bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive deficits found in a pro-inflammatory state are independent of ERK 1/2 signaling in the murine brain hippocampus treated with Shiga toxin 2 from enterohemorrhagicEscherichia Coli
Authors: Berdasco Clara , Pinto Alipio , Blake Mariano , Correa Fernando , Longo Carbajosa Nadia A. , Geogeghan Patricia , Cangelosi Adriana , Gironacci Mariela M. , Goldstein Jorge
Published: August 2020

Shiga toxin 2 (Stx2) from enterohemorrhagicEscherichia coli(EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS) and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. Results demonstrate that systemic administration of a sublethal dose of Stx2 reduced memory index and produced depression like behavior, pro-inflammatory cytokine release and NF-kB activation independent of the ERK 1/2 signaling pathway. On the other hand, LPS activated NF-kB dependent on ERK 1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.
Statistics of spatial rotations and projection directions considering molecular symmetry in 3D electron cryo-microscopy
Authors: Zhang Qi , Lin Hai , Hu Mingxu
Published: August 2020

Electron cryo-microscopy (cryoEM) three-dimensional (3D) reconstruction is based on estimations of orientations of projection images or 3D volumes. It is common that the macromolecules studied by cryoEM have molecular symmetry, which, unfortunately, has not been taken into consideration by any statistics for either spatial rotations or projection directions at this point. Meanwhile, there are growing needs to adopt advanced statistical methods, and further, modern machine learning techniques in cryoEM. Since those methodologies are built heavily upon statistical learning cornerstones, the absence of their domain-specific statistical justification limits their applications in cryoEM. In this research, based on the concept of non-unique-games (NUG), we propose two key statistical measurements, the mean and the variance, of both spatial rotations and projection directions when molecular symmetry is considered. Such methods are implemented in the open-source python package pySymStat.
Large vs small genomes inPassiflora: the influence of the mobilome and the satellitome
Authors: Sader Mariela , Vaio Magdalena , Cauz-Santos Luiz Augusto , Dornelas Marcelo Carnier , Vieira Maria Lucia Carneiro , Melo Natoniel , Pedrosa-Harand Andrea
Published: August 2020

Repetitive sequences are ubiquitous and fast-evolving elements responsible for size variation and large-scale organization of plant genomes. WithinPassifloragenus, a ten-fold variation in genome size, not attributed to polyploidy, is known. Here, we applied a combinedin silicoand cytological approach to study the organization and diversification of repetitive elements in three species of these genera representing its known range in genome size variation. Sequences were classified in terms of type and repetitiveness and the most abundant were mapped to chromosomes. We identified Long Terminal Repeat (LTR) retrotransposons as the most abundant elements in the three genomes, showing a considerable variation among species. Satellite DNAs (satDNAs) were less representative, but highly diverse between subgenera. Our results clearly confirm that the largest genome species (Passiflora quadrangularis) presents a higher accumulation of repetitive DNA sequences, specially Angela and Tekay elements, making up most of its genome.Passiflora cincinnata, with intermediate genome and from the same subgenus, showed similarity withP. quadrangularisregarding the families of repetitive DNA sequences, but in different proportions. On the other hand,Passiflora organensis, the smallest genome, from a different subgenus, presented greater diversity and the highest proportion of satDNA. Altogether, our data indicate that while large genome evolve by an accumulation of retrotransponsons, small genomes most evolved by diversification of different repeat types, particularly satDNAs.

MAIN CONCLUSIONS

While two lineages of retrotransposons were more abundant in largerPassifloragenomes, the satellitome was more diverse and abundant in the smallest genome.
Vertebrate features revealed in the rudimentary eye of the Pacific hagfish (Eptatretus stoutii)
Authors: Dong Emily M. , Allison W. Ted
Published: August 2020

Hagfish eyes are markedly basic compared to the eyes of other vertebrates, lacking a pigmented epithelium, a lens, and a retinal architecture built of three cell layers – the photoreceptors, interneurons & ganglion cells. Concomitant with hagfish belonging to the earliest-branching vertebrate group (the jawless Agnathans), this lack of derived characters has prompted competing interpretations that hagfish eyes represent either a transitional form in the early evolution of vertebrate vision, or a regression from a previously elaborate organ. Here we show the hagfish retina is not extensively degenerating during its ontogeny, but instead grows throughout life via a recognizable Pax6+ ciliary marginal zone. The retina has a distinct layer of photoreceptor cells that appear to homogeneously express a single opsin of therh1rod opsin class. The epithelium that encompasses these photoreceptors is striking because it lacks the melanin pigment that is universally associated with animal vision; notwithstanding, we suggest this epithelium is a homolog of gnathosome Retinal Pigment Epithelium (RPE) based on its robust expression of RPE65 and its engulfment of photoreceptor outer segments. We infer that the hagfish retina is not entirely rudimentary in its wiring, despite lacking a morphologically distinct layer of interneurons: multiple populations of cells exist in the hagfish inner retina that differentially express markers of vertebrate retinal interneurons. Overall, these data clarify Agnathan retinal homologies, reveal characters that now appear to be ubiquitous across the eyes of vertebrates, and refine interpretations of early vertebrate visual system evolution.

HIGHLIGHTS

Hagfish eyes aredegeneratebut notdegenerating, i.e.rudimentarybutgrowing

Retinal interneurons discovered implying ancestral hagfish had derived retinas & vision

Despite lacking pigment, a Retinal Pigmented Epithelium homolog functions in hagfish

Revised synapomorphies illuminate the dimly lit origins of vertebrate eye evolution

GRAPHICAL ABSTRACT
Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma
Authors: Campbell Nathaniel R. , Rao Anjali , Zhang Maomao , Baron Maayan , Heilmann Silja , Deforet Maxime , Kenny Colin , Ferretti Lorenza , Huang Ting-Hsiang , Garg Manik , Nsengimana Jérémie , Montal Emily , Tagore Mohita , Hunter Miranda , Newton-Bishop Julia , Middleton Mark R. , Corrie Pippa , Adams David J. , Rabbie Roy , Levesque Mitchell P. , Cornell Robert A. , Yanai Itai , Xavier Joao B. , White Richard M.
Published: August 2020

In melanoma, transcriptional profiling has revealed multiple co-existing cell states, including proliferative versus invasive sub-populations that have been posited to represent a “go or grow” tradeoff. Both of these populations are maintained in tumors, but how they physically interact to promote metastasis is unknown. We demonstrate that these subpopulations form spatially structured heterotypic clusters that cooperate in the seeding of metastasis. We unexpectedly found that INV cells were tightly adherent to each other, and formed clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation between these populations, in which the INV cells facilitated the spread of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of both clustering and the PRO/INV states. Our data suggest a framework for the co-existence of these two divergent cell populations, in which differing cell states form heterotypic clusters that promote metastasis via cell-cell cooperation.
A neural circuit for competing approach and avoidance underlying prey capture
Authors: Rossier Daniel , La Franca Violetta , Salemi Taddeo , Gross Cornelius T.
Published: August 2020

Predators must frequently balance competing approach and avoidance behaviors elicited by a moving and potentially dangerous prey. Several brain circuits supporting predation have recently been localized. However, the mechanisms by which these circuits balance the conflict between approach and avoidance responses remain unknown. Laboratory mice initially show alternating approach and avoidance responses toward cockroaches, a natural prey, but with repeated exposure become avid hunters. Here we usedin vivoneural activity recording and cell-type specific manipulations in hunting mice to identify neurons in the lateral hypothalamus and periaqueductal grey that encode and control predatory approach and avoidance. We found a subset of GABAergic neurons in lateral hypothalamus that specifically encoded hunting behaviors and whose stimulation triggered predation, but not feeding. This population projects to the periaqueductal grey and stimulation of these projections promoted predation. Neurons in periaqueductal grey encoded both approach and avoidance behaviors, but only initially when the mouse showed high levels of fear of the prey. Our findings allow us to propose that GABAergic neurons in lateral hypothalamus facilitate predation in part by suppressing defensive responses to prey encoded in the periaqueductal grey. Our findings reveal a neural circuit mechanism for controlling the balance between conflicting approach and avoidance behaviors elicited by the same stimulus.
Cell-type-specific epigenomic variations associated withBRCA1mutation in pre-cancer human breast tissues
Authors: Hsieh Yuan-Pang , Naler Lynette B. , Ma Sai , Lu Chang
Published: August 2020

BRCA1germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here we report cell-type-specific profiling of genome-wide histone modifications including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal, and stromal cells extracted from pre-cancerBRCA1mutation carriers and non-carriers, conducted using a low-input technology that we developed. We discover that basal and stromal cells present the most extensive epigenomic differences between mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+) while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due toBRCA1mutation appear to facilitate their transformation into luminal progenitor cells. Our findings shed light on the pre-cancer epigenomic dynamics due toBRCA1mutation and how they may contribute to eventual development of predominantly basal-like breast cancer.
Single-cell mapper (scMappR): using scRNA-seq to infer cell-type specificities of differentially expressed genes
Authors: Sokolowski Dustin J. , Faykoo-Martinez Mariela , Erdman Lauren , Hou Huayun , Chan Cadia , Zhu Helen , Holmes Melissa M. , Goldenberg Anna , Wilson Michael D.
Published: August 2020

RNA sequencing (RNA-seq) is widely used to identify differentially expressed genes (DEGs) and reveal biological mechanisms underlying complex biological processes. RNA-seq is often performed on heterogeneous samples and the resulting DEGs do not necessarily indicate the cell types where the differential expression occurred. While single-cell RNA-seq (scRNA-seq) methods solve this problem, technical and cost constraints currently limit its widespread use. Here we present single cell Mapper (scMappR), a method that assigns cell-type specificity scores to DEGs obtained from bulk RNA-seq by integrating cell-type expression data generated by scRNA-seq and existing deconvolution methods. After benchmarking scMappR using RNA-seq data obtained from sorted blood cells, we asked if scMappR could reveal known cell-type specific changes that occur during kidney regeneration. We found that scMappR appropriately assigned DEGs to cell-types involved in kidney regeneration, including a relatively small proportion of immune cells. While scMappR can work with any user supplied scRNA-seq data, we curated scRNA-seq expression matrices for ∼100 human and mouse tissues to facilitate its use with bulk RNA-seq data alone. Overall, scMappR is a user-friendly R package that complements traditional differential expression analysis available at CRAN.

Highlights

scMappR integrates scRNA-seq and bulk RNA-seq to re-calibrate bulk differentially expressed genes (DEGs).

scMappR correctly identified immune-cell expressed DEGs from a bulk RNA-seq analysis of mouse kidney regeneration.

scMappR is deployed as a user-friendly R package available at CRAN.
The recombination landscape and multiple QTL mapping in aSolanum tuberosumcv. ‘Atlantic’-derived F1population
Authors: Silva Pereira Guilherme da , Mollinari Marcelo , Schumann Mitchell J. , Clough Mark E. , Zeng Zhao-Bang , Yencho G. Craig
Published: August 2020

There are many challenges involved with the genetic analyses of autopolyploid species, such as the tetraploid potato,Solanum tuberosum(2n= 4x= 48). The development of new analytical methods has made it valuable to re-analyze an F1 population (n= 156) derived from a cross involving ‘Atlantic’, a widely grown chipping variety in the USA. A fully integrated genetic map with 4,285 single nucleotide polymorphisms, spanning 1,630 cM, was constructed with MAPpoly software. We observed that bivalent configurations were the most abundant ones (51.0∼72.4% depending on parent and linkage group), though multivalent configurations were also observed (2.2∼39.2%). Seven traits were evaluated over four years (2006-8 and 2014) and quantitative trait loci (QTL) mapping was carried out using QTLpoly software. Based on a multiple-QTL model approach, we detected 21 QTL for 15 out of 27 trait-year combination phenotypes. A hotspot on linkage group 5 was identified as QTL for maturity, plant yield, specific gravity and internal heat necrosis resistance over different years were co-located. Additional QTL for specific gravity and dry matter were detected with maturity-corrected phenotypes. Among the genes around QTL peaks, we found those on chromosome 5 that have been previously implicated in maturity (StCDF1) and tuber formation (POTH1). These analyses have the potential to provide insights into the biology and breeding of tetraploid potato and other autopolyploid species.
Fast Ion Beam Inactivation of Viruses, Where Radiation Track Structure Meets RNA Structural Biology
Authors: Villagomez-Bernabe B. , Chan S. W. , Coulter J. A. , Roseman A. M. , Currell F. J.
Published: August 2020

Here we show an interplay between the structures present in ionization tracks and nucleocapsid RNA structural biology, using fast ion beam inactivation of the severe acute respiratory syndrome coronavirus (SARS-CoV) virion as an example. This interplay is one of the key factors in predicting dose-inactivation curves for high energy ion beam inactivation of virions. We also investigate the adaptation of well-established cross-section data derived from radiation interactions with water to the interactions involving the components of a virion, going beyond the density-scaling approximation developed previously. We conclude that solving one of the grand challenges of structural biology — the determination of RNA tertiary/quaternary structure — is intimately linked to predicting ion-beam inactivation of viruses and that the two problems can be mutually informative. Indeed, our simulations show that fast ion beams have a key role to play in elucidating RNA tertiary/quaternary structure.
Structural control of fibrin bioactivity by mechanical deformation
Authors: Kumar Sachin , Wang Yujen , Rausch Manuel K. , Parekh Sapun H.
Published: August 2020

Fibrin is a fibrous protein network that entraps blood cells and platelets to form blood clots following vascular injury. As a biomaterial, fibrin acts a biochemical scaffold as well as a viscoelastic patch that resists mechanical insults. The biomechanics and biochemistry of fibrin have been well characterized independently, showing that fibrin is a hierarchical material with numerous binding partners. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry at the molecular level? In this study, we show how mechanically-induced molecular structural changes in fibrin affect fibrin biochemistry and fibrin-platelet interaction. We found that tensile deformation of fibrin lead to molecular structural transitions of α-helices to β-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrinolysis, at the network and single fiber level. Moreover, binding of tPA and Thioflavin T (ThT), a commonly used β-sheet marker, was primarily mutually exclusive such that tPA bound to native (helical) fibrin whereas ThT bound to strained fibrin. Finally, we demonstrate that conformational changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to attenuated αIIbβ3integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and fibrin biological activity in an elegant mechano-chemical feedback loop, which likely influences fibrinolysis and wound healing kinetics.
Effects of a combined enrichment intervention on the behavioural and physiological welfare of captive Asiatic lions (Panthera leo persica)
Authors: Goswami Sitendu , Patel Shiv Kumari , Kadivar Riyaz , Tyagi Praveen Chandra , Malik Pradeep Kumar , Mondol Samrat
Published: August 2020

The endangered Asiatic lion (Panthera leo persica) is currently distributed as a single wild population of 670 individuals and ∼400 captive animals globally. Although the captive lions are major hope for the species’ long-term conservation through repatriation, their welfare status and management practises need research attention. To this end, we tested the efficacy of feeding, sensory and manipulable enrichment interventions on the welfare of Asiatic lions at the conservation breeding centre of Sakkarbaug Zoological Garden, Gujarat. We adopted a holistic approach by measuring physiological and behavioural responses of 35 captive Asiatic lions, divided into control (n=16) and test (n=19) groups. The test subjects approached feeding devices first and manipulable devices for a longer duration. Manipulable devices were used homogenously with two significant time peaks, but sensory devices were used sporadically throughout the day with no discernible peak usage. The control subjects remained unchanged in all welfare parameters compared to their pre-treatment levels. However, post-enrichment behavioural assessments showed higher behaviour diversity (95% increase from the baseline period), reduced enclosure zone bias (40.25% reduction) and aberrant repetitive behaviours (80.68%) in test samples. Similarly, faecal corticosterone measures showed lower stress levels in test samples (58% decrease), confirming significant improvement in all welfare indices than control groups. These results have universal applicability to assess welfare indices of other captive species in Indian zoos. We hope that the results will encourage zoo managers and regulatory agencies to improve animal welfare practices.
Surviving heatwaves: thermal experience predicts life and death in a Southern Ocean diatom
Authors: Samuels Toby , Rynearson Tatiana A. , Collins Sinéad
Published: August 2020

Extreme environmental fluctuations such as marine heatwaves (MHWs) can have devastating effects on ecosystem health and functioning through rapid population declines and destabilisation of trophic interactions. However, recent studies have highlighted that population tolerance to MHWs is variable, with some populations even benefitting from MHWs. A number of factors can explain variation in responses between populations including their genetic variation, previous thermal experience and the intensity and duration of the heatwave itself. We disentangle the contributions of these factors on population survival and post-heatwave growth rates by experimentally simulating heatwaves (7.5 or 9.2 °C, for up to nine days) for three genotypes of the Southern Ocean diatomActinocyclus actinochilus. The effects of simulated heatwaves on mortality and population growth varied with both genotype and thermal experience. Firstly, hotter and longer heatwaves increased mortality and decreased post-heatwave growth rates relative to milder, shorter heatwaves. Secondly, growth above the thermal optimum before heatwaves exacerbated heatwave-associated negative effects, leading to higher mortality during heatwaves and slower growth after heatwaves. Thirdly, hotter and longer heatwaves resulted in more pronounced changes to thermal optima (Topt) immediately following heatwaves. Finally, there is substantial intraspecific variation in mortality during heatwaves and in post-heatwave growth. Our findings shed light on the potential of Southern Ocean diatoms to tolerate MHWs, which will increase both in frequency and in intensity under future climate change.
Employing scan-SCAM to identify residues that compose transmembrane helix 1 (TM1) of EnvZ
Authors: Chavalwan Thanwarat , Hasan Fadhael Alrahman H. , Cheesman Phillipa , Yusuf Rahmi , Draheim Roger R.
Published: August 2020

TheEscherichia colisensor kinase EnvZ modulates porin expression in response to various stimuli including intracellular osmolarity, intracellular pH and periplasmic interaction with MzrA. The expression of two major outer membrane porins, OmpF and OmpC, are regulated by EnvZ, and act as passive diffusion-limited pores allowing compounds, including certain classes of antibiotics such as β-lactams and fluoroquinolones, to enter the bacterial cell. Even though allosteric processing occurs within both the periplasmic and cytoplasmic domains of EnvZ, how the transmembrane domain bi-directionally transmits these signals remains not fully understood. Here, we employ a library of single-Cys-containing EnvZ proteins to perform scan-SCAM in order to map the precise residue composition of TM1. Our results demonstrate that residue positions 19 through 30 reside within the membrane core and compose a tightly packed portion of TM1. We also show that positions 15 through 18 and position 31 are interfacial and slightly splayed apart compared to those tightly packed within the hydrophobic core. Finally, we reveal that residue positions 33 and 34 reside in the periplasm and participate in robust protein-protein interactions, while the periplasmic positions 35 through 41 exhibit helical periodicity. We conclude by synthesizing these new insights with recent high-resolution structural information into a model of membrane-spanning allosteric coupling between the periplasmic and cytoplasmic domains of EnvZ.
Multivariate associative patterns between the gut microbiota and large-scale brain network connectivity
Authors: Kohn N. , Szopinska-Tokov J. , Llera A. , Beckmann C. , Arias Vasquez A. , Aarts E.
Published: August 2020

Research on the gut-brain axis has accelerated substantially over the course of the last years. Many reviews have outlined the important implications of understanding the relation of the gut microbiota with human brain function and behavior. One substantial drawback in integrating gut microbiome and brain data is the lack of integrative multivariate approaches that enable capturing variance in both modalities simultaneously. To address this issue, we applied a linked independent component analysis (LICA) to microbiota and brain connectivity data.

We analyzed data from 58 healthy females (mean age = 21.5 years). Magnetic Resonance Imaging data were acquired using resting state functional imaging data. The assessment of gut microbial composition from feces was based on sequencing of the V4 16S rRNA gene region. We used the LICA model to simultaneously factorize the subjects’ large-scale brain networks and microbiome relative abundance data into 10 independent components of spatial and abundance variation.

LICA decomposition resulted in four components with non-marginal contribution of the microbiota data. The default mode network featured strongly in three components, whereas the two-lateralized fronto-parietal attention networks contributed to one component. The executive-control (with the default mode) network was associated to another component. We found the abundance ofPrevotellagenus was associated to the strength of expression of all networks, whereasBifidobacteriumwas associated with the default mode and frontoparietal-attention networks.

We provide the first exploratory evidence for multivariate associative patterns between the gut microbiota and brain network connectivity in healthy humans, taking into account the complexity of both systems.
Dual inhibition of BRAF and mTOR in BRAFV600E-mutant pediatric, adolescent, and young adult brain tumors
Authors: Sen Shiraj , Tanaka Ryuma , Khatua Soumen , Zaky Wafik , Janku Filip , Penas-Prado Marta , Weathers Shiao-Pei , Behrang Amini , Roszik Jason , Subbiah Vivek
Published: August 2020

Although BRAF inhibition has demonstrated activity in BRAFV600–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAFV600-mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.
A novel missense variant and multiexon deletion causing a delayed presentation of xeroderma pigmentosum, group C
Authors: Macke Erica L. , Morales-Rosado Joel A. , Gupta Aditi , Schmitz Christopher T. , Kruisselbrink Teresa , Lanpher Brendan , Klee Eric W.
Published: August 2020

Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor (XPC) are the cause of xeroderma pigmentosum, group C (MIM: 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14–15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics. Prior to age 36, she had more than 60 skin biopsies that showed dysplastic nevi, many of which had atypia. At age 36 she presented with her first melanoma in situ, and since then has had more than 10 melanomas. The proband underwent research whole-exome sequencing (WES) through the Mayo Clinic's Center for Individualized Medicine and a novel heterozygous variant of uncertain significance (VUS) in XPC (c.1709T > G, p.Val570Gly) was identified. Clinical confirmation pursued via XPC gene sequencing and deletion/duplication analysis of XPC revealed a pathogenic heterozygous deletion of ∼1 kb within XPC, including exons 14 and 15. Research studies determined the alterations to be in trans. Although variants in XPC generally result in early-onset skin cancer in childhood, the proband is atypical in that she did not present with her first melanoma until age 36. Review of the patient's clinical, pathological, and genetic findings points to a diagnosis of delayed presentation of xeroderma pigmentosum.
Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma
Authors: Anderson Ashley N. , McClanahan Danielle , Jacobs James , Jeng Sophia , Vigoda Myles , Blucher Aurora S. , Zheng Christina , Yoo Yeon Jung , Hale Carolyn , Ouyang Xiaoming , Clayburgh Daniel , Andersen Peter , Tyner Jeffrey W. , Bar Anna , Lucero Olivia M. , Leitenberger Justin J. , McWeeney Shannon K. , Kulesz-Martin Molly
Published: August 2020

Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.
Successful BRAF/MEK inhibition in a patient with BRAFV600E-mutated extrapancreatic acinar cell carcinoma
Authors: Busch Elena , Kreutzfeldt Simon , Agaimy Abbas , Mechtersheimer Gunhild , Horak Peter , Brors Benedikt , Hutter Barbara , Fröhlich Martina , Uhrig Sebastian , Mayer Philipp , Schröck Evelin , Stenzinger Albrecht , Glimm Hanno , Jäger Dirk , Springfeld Christoph , Fröhling Stefan , Zschäbitz Stefanie
Published: August 2020

Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAFV600E-mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAFV600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
Diffuse midline glioma with novel, potentially targetable, FGFR2–VPS35 fusion
Authors: Zanazzi George , Liechty Benjamin L. , Pendrick Danielle , Krasnozhen-Ratush Olga , Snuderl Matija , Allen Jeffrey C. , Garvin James H. , Mansukhani Mahesh M. , Roth Kevin A. , Hsiao Susan J.
Published: August 2020

We report a case of a slow-growing, diffuse, infiltrating glioma in the right brainstem of a 9-yr-old boy. The tumor was negative by immunohistochemical staining for histone H3 K27M, BRAF V600E, and IDH1 R132H mutations. Fluorescence in situ hybridization did not reveal a BRAF duplication. Genomic profiling of the tumor, by DNA methylation array and cancer whole-exome and transcriptome sequencing, was performed. This analysis showed copy-number alterations, including gains of several chromosomes. In addition, a novel fusion involving the first 17 exons of FGFR2 fused to exon 2 of VPS35 was identified. This novel fusion is predicted to result in activation of fibroblast growth factor receptor (FGFR) signaling and is potentially targetable using FGFR inhibitors. This tumor expands the spectrum of pediatric diffuse gliomas.
Synthesis, crystal structure determination of a novel phosphate Ag1.64Zn1.64Fe1.36(PO4)3 with an alluaudite-like structure
Authors: Khmiyas Jamal , Assani Abderrazzak , Saadi Mohamed , El Ammari Lahcen
Published: August 2020

Single crystals of Ag1.64Zn1.64Fe1.36(PO4)3 [silver zinc iron phosphate (1.64/1.64/1.36/3)] have been synthesized by a conventional solid-state reaction and structurally characterized by single-crystal X-ray diffraction. The title compound crystallizes with an alluaudite-like structure. All atoms of the structure are in general positions except for four, which reside on special positions of the space group, C2/c. The Ag+ cations reside at full occupancy on inversion centre sites and at partial occupancy (64%) on a twofold rotation axis. In this structure, the unique Fe3+ ion with one of the two Zn2+ cations are substitutionally disordered on the same general position (Wyckoff site 8f), with a respective ratio of 0.68/0.32 (occupancies were fixed so as to ensure electrical neutrality for the whole structure). The remaining O and P atoms are located in general positions. The three-dimensional framework of this structure consists of kinked chains of edge-sharing octahedra stacked parallel to [10\overline{1}]. These chains are built up by a succession of [MO6] (M = Zn/Fe or Zn) units. Adjacent chains are connected by the PO4 anions, forming sheets oriented perpendicular to [010]. These interconnected sheets generate two types of channels parallel to the c axis, in which the Ag+ cations are located. The validity and adequacy of the proposed structural model of Ag1.64Zn1.64Fe1.36(PO4)3 was established by means of bond-valence-sum (BVS) and charge-distribution (CHARDI) analysis tools.
Crystal structure of bacteriophage T4 Spackle as determined by native SAD phasing
Authors: Shi Ke , Kurniawan Fredy , Banerjee Surajit , Moeller Nicholas H. , Aihara Hideki
Published: August 2020

The crystal structure of a bacteriophage T4 early gene product, Spackle, was determined by native sulfur single-wavelength anomalous diffraction (SAD) phasing using synchrotron radiation and was refined to 1.52 Å resolution. The structure shows that Spackle consists of a bundle of five α-helices, forming a relatively flat disc-like overall shape. Although Spackle forms a dimer in the crystal, size-exclusion chromatography with multi-angle light scattering shows that it is monomeric in solution. Mass spectrometry confirms that purified mature Spackle lacks the amino-terminal signal peptide and contains an intramolecular disulfide bond, consistent with its proposed role in the periplasm of T4 phage-infected Escherichia coli cells. The surface electrostatic potential of Spackle shows a strikingly bipolar charge distribution, suggesting a possible mode of membrane association and inhibition of the tail lysozyme activity in T4 bacteriophage superinfection exclusion.
Does a diverse board matter? A mediation analysis of board racial diversity and firm performance
Authors: Vairavan Ashok , Zhang G. Peter
Published: August 2020

Purpose

This paper aims to reexamine the link between board racial diversity and firm performance. It focuses on the mechanism through which board racial diversity could affect performance. The paper proposes and empirically tests the role of employee productivity and R&D productivity in the relationship between board racial diversity and firm financial performance.

Design/methodology/approach

The paper adopts a mediation analysis framework with the bootstrapping method to test both the direct and indirect effect of board diversity on firm performance. The data used in the study come from S&P 1500 with variables composed from COMPUSTAT, Institutional Shareholder Services and Wharton Research Data Services.

Findings

Contrary to prior findings, the results indicate that there is neither direct effect of board racial diversity on firm performance nor is there an indirect effect through either employee productivity or R&D productivity.

Research limitations/implications

Because the data used in the paper are based on large public firms, the results may not generalize to small or private firms.

Practical implications

The findings of the paper suggest that not all diversity measures matter in the same way and firms should carefully make board appointments to reduce the perception that they select directors for any reason other than qualifications.

Originality/value

The paper advances the literature on board diversity by examining two previously unexplored mediating variables of employee productivity and R&D productivity. It also uses more rigorous mediation analysis with bootstrapping method and a validation sample to improve robustness of the results.
A scientometric review and meta-analysis of the health and safety of women in construction: structure and research trends
Authors: Mariam Akinlolu Temisola , Olalusi Oladimeji Benedict , Haupt Theo C.
Published: August 2020

Purpose

This paper aims to present a meta-analysis and scientometric review to explore the intellectual evolution of research on the health and safety of women in construction, identify trends and research patterns and workplace stressors and hazards encountered by women in the construction industry.

Design/methodology/approach

A combination of scientometric analysis and meta-analysis was adopted to systematically review 32 relevant studies from 1984 to 2020, to provide a holistic review of research on women’s health and safety in construction aimed to identify the trend of research development. Techniques such as co-authorship, keyword co-occurring and cluster analysis were adopted.

Findings

Five main themes summarized by clustering focusing on Workplace Psychological Health, HIV/AIDS and Construction Work, Occupational Health and Safety Injuries, Gender Inclusivity and Sexism in Construction and Gender-specific Health and Safety Analysis. Findings revealed a slow growth in women’s health and safety research with the USA, South Africa, Australia and Japan leading research development. Additionally, the major stressors or hazards faced by women in construction were found to be biological related hazards.

Research limitations/implications

The findings of the study are limited, resulting from the use of one abstract and citation database.

Practical implications

Findings from the study provide insights to the health and safety challenges of women in construction and identifies of knowledge gaps in the existing literature could provide researchers and industry practitioners with a comprehensive insight into intellectual landscapes, potential research frontiers on technologies for women’s construction health and safety.

Originality/value

While numerous studies have focused on the health and safety of workers in the construction industry, research on women’s health and safety is lacking. The study adopted a scientometric and meta-analysis approach to explore the intellectual evolution and reflect the research status on the subject.
SPARK-ing innovation: a model for elementary classrooms as COVID-19 unfolds
Authors: Powers Jeanne M. , Brown Mary , Wyatt Lisa G.
Published: August 2020

Purpose

The purpose of this paper is to describe SPARK, an innovative elementary school that highlights the possibilities for elementary education as COVID-19 continues to unfold.

Design/methodology/approach

The authors’ analysis is based on a research synthesis of the main features of the SPARK model, as it was operating when schools in Arizona closed because of the coronavirus pandemic: project-based learning, a teaming model, heterogeneously grouped multi-age classes, blended learning, supporting students' development as self-directed learners, mindfulness and looping.

Findings

This paper outlines the empirical grounding for the main features of the model and suggests how they might address elementary students' learning and social emotional needs when schools in Arizona reopen for in-person instruction either as full-service schools or on a staggered or hybrid schedule.

Originality/value

Educators from other districts can use this model as a springboard for reimagining their own educational spaces and practices in this new and still uncertain period when schools and school districts consider how to move forward. While many of these practices are not novel, the authors’ research synthesis highlights how SPARK combines them in a way that is unique and particularly relevant for the present moment.
Network‐level consequences of outgroup threats in banded mongooses: Grooming and aggression between the sexes
Authors: Preston Elizabeth F. R. , Thompson Faye J. , Ellis Samuel , Kyambulima Solomon , Croft Darren P. , Cant Michael A.
Published: August 2020

Animal groups are heterogeneous assemblages of individuals with differing fitness interests, which may lead to internal conflict over investment in group territorial defence. Differences between individuals may lead to different behavioural responses to intergroup conflict, particularly between the sexes. These potential impacts have been little studied.

We used social network analysis to investigate the impact of simulated intergroup conflicts on social relationships in groups of wild banded mongooses Mungos mungo, in which intergroup fights are more costly for males than females. We predicted that social cohesion (specifically male‐to‐male and female‐to‐male grooming) would increase after conflict, and aggression would decrease, to minimize conflict between the sexes.

Simulated intergroup conflicts were performed by exposing banded mongoose groups to scents, ‘war cry’ playbacks, and live intruders from a rival group. All grooming and aggression interactions between individuals were recorded, and grooming and aggression social networks were created for the 2 days preceding a simulated intergroup conflict (pre‐conflict network) and the 2 days after (post‐conflict network).

We found no evidence of an increase in social cohesion after simulated conflicts, measured as grooming eigenvector centrality. Male‐to‐male, male‐to‐female and female‐to‐male grooming strength decreased after simulated intrusions compared to female‐to‐female grooming strength. However, male–female aggression decreased in intrusion trials compared to other interaction types, consistent with the hypothesis that intergroup encounters reduce the level of intragroup conflict between males and females. Males were more affected socially by intergroup encounters than females, which may be because they are investing in defence rather than internal relationships.

Focusing on individual relationship changes, using social network analysis, can reveal changes in the directionality of behaviour in response to intergroup encounters, and highlight how individual responses to conflict may scale up to affect social networks and, potentially, group performance. This study highlights the importance of studying both group‐level behaviours and individual relationships to more fully understand responses to intergroup encounters.
Coordinate overexpression of two RND efflux systems, ParXY and TtgABC, is responsible for multidrug resistance in Pseudomonas putida
Authors: Puja Hélène , Comment Gwendoline , Chassagne Sophie , Plésiat Patrick , Jeannot Katy
Published: August 2020

Resistance Nodulation cell Division (RND) efflux pumps are known to contribute to the tolerance of Pseudomonas putida to aromatic hydrocarbons, but their role in antibiotic resistance has not been fully elucidated. In this study, two types of single‐step multidrug‐resistant (MDR) mutants were selected in vitro from reference strain KT2440. Mutants of the first type were more resistant to fluoroquinolones and β‐lactams except imipenem, and overproduced the efflux system TtgABC as a result of mutations occurring in regulator TtgR. In addition to TtgABC, mutants of the second type such as HPG‐5 were found to upregulate a novel RND pump, dubbed ParXY/TtgC, which accommodates cefepim, fluoroquinolones and aminoglycosides. As demonstrated by gene deletion experiments, TtgABC and ParXY/TtgC are both under the positive control of a two‐component system, PpeRS. Whole‐genome sequence analyses revealed that mutant HPG‐5 harbours a mutation inactivating the gene (sucD) of succinyl‐CoA synthetase, an enzyme of the tricarboxylic cycle. Disruption of sucD in strain KT2440 reproduced the resistance phenotype of HPG‐5, and activated the glyoxylate shunt. Finally, identification of two MDR clinical strains of P. putida that jointly overexpress TtgABC and ParXY/TtgC, of which one is a sucD mutant, highlights the role of these efflux systems as determinants of antibiotic resistance.
Climate Risk and Technology Adoption in the Midstream of Crop Value Chains: Evidence from Nigerian Maize Traders
Authors: Liverpool‐Tasie Lenis Saweda O , Parkhi Charuta M.
Published: August 2020

Climate induced events exacerbate food production and distribution risks, posing a threat to global food security. Though many studies focus on farmer adaptation to climate change, there are few studies of actors in the middle of agricultural value chains such as traders, logistics providers, and processors. The activities of these actors, referred to as the ‘hidden middle’, are key determinants of the prices received by farmers and the price and quality of food products for consumers. We explore how climate events and risk perceptions affect the adoption of value‐adding and damage control strategies among maize traders in Nigeria, Africa’s largest economy and most populous country. We find consistent evidence that climate events and climate risk perception discourage the adoption of value‐adding practices including storage. This potentially affects the availability and price of maize for consumers (household and industry) in the lean season. However, once traders store maize, climate risk does not affect the adoption of damage control, but training and social networks do. These findings suggest that actors in the midstream of food value chains are responding to climate change and more attention needs to be paid to these actors to maintain the availability of affordable and safe maize products throughout the year. There is also a need for strategies to reduce the risks of trading activities due to climate change.