bluuebunny/crossref_metadata_2025 huggingface dataset:
MutSigCVsyn: Identification of Thirty Synonymous Cancer Drivers
Authors: Rao Yiyun , Ahmed Nabeel , Pritchard Justin , O’Brien Edward
Published: January 2022

Synonymous mutations, which change only the DNA sequence but not the encoded protein sequence, can affect protein structure and function, mRNA maturation, and mRNA half-lives. The possibility that synonymous mutations can act as cancer drivers has been explored in several recent studies. However, none of these studies control for all three levels (patient, histology, and gene) of mutational heterogeneity that are known to affect the accurate identification of non-synonymous cancer drivers. Here, we create an algorithm, MutSigCVsyn, an adaptation of MutSigCV, to identify synonymous cancer drivers based on a novel non-coding background model that takes into account the mutational heterogeneity across these levels. Examining 2,572 PCAWG cancer whole-genome sequences, MutSigCVsyn identifies 30 novel synonymous drivers that include mutations in promising candidates like BCL-2. By bringing the best practices in non-synonymous driver identification to the analysis of synonymous drivers, these are promising candidates for future experimental study.
Blocking Kir6.2 channels with SpTx1 potentiates glucose-stimulated insulin secretion from murine pancreatic β cells and lowers blood glucose in diabetic mice
Authors: Ramu Yajamana , Yamakaze Jayden , Zhou Yufeng , Hoshi Toshinori , Lu Zhe
Published: January 2022

ATP-sensitive K+ (KATP) channels in pancreatic β cells comprise pore-forming subunits (Kir6.2) and modulatory sulfonylurea receptor subunits (SUR1). The ATP sensitivity of these channels enables them to couple metabolic state to insulin secretion in β cells. Antidiabetic sulfonylureas such as glibenclamide target SUR1 and indirectly suppress Kir6.2 activity. Glibenclamide acts as both primary and secondary secretagogues to trigger insulin secretion and potentiate glucose-stimulated insulin secretion, respectively. We tested whether blocking Kir6.2 itself causes the same effects as glibenclamide, and found that the Kir6.2 pore-blocker SpTx1 acts as a strong secondary, but not a primary, secretagogue. SpTx1 triggered a transient rise of plasma insulin and lowered the elevated blood glucose of diabetic mice over-expressing Kir6.2 but did not affect those of non-diabetic mice. This proof-of-concept study suggests that blocking Kir6.2 may serve as an effective treatment for diabetes and other diseases stemming from Kir6.2 hyperactivity that cannot be suppressed with sulfonylureas.
Mod(mdg4) variants repress telomeric retrotransposon HeT-A by blocking subtelomeric enhancers
Authors: Takeuchi Chikara , Yokoshi Moe , Kondo Shu , Shibuya Aoi , Saito Kuniaki , Fukaya Takashi , Siomi Haruhiko , Iwasaki Yuka W.
Published: January 2022

Telomeres in Drosophila are composed of sequential non-LTR retrotransposons: HeT-A, TART, and TAHRE. Although they are repressed by the piRNA pathway in the germline, how these retrotransposons are regulated in somatic cells is poorly understood. Here, we show that specific splice variants of Mod(mdg4) repress HeT-A by blocking subtelomeric enhancers in ovarian somatic cells. We found that the Mod(mdg4)-N variant represses HeT-A expression most efficiently among the variants. Mod(mdg4)-N mutant flies show elevated HeT-A expression and female sterility. Mod(mdg4)-N-binding subtelomeric sequences exhibit enhancer-blocking activity, and recruitment of RNA polymerase II (Pol II) on subtelomeres by Mod(mdg4)-N is essential for this enhancer-blocking. Moreover, Mod(mdg4)-N functions to form chromatin boundaries of higher-order chromatin conformation but this mechanism is independent of its Pol II recruitment activity at telomeres/subtelomeres. This study provides a link between enhancer-blocking and telomere regulation, and two different molecular mechanisms exhibited by an insulator protein to orchestrate precise gene expression.
Task-specific neural processes underlying conflict resolution during cognitive control
Authors: Xiao Yuchen , Chou Chien-Chen , Cosgrove Garth Rees , Crone Nathan E , Stone Scellig , Madsen Joseph R , Reucroft Ian , Shih Yen-Cheng , Weisholtz Daniel , Yu Hsiang-Yu , Anderson William S. , Kreiman Gabriel
Published: January 2022

Cognitive control involves flexibly combining multiple sensory inputs with task-dependent goals during decision making. Several tasks have been proposed to examine cognitive control, including Stroop, Eriksen-Flanker, and the Multi-source interference task. Because these tasks have been studied independently, it remains unclear whether the neural signatures of cognitive control reflect abstract control mechanisms or specific combinations of sensory and behavioral aspects of each task. To address this question, here we recorded invasive neurophysiological signals from 16 subjects and directly compared the three tasks against each other. Neural activity patterns in the theta and high-gamma frequency bands differed between incongruent and congruent conditions, revealing strong modulation by conflicting task demands. These neural signals were specific to each task, generalizing within a task but not across tasks. These results highlight the complex interplay between sensory inputs, motor outputs, and task demands and argue against a universal and abstract representation of conflict.
Using strain-resolved analysis to identify contamination in metagenomics data
Authors: Lou Yue Clare , Hoff Jordan , Olm Matthew R. , West-Roberts Jacob , Diamond Spencer , Firek Brian A. , Morowitz Michael J. , Banfield Jillian F.
Published: January 2022

Metagenomics analyses can be negatively impacted by DNA contamination. While external sources of contamination such as DNA extraction kits have been widely reported and investigated, contamination originating within the study itself remains underreported. Here we applied high-resolution strain-resolved analyses to identify contamination in two large-scale clinical metagenomics datasets. By mapping strain sharing to DNA extraction plates, we identified well-to-well contamination in both negative controls and biological samples in one dataset. Such contamination is more likely to occur among samples that are on the same or adjacent columns or rows of the extraction plate than samples that are far apart. Our strain-resolved workflow also reveals the presence of externally derived contamination, primarily in the other dataset. Overall in both datasets, contamination is more significant in samples with lower biomass. Our work demonstrates that genome-resolved strain tracking, with its essentially genome-wide nucleotide-level resolution, can be used to detect contamination in sequencing-based microbiome studies. Our results underscore the value of strain-specific methods to detect contamination and the critical importance of looking for contamination beyond negative and positive controls.
Criticality and network structure drive emergent oscillations in a stochastic whole-brain model
Authors: Barzon Giacomo , Nicoletti Giorgio , Mariani Benedetta , Formentin Marco , Suweis Samir
Published: January 2022

Understanding the relation between the structure of brain networks and its functions is a fundamental open question. Simple models of neural activity based on real anatomical networks have proven to be effective in describing features of whole-brain spontaneous activity when tuned at their critical point. In this work, we show that indeed structural networks are a crucial ingredient in the emergence of collective oscillations in a whole-brain stochastic model at criticality. We study analytically a stochastic Greenberg-Hastings cellular automaton in the mean-field limit, showing that it undergoes an abrupt phase transition with a bistable region. In particular, no global oscillations emerge in this limit. Then, we show that by introducing a network structure in the homeostatic normalization regime, the bistability may be disrupted, and the transition may become smooth. Concomitantly, through an interplay between the network topology and weights, a large peak in the power spectrum appears around the transition point, signaling the emergence of collective oscillations. Hence, both the structure of brain networks and criticality are fundamental in driving the collective responses of whole-brain stochastic models.
piggyBac-Mediated Genomic Integration of Linear dsDNA-Based Library for Deep Mutational Scanning in Mammalian Cells
Authors: Wang Yi , Zhao Yanjie , Li Yifan , Zhang Kaili , Fan Yan , Su Weijun , Li Shuai
Published: January 2022

Deep mutational scanning (DMS) makes it possible to perform massively parallel quantification of the relationship between genetic variants and phenotypes of interest. However, the difficulties in introducing large variant libraries into mammalian cells greatly hinder DMS under physiological states. Here we developed two novel strategies for DMS library construction in mammalian cells, namely ‘piggyBac-in-vitroligation’ and ‘piggyBac-in-vitroligation-PCR’. For the first strategy, we took the ‘in-vitroligation’ approach to prepare high-diversity linear dsDNAs, and integrate them into the mammalian genome with a piggyBac transposon system. For the second strategy, we further added a PCR step using thein-vitroligation dsDNAs as templates, for the construction of high-content genome-integrated libraries via large-scale transfection. Both strategies could successfully establish genome-integrated EGFP-chromophore randomized libraries in HEK293T cells and enrich the green fluorescence-chromophore amino acid sequences. And we further identified a novel transcriptional activator peptide with the ‘piggyBac-in-vitroligation-PCR’ strategy. Our novel strategies greatly facilitate the construction of large variant DMS library in mammalian cells, and may have great application potential in the future.
The central role of the interspecific interactions in the evolution of microbial communities
Authors: Raynaud Tiffany , Blouin Manuel , Devers-Lamrani Marion , Garmyn Dominique , Spor Aymé
Published: January 2022

The interspecific interactions play an important role in the establishment of a community phenotype. Furthermore, the evolution of a community can not only occur through an evolution of the species composing the community but also of the interactions among them. In this study, we investigated how widespread was the evolution of interspecific interactions in the evolutionary response of eight two-bacterial species communities regarding productivity. We found evidence for an evolution of the interactions in half of the studied communities which gave rise to a mean change of 15% in community productivity as compared to what was expected from the individual responses. Even when the interactions did not evolve themselves, they influenced the evolutionary responses of the bacterial strains within the communities which further affected community response. We found that the evolution within a community often promoted an adaptation of the bacterial strains to the abiotic environment, especially for the dominant strain in a community. Overall, this study suggested that the evolution of the interspecific interactions was frequent and that it could increase community response to evolution. We propose that the existence of an evolution of the interspecific interactions can justify the consideration of the community as a unit of selection.
Mucosal associated invariant T cells are altered in patients with Hidradenitis Suppurativa and contribute to the inflammatory milieu
Authors: Gallagher Catriona , Mahon Julie Mac , O’Neill Chloe , Cassidy Féaron C. , Dunbar Hazel , De Barra Conor , Cadden Caoimhe , Pisarska Marta M. , Wood Nicole , Masterson Joanne C. , McNamee Eoin N. , English Karen , O’Shea Donal , Tobin Anne Marie , Hogan Andrew E.
Published: January 2022

Mucosal Associated Invariant T cells are a population of “innate” T cells, which express the invariant T cell receptor (TCR) α chain Vα 7.2-Jα 33 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-γ and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin. On-going research has highlighted their involvement in numerous inflammatory diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is currently unknown. In this study we show for the first time, that MAIT cells are altered in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17 cytokine bias. We show that CCL20 expression is elevated in lesions of patients with H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT cells can accumulate in the lesions from patients with H.S. when compared to adjacent skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation of dermal fibroblasts, promoting the expression of chemotactic signals including CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively our data details IL-17 producing MAIT cells as a novel player in the pathogenesis of H.S and highlights the potential of RORyt inhibition as a novel therapeutic strategy.
Cell morphological profiling enables high-throughput screening for PROteolysis TArgeting Chimera (PROTAC) phenotypic signature
Authors: Trapotsi Maria-Anna , Mouchet Elizabeth , Williams Guy , Monteverde Tiziana , Juhani Karolina , Turkki Riku , Miljković Filip , Martinsson Anton , Mervin Lewis , Müllers Erik , Barrett Ian , Engkvist Ola , Bender Andreas , Moreau Kevin
Published: January 2022

PROTACs (PROteolysis TArgeting Chimeras) use the ubiquitin-proteasome system to degrade a protein of interest for therapeutic benefit. Advances in targeted protein degradation technology have been remarkable with several molecules moving into clinical studies. However, robust routes to assess and better understand the safety risks of PROTACs need to be identified, which is an essential step towards delivering efficacious and safe compounds to patients. In this work, we used Cell Painting, an unbiased high content imaging method, to identify phenotypic signatures of PROTACs. Chemical clustering and model prediction allowed the identification of a mitotoxicity signature that could not be expected by screening the individual PROTAC components. The data highlighted the benefit of unbiased phenotypic methods for identifying toxic signatures and the potential to impact drug design.

Highlights

Morphological profiling detects various PROTACs’ phenotypic signatures

Phenotypic signatures can be attributed to diverse biological responses

Chemical clustering from phenotypic signatures separates on drug selection

Trained in-silico machine learning models to predict PROTACs’ mitochondrial toxicity
HITS-CLIP analysis of human ALKBH8 points towards its role in tRNA and noncoding RNA regulation
Authors: Cavallin Ivana , Bartošovič Marek , Skalický Tomas , Rengaraj Praveenkumar , Schmidt-Dengler Martina Christina , Drino Aleksej , Helm Mark , Vaňáčová Štěpánka
Published: January 2022

Transfer RNAs acquire a large plethora of chemical modifications. Among those, modifications of the anticodon loop play important roles in translational fidelity and tRNA stability. Four human wobble U containing tRNAs obtain 5-methoxycarbonylmethyluridine (mcm5U34) or 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U34), which play a role in decoding. This mark involves a cascade of enzymatic activities. The last step is mediated by Alkylation Repair Homolog 8 (ALKBH8). In this study, we performed a transcriptome-wide analysis of the repertoire of ALKBH8 RNA targets. Using a combination of HITS-CLIP-seq and RIP-seq analyses, we uncover ALKBH8-bound RNAs. It targets an additional wobble U-containing tRNA tRNALys(UUU). More interestingly, the spectrum of bound RNAs includes other types of non-coding RNAs, such as C/D box snoRNAs, 7SK RNA or some miRNAs, respectively.
Basis of narrow-spectrum activity of fidaxomicin on gut pathogen Clostridioides difficile
Authors: Cao Xinyun , Boyaci Hande , Chen James , Bao Yu , Landick Robert , Campbell Elizabeth A.
Published: January 2022

Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections (CDIs), but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains enigmatic. CDIs are a leading cause of nosocomial deaths. Fdx, which inhibits RNA polymerase (RNAP), targets Cdiff with minimal effects on gut commensals, reducing CDI recurrence. Here, we present the cryo-electron microscopy structure of Cdiff RNAP in complex with Fdx, allowing us to identify a crucial Fdx-binding determinant of Cdiff RNAP that is absent in most gut microbiota like Proteobacteria and Bacteroidetes. By combining structural, biochemical, and bioinformatic analyses, we establish that a single RNAP residue is a sensitizing element for Fdx narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen.
Quantitative Models of Lipid Transfer and Membrane Contact Formation
Authors: Zhang Yongli , Ge Jinghua , Bian Xin , Kumar Avinash
Published: January 2022

Lipid transfer proteins (LTPs) transport lipids between different organelles in the cell, and thus play key roles in lipid homeostasis and organelle dynamics. The lipid transfer process often occurs at the membrane contact sites (MCS), where two membranes are held within 10-30 nm by LTPs and other membrane tethering factors. While most LTPs act as a shuttle to transfer lipids via their lipid-binding cavities, recent experiments reveal a new category of eukaryotic LTPs that may serve as a bridge to transport lipids in bulk at MCSs, leading to membrane expansion involved in organelle biogenesis. However, the molecular mechanisms underlying lipid transfer and membrane contact formation are not well understood. Here, we first review two recent studies of extended synaptotagmin (E-Syt)-mediated membrane binding and lipid transfer using optical tweezers and DNA origami, respectively. Then we describe mathematical models to quantify the kinetics of lipid transfer by shuttle LTPs based on a lipid exchange mechanism. We find that simple lipid mixing among similar membranes and/or lipid partitioning among different membranes can explain lipid transfer against a concentration gradient widely observed for LTPs. Based on these calculations, we hypothesize that lipid exchange is a general mechanism for lipid transfer by shuttle LTPs. We predict that selective transport of lipids, but not membrane proteins, by bridge LTPs leads to osmotic membrane tension in analog to the osmotic pressure across a semipermeable membrane. A gradient of such osmotic membrane tension and the conventional membrane tension may drive bulk lipid flow through bridge LTPs at a speed consistent with the fast membrane expansion observed in vivo. Finally, we discuss the implications of membrane tension and lipid transfer in organelle biogenesis and membrane morphologies. Overall, the quantitative models may help clarify the mechanisms of MCS formation by E-Syts and lipid transfer by LTPs in general.
Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction
Authors: Sugihara Kohei , Kitamoto Sho , Saraithong Prakaimuk , Nagao-Kitamoto Hiroko , McCarthy Caroline , Hoostal Matthew , Rosevelt Alexandra , Muraleedharan Chithra K , Gillilland Merritt G. , Imai Jin , Omi Maiko , Bishu Shrinivas , Kao John Y. , Alteri Christopher J. , Barnich Nicolas , Schmidt Thomas M. , Nusrat Asma , Inohara Naohiro , Golob Jonathan L. , Kamada Nobuhiko
Published: January 2022

Pathobionts employ unique metabolic adaptation mechanisms to maximize their growth in disease conditions. Adherent–invasive Escherichia coli (AIEC), a pathobiont enriched in the gut mucosa of patients with inflammatory bowel disease (IBD), utilizes diet-derived L-serine to adapt to the inflamed gut. Therefore, the restriction of dietary L-serine starves AIEC and limits its fitness advantage. Here, we find that AIEC can overcome this nutrient limitation by switching the nutrient source from the diet to the host cells in the presence of mucolytic bacteria. During diet-derived L-serine restriction, the mucolytic symbiont Akkermansia muciniphila promotes the encroachment of AIEC to the epithelial niche by degrading the mucus layer. In the epithelial niche, AIEC acquires L-serine from the colonic epithelium and thus proliferates. Our work suggests that the indirect metabolic network between pathobionts and commensal symbionts enables pathobionts to overcome nutritional restriction and thrive in the gut.
Development of efficient RNAi methods in the corn leafhopper Dalbulus maidis, a promising application for pest control
Authors: Dalaisón-Fuentes L.I. , Pascual A. , Gazza E. , Welchen E. , Rivera-Pomar R. , Catalano M.I.
Published: January 2022

BACKGROUND

The corn leafhopper Dalbulus maidis is the main vector of three important stunting pathogens that affect maize production. The most common control strategy against this species is the use of insecticides that provide minimal, short-term protection. In this context, genomic-based technologies such as RNA interference (RNAi) could be a suitable approach to control this pest in a highly specific manner, avoiding the adverse effects associated with insecticide misuse. Therefore, the objective of the present work was to assess the application of RNAi on D. maidis through different dsRNA delivery methods and known the function of target gene, Bicaudal C (BicC).

RESULTS

We have identified and characterized the core components of the RNAi machinery in silico and established two methods of exogenous double-stranded RNAs (dsRNA) delivery to D. maidis. BicC -an important regulator of insect oogenesis-dsRNA was successfully delivered via injection or ingestion to adult females, causing significant reductions in the transcript levels and ovipositions and observable phenotypes in the ovaries when compared to control females. The small doses of dsRNABicC administered were enough to trigger a strong RNAi response, demonstrating that D. maidis is highly sensitive to RNAi.

CONCLUSION

This is, to our knowledge, the first report describing RNAi application in D. maidis, a tool that can be used to advance towards a novel, insecticide-free control strategy against this pest.
Brainwide input-output architecture of paraventricular oxytocin and vasopressin neurons
Authors: Freda S.N. , Priest M.F. , Badong D. , Xiao L. , Liu Y. , Kozorovitskiy Y.
Published: January 2022

Oxytocin and vasopressin are pleiotropic neuropeptides with well-established roles in the regulation of social behavior and homeostatic functions. Their structural similarity and conserved functions in vertebrate social behavior suggest that neurohypophyseal peptides may represent a single integrative neuromodulatory system, yet both peptides subserve sexually dimorphic functions at the behavioral level. The extent to which central oxytocin and vasopressin systems share similar circuit architecture has not been previously studied. Sex differences in the central circuitry of the oxytocin and vasopressin systems may underlie sex-variant behaviors, but it is currently unknown whether the synaptic inputs or outputs of each neuropeptidergic system vary across males and females. To close this gap, we generated quantitative anterograde and retrograde maps of the paraventricular oxytocin and vasopressin systems in mice. We observed that both oxytocinergic and vasopressinergic neurons share highly similar synaptic inputs that are sex-conserved. Projection patterns differed across systems and showed sex differences, more pronounced in the vasopressin neurons. Together our data represent the first comparative study of oxytocin and vasopressin input-output architecture highlighting how these neurohypopheseal peptides can play complementary and overlapping roles that are sex-dependent.
The Streptococcus agalactiae R3 surface protein is encoded by sar5
Authors: Dragset Marte Singsås , Basson Adelle , Olaisen Camilla , Selvik Linn-Karina , Lyng Randi Valsø , Lysvand Hilde , Aas Christina Gabrielsen , Afset Jan Egil
Published: January 2022

Streptococcus agalactiae (a group B streptococcus; GBS) is an important human pathogen causing pneumonia, sepsis and meningitis in neonates, as well as infections in pregnant women, immunocompromised individuals, and the elderly. For the future control of GBS-inflicted disease, GBS surface exposed proteins are particularly relevant as they may act as antigens for vaccine development and/or as serosubtype markers in epidemiological settings. Even so, the genes encoding some of the surface proteins established as serosubtype markers by antibody-based methods are still unknown. Here, we identify sar5 as the gene encoding the R3 surface protein, a serosubtype marker of hitherto unknown genetic origin.
The voltage-gated Cav Ca2+ channel subunit α2δ-4 is required for locomotor behavior and sensorimotor gating in mice
Authors: Klomp Annette , Omichi Ryotaro , Iwasa Yoichiro , Smith Richard J. , Usachev Yuriy M. , Russo Andrew F. , Narayanan Nandakumar , Lee Amy
Published: January 2022

Voltage-gated Cav Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor learning/coordination in the rotarod assay. Female but not male α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in cognitive and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.
Collateral cleavage of 28s rRNA by RfxCas13d causes death of mice
Authors: Li Yunfei , Xu Junjie , Guo Xuefei , Li Zhiwei , Cao Lili , Liu Shengde , Guo Ying , Wang Guodong , Luo Yujie , Zhang Zeming , Wei Xuemei , Zhao Yingchi , Liu Tongtong , Wang Xiao , Xia Huawei , Kuang Ming , Guo Qirui , Li Junhong , Chen Luoying , Wang Yibing , Li Qi , Wang Fengchao , Liu Qinghua , You Fuping
Published: January 2022

The CRISPR-Cas13 system is an RNA-guided RNA-targeting system, and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells. Here, we found that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which was not resulted from the loss of target gene function or off-target effects. Mechanistically, we showed that RfxCas13d exhibited collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAKα-JNK/p38-immediate early gene (IEG) pathway. These results provide new mechanistic insights into the collateral activity of RfxCas13d and warn that the biosafety of CRISPR-Cas13 system needs further evaluation before applying it to clinical treatments.
The Idiopathic Pulmonary Fibrosis-associated single nucleotide polymorphism rs35705950 is transcribed in a MUC5B Promoter Associated Long Non-Coding RNA (AC061979.1)
Authors: Neatu R. , Thompson D.J. , Enekwa I. , Schwalbe E.C. , Fois G. , Frick M. , Braubach P. , Moschos S.A.
Published: January 2022

LncRNAs are involved in regulatory processes in the human genome, including gene expression. The rs35705950 SNP, previously associated with IPF, overlaps the recently annotated lncRNA AC061979.1, a 1,712 nucleotide transcript located within the MUC5B promoter at chromosome 11p15.5. To document the expression pattern of the transcript, we processed 3.9 TBases of publicly available RNA-SEQ data across 27 independent studies involving lung airway epithelial cells. Epithelial lung cells showed expression of this putative pancRNA. The findings were independently validated in cell lines and primary cells. The rs35705950 is found within a conserved region (from fish to primates) within the expressed sequence indicating functional importance. These results implicate the rs35705950-containing AC061979.1 pancRNA as a novel component of the MUC5B expression control minicircuitry.
Dysregulation ofNpas4andInhbaexpression and an altered excitation–inhibition balance are associated with cognitive deficits in DBA/2 mice
Authors: Oberländer Kristin , Witte Victoria , Mallien Anne Stephanie , Gass Peter , Bengtson C. Peter , Bading Hilmar
Published: January 2022

Differences in the learning associated transcriptional profiles between mouse strains with distinct learning abilities could provide insight into the molecular basis of learning and memory. The inbred mouse strain DBA/2 shows deficits in hippocampus-dependent memory, yet the transcriptional responses to learning and the underlying mechanisms of the impairments are unknown. Comparing DBA/2J mice with the reference standard C57BL/6N mouse strain we verify an enhanced susceptibility to kainic acid induced seizures, confirm impairments in hippocampus-dependent spatial memory tasks and uncover additional behavioral abnormalities including deficits in hippocampus-independent learning. Surprisingly, we found no broad dysfunction of the DBA/2J strain in immediate early gene (IEG) activation but instead report brain region-specific and gene-specific alterations. The learning-associated IEGsArc,c‐Fos, andNr4a1showed no DBA/2J deficits in basal or synaptic activity induced gene expression in hippocampal or cortical primary neuronal cultures or in the CA1, CA3, or retrosplenial cortex following spatial object recognition (SOR) training in vivo. However, the parietal cortex showed reduced and the dentate gyrus showed enhanced SOR-evoked induction of most IEGs. All DBA/2J hippocampal regions exhibited elevated basal expression of inhibin β A (Inhba) and a learning-associated superinduction of the transcription factor neuronal Per-Arnt-Sim domain protein 4 (Npas4) known to regulate the synaptic excitation–inhibition balance. In line with this, CA1 pyramidal neurons of DBA/2J mice showed fewer inhibitory and more excitatory miniature postsynaptic currents but no alteration in most other electrophysiological properties or gross dendritic morphology. The dysregulation ofNpas4andInhbaexpression and synaptic connectivity may underlie the cognitive deficits and increased susceptibility to seizures of DBA/2J mice.
Wiggler radiation at a low-emittance storage ring and its usage for X-ray absorption spectroscopy
Authors: Klementiev Konstantin , Tarawneh Hamed , Tavares Pedro Fernandes
Published: January 2022

A wiggler is a high-power insertion device that was used in the past to produce a smooth wide-band X-ray spectrum. It is widely believed that on low-emittance synchrotrons this X-ray source loses its spatial and spectral homogeneity and therefore becomes less ideal than a scanning undulator. In this paper, we report on experimental and computational studies of an in-vacuum wiggler installed on the first fourth-generation synchrotron MAX IV. We investigate how several physical parameters affect the wiggler spectrum and propose a combination of a few of them that results in significant spectral smoothing. We also examine EXAFS spectra for possible distortions originating from the source imperfection. For this purpose, we scrutinize samples of various homogeneity. We conclude that wigglers are still an appropriate class of insertion devices, also on low-emittance synchrotrons.
Visualizing the valence states of europium ions in Eu-doped BaAl2O4 using X-ray nanoprobe mapping
Authors: Wu Yu-Hao , Lin Yung-Yang , Chen Jeng-Lung , Fu Shih-Yu , Huang Shu-Chi , Lee Chien-yu , Chen Bo-Yi , Yin Gung-Chian , Huang E-Wen , Tang Mau-Tsu , Lin Bi-Hsuan
Published: January 2022

This study develops and successfully demonstrates visualization methods for the characterization of europium (Eu)-doped BaAl2O4 phosphors using X-ray nanoprobe techniques. X-ray fluorescence (XRF) mapping not only gives information on the elemental distributions but also clearly reveals the valence state distributions of the Eu2+ and Eu3+ ions. The accuracy of the estimated valence state distributions was examined by performing X-ray absorption spectroscopy (XAS) across the Eu L
3-edge (6.977 keV). The X-ray excited optical luminescence (XEOL) spectra exhibit different emission lines in the selected local areas. Their corresponding emission distributions can be obtained via XEOL mapping. The emission properties can be understood through correlation analysis. The results demonstrate that the main contribution to the luminescence intensity of the Eu-doped BaAl2O4 comes from the Eu2+ activator and the emission intensity will not be influenced by the concentration of Eu2+ or Eu3+ ions. It is anticipated that X-ray nanoprobes will open new avenues with significant characterization ability for unravelling the emission mechanisms of phosphor materials.
MicroED: conception, practice and future opportunities
Authors: Clabbers Max T. B. , Shiriaeva Anna , Gonen Tamir
Published: January 2022

This article documents a keynote seminar presented at the IUCr Congress in Prague, 2021. The cryo-EM method microcrystal electron diffraction is described and put in the context of macromolecular electron crystallography from its origins in 2D crystals of membrane proteins to today's application to 3D crystals a millionth the size of that needed for X-ray crystallography. Milestones in method development and applications are described with an outlook to the future.
Crystal structure of bismuth-containing NdFe3(BO3)4 in the temperature range 20–500 K
Authors: Smirnova Ekaterina S. , Alekseeva Olga A. , Dudka Alexander P. , Verin Igor A. , Artemov Vladimir V. , Lyubutina Marianna V. , Gudim Irina A. , Frolov Kirill V. , Lyubutin Igor S.
Published: January 2022

Neodymium iron borate NdFe3(BO3)4 is an intensively studied multiferroic with high electric polarization values controlled by a magnetic field. It is characterized by a large quadratic magnetoelectric effect, rigidity in the base plane and a rather strong piezoelectric effect. In this work, the atomic structure of (Nd0.91Bi0.09)Fe3(BO3)4 was studied by single-crystal X-ray diffraction in the temperature range 20–500 K (space group R32, Z = 3). The Bi atoms found in the composition partially substitute the Nd atoms in the 3a position; they entered the structure due to the growth conditions in the presence of Bi2Mo3O12. It was shown that in the temperature range 20–500 K there is no structural phase transition R32→P3121, which occurs in rare-earth iron borates (RE = Eu–Er, Y) with an effective rare-earth cation radius smaller than that of Nd. The temperature dependence of the unit-cell c parameter reveals a slight increase on cooling below 90 K, which is similar to the results obtained previously for iron borates of Gd, Y and Ho. The atomic distances (Nd,Bi)—O, (Nd,Bi)—B, (Nd,Bi)—Fe, Fe—O, Fe—B and Fe—Fe in the iron chains and between chains decrease steadily with decreasing temperature from 500 to 90 K, whereas the B1(3b)—O distance does not change and the average B2(9e)—O distance increases slightly. There is a uniform decrease in the atomic displacement parameters with decreasing temperature, with a more pronounced decrease for the Nd(3a) and O2(9e) atoms. The O2(9e) atoms are characterized by the maximum atomic displacement parameters and the most elongated atomic displacement ellipsoids. The characteristic Debye and Einstein temperatures, and the static component in the atomic displacements were determined for cations using multi-temperature diffraction data. It was shown that the Nd cations have the weakest bonds with the surrounding atoms and the B cations have the strongest.
Bis(2,6-diisopropylphenyl) tellurone: a well-defined monomeric diorganotellurone without cocrystallized solvents and without stabilizing intramolecular contacts
Authors: Shibuya Yuga , Koguchi Shinichi , Oba Makoto
Published: January 2022

Only two crystal structures of diorganotellurones have been reported to date, both of which contain cocrystallized solvents and one of which is stabilized by intramolecular Te—N secondary bonding interactions. This work describes the crystal structure of bis(2,6-diisopropylphenyl) tellurone, (C12H17)2TeO2 or C24H34O2Te, the first well-defined diorganotellurone without cocrystallized solvents and without stabilizing intramolecular contacts. The molecule has crystallographic twofold symmetry, with half the molecule as the asymmetric unit. The molecular structure is compared to previously reported tellurones and those computed at the density functional theory DFT/B3PW91 level. The molecules form two-dimensional layers as a result of a weak intermolecular hydrogen-bonding network. The layers are then stacked in an antiparallel manner to form the crystal packing structure. The Hirshfeld surface analysis was employed to visualize and quantify the intermolecular contacts in the molecular crystal structure, and the contribution of O...H and H...H interactions was found to be the dominating factor.
Development of special needs classroom prototypes to respond to the sensory needs of students with exceptionalities
Authors: Patel Tina , Dorff Juliann , Baker Allison
Published: January 2022

Purpose

The observation by the authors, based on their extensive experience working in K-8 public schools in the region showed the special needs classrooms catering to children with exceptionalities such as Autism Spectrum Disorder (ASD), Intellectual Disability (ID) and Emotional Disturbance (ED) are typically makeshift arrangements with no consideration given to students' unseen sensory needs. A thorough literature review indicates that there are no holistic design guidelines in place to meet the sensory needs of students with ASD, ID and ED. This study seeks to address this gap by providing considerations to meet the sensory needs impacting these students' focus, behavior and classroom engagement with course content and peers.

Design/methodology/approach

Sensory design guidelines were established utilizing a qualitative method, providing a foundation for the development of classroom prototypes that address the sensory needs of students with ASD, ID and ED.

Findings

The new guidelines, which correlated interior design strategies with the sensory needs of children with ASD, ID and ED, and the resulting prototypes provide a basis for the further development of design standards and takes designers closer to creating more conducive and inclusive environments.

Practical implications

This study reinforced the belief that these recommendations should be considered in the school-wide design. Many students can be included with their typical peers for all or part of their school day if space has been designed to accommodate their differences.

Originality/value

This study bridges the gap while documenting the correlation between design factors and sensory needs of students with exceptionalities, in this case, ASD, ID and ED.
Linking perceived institutional force and environmental strategy: the moderating role of institutional incompleteness
Authors: Feng Taiwen , Liu Shasha , Zhang Qiansong
Published: January 2022

Purpose

This study aims to examine the impact of perceived institutional force on environmental strategy, and the moderating role of institutional incompleteness.

Design/methodology/approach

This study tests hypotheses employing hierarchical regression model based on a survey of 317 Chinese manufacturers.

Findings

The results reveal that perceived business and social force have positive impacts on symbolic environmental strategy. Perceived social force has a positive impact on substantive environmental strategy and a negative impact on greenwashing. Further analysis suggests that perceived social force has a stronger effect on substantive environmental strategy than perceived business force. Moreover, institutional incompleteness strengthens the impact of perceived business force on substantive environmental strategy, and the impact of perceived social force on symbolic and substantive environmental strategy.

Originality/value

This study establishes a framework integrating distinct types of perceived institutional force and environmental strategy and provides a new perspective on measuring greenwashing to extend environmental strategy literature.
Dietary intervention of prebiotics and vitamins on gut health of children
Authors: Kaushal Deepti , Kalsi Gurpreet
Published: January 2022

Purpose

Gut health has multidimensional impact on childhood growth and development. Diet being the major modulator of gut health, this study aims to hypothesize if supplementation of dietary prebiotics and vitamins can impact gut environment of healthy children.

Design/methodology/approach

A double-blind placebo-controlled trial was conducted with parallel allocation of children 8–13 years of age to placebo or test group. Test group was supplemented with 1.5 g of formulation comprising prebiotics and vitamins, and to placebo, maltodextrin (1.5 g) was supplemented. After four weeks, the effect on markers of gut health (i.e. beneficial microbes, and gut integrity markers such as secretory Immunoglobulin A [sIgA] and calprotectin concentration) was evaluated in feces of children.

Findings

Significant increase of 17.1% in fecal bifidobacteria counts (p = 0.04) was observed in the test group compared to placebo after four weeks. Also, fecal calprotectin concentration decreased (20%) significantly (p = 0.01) in test group compared to placebo. In addition, the test group showed significant improvement in fecal sIgA and lactobacilli compared to baseline concentration (p = 0.01 and 0.001, respectively).

Research limitations/implications

This study demonstrates that prebiotic (and vitamin) intervention may influence health outcomes in children by positively modulating markers of gut health.

Originality/value

There are limited studies demonstrating the efficacy of prebiotic and vitamins on gut health of school age children.
Authoritarian and benevolent leadership: the role of follower homophily, power distance orientation and employability
Authors: Koveshnikov Alexei , Ehrnrooth Mats , Wechtler Heidi
Published: January 2022

Purpose

Drawing on follower-centric leadership theory, the study examines the role of perceived homophily between the leader and the follower, follower's individual-level power distance orientation (PDO) and follower's perceived employability in moderating the effects of authoritarian and benevolent paternalistic leadership (BPL) on followers' turnover intentions.

Design/methodology/approach

The study analyzes a sample of 403 white-collar Russian employees.

Findings

Whereas both leadership styles generally decrease followers' turnover intentions, they operate differently. Authoritarian leadership (AL) is more effective among followers with higher follower-leader homophily and PDO, whereas BPL is effective only among followers with low perceived homophily and PDO, and more effective among followers with higher perceived employability.

Originality/value

The study extends research on non-participative styles of leadership, their effects and boundary conditions.
What sort of collective bargaining is emerging in Nigeria?
Authors: Opute John Ebinum , Mahmoud Ali B.
Published: January 2022

Purpose

Nigeria is experiencing an expanding variety of what is termed collective bargaining, which is being propelled by socio-economic challenges and the emerging political dispensation that had long eluded the country, albeit the numerous contours needing some pragmatic approaches from the state, employers of labour and the trade unions at the local and national levels. Therefore, this study represents an attempt to illustrate the rising collective bargaining pattern in Nigeria.

Design/methodology/approach

This study drew on employee and employer sectoral associations examples together with labour union structures of the state to assess what underlined collective bargaining developments from the broad context of collective bargaining and the industrial relations implications. Content analysis was employed to analyse the secondary data (found in relevant company handbooks, policies, collective agreements, etc.) and primary data obtained through unstructured interviews.

Findings

A form of collective bargaining is emerging where the trade unions are embracing symbiotic agreements at plant levels to improve conditions of employment and thus weakening the hold of the national union from collective bargaining – a move that may challenge the conceptual framework of collective bargaining as conceived by many states in developing economies.

Originality/value

This is an investigative paper, carefully trailing the framework of collective bargaining from direct contacts with all stakeholders in the labour corridors of Nigeria – such as the Nigeria Labour Congress, Nigeria Employers’ Consultative Association, Chemical and Non-Metallic Products Employer's Federation, Metal Products Workers Union of Nigeria and Personnel Practitioners, cutting across all the segments of the political and economic development of the country.
Harmonizing taxon names in biodiversity data: A review of tools, databases and best practices
Authors: Grenié Matthias , Berti Emilio , Carvajal‐Quintero Juan , Dädlow Gala Mona Louise , Sagouis Alban , Winter Marten
Published: January 2022

The process of standardizing taxon names, taxonomic name harmonization, is necessary to properly merge data indexed by taxon names. The large variety of taxonomic databases and related tools are often not well described. It is often unclear which databases are actively maintained or what is the original source of taxonomic information. In addition, software to access these databases is developed following non‐compatible standards, which creates additional challenges for users. As a result, taxonomic harmonization has become a major obstacle in ecological studies that seek to combine multiple datasets.

Here, we review and categorize a set of major taxonomic databases publicly available as well as a large collection of R packages to access them and to harmonize lists of taxon names. We categorized available taxonomic databases according to their taxonomic breadth (e.g. taxon specific vs. multi‐taxa) and spatial scope (e.g. regional vs. global), highlighting strengths and caveats of each type of database. We divided R packages according to their function, (e.g. syntax standardization tools, access to online databases, etc.) and highlighted overlaps among them. We present our findings (e.g. network of linkages, data and tool characteristics) in a ready‐to‐use Shiny web application (available at: https://mgrenie.shinyapps.io/taxharmonizexplorer/).

We also provide general guidelines and best practice principles for taxonomic name harmonization. As an illustrative example, we harmonized taxon names of one of the largest databases of community time series currently available. We showed how different workflows can be used for different goals, highlighting their strengths and weaknesses and providing practical solutions to avoid common pitfalls.

To our knowledge, our opinionated review represents the most exhaustive evaluation of links among and of taxonomic databases and related R tools. Finally, based on our new insights in the field, we make recommendations for users, database managers and package developers alike.