bluuebunny/crossref_metadata_2025 huggingface dataset:
Extent of cord pathology in the lumbosacral enlargement in non-traumatic versus traumatic spinal cord injury
Authors: David Gergely , Vallotton Kevin , Hupp Markus , Curt Armin , Freund Patrick , Seif Maryam
Published: October 2021

Objectives

This study compares remote neurodegenerative changes caudal to a cervical injury in degenerative cervical myelopathy (DCM) (i.e. non-traumatic) and incomplete traumatic spinal cord injury (tSCI) patients, using MRI-based tissue area measurements and diffusion tensor imaging (DTI).

Methods

Eighteen mild to moderate DCM patients with sensory impairments (mean mJOA score: 16.2), 14 incomplete tetraplegic tSCI patients (AIS C&D), and 20 healthy controls were recruited. All participants received DTI and T2*-weighted scans in the lumbosacral enlargement (caudal to injury) and at C2/C3 (rostral to injury). MRI readouts included DTI metrics in the white matter (WM) columns and cross-sectional WM and gray matter area. One-way ANOVA with Tukey post-hoc comparison (p<0.05) was used to assess group differences.

Results

In the lumbosacral enlargement, compared to DCM, tSCI patients exhibited decreased fractional anisotropy in the lateral (tSCI vs. DCM, −11.9%, p=0.007) and ventral WM column (−8.0%, p=0.021), and showed trend toward lower values in the dorsal column (−8.9%, p=0.068). At C2/C3, no differences in DTI metrics were observed between DCM and tSCI, but compared to controls, fractional anisotropy was lower in both groups in the dorsal (DCM vs. controls, −7.9%, p=0.024; tSCI vs. controls, −10.0%, p=0.007) and in the lateral column (DCM: −6.2%, p=0.039; tSCI: −13.3%, p<0.001). WM areas were not different between patient groups, but were significantly lower compared to healthy controls both in the lumbosacral enlargement (DCM: −16.9%, p<0.001; tSCI, −10.5%, p=0.043) and at C2/C3 (DCM: −16.0%, p<0.001; tSCI: −18.1%, p<0.001).

Conclusion

In conclusion, mild to moderate DCM and incomplete tSCI lead to similar degree of degeneration of the dorsal and lateral columns at C2/C3, but tSCI results in more widespread white matter damage in the lumbosacral enlargement. These remote changes are likely to contribute to the impairment and recovery of the patients. Diffusion MRI is a sensitive tool to assess remote pathological changes in DCM and tSCI patients.
Signed Distance Correlation (SiDCo): A network analysis application of distance correlation for identifying metabolic networks disrupted in Dementia with Lewy Bodies
Authors: Čuperlović-Culf Miroslava , Yilmaz Ali , Stewart David , Surendra Anuradha , Akyol Sumeyya , Vishweswaraiah Sangeetha , Shao Xiaojian , Alecu Irina , Nguyen-Tran Thao , McGuinness Bernadette , Passmore Peter , Kehoe Patrick G. , Maddens Michael E. , Green Brian D. , Graham Stewart F. , Bennett Steffany A.L.
Published: October 2021

Motivation

Identifying pathological metabolic changes in complex disease such as Dementia with Lewy Bodies (DLB) requires a deep understanding of functional modifications in the context of metabolic networks. Network determination and analysis from metabolomics and lipidomics data remains a major challenge due to sparse experimental coverage, a variety of different functional relationships between metabolites and lipids, and only sporadically described reaction networks.

Results

Distance correlation, measuring linear and non-linear dependences between variables as well as correlation between vectors of different lengths, e.g. different sample sizes, is presented as an approach for data-driven metabolic network development. Additionally, novel approaches for the analysis of changes in pair-wise correlation as well as overall correlations for metabolites in different conditions are introduced and demonstrated on DLB data. Distance correlation and signed distance correlation was utilized to determine metabolic network in brain in DLB patients and matching controls and results for the two groups are compared in order to identify metabolites with the largest functional change in their network in the disease state. Novel correlation network analysis showed alterations in the metabolic network in DLB brains relative to the controls, with the largest differences observed in O-phosphocholine, fructose, propylene-glycol, pantothenate, thereby providing novel insights into DLB pathology only made apparent through network investigation with presented methods.
Co-administration of treatment for rifampicin-resistant tuberculosis and chronic hepatitis C virus infection: a TBnet and ESGMYC study
Authors: Tunesi Simone , Dû Damien Le , Gualano Gina , Millet Joan-Pau , Skrahin Aliaksandr , Bothamley Graham , Casas Xavier , Goletti Delia , Lange Christoph , Musso Maria , Palmieri Fabrizio , Pourcher Valérie , Rioux Christophe , Skrahina Alena , Veziris Nicolas , Viatushka Dzmitry , Jachym-Fréchet Mathilde , Guglielmetti Lorenzo ,   for the TBnet,   the ESGMYC,   the French MDR-TB Group
Published: October 2021

Concomitant treatment for chronic hepatitis C virus infection and multidrug-resistant tuberculosis is safe and effective.
Durability of antibody responses and frequency of clinical and subclinical SARS-CoV-2 infection six months after BNT162b2 COVID-19 vaccination in healthcare workers
Authors: Laing Eric D. , Weiss Carol D. , Samuels Emily C. , Coggins Si’Ana A. , Wang Wei , Wang Richard , Vassell Russell , Sterling Spencer L. , Tso Marana A. , Conner Tonia , Goguet Emilie , Moser Matthew , Jackson-Thompson Belinda M. , Illinik Luca , Davies Julian , Ortega Orlando , Parmelee Edward , Hollis-Perry Monique , Maiolatesi Santina E. , Wang Gregory , Ramsey Kathleen F. , Reyes Anatalio E. , Alcorta Yolanda , Wong Mimi A. , Lindrose Alyssa R. , Duplessis Christopher A. , Tribble David R. , Malloy Allison M.W. , Burgess Timothy H. , Pollett Simon D. , Olsen Cara H. , Broder Christopher C. , Mitre Edward
Published: October 2021

Antibodies against SARS-CoV-2 decay but persist six months post-vaccination, with lower levels of neutralizing titers against Delta than wild-type. Only 2 of 227 vaccinated healthcare workers experienced outpatient symptomatic breakthrough infections despite 59 of 227 exhibiting serological evidence of exposure to SARS-CoV-2 as defined by development of anti-nucleocapsid protein antibodies.
Can infrared camera images be used for screening in Adolescent Idiopathic Scoliosis?
Authors: Ka Natalie Lam Oi , Peng James Cheng , Zhang Teng , Yip Joanne , Fok Queenie , Lee Maple , Wong Charlotte , Kwan Kenny , Cheung Kenneth MC
Published: October 2021

Introduction/Background context

Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis, and affects up to 4% of adolescents in early stages1. The deformity can develop during any of the rapid periods of growth in children2, and the time of pubertal growth spurt also plays a role in spinal curve progression3. Hence it is crucial to detect the disease early, to provide timely intervention.

Detection of scoliosis when it is mild or before the growth spurt can be conducted via various screening methods. Adam’s forward bend test (FBT) and scoliometer measurement of the angle of trunk rotation (ATR) are commonly used4, to observe lateral bending and rotation of the spine, causing a visible rib hump. Moiré topography can also be used, but is reserved for second tier due to some degree of ambiguity5. X-rays (XR) remain the best way to diagnose scoliosis, as it provides a clear image of the spine and allows measurement of Cobb angle; however it has risks associated including requirement of the use of ionising radiation6.

Infrared (IR) thermography can be used to measure surface temperature and is performed with an IR camera. The temperature distribution and data matrix can be visualised into a thermal map, which has previously been studied and associated with the thermal asymmetry in paraspinal muscles7, as well as significant temperature differences between the convex and concave side of the spinal curvature for idiopathic scoliotic patients8. We hypothesize that such asymmetry and temperature differences may produce a detectable pattern on IR thermography, which would prompt further confirmatory investigations to reach a fast and non-radiation screening of AIS.

Aims and Objectives

For the purposes of this study, the hypothesised thermal pattern detected by IR thermography will be compared to the spinal deformities observed on XR, the ground truth as labelled by specialists. This will allow us to establish a paired dataset comparing spine visualisation between the two imaging modalities. Thus, the compared dataset would enable the generation of a machine learning model capable of automated classification of the deformity severities. The predictive accuracy of the model will be evaluated by the specialists’ assessment results. The aim of the project is to use IR to predict the severity of the scoliotic curve, opening up the possibility of using IR thermography with no radiation exposure and fully automated analytical pipeline for the screening of AIS.
Computer skills of health workers in rural Ghana and their use of social media: Implications for increased use of information technology in service delivery
Authors: Ofori Sylvia K , Akowuah Emmanuel A , Babatunde Doyinsola , Cowan Logan , Baiden Frank
Published: October 2021

Background

Information and Communication Technologies (ICTs) have improved the delivery of healthcare worldwide especially in disease control, patient management, and health data analysis. However, access to infrastructure like computers and knowledge of ICT is a major problem to various digital health initiatives among health professionals.

Objective

The aim of the present study was, to assess healthcare workers’ basic computer skills and use of social media and identify specific deficiencies that require training to help them function effectively.

Methods

We conducted a cross-sectional study among 51 healthcare workers in seven health centers in a region in Ghana over three months using a self-administered pre-tested questionnaire.

Results

Half of the participants had adequate basic computer skills, of which 60.87% were women (P=0.0205). Only 15.69%, who were all males, of participants used computer software at least once a month. Most participants also used Facebook and WhatsApp.

Conclusion

Health professionals in the health centers need to be trained on basic computer skills and, information technology should be incorporated into the health systems for efficient health delivery.
HEAT SHOCK FACTOR BINDING PROTEIN limits meiotic crossovers by repressing HEI10 transcription
Authors: Kim Juhyun , Park Jihye , Kim Heejin , Son Namil , Lambing Christophe , Kim Eun-Jung , Kim Jaeil , Byun Dohwan , Lee Youngkyung , Park Yeong Mi , Nageswaran Divyashree C. , Kuo Pallas , Dang Tuong Vi T. , Hwang Ildoo , Henderson Ian R. , Choi Kyuha
Published: October 2021

The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a sensitive fluorescent seed crossover reporter in Arabidopsis thaliana we identify heat shock factor binding protein (HSBP) as a repressor of HEI10 transcription and crossover numbers. Using genome-wide crossover mapping and cytogenetics, we show that hsbp mutations or meiotic HSBP knockdowns increase ZMM-dependent crossovers towards the telomeres, mirroring the effects of HEI10 overexpression. Through RNA sequencing, DNA methylome and chromatin immunoprecipitation analysis, we reveal that HSBP directly represses HEI10 transcription by binding with heat shock factors (HSFs) at the HEI10 promoter and maintaining DNA methylation over the HEI10 5′ untranslated region. Our findings provide insights into how the temperature response regulator HSBP restricts meiotic HEI10 transcription and crossover number by attenuating HSF activity.
Plant-based production of SARS-CoV-2 antigens for use in a subunit vaccine
Authors: Demone Jordan , Nourimand Maryam , Maltseva Mariam , Nasr-Sharif Mina , Galipeau Yannick , Langlois Marc-André , MacLean Allyson M.
Published: October 2021

The COVID-19 pandemic has brought to the forefront an urgent need for the rapid development of highly efficacious vaccines, particularly in light of the ongoing emergence of multiple variants of concern. Plant-based recombinant protein platforms are emerging as cost-effective and highly scalable alternatives to conventional protein production. Viral glycoproteins, however, are historically challenging to produce in plants. Herein, we report the production of plant-expressed wild-type glycosylated SARS-CoV-2 Spike RBD (receptor-binding domain) protein that is recognized by anti-RBD antibodies and exhibits high-affinity binding to the SARS-CoV-2 receptor ACE2 (angiotensin-converting enzyme 2). Moreover, our plant-expressed RBD was readily detected by IgM, IgA, and IgG antibodies from naturally infected convalescent, vaccinated, or convalescent and vaccinated individuals. We further demonstrate that RBD binding to the ACE2 receptor was efficiently neutralized by antibodies from sera of SARS-CoV-2 convalescent and partially and fully vaccinated individuals. Collectively, these findings demonstrate that recombinant RBD produced in planta exhibits suitable biochemical and antigenic features for use in a subunit vaccine platform.
Outsourced hearing in an orb-weaving spider that uses its web as an auditory sensor
Authors: Zhou Jian , Lai Junpeng , Menda Gil , Stafstrom Jay A. , Miles Carol I. , Hoy Ronald R. , Miles Ronald N.
Published: October 2021

Hearing is a fundamental sense of many animals, including all mammals, birds, some reptiles, amphibians, fish, and arthropods. The auditory organs of these animals are extremely diverse in anatomy after hundreds of millions of years of evolution, yet all are made up of cellular tissues and are morphologically part of bodies of animals. Here we show hearing in the orb-weaving spider, Larinioides sclopetarius is not constrained by the organism’s body but is extended through outsourcing hearing to its extended phenotype, the proteinaceous, self-manufactured orb-web. We find the wispy, wheel-shaped orb-web acts as a hyperacute acoustic “antenna” to capture the sound-induced air particle movements that approach the maximum physical efficiency, better than the acoustic responsivity of all previously known eardrums. By sensing the motion of web threads, the spider remotely detects and localizes the source of an incoming airborne acoustic wave such as those emitted by approaching prey or predators. By outsourcing its acoustic sensors to its web, the spider is released from body size constraints and permits the araneid spider to increase its sound-sensitive surface area enormously, up to 10,000 times greater than the spider itself. The spider also enables the flexibility to functionally adjust and regularly regenerate its “external eardrum” according to its needs. The “outsourcing” and “supersizing” of auditory function in spiders provides unique features for studying extended and regenerative sensing, and designing novel acoustic flow detectors for precise fluid dynamic measurement and manipulation.
Dynamic changes in spatial representation within the posterior parietal cortex in response to visuomotor adaptation
Authors: Schintu S , Kravitz DJ , Silson EH , Cunningham CA , Wassermann EM , Shomstein S
Published: October 2021

Recent studies used fMRI population receptive field (pRF) mapping to demonstrate that retinotopic organization extends from primary visual cortex to ventral and dorsal visual pathways by quantifying visual field maps, receptive field size, and laterality throughout multiple areas. Visuospatial representation in the posterior parietal cortex (PPC) is modulated by attentional deployment, raising the question of whether spatial representation in the PPC is dynamic and flexible and that this flexibility contributes to visuospatial learning. To answer this question, changes in spatial representation within PPC, as measured with pRF mapping, were recorded before and after visuomotor adaptation. Visuospatial input was laterally manipulated, rightward or leftward, via prism adaptation, a well-established visuomotor technique that modulates visuospatial performance. Based on existing models of prism adaptation mechanism of action, we predicted left prism adaptation to produce a right visuospatial bias via an increasing pRF size in the left parietal cortex. However, our hypothesis was agnostic as to whether right PPC will show an opposite effect given the bilateral bias to right visual field. Findings show that adaptation to left-shifting prisms increases pRF size in both PPCs, while leaving space representation in early visual cortex unchanged. This is the first evidence that prism adaptation drives a dynamic reorganization of response profiles in the PPC. Our results show that spatial representation in the PPC not only reflects changes driven by attentional deployment but dynamically changes in response to visuomotor adaptation. Furthermore, our results provide support for using prism adaptation as a tool to rehabilitate visuospatial deficits.

SIGNIFICANCE STATEMENT

Representation of space in the posterior parietal cortex (PPC) is reflective of attentional selection. Deploying attention to a certain spatial location modulates response profiles of a corresponding set of neurons with receptive fields in the corresponding spatial location. Here, we show that visuomotor adaptation accomplished through left-shifting prism adaptation dynamically changes the representation of space in the PPC while preserving early visual representations. This is the first evidence that visuomotor adaptation drives an instant reorganization of spatial representation in PPC. This result has implications for understanding the dynamic organization of spatial representation in the PPC and for the rehabilitation of patients with neglect syndrome, whose spatial attention is compromised.
Hiding in the yolk: a unique feature ofLegionella pneumophilainfection of zebrafish
Authors: Viana Flávia , Boucontet Laurent , Laghi Valerio , Schator Daniel , Ibranosyan Marine , Jarraud Sophie , Colucci-Guyon Emma , Buchrieser Carmen
Published: October 2021

The zebrafish has become a powerful model organism to study host-pathogen interactions. Here, we developed a zebrafish model ofLegionella pneumophilainfection to dissect innate immune responses. We show thatL. pneumophilacause zebrafish larvae death in a dose dependent manner, and that macrophages are the first line of defence, with neutrophils cooperating to clear the infection. When either macrophages or neutrophils are depleted, these “immunocompromised” larvae become lethally sensitive toL. pneumophilasimilar to what is known for humans that develop pneumonia. Also as observed in human infections, the adaptor signalling molecule Myd88 is not required to control disease in the larvae. Furthermore, proinflammatory cytokine genesil1ßandtnfαwere upregulated during infection, recapitulating key immune responses seen in human infection. Strikingly, we uncovered a previously undescribed infection phenotype in zebrafish larvae, whereby bloodborne, wild typeL. pneumophilainvade and grow in the larval yolk region, a phenotype not observed with a type IV secretion system deficient mutant that cannot translocate effectors into its host cell. Thus, zebrafish larva represents an innovativeL. pneumophilainfection model that that on one hand mimics important aspects of the human immune response toL. pneumophilainfection and that on the other hand will allow to elucidate the mechanisms by which type IV secretion effectors allowL. pneumophilato cross membranes and to obtain nutrients from nutrient rich environments.
Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing
Authors: Katsman Efrat , Orlanski Shari , Martignano Filippo , Fox-Fisher Ilana , Shemer Ruth , Dor Yuval , Zick Aviad , Eden Amir , Petrini Iacopo , Conticello Silvestro G. , Berman Benjamin P.
Published: October 2021

The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for clinical sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNA) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell-type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy, especially real-time medical applications.
Widespread Utilization of Diverse Organophosphate Pollutants by Marine Bacteria
Authors: Despotović Dragana , Aharon Einav , Trofimyuk Olena , Dubovetskyi Artem , Cherukuri Kesava Phaneendra , Ashani Yacov , Leader Haim , Castelli Andrea , Fumagalli Laura , Savidor Alon , Levin Yishai , Longo Liam M. , Segev Einat , Tawfik Dan S.
Published: October 2021

Anthropogenic organophosphates (AOPs), such as phosphotriesters, are used extensively as plasticizers, flame retardants, nerve agents and pesticides. Soil bacteria bearing a phosphotriesterase (PTE) can degrade AOPs, but whether bacteria are capable of utilizing AOPs as a phosphorus source, and how widespread PTEs are in nature, remains unclear. Here, we report the utilization of diverse AOPs by four model marine bacteria and seventeen bacterial isolates from seawater samples. To unravel the details of AOP utilization, two novel PTEs from marine bacteria were isolated and characterized. When expressed in E. coli, these PTEs enabled growth on a pesticide analog as the sole phosphorus source. Utilization of AOPs provides bacteria with a source of phosphorus in depleted environments and offers a new prospect for the bioremediation of a pervasive class of anthropogenic pollutants.

One sentence summary

Widespread utilization of diverse organophosphate pollutants by over 20 marine bacterial strains represents a new hope for ocean bioremediation.
ARGONAUTE proteins regulate a specific network of genes through KLF4 in mouse embryonic stem cells
Authors: Müller Madlen , Schaefer Moritz , Fäh Tara , Spies Daniel , Peña-Hernández Rodrigo , Santoro Raffaella , Ciaudo Constance
Published: October 2021

The Argonaute proteins (AGO) are well-known for their essential role in post-transcriptional gene silencing in the microRNA (miRNA) biogenesis pathway. Only two AGOs (AGO1 and AGO2) are expressed in mouse embryonic stem cells (mESCs). The transcriptome ofAgomutant mESCs revealed a large and specific set of misregulated genes, compared to other miRNA biogenesis factor mutant cells, suggesting additional functions for the AGOs in stem cells. In this study, we endeavored to understand miRNA-independent roles of the AGOs in gene expression regulation through the integration of multiple datasets. Correlation ofAgomutant differential gene expression with ENCODE histone modification data of WT mESCs revealed that affected genes were regulated by the repressive histone modification H3K27me3. We validated this observation by performing chromatin immunoprecipitation followed by sequencing and observed a global loss of H3K27me3 inAgomutant cells. Nevertheless, this reduction explains only a small part of the specific differential gene expression observed inAgomutant mESCs. By integrating chromatin accessibility data in conjunction with prediction of transcription factor binding sites, we identified differential binding for five transcription factors, including KLF4 as a key modulator of more than half of the specific misregulation of gene expression in the absence of AGO proteins. Our findings illustrate that in addition to chromatin state, information about transcription factor binding is more revelatory in understanding the multi-layered mechanism adopted by cells to regulate gene expression. These data also highlight the importance of an integrative approach to unravel the variety of noncanonical functions of AGOs in mESCs.
Concentration fluctuations due to size-dependent gene expression and cell-size control mechanisms
Authors: Jia Chen , Singh Abhyudai , Grima Ramon
Published: October 2021

Intracellular reaction rates depend on concentrations and hence their levels are often regulated. However classical models of stochastic gene expression lack a cell size description and cannot be used to predict noise in concentrations. Here, we construct a model of gene product dynamics that includes a description of cell growth, cell division, size-dependent gene expression, gene dosage compensation, and size control mechanisms that can vary with the cell cycle phase. We obtain expressions for the approximate distributions and power spectra of concentration fluctuations which lead to insight into the emergence of concentration homeostasis. Furthermore, we find that (i) the conditions necessary to suppress cell division-induced concentration oscillations are difficult to achieve; (ii) mRNA concentration and number distributions can have different number of modes; (iii) certain size control strategies are ideal because they maintain constant mean concentrations whilst minimising concentration noise. Predictions are confirmed using lineage data for E. coli, fission yeast and budding yeast.
Remembering the pattern: A longitudinal case study on statistical learning in spatial navigation and memory consolidation
Authors: Graves Kathryn N. , Sherman Brynn E. , Huberdeau David , Damisah Eyiyemisi , Quraishi Imran H. , Turk-Browne Nicholas B.
Published: October 2021

Distinct brain systems are thought to support statistical learning over different timescales. Regularities encountered during online perceptual experience can be acquired rapidly by the hippocampus. Further processing during offline consolidation can establish these regularities gradually in cortical regions, including the medial prefrontal cortex (mPFC). These mechanisms of statistical learning may be critical during spatial navigation, for which knowledge of the structure of an environment can facilitate future behavior. Rapid acquisition and prolonged retention of regularities have been investigated in isolation, but how they interact in the context of spatial navigation is unknown. We had the rare opportunity to study the brain systems underlying both rapid and gradual timescales of statistical learning using intracranial electroencephalography (iEEG) longitudinally in the same patient over a period of three weeks. As hypothesized, spatial patterns were represented in the hippocampus but not mPFC for up to one week after statistical learning and then represented in the mPFC but not hippocampus two and three weeks after statistical learning. Taken together, these findings clarify that the hippocampus may do the initial work of extracting regularities and transfer these integrated memories to cortex, rather than only storing individual experiences and leaving it up to cortex to extract regularities.

Highlights

Case study of an epilepsy patient tested longitudinally over three weeks.

We tracked time-dependent changes in neural representations of spatial patterns.

Representations reconstructed from hippocampal activity reflected patterns learned within a week.

Representations reconstructed from activity in the mPFC reflected patterns learned 2–3 weeks ago.
Release of the ribosome biogenesis factor Bud23 from small subunit precursors in yeast
Authors: Black Joshua J. , Johnson Arlen W.
Published: October 2021

Ribosomes are the universally conserved ribonucleoprotein complexes that synthesize proteins. The two subunits of the eukaryotic ribosome are produced through a quasi-independent assembly-line-like pathway involving the hierarchical actions of numerous trans-acting biogenesis factors and the incorporation of ribosomal proteins. The factors work together to shape the nascent subunits through a series of intermediate states into their functional architectures. The earliest intermediate of the small subunit (SSU or 40S) is the SSU Processome which is subsequently transformed into the pre-40S intermediate. This transformation is, in part, facilitated by the binding of the methyltransferase Bud23. How Bud23 is released from the resultant pre-40S is not known. The ribosomal proteins Rps0, Rps2, and Rps21, termed the Rps0-cluster proteins, and several biogenesis factors are known to bind the pre-40S around the time that Bud23 is released, suggesting that one or more of these factors induce Bud23 release. Here, we systematically examined the requirement of these factors for the release of Bud23 from pre-40S particles. We found that the Rps0-cluster proteins are needed but not sufficient for Bud23 release. The atypical kinase/ATPase Rio2 shares a binding site with Bud23 and is thought to be recruited to pre-40S after the Rps0-cluster proteins. Depletion of Rio2 prevented the release of Bud23 from the pre-40S. More importantly, the addition of recombinant Rio2 to pre-40S particles affinity-purified from Rio2-depleted cells was sufficient for Bud23 release in vitro. The ability of Rio2 to displace Bud23 was independent of nucleotide hydrolysis. We propose a novel role for Rio2 in which its binding to the pre-40S actively displaces Bud23 from the pre-40S, and we suggest a model in which the binding of the Rps0-cluster proteins and Rio2 promote the release of Bud23.
Two distinct classes of co-chaperones compete for the EEVD motif in heat shock protein 70 (Hsp70) to tune its activity
Authors: Johnson Oleta T. , Nadel Cory M. , Carroll Emma C. , Arhar Taylor , Gestwicki Jason E.
Published: October 2021

Chaperones of the heat shock protein 70 (Hsp70) family engage in protein-protein interactions (PPIs) with many co-chaperones. One hotspot for co-chaperone binding is the EEVD motif that is found at the extreme C-terminus of cytoplasmic Hsp70s. This motif is known to bind tetratricopeptide repeat (TPR) domain co-chaperones, such as the E3 ubiquitin ligase CHIP, and Class B J-domain proteins (JDPs), such as DnaJB4. Although complexes between Hsp70-CHIP and Hsp70-DnaJB4 are both important for chaperone functions, the molecular determinants that dictate the competition between these co-chaperones are not clear. Using a collection of EEVD-derived peptides, we find that DnaJB4 binds to the IEEVD motif of Hsp70s, but not the related MEEVD motif of cytoplasmic Hsp90s. Then, we explored which residues are critical for binding to CHIP and DnaJB4, revealing that they rely on some shared features of the IEEVD motif, such as the C-terminal carboxylate. However, they also had unique preferences, especially at the isoleucine position. Finally, we observed a functionally important role for competition between CHIP and DnaJB4 in vitro, as DnaJB4 can limit the ubiquitination activity of the Hsp70-CHIP complex, while CHIP suppresses the chaperone activities of Hsp70-DnaJB4. Together, these results suggest that the EEVD motif has evolved to support diverse PPIs, such that competition between co-chaperones could help guide whether Hsp70-bound proteins are folded or degraded.
Cryo-ET distinguishes platelets during pre-acute myeloid leukemia from steady state hematopoiesis
Authors: Wang Yuewei , Huo Tong , Tseng Yu-Jung , Dang Lan , Yu Zhili , Yu Wenjuan , Foulks Zachary , Ludtke Steven J. , Nakada Daisuke , Wang Zhao
Published: October 2021

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes in the overall shape and depletion of organelles in AML. Notably, 23% of platelets in pre-leukemic cells exhibit abnormal, round mitochondria with unfolded cristae, accompanied by a significant drop in ATP levels and altered expression of metabolism-related gene signatures. Our study demonstrates that detectable structural changes in pre-leukemic platelets may serve as a biomarker for the early diagnosis of AML.
p38α-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic AD mice
Authors: Luo Qinghua , Schnöder Laura , Hao Wenlin , Litzenburger Kathrin , Decker Yann , Tomic Inge , Menger Michael D. , Fassbender Klaus , Liu Yang
Published: October 2021

Microglial activation is a hall marker of Alzheimer’s disease (AD); its pathogenic role and regulating mechanisms are unclear. p38α-MAPK, a stress-responding kinase, is activated in AD brain in early disease stages. In APP-transgenic mice, we deleted p38α-MAPK in whole myeloid cells from birth or specifically in microglia from 9 months, and analysed AD pathology at the age of 4, 9 and 12 months. In both experimental settings, p38α-MAPK deficiency decreased cerebral Aβ and improved cognitive function of AD mice; however, p38α-MAPK-deficient myeloid cells were more effective than p38α-MAPK-deficient microglia in preventing AD pathogenesis. Deficiency of p38α-MAPK in myeloid cells inhibited the inflammatory activation of individual microglia by 4 months, but enhanced it by 9 months. Inflammatory activation was essential for p38α-MAPK deficiency to promote microglial internalization of Aβ. Interestingly, p38α-MAPK deficiency in peripheral myeloid cells reducedil-17atranscription in CD4-positive spleen cells. By cross-breeding APP-transgenic mice and IL-17a knockout mice, we further observed that IL-17a deficiency activated microglia and decreased Aβ deposits in AD mouse brain. Thus, p38α-MAPK deficiency in myeloid cells prevents AD pathogenesis, perhaps through reducing IL-17a-expressing T lymphocytes, and promoting Aβ clearance in the brain. Our study supports p38α-MAPK as a novel target for AD therapy.
EZTraits: a Programmable Tool to Evaluate Multi-site Deterministic Traits
Authors: Carland Matt , Bose Madhuchanda , Novković Biljana , Pedersen Haley , Manson Charles , Lahan Shany , Pavlenko Alex , Yazdi Puya G. , Grabherr Manfred G.
Published: October 2021

The vast majority of human traits, including many disease phenotypes, are affected by alleles at numerous genomic loci. With a continually increasing set of variants with published clinical disease or biomarker associations, an easy-to-use tool for non-programmers to rapidly screen VCF files for risk alleles is needed. We have developed EZTraits as a tool to quickly evaluate genotype data (e.g., from microarrays) against a set of rules defined by the user. These rules can be defined directly in the scripting language Lua, for genotype calls using variant ID (RS number) or chromosomal position. Alternatively, EZTraits can parse simple and intuitive text including concepts like ‘any’ or ‘all’. Thus, EZTraits is designed to support rapid genetic analysis and hypothesis-testing by researchers, regardless of programming experience or technical background. The software is implemented in C++ and compiles and runs on Linux and MacOS. The source code is available under the MIT license from https://github.com/selfdecode/rd-eztraits

Contact: manfred@selfdecode.com
Positive selection in noncoding genomic regions of vocal learning birds is associated with genes implicated in vocal learning and speech functions in humans
Authors: Cahill James A. , Armstrong Joel , Deran Alden , Khoury Carolyn J. , Paten Benedict , Haussler David , Jarvis Erich D.
Published: October 2021

Vocal learning, the ability to imitate sounds from conspecifics and the environment, is a key component of human spoken language and learned song in three independently evolved avian groups—oscine songbirds, parrots, and hummingbirds. Humans and each of these three bird clades exhibit specialized behavioral, neuroanatomical, and brain gene expression convergence related to vocal learning, speech, and song. To understand the evolutionary basis of vocal learning gene specializations and convergence, we searched for and identified accelerated genomic regions (ARs), a marker of positive selection, specific to vocal learning birds. We found avian vocal learner-specific ARs, and they were enriched in noncoding regions near genes with known speech functions or brain gene expression specializations in humans and vocal learning birds, including FOXP2, NEUROD6, ZEB2, and MEF2C, and near genes with major neurodevelopmental functions, including NR2F1, NRP2, and BCL11B. We also found enrichment near the SFARI class S genes associated with syndromic vocal communication forms of autism spectrum disorders. These findings reveal strong candidate noncoding regions near genes for the evolutionary adaptations that distinguish vocal learning species from their close vocal nonlearning relatives and provide further evidence of molecular convergence between birdsong and human spoken language.
Potential benefit of treatment with MEK inhibitors and chemotherapy in BRAF-mutated KRAS wild-type pancreatic ductal adenocarcinoma patients: a case report
Authors: Ardalan Bach , Azqueta Jose Ignacio , England Jonathan , Eatz Tiffany Alyssa
Published: October 2021

This is the first case report of a 60-yr-old female who underwent therapy for metastatic pancreatic cancer with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Upon the progression of her disease, she was switched to gemcitabine and nab-paclitaxel. Per genomic sequencing, her tumor was found to be a KRAS wild-type and BRAF V600E mutation, which then warranted treatment with the MEK1 and MEK2 inhibitor, cobimetinib. The patient has achieved a complete response (CR) to a combination of gemcitabine, nab-paclitaxel, and cobimetinib. It has been 16 mo since the start of the treatment, and the patient continues to demonstrate a complete durable response both serologically and radiologically.
Maternal mosaicism for a missense variant in the SMS gene that causes Snyder–Robinson syndrome
Authors: Marhabaie Mohammad , Hickey Scott E. , Miller Katherine , Grischow Olivia , Schieffer Kathleen M. , Franklin Samuel J. , Gordon David M. , Choi Samantha , Mihalic Mosher Theresa , White Peter , Koboldt Daniel C. , Wilson Richard K.
Published: October 2021

There is increasing recognition for the contribution of genetic mosaicism to human disease, particularly as high-throughput sequencing has enabled detection of sequence variants at very low allele frequencies. Here, we describe an infant male who presented at 9 mo of age with hypotonia, dysmorphic features, congenital heart disease, hyperinsulinemic hypoglycemia, hypothyroidism, and bilateral sensorineural hearing loss. Whole-genome sequencing of the proband and the parents uncovered an apparent de novo mutation in the X-linked SMS gene. SMS encodes spermine synthase, which catalyzes the production of spermine from spermidine. Inactivation of the SMS gene disrupts the spermidine/spermine ratio, resulting in Snyder–Robinson syndrome. The variant in our patient is absent from the gnomAD and ExAC databases and causes a missense change (p.Arg130Cys) predicted to be damaging by most in silico tools. Although Sanger sequencing confirmed the de novo status in our proband, polymerase chain reaction (PCR) and deep targeted resequencing to ∼84,000×–175,000× depth revealed that the variant is present in blood from the unaffected mother at ∼3% variant allele frequency. Our findings thus provided a long-sought diagnosis for the family while highlighting the role of parental mosaicism in severe genetic disorders.
The crystal structures of the enzyme hydroxymethylbilane synthase, also known as porphobilinogen deaminase
Authors: Helliwell John R.
Published: October 2021

The enzyme hydroxymethylbilane synthase (HMBS; EC 4.3.1.8), also known as porphobilinogen deaminase, catalyses the stepwise addition of four molecules of porphobilinogen to form the linear tetrapyrrole 1-hydroxymethylbilane. Thirty years of crystal structures are surveyed in this topical review. These crystal structures aim at the elucidation of the structural basis of the complex reaction mechanism involving the formation of tetrapyrrole from individual porphobilinogen units. The consistency between the various structures is assessed. This includes an evaluation of the precision of each molecular model and what was not modelled. A survey is also made of the crystallization conditions used in the context of the operational pH of the enzyme. The combination of 3D structural techniques, seeking accuracy, has also been a feature of this research effort. Thus, SAXS, NMR and computational molecular dynamics have also been applied. The general framework is also a considerable chemistry research effort to understand the function of the enzyme and its medical pathologies in acute intermittent porphyria (AIP). Mutational studies and their impact on the catalytic reaction provide insight into the basis of AIP and are also invaluable for guiding the understanding of the crystal structure results. Future directions for research on HMBS are described, including the need to determine the protonation states of key amino-acid residues identified as being catalytically important. The question remains – what is the molecular engine for this complex reaction? Thermal fluctuations are the only suggestion thus far.
Crystal structure of acetylxylan esterase from Caldanaerobacter subterraneus subsp. tengcongensis
Authors: Sasamoto Kohei , Himiyama Tomoki , Moriyoshi Kunihiko , Ohmoto Takashi , Uegaki Koichi , Nishiya Yoshiaki , Nakamura Tsutomu
Published: October 2021

The acetylxylan esterases (AXEs) classified into carbohydrate esterase family 4 (CE4) are metalloenzymes that catalyze the deacetylation of acetylated carbohydrates. AXE from Caldanaerobacter subterraneus subsp. tengcongensis (TTE0866), which belongs to CE4, is composed of three parts: a signal sequence (residues 1–22), an N-terminal region (NTR; residues 23–135) and a catalytic domain (residues 136–324). TTE0866 catalyzes the deacetylation of highly substituted cellulose acetate and is expected to be useful for industrial applications in the reuse of resources. In this study, the crystal structure of TTE0866 (residues 23–324) was successfully determined. The crystal diffracted to 1.9 Å resolution and belonged to space group I212121. The catalytic domain (residues 136–321) exhibited a (β/α)7-barrel topology. However, electron density was not observed for the NTR (residues 23–135). The crystal packing revealed the presence of an intermolecular space without observable electron density, indicating that the NTR occupies this space without a defined conformation or was truncated during the crystallization process. Although the active-site conformation of TTE0866 was found to be highly similar to those of other CE4 enzymes, the orientation of its Trp264 side chain near the active site was clearly distinct. The unique orientation of the Trp264 side chain formed a different-shaped cavity within TTE0866, which may contribute to its reactivity towards highly substituted cellulose acetate.
Getting our voice heard: empowering people with a learning disability to influence adult safeguarding policy
Authors: Montgomery Lorna , Davidson Gavin , Kelly Berni , McKendry Linda , Newton Leslie-Anne , Webb Paul , Wood Lisamarie
Published: October 2021

Purpose

The purpose of this paper is to present an examination of the development of adult safeguarding policy from the perspectives of both policymakers and those who have sought to influence policy, to empower individuals with a learning disability to have a say in how policies, that influence their life and impact their right to independence, are developed.

Design/methodology/approach

This paper is based on a project which was led by a UK-wide interdisciplinary and multi-agency team, which included the central involvement of peer researchers who had lived experience of learning disability. It was based on a participatory disability research design.

Findings

Factors which enabled or restrained individuals with a learning disability, and their supporting organisations, from getting their voice heard in policy development, are identified.

Originality/value

This paper builds on policy theory and research, making recommendations for policy makers, disabled people and their supporting organisations as to how adult safeguarding policy, could be more effectively informed and influenced.
Application of tools to support Linked Open Data
Authors: Saha Sujan , Mandal Sukumar
Published: October 2021

Purpose

These projects aim to improve library services for users in the future by combining Link Open Data (LOD) technology with data visualization. It displays and analyses search results in an intuitive manner. These services are enhanced by integrating various LOD technologies into the authority control system.

Design/methodology/approach

The technology known as LOD is used to access, recycle, share, exchange and disseminate information, among other things. The applicability of Linked Data technologies for the development of library information services is evaluated in this study.

Findings

Apache Hadoop is used for rapidly storing and processing massive Linked Data data sets. Apache Spark is a free and open-source data processing tool. Hive is a SQL-based data warehouse that enables data scientists to write, read and manage petabytes of data.

Originality/value

The distributed large data storage system Apache HBase does not use SQL. This study’s goal is to search the geographic, authority and bibliographic databases for relevant links found on various websites. When data items are linked together, all of the data bits are linked together as well. The study observed and evaluated the tools and processes and recorded each data item’s URL. As a result, data can be combined across silos, enhanced by third-party data sources and contextualized.
Impact of interactional context on relationship between ethical leadership and unethical behaviors: a serial mediation model
Authors: Yağmur Ali
Published: October 2021

Purpose

Behavioral effects of contextual factors that organizations subject to daily life and social dynamics of ongoing organizational life are conveyed to interactional context. It is considered as a form of coorientation blending organizational and individual ethics in relational form. This study aims to examine well-known effects of ethical leadership on unethical behaviors in interactional context. Sequentially related mediator effects of leader member exchange and symmetrical communication in this relationship are empirically explored.

Design/methodology/approach

Survey is applied to 494 personnel from 29 large companies. Obtained survey data is analyzed by confirmatory factory analysis, and hypotheses are tested for serial mediation by structural equation modelling with bootstrapping procedure.

Findings

Study proves the impact of interactional context on organizational constructs. It is demonstrated that individual behaviors are influenced by interactional, dynamical, contextual and social factors. Study finds that leadership effect can be empowered by socialization processes. Quality of social relationships and social interactions; socializing impact of symmetrical communication can foster ethical management. Interactional context can facilitate organizations’ adaptation to changing conditions.

Originality/value

A human is a relational being. They cannot act in vacuum, rather, act in ongoing context of relationships. Taking account of relational aspect of individual–organizational interaction, this study contributes to literature by proposing a definition of interactional context and by exploring the impact of interactional context on organizational behaviors. Also, the impact of ethical leadership on unethical behaviors is empirically explored in relational dimension which seems to be neglected by ethics literature.