NMR spectroscopy, a simpler and faster method (in terms of sample preparation), has gathered more and more attention in wine analysis, even if it still lacks official recognition. This technique makes targeted quantitative determination of wine ingredients and nontargeted detection of the metabolomic fingerprint of a wine sample possible. This review summarizes the possibilities and limitations of 1H NMR spectroscopy in analytical wine authentication, by reviewing its applications as reported in the literature. Examples of commercial and open‐source solutions combining NMR spectroscopy and chemometrics are also examined herein, together with its opportunities of becoming an official method.
Histamine accumulation in dairy products: Microbial causes, techniques for the detection of histamine‐producing microbiota, and potential solutions
Authors: Moniente Marta , García‐Gonzalo Diego , Ontañón Ignacio , Pagán Rafael , Botello‐Morte Laura 
Published: January 2021

AbstractHistamine poisoning is a significant public health and safety concern. Intoxication from ingestion of food containing high amounts of histamine may cause mild or severe symptoms that can even culminate in cardiac arrest. Nonetheless, although histamine levels in dairy products are not subject to any regulation, important outbreaks and severe adverse health effects have been reported due to intake of dairy products with a high histamine content, especially ripened cheeses. Histamine, a biogenic amine, can accumulate in dairy products as a result of the metabolism of starter and nonstarter lactic acid bacteria, as well as yeasts that contribute to the ripening or flavoring of the final product, or even as a result of spoilage bacteria. The aim of this review is to describe the microbiological causes of the presence of histamine in fermented milk products, and to propose control measures and potential methods for obtaining histamine‐free dairy products. Thus, this manuscript focuses on histamine‐producing microbiota in dairy products, highlighting the detection of histamine‐producing bacteria through traditional and novel techniques. In addition, this review aims to explore control measures to prevent the access of histamine‐producing microbiota to raw materials, as well as the formation of histamine in dairy products, such as a careful selection of starter cultures lacking the ability to produce histamine, or even the implementation of effective food processing technologies to reduce histamine‐producing microbiota. Finally, the removal of histamine already formed in dairy products through histamine‐degrading microorganisms or by enzymatic degradation will also be explored.
A review of microbes and chemical contaminants in dairy products in sub‐Saharan Africa
Authors: Akinyemi Muiz O. , Ayeni Kolawole I. , Ogunremi Omotade R. , Adeleke Rasheed A. , Oguntoyinbo Folarin A. , Warth Benedikt , Ezekiel Chibundu N. 
Published: January 2021

AbstractAnimal milk types in sub‐Saharan Africa (SSA) are processed into varieties of products using different traditional methods and are widely consumed by households to support nutritional intake and diet. Dairy products contain several microorganisms, their metabolites, and other chemical compounds, some with health benefits and many others considered as potential health hazards. Consumption of contaminated milk products could have serious health implications for consumers. To access the safety of milk products across SSA, studies in the region investigating the occurrences of pathogens as well as chemical compounds such as heat stable toxins and veterinary drug residues in animal milk and its products were reviewed. This is done with a holistic view in light of the emerging exposome paradigm for improving food safety and consumer health in the region. Herein, we showed that several published studies in SSA applied conventional and/or less sensitive methods in detecting microbial species and chemical contaminants. This has serious implications in food safety because the correct identity of a microbial species and accurate screening for chemical contaminants is crucial for predicting the potential human health effects that undermine the benefits from consumption of these foods. Furthermore, we highlighted gaps in determining the extent of viral and parasitic contamination of milk products across SSA as well as investigating multiple classes of chemical contaminants. Consequently, robust studies should be conducted in this regard. Also, efforts such as development cooperation projects should be initiated by all stakeholders including scientists, regulatory agencies, and policy makers to improve the dairy product chain in SSA in view of safeguarding consumer health.