bluuebunny/crossref_metadata_2025 huggingface dataset:
B LYMPHOCYTES, BUT NOT DENDRITIC CELLS, EFFICIENTLY HIV-1TRANS-INFECT NAÏVE CD4+T CELLS: IMPLICATIONS FOR THE VIRAL RESERVOIR
Authors: Gerberick Abigail , DeLucia Diana C. , Piazza Paolo , Alaoui-El-Azher Mounia , Rinaldo Charles R. , Sluis-Cremer Nicolas , Rappocciolo Giovanna
Published: October 2020

Insight into the establishment and maintenance of HIV-1 infection in resting CD4+T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+naïve T cells (TN) compared to the memory T cell subsets, recent studies have shown that TNcells harbor a large pool of replication-competent virus. Interestingly, however, TNcells are highly resistant to direct (cis) HIV-1 infectionin vitro, in particular to R5-tropic HIV-1, as TNcells do not express CCR5. In this study, we investigated whether TNcells could be efficiently HIV-1trans-infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficientlytransinfect TNcellsin vitro. In contrast, both B cells and DC mediated HIV-1transinfection of memory and activated CD4+T cells. Moreover, we found that TNisolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA compared to TNisolated from progressors. This is consistent with our previous finding that APC derived from NP do not efficientlytrans-infect CD4+T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediatedtransinfection of TNcells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression.

Importance

The latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication competent HIV-1 has been isolated from naïve T cells, and CCR5-tropic HIV-1 has been recovered from CCR5negTNcells from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5negTNcells are efficientlytransinfected with R-5 tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TNisolated from NP harbor no or significantly less copies of HIV-1 DNA compared to ART-suppressed progressors. These findings support that B cell-mediatedtransinfection of TNcells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.
SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and alters gene expression via direct interaction with host mRNAs
Authors: Nabeel-Shah Syed , Lee Hyunmin , Ahmed Nujhat , Marcon Edyta , Farhangmehr Shaghayegh , Pu Shuye , Burke Giovanni L. , Ashraf Kanwal , Wei Hong , Zhong Guoqing , Tang Hua , Yang Jianyi , Blencowe Benjamin J. , Zhang Zhaolei , Greenblatt Jack F.
Published: October 2020

The COVID-19 pandemic has caused over one million deaths thus far. There is an urgent need for the development of specific viral therapeutics and a vaccine. SARS-CoV-2 nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for both antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we initially catalogued the protein-protein interactions of 21 SARS-CoV-2 proteins in HEK293 cells, finding that the stress granule resident proteins G3BP1 and G3BP2 copurify with N with high specificity. We demonstrate that N protein expression in human cells sequesters G3BP1 and G3BP2 through its physical interaction with these proteins, attenuating stress granule (SG) formation. The ectopic expression of G3BP1 in N-expressing cells was sufficient to reverse this phenotype. Since N is an RNA-binding protein, we performed iCLIP-sequencing experiments in cells, with or without exposure to oxidative stress, to identify the host RNAs targeted by N. Our results indicate that SARS-CoV-2 N protein binds directly to thousands of mRNAs under both conditions. Like the G3BPs stress granule proteins, N was found to predominantly bind its target mRNAs in their 3’UTRs. RNA sequencing experiments indicated that expression of N results in wide-spread gene expression changes in both unstressed and oxidatively stressed cells. We suggest that N regulates host gene expression by both attenuating stress granules and binding directly to target mRNAs.
The Oscillatory Effects of Rhythmic Median Nerve Stimulation
Authors: Houlgreave Mairi S. , Maiquez Barbara Morera , Brookes Matthew J. , Jackson Stephen R.
Published: October 2020

Entrainment of brain oscillations can be achieved using rhythmic non-invasive brain stimulation, and stimulation of the motor cortex at a frequency associated with sensorimotor inhibition can impair motor responses. Despite the potential for therapeutic application, these techniques do not lend themselves to use outside of a clinical setting. Here, the aim was to investigate whether rhythmic median nerve stimulation (MNS) could be used to entrain oscillations related to sensorimotor inhibition. MEG data were recorded from 20 participants during 400 trials, where for each trial 10 pulses of MNS were delivered either rhythmically or arrhythmically at 12 or 20Hz. Our results demonstrate a frequency specific increase in relative amplitude in the contralateral somatosensory cortex during rhythmic but not arrhythmic stimulation. This was coupled with an increase in inter-trial phase coherence at the same frequency, suggesting that the oscillations synchronised with the pulses of MNS. While the results show that 20Hz rhythmic peripheral nerve stimulation can produce entrainment, the response to 12Hz stimulation was largely due to the presence of rhythmic sensory evoked potentials. Regardless, rhythmic MNS resulted in synchronous firing of neuronal populations within the contralateral somatosensory cortex meaning these neurons were ‘occupied’ in processing of the afferent input. Therefore, MNS could prove therapeutically useful in disorders associated with hyperexcitability within the sensorimotor cortices.
Functional Molecular Switches of Mammalian G Protein-Coupled Bitter-Taste Receptors
Authors: Topin Jérémie , Bouysset Cédric , Pacalon Jody , Kim Yiseul , Rhyu MeeRa , Fiorucci Sébastien , Golebiowski Jérôme
Published: October 2020

Bitter taste receptors (TAS2Rs) are a poorly understood subgroup of G protein-coupled receptors (GPCRs). The experimental structure of these receptors has yet to be determined, and key-residues controlling their function remain mostly unknown. We designed an integrative approach to improve comparative modeling of TAS2Rs. Using current knowledge on class A GPCRs and existing experimental data in the literature as constraints, we pinpointed conserved motifs to entirely re-align the amino-acid sequences of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis andin vitrofunctional assays. This combination ofin silicoandin vitroresults clarify sequence-function relationships and identify the functional molecular switches that encode agonist sensing and downstream signaling mechanisms within mammalian TAS2Rs sequences.

Classification

Biological sciences, Computational biology, and bioinformatics
Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
Authors: Baca Sylvan C. , Takeda David Y. , Seo Ji-Heui , Hwang Justin , Ku Sheng Yu , Arafeh Rand , Arnoff Taylor , Agarwal Supreet , Bell Connor , O’Connor Edward , Qiu Xintao , Alaiwi Sarah Abou , Corona Rosario I. , Fonseca Marcos A. S. , Giambartolomei Claudia , Cejas Paloma , Lim Klothilda , He Monica , Sheahan Anjali , Nassar Amin , Berchuck Jacob E. , Brown Lisha , Nguyen Holly M. , Coleman Ilsa M. , Kaipainen Arja , De Sarkar Navonil , Nelson Peter S. , Morrissey Colm , Korthauer Keegan , Pomerantz Mark M. , Ellis Leigh , Pasaniuc Bogdan , Lawrenson Kate , Kelly Kathleen , Zoubeidi Amina , Hahn William C. , Beltran Himisha , Long Henry W. , Brown Myles , Corey Eva , Freedman Matthew L.
Published: October 2020

Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer1,2. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. To investigate the epigenomic basis of this resistance mechanism, we profiled histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identified a vast network ofcis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium3,4, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying novel cancer dependencies through epigenomic profiling.
External light dark cycle shapes gut microbiota through intrinsically photosensitive retinal ganglion cells
Authors: Lee Chi-Chan , Lu Tsung-Hao , Lee I-Chi , Zou Yan-Fang , Yu Hon-Tsen , Chen (Alen) Shih-Kuo
Published: October 2020

Gut microbiota has been shown to involve in many physiological functions such as metabolism, brain development, and neuron degeneration disease. Intriguingly, many microbes in the digestive tract do not maintain a constant level of their relative abundance but show daily oscillations under normal conditions. Recent evidence indicates that chronic jetlag, constant darkness, or deletion of the circadian core gene can alter the composition of gut microbiota and dampen the daily oscillation of gut microbes. These studies suggest that the interaction between the host circadian clock and the light-dark cycle plays an important role in gut homeostasis and microbiota. However, how or whether environmental factors such as the light-dark cycle could modulate gut microbiota is still poorly understood. Using genetic mouse models and 16s rRNA metagenomic analysis, we found that light-dark cycle information transmitted by the ipRGC-sympathetic circuit was essential for daily oscillations of gut microbes under temporal restricted high fat diet condition. Furthermore, aberrant light exposure such as dim light at night (dLAN), acting through intrinsically photosensitive retinal ganglion cells (ipRGCs), could alter the composition, relative abundance, and daily oscillations of gut microbiota. Together, our results indicate that external stimulation, such as light-dark cycle information, through the sensory system can modulate gut microbiota in the direction from the brain to the gut.
Performance and impact of using a rapid molecular test to detectChlamydia trachomatisandNeisseria gonorrhoeaein women suspected of having pelvic inflammatory disease
Authors: Munrós J , Vergara A , Bataller E , Restovic G , García-Lorenzo B , Álvarez-Martínez MJ , Mira A , Carmona F , Vila J , Bosch J
Published: October 2020

Objective

The diagnosis of pelvic inflammatory disease (PID) is challenging. Testing forChlamydia trachomatis(CT) andNeisseria gonorrhoeae(NG) in the lower genital tract is recommended, since a positive result supports the diagnosis. The aim of this study was to investigate the prevalence of CT/NG infection in women suspected of having PID and the usefulness of a rapid molecular test to detect CT/NG.

Methods

This observational study included 3 groups of patients: mild-to-moderate PID (n=33), severe PID (n=29) and non-specific lower abdominal pain (NSAP) (n=13). CT/NG infection were analyzed using a standard and a rapid test. A cost analysis was carried out.

Results

The presence of CT/NG was determined in 75 endocervical and urine samples. Endocervical samples of 19 patients (25.3%) were CT/ NG positive (two cases of co-infection). NG was not detected in urine in one case. Concordance between rapid and standard tests was 100%. However, the mean time to achieve results was shorter with the rapid test: 2.22vs.24.37 hours, respectively (p< 0.001). No significant differences were observed in the presence of CT/NG in mild-to-moderate compared to severe PID. Costs differed according only to disease severity but to the presence of CT/NG. Only one patient with NSAP was positive for CT.

Conclusions

Rapid molecular tests could help with the diagnosis of PID in sexually active women in clinical settings in which a standard technique is not available. Nonetheless, a positive test for CT/NG may not be determinant of the clinical management. The only cost difference relates to disease severity.
PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma
Authors: Edge Sarah D. , Renard Isaline , Pyne Emily , Moody Hannah , Roy Rajarshi , Beavis Andrew W. , Archibald Stephen J. , Cawthorne Christopher J. , Maher Stephen G. , Pires Isabel M.
Published: October 2020

Objectives

Neoadjuvant chemo-radiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whistin vitromiR-187 overexpression enhanced radio-sensitivity and upregulatedPTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC.

Methods

The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and western blotting.PTENexpression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in 2D and 3D OAC modelsin vitroand as a single agentin vivo. Radiation responsein vitrowas assessed via clonogenic assay.

Results

PTENexpression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulatedPTENexpression and inhibited downstream PI3K signallingin vitro. GDC-0941 significantly reduced viability and enhanced radiation responsein vitroand led to tumour growth inhibition as a single agentin vivo.

Conclusions

Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT.

Advances in knowledge

This is the first study evaluating the effect of PI3K inhibition on radio-sensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the 1sttime that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.
Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections
Authors: Santi Isabella , Manfredi Pablo , Maffei Enea , Egli Adrian , Jenal Urs
Published: October 2020

The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we usedin vitroevolution and analyzed inpatient microevolution ofPseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistancein vitroand we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections,P. aeruginosafirst acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multi-drug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.
Amplification of potential thermogenetic mechanisms in cetacean brains
Authors: Manger Paul R. , Patzke Nina , Spocter Muhammad A. , Bhagwandin Adhil , Karlsson Karl Æ. , Bertelsen Mads F. , Alagaili Abdulaziz N. , Bennett Nigel C. , Mohammed Osama B. , Herculano-Houzel Suzana , Hof Patrick R. , Fuxe Kjell
Published: October 2020

To elucidate causality underlying the evolution of large brains in cetaceans, we examined the brains of 16 cetartiodactyl species for evidence of non-shivering thermogenesis. In comparison to the artiodactyl brain, the cetacean brain exhibits an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that dissipate the proton gradient to generate heat) in cortical neurons, localization of UCP4 within a substantial proportion of glia throughout the brain, and an increased density of noradrenergic axonal boutons (noradrenaline functioning to control concentrations of and activate UCPs). Thus, cetacean brains possess multiple characteristics indicative of intensified thermogenetic functionality that can be related to their current and historical obligatory aquatic niche. These findings necessitate reassessment of our concepts regarding the reasons for large brain evolution and associated functional capacities in cetaceans.
Neural Mechanism of Hunger-gated Food-seeking and Evaluating
Authors: Lee Young Hee , Kim You Bin , Kim Kyu Sik , Song Ha Young , Jang Mirae , Ha Dong-Soo , Park Joon Seok , Jung Sang-Ho , Lee Jaegeon , Kim Kyung Min , Cheon Deok-Hyeon , Baek Inhyeok , Shin Min-Gi , Lee Eun Jeong , Kim Sang Jeong , Choi Hyung Jin
Published: October 2020

The physiological need for energy evokes motivated feeding behaviours that help to ensure survival. However, the neural mechanisms underlying the generation of food motivation remain poorly understood. We investigated these mechanisms by subdividing feeding-related motivated behaviours into food-seeking, evaluating, and swallowing. Micro-endoscopic results indicated that neurons containing leptin receptors (LepRs) in the lateral hypothalamus (LH) are the major food-specific subpopulation of LHGABAneurons. Optogenetic manipulation of LHLepRneurons bidirectionally regulated both food-seeking and evaluating. Furthermore, micro-endoscope data revealed that distinct LHLepRneurons encode seeking and evaluating. Computational modelling analysis demonstrated that LHLepRneurons encode motivation, whereas neurons containing agouti-related peptide and neuropeptide Y (AgRP/NPY) encode the need for food. Additionally, slice studies revealed that NPY decreases inhibitory input to LHLepRneurons via LHGABAinterneurons. This mechanism explains the permissive gate role of hunger (food need) in seeking/evaluating motivation. Together, the present study provides a comprehensive neural mechanism of how physiological needs drive distinct motivated behaviours.
Retrograde suppression of post-tetanic potentiation at the mossy fiber-CA3 pyramidal cell synapse
Authors: Makani Sachin , Lutzu Stefano , Lituma Pablo J. , Hunt David L. , Castillo Pablo E.
Published: October 2020

In the hippocampus, the excitatory synapse between dentate granule cell axons – or mossy fibers (MF) – and CA3 pyramidal cells (MF-CA3) expresses robust forms of short-term plasticity, such as frequency facilitation and post-tetanic potentiation (PTP). These forms of plasticity are due to increases in neurotransmitter release, and can be engaged when dentate granule cells fire in bursts (e.g. during exploratory behaviors) and bring CA3 pyramidal neurons above threshold. While frequency facilitation at this synapse is limited by endogenous activation of presynaptic metabotropic glutamate receptors, whether MF-PTP can be regulated in an activity-dependent manner is unknown. Here, using physiologically relevant patterns of mossy fiber stimulation in acute mouse hippocampal slices, we found that disrupting postsynaptic Ca2+dynamics increases MF-PTP, strongly suggesting a form of Ca2+-dependent retrograde suppression of this form of plasticity. PTP suppression requires a few seconds of MF bursting activity and Ca2+release from internal stores. Our findings raise the possibility that the powerful MF-CA3 synapse can negatively regulate its own strength not only during PTP-inducing activity typical of normal exploratory behaviors, but also during epileptic activity.

SIGNIFICANCE STATEMENT

The powerful mossy fiber-CA3 synapse exhibits strong forms of plasticity that are engaged during location-specific exploration, when dentate granule cells fire in bursts. While this synapse is well-known for its presynaptically-expressed LTP and LTD, much less is known about the robust changes that occur on a shorter time scale. How such short-term plasticity is regulated, in particular, remains poorly understood. Unexpectedly, anin vivo-like pattern of presynaptic activity induced robust post-tetanic potentiation (PTP) only when the postsynaptic cell was loaded with a high concentration of Ca2+buffer, indicating a form of Ca2+–dependent retrograde suppression of PTP. Such suppression may have profound implications for how environmental cues are encoded into neural assemblies, and for limiting network hyperexcitability during seizures.
Mitochondrial ATP Synthase Trafficking along Microtubules to Cell Surface Depends on KIF5B and DRP1
Authors: Chang Yi-Wen , Yang T. Tony , Chen Min-Chun , Liaw Y-geh , Yin Chieh-Fan , Huang Ting-Yu , Hou Jen-Tzu , Hung Yi-Hsuan , Hsu Chia-Lang , Huang Hsuan-Cheng , Juan Hsueh-Fen
Published: October 2020

Ectopic adenosine triphosphate (eATP) synthase, located on the cell surface instead of the mitochondrial inner membrane, has been discovered to be a novel target for the treatment of various types of cancer. However, the mechanism of eATP synthase trafficking toward the cell surface remains unclear. In this study, we used an integrative approach incorporating multiomics, super-resolution imaging, real-time live-cell tracing, and various functional analyses to derive a transport model of eATP synthase from the mitochondria to the plasma membrane in cancer cells. We determined that the ATP synthase complex is first assembled in the mitochondria and subsequently delivered to the cell surface through the microtubule-mediated mitochondrial transport pathway. We also found that dynamin-related protein 1 (DRP1) enhances mitochondrial fission and subsequently associates with microtubule motor protein kinesin family member 5B (KIF5B) to promote the subcellular transportation of eATP synthase. Consequently, our work provides a blueprint for eATP synthase trafficking from the mitochondria toward the cell surface.
Corticostriatal Projections of Macaque Area 44
Authors: Korponay Cole , Choi Eun Young , Haber Suzanne N.
Published: October 2020

Ventrolateral frontal area 44 is implicated in inhibitory motor functions and facilitating prefrontal control over vocalization. Yet, the corticostriatal circuitry that may contribute to area 44 functions is not clear, as prior investigation of area 44 corticostriatal projections is limited. Here, we used anterograde and retrograde tracing in macaques to map the innervation zone of area 44 corticostriatal projections, quantify their strengths, and evaluate their convergence with corticostriatal projections from non-motor and motor-related frontal regions. First, terminal fields from a rostral area 44 injection site were found primarily in the central caudate nucleus, whereas those from a caudal area 44 injection site were found primarily in the ventrolateral putamen. Second, amongst sampled striatal retrograde injection sites, area 44 input as a percentage of total frontal cortical input was highest in the ventral putamen at the level of the anterior commissure. Third, area 44 projections converged with both orofacial premotor area 6VR and other motor related projections (in the putamen), and with non-motor prefrontal projections (in the caudate nucleus). These findings support the role of area 44 as an interface between motor and non-motor functional domains, possibly facilitated by rostral and caudal area 44 subregions with distinct corticostriatal connectivity profiles.
Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19
Authors: Le Brian L. , Andreoletti Gaia , Oskotsky Tomiko , Vallejo-Gracia Albert , Rosales Romel , Yu Katharine , Kosti Idit , Leon Kristoffer E. , Bunis Daniel G. , Li Christine , Kumar G. Renuka , White Kris M. , García-Sastre Adolfo , Ott Melanie , Sirota Marina
Published: October 2020

The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated sixteen of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.
Biomolecular models of EPI-X4 binding to CXCR4 allow the rational optimization of peptides with therapeutic potential
Authors: Sokkar Pandian , Harms Mirja , Stürzel Christina , Gilg Andrea , Kizilsavas Gönül , Raasholm Martina , Preising Nico , Wagner Manfred , Ständker Ludger , Weidinger Gilbert , Münch Jan , Sanchez-Garcia Elsa
Published: October 2020

The Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) is a body-own fragment of albumin and specific antagonist of the CXC-motif-chemokine receptor 4 (CXCR4). CXCR4 signaling is induced by its sole chemokine ligand CXCL12 and is involved in a plethora of functions including cell homing, differentiation, survival and angiogenesis. Consequently, dysregulation of CXCR4 is involved in a variety of disorders, such as cancer or inflammatory diseases, making CXCR4 an attractive drug target. EPI-X4 and derivatives with increased CXCR4 binding affinities represent promising leads as CXCR4 antagonists and have shown therapeutic activity in mouse models of inflammatory diseases. However, it is currently unclear how EPI-X4 and its derivatives interact with CXCR4. Here, by combining biomolecular simulations with experimental mutagenesis and activity studies we investigated the binding behavior of EPI-X4 to CXCR4 at the molecular level. Our work allowed us to show that the EPI-X4 peptide interacts primarily in the minor pocket of CXCR4 through its N-terminal residues. The biomolecular interactions highlighted by the computational studies are in good agreement with the experimental mutagenesis data. Moreover, we found that the N-terminal seven amino-acids of EPI-X4 (a 16-mer) and its improved derivatives (12-mers) are sufficient for CXCR4 binding, which led to the development of shorter leads with optimized CXCR4 antagonizing properties. Collectively, we here established how EPI-X4 binds to its receptor and used this knowledge for rational drug design. The new peptide variants developed by us are more potent in terms of inhibiting CXCR4-downstream signaling and cancer cell migration, without toxic effects.
Chemoprophylaxis vaccination with aPlasmodiumliver stage autophagy mutant affords enhanced and long-lasting protection
Authors: Sahu Tejram , Gehrke Ella J. , Flores-Garcia Yevel , Mlambo Godfree , Romano Julia D. , Coppens Isabelle
Published: October 2020

Genetically-attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Though CVac with WT sporozoites confers better immunity, the overhanging threat of drug resistance limits its use as a vaccine. Here, we demonstrate that a liver stage-specific mutant ofPlasmodium bergheiwhen used as a vaccine under a CVac regimen provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+T-cell response through an IFN-γ-independent mechanism and is associated with a stable population of antigen-experienced CD8+T cells. Jointly, our findings support the benefit of liver stage mutants as vaccines over WT, under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.
Differences in the gut microbiomes of distinct ethnicities within the same geographic area are linked to host metabolic health
Authors: Ang Qi Yan , Alba Diana L. , Upadhyay Vaibhav , Bisanz Jordan E. , Cai Jingwei , Lee Ho Lim , Barajas Eliseo , Wei Grace , Noecker Cecilia , Patterson Andrew D. , Koliwad Suneil K. , Turnbaugh Peter J.
Published: October 2020

Background

The human gut microbiota exhibits marked variation around the world, which has been attributed to dietary intake and other environmental factors. However, the degree to which ethnicity-associated differences in gut microbial community structure and function are maintained following immigration or in the context of metabolic disease is poorly understood.

Results

We conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area. 16S rRNA gene sequencing revealed significant differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degradingAkkermansia muciniphila.East Asian participants had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White groups could not be explained by reported dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice confirmed that the differences in the gut microbiota of the East Asian and White individuals we analyzed are independent of diet and that they differentially impact host body weight and adiposity in genetically identical mouse recipients.

Conclusions

The reported findings emphasize the utility of studying diverse ethnic groups within a defined geographical location and provide a starting point for dissecting the mechanisms contributing to the complex interactions between the gut microbiome and ethnicity-associated lifestyle, demographic, metabolic, and genetic factors.
Viral mimicry of p65/RelA transactivation domain to inhibit NF-κB activation
Authors: Albarnaz Jonas D. , Ren Hongwei , Torres Alice A. , Shmeleva Evgeniya V. , Melo Carlos A. , Bannister Andrew J. , Brember Matthew P. , Chung Betty Y.-W. , Smith Geoffrey L.
Published: October 2020

Sensing of virus infection activates NF-κB to induce the expression of interferons, cytokines and chemokines to initiate the antiviral response. Viruses antagonise these antiviral defences by interfering with immune sensing and blocking the actions of antiviral and inflammatory molecules. Here, we show that a viral protein mimics the transactivation domain of the p65 subunit of NF-κB. The C terminus of vaccinia virus (VACV) protein F14 (residues 51-73) activates transcription when fused to a DNA-binding domain-containing protein and F14 associates with NF-κB co-activator CBP, disrupting p65-CBP interaction. Consequently, F14 diminishes CBP-mediated acetylation of p65 and the downstream recruitment of the transcriptional regulator BRD4 to the promoter of the NF-κB-responsive genesCXCL10andCCL2, hence inhibiting their expression. Conversely, the recruitment of BRD4 to the promoters ofNFKBIA, which encodes the inhibitor of NF-κB (IκBα), andCXCL8remains unaffected in the presence of either F14 or JQ1, a competitive inhibitor of BRD4 bromodomains, indicating its recruitment is acetylation-independent. Therefore, unlike other viral NF-κB antagonists, F14 is a selective inhibitor of NF-κB-dependent gene expression. A VACV strain lacking F14 showed that it contributes to virulence in an intradermal model of infection. Our results uncover a mechanism by which viruses disarm the antiviral defences through molecular mimicry of a conserved host protein and provide insight into the regulation of NF-κB-dependent gene expression by BRD4.
Identification bioactive compounds from marine microorganism and exploration of structure–activity relationships (SARs)
Authors: Dinarvand Mojdeh , Spain Malcolm P.
Published: October 2020

Marine natural products (MNPs) have become new strong leads for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein we report the bioassay guided fractionation of marine extracts from spongesLendenfeldia, IrciniaandDysideathat led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: anilines1, benzylamines2, tertiary amines3and4, and quaternary amine salt5, along with three known compounds (6-8) were isolated from a crude extract and MeOH eluent marine extracts. The absolute configurations of the new compounds were assigned based on tandem mass spectrometry (MS) analysis. Several of the compounds exhibited potentin-vitroantibacterial activity, especially againstMethicillin-resistant Staphylococcus aureus(MRSA) (MICs from 15.6 to 62.5 micro g/mL). Herein, we also, report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure activity relationships (SARs) results clearly demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity towards different biological activity. Several commercially available compounds, which are structurally related to the molecules we discovered showed broad spectrum antimicrobial activity against different test pathogens with an MIC50 range of 50 to 0.01 microM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential lead molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds with increased bioactivity
Isolation and characterization of a novel phage SaGU1 that infectsStaphylococcus aureusclinical isolates from patients with atopic dermatitis
Authors: Shimamori Yuzuki , Pramono Ajeng K. , Kitao Tomoe , Suzuki Tohru , Aizawa Shin-ichi , Kubori Tomoko , Nagai Hiroki , Takeda Shigeki , Ando Hiroki
Published: October 2020

The bacteriumStaphylococcus aureus, which grows on healthy human skin, may cause diseases such as atopic dermatitis (AD). Treatment for such AD cases involves antibiotic use; however, alternate treatments are preferred owing to the development of antimicrobial resistance. This study aimed to characterize the novel bacteriophage SaGU1 as a potential agent for phage therapy to treatS. aureusinfections. SaGU1 that infectsS. aureusstrains previously isolated from the skin of patients with AD was screened from sewage samples in Gifu, Japan. Its genome was sequenced and analyzed using bioinformatics tools, and the morphology, lytic activity, stability, and host range of the phage were determined. The SaGU1 genome consisted of 140,909 bp with an average GC content of 30.2%. The viral chromosome contained putative 225 protein-coding genes and four tRNA genes, carrying neither toxic nor antibiotic resistance genes. Electron microscopy analysis revealed that SaGU1 belongs to theMyoviridaefamily. Stability tests showed that SaGU1 was heat-stable under physiological and acidic conditions. Host-range testing revealed that SaGU1 could infect a broad range ofS. aureusclinical isolates present on the skin of patients with AD, whereas it did not kill strains ofStaphylococcus epidermidis, which are symbiotic bacteria in the human skin microbiota. Our data suggest that SaGU1 is a potential candidate for developing a phage therapy to treat AD caused by pathogenicS. aureus.
Can databases facilitate accountability? The case of Australian mercury accounting via the National Pollutant Inventory
Authors: Ullah Md. Hafij , Hazelton James , Nelson Peter F
Published: October 2020

Purpose

This paper furthers research into the potential contribution of pollutant databases for corporate accountability. We evaluate the quality of corporate and government mercury reporting via the Australian National Pollutant Inventory (NPI), which underpins Australia's reporting under the Minamata Convention, a global agreement to reduce mercury pollution.

Design/methodology/approach

The qualitative characteristics of accounting information are used as a theoretical frame to analyse ten interviews with thirteen interviewees as well as 54 submissions to the 2018 governmental enquiry into the NPI.

Findings

While Australian mercury accounting using the NPI is likely sufficient to meet the expected Minamata reporting requirements (especially in comparison to developing countries), we find significant limitations in relation to comparability, accuracy, timeliness and completeness. These limitations primarily relate to government (as opposed to industry) deficiencies, caused by insufficient funding. The findings suggest that multiple factors are required to realise the potential of pollutant databases for corporate accountability, including appropriate rules, ideological commitment and resourcing

Practical implications

The provision of additional funding would enable the NPI to be considerably improved (for mercury as well as other pollutants), particularly in relation to the measurement and reporting of emissions from diffuse sources.

Originality/value

Whilst there have been prior reviews of the NPI, none have focused on mercury, whilst conversely prior studies which have discussed mercury information have not focused on the NPI. In addition, no prior NPI studies have utilised interviews nor have engaged directly with NPI regulators. There has been little prior engagement with pollutant databases in social and environmental accounting (SEA) research.
Influence of support on work engagement in nursing staff: the mediating role of possibilities for professional development
Authors: Contreras Francoise , Abid Ghulam , Govers Mark , Saman Elahi Natasha
Published: October 2020

Purpose

The purpose of this study is to examine the effects of colleague and supervisor support on work engagement, examining the mediating role of possibilities for professional development in a healthcare setting.

Design/methodology/approach

A cross-sectional survey design was used. A sample of 253 Colombian nurses from a private hospital completed a series of questionnaires.

Findings

According to the results, support from both colleagues and supervisors influences the work engagement of healthcare personnel. This research provides evidence about how to encourage work engagement in nursing staff through an adequate environment characterized by support and opportunities for career advancement.

Research limitations/implications

In this study, a cross-sectional design was used; therefore, the generalization is limited, and it is not possible to infer causality.

Originality/value

Providing certain conditions can promote not only work engagement with its desirable effects, but it may also mitigate the burden of a complex environment such as healthcare.
Changing the narrative: shaping legislation to advance diversity on boards in Canada
Authors: Cukier Wendy , Gagnon Suzanne , Latif Ruby
Published: October 2020

Purpose

This paper examines actors and discourses shaping new Canadian legislation designed to advance diversity in corporate governance.

Design/methodology/approach

This paper performs a stakeholder and discourse analysis drawing on texts of parliamentary debates.

Findings

The paper illuminates tensions regarding definitions of diversity, its importance for boards of directors and the mechanisms favoured for implementation. Official discourses examined show that, unlike for other political issues, opposition was largely muted, and most stakeholders engaged in the process supported legislation advancing diversity. Nonetheless areas of debate and positioning by actors and suggest important differences, with outcomes linked to non-traditional power bases.

Research limitations/implications

This study provides insights into the discursive environments of organizations and processes relating to promoting diversity and equality in the political decision-making domain, a critical venue for understanding advancement of equity, often neglected in organizational studies.

Practical implications

By understanding the complex and competing discourses surrounding diversity and inclusion at the macro level this paper provides a context for understanding organizational (meso) and individual (micro) beliefs and behaviours.

Social implications

This study shows how advocacy shapes how policy and legislation are framed and the ways mainstream organizations, including women's groups, may advance gender equality without regard to other dimensions of diversity or intersectionality.

Originality/value

This study maps the political discourse around recent Canadian legislation designed to improve diversity on boards that must, in the Canadian context, address more than gender.
The impact of social media on disaster relief effort – recovery coordination for Hurricane Harvey
Authors: Hazarika Bidyut , Rea Alan , Mousavi Reza , Chen Kuanchin
Published: October 2020

Purpose

This study aims to investigate patterns of social media posting occurring during the initial post-disaster recovery period. In addition, the study investigates the antecedents of user engagement with Twitter posts or “tweets.”

Design/methodology/approach

This study uses Hurricane Harvey as the research focus because of its $125bn in damage and the recovery effort associated with it. Analyzing nearly 38,000 tweets related to 2017’s Hurricane Harvey and specifically focuses on rescuers who became to be known as the “Cajun Navy.”

Findings

The popularity of the tweet significantly influences social media engagement; disaster relief organizations first should seek out alliances and partnerships with those who already are well-known or influential in social media. In addition, by regularly monitoring and participating in social media, such as encouraging retweets and mentions even when not responding to a disaster, agencies will gain social media followers and influence when these are most needed.

Research limitations/implications

By analyzing patterns of social media posts during and after Hurricane Harvey, this study attempts to quantify social media’s effectiveness during this disaster, in particular with a focus on what characteristics of Harvey-related Twitter posts most influenced user engagement.

Practical implications

Findings underscore the need for agencies to strengthen their social media presence and use it in all three phases of disaster conceptualization. Beyond managing communication with other agencies and the community, which alone is critical for an agency’s impact, social media offers the world as a potential audience for agencies that can deftly leverage it.

Originality/value

Social media has revolutionized not only communication but also inter-connectivity as people have normalized its use. Its ubiquity and efficiency have seen its incorporation into the critical area of emergency management, both during and after disasters. The main objective of this paper is to investigate and evaluate the usefulness of social media in disaster recovery efforts, focusing on its advantages in relation to a recent disaster event.
The HPWS and AMO: a dynamic study of system- and individual-level effects
Authors: Edgar Fiona , Zhang Jing A. , Blaker Nancy M.
Published: October 2020

Purpose

Drawing on the dynamic model of ability, motivation, opportunity (AMO) for human resource research, this study aims to examine how organizational system-level (i.e. the high-performance work system (HPWS)) and individual-level AMO affect employees' performance. Specifically, this paper proposes that employee task performance is resultant from the integration of system- and individual-level AMO factors with employee contextual performance.

Design/methodology/approach

A survey design is employed with data collected from 250 employees working in New Zealand's service sector.

Findings

This study finds both organizational system (HPWS) and individual AMO dimensions have positive associations with employees' performance. At the system level, the supportive role played by contextual performance is highlighted with pro-social behaviors fully mediating the relationship between the HPWS and task performance. At the individual level, contextual performance is found to partially mediate the relationship between ability and task performance and fully mediate the relationship between motivation and task performance. Opportunity, on the other hand, is significantly associated with task but not contextual performance.

Originality/value

In acknowledging there are a plurality of factors that impact performance, this study enriches our understanding of AMO's influence in the context of people management.