bluuebunny/crossref_metadata_2025 huggingface dataset:
A Qualitative Study Exploring the Consumer Experience of Receiving Self-Initiated Polygenic Risk Scores from a Third-Party Website
Authors: Lowes Kiara , Borle Kennedy , Folkersen Lasse , Austin Jehannine
Published: July 2022

The number of people accessing their own polygenic risk scores (PRSs) online is rapidly increasing, yet little is known about why people are doing this, how they react to the information, and what they do with it. We conducted a qualitative interview-based study with people who pursued PRSs through Impute.me, to explore their motivations for seeking PRS information, their emotional reactions, and actions taken in response to their results. Using interpretive description, we developed a theoretical model describing the experience of receiving PRSs in a direct-to-consumer (DTC) context. Dissatisfaction with healthcare was an important motivator for seeking PRS information. Participants described having medical concerns dismissed, and experiencing medical distrust, which drove them to self-advocate for their health, which in turn ultimately led them to seek PRSs. Polygenic risk scores were often empowering for participants, but could be distressing when PRS information did not align with participants’ perceptions of their personal or family histories. Behavioural changes made in response to PRS results included dietary modifications, changes in vitamin supplementation and talk-based therapy. Our data provides the first qualitative insight into how people’s lived experience influence their interactions with DTC PRSs.
Association between skull bone mineral density and periodontitis: evidence from the National Health and Nutrition Examination Survey (2011-2014)
Authors: Jin Fuqian , Song Jukun , Luo Yi , Wang Beichuan , Ding Ming , Hu Jiaxin , Chen Zhu
Published: July 2022

Background and Objective

Bone mineral density (BMD) and periodontitis have been the subject of many studies. However, the relationship between skull (including mandible) BMD and periodontitis has not been extensively studied. An objective of this cross-sectional study was to examine the relationship between skull BMD and periodontitis using data from the National Health and Nutrition Examination Surveys (NHANES) for 2011-2012 and 2013-2014.

Materials and Methods

From 19,931 participants, 3,802 were screened and included with no missing values in the study. We examined the distribution of variables by grouping the skull BMD levels into quartiles. Periodontitis is defined by the Centers for Disease Control and Prevention (CDC) and the American Periodontal Association (AAP) in 2012. An interaction test was conducted using stratified and adjusted logistic regression models, and multivariate logistic regression analysis was performed, along with curve fitting and a threshold effect analysis were performed on the relationship between skull BMD and periodontitis.

Results

The results showed a negatively relationship between skull BMD and the risk of periodontitis. Although the inflection point was found (the skull BMD= 2.89g/cm2), it was not statistically significant, indicating that the skull BMD and periodontitis are linearly related, which 1 unit increase in the skull BMD (g/cm2) was associated with a 30% (OR=0.70; CI=0.57, 0.87; p=0.0010) reduction in the risk of periodontitis events.

Conclusions

Periodontal disease may be related to low skull BMD, for those people, oral hygiene and health care should be more closely monitored. Validation of our findings will require further research.
A Bayesian nonparametric method for detecting rapid changes in disease transmission
Authors: Creswell Richard , Robinson Martin , Gavaghan David , Parag Kris V , Lei Chon Lok , Lambert Ben
Published: July 2022

Whether an outbreak of infectious disease is likely to grow or dissipate is determined through the time-varying reproduction number,Rt. Real-time or retrospective identification of changes inRtfollowing the imposition or relaxation of interventions can thus contribute important evidence about disease transmission dynamics which can inform policymaking. Here, we present a method for estimating shifts inRtwithin a renewal model framework. Our method, which we call EpiCluster, is a Bayesian nonparametric model based on the Pitman-Yor process. We assume thatRtis piecewise-constant, and the incidence data and priors determine when or whetherRtshould change and how many times it should do so throughout the series. We also introduce a prior which induces sparsity over the number of changepoints. Being Bayesian, our approach yields a measure of uncertainty inRtand its changepoints. EpiCluster is fast, straightforward to use, and we demonstrate that it provides automated detection of rapid changes in transmission, either in real-time or retrospectively, for synthetic data series where theRtprofile is known. We illustrate the practical utility of our method by fitting it to case data of outbreaks of COVID-19 in Australia and Hong Kong, where it finds changepoints coinciding with the imposition of non-pharmaceutical interventions. Bayesian nonparametric methods, such as ours, allow the volume and complexity of the data to dictate the number of parameters required to approximate the process and should find wide application in epidemiology.

Highlights

Identifying periods of rapid change in transmission is important for devising strategies to control epidemics.

We assume that the time-varying reproduction number,Rt, is piecewise-constant and transmission is determined by a Poisson renewal model.

We develop a Bayesian nonparametric method, called EpiCluster, which uses a Pitman Yor process to infer changepoints inRt.

Using simulated incidence series, we demonstrate that our method is adept at inferring changepoints.

Using real COVID-19 incidence series, we infer abrupt changes in transmission at times coinciding with the imposition of non-pharmaceutical interventions.
Drivers of Mortality in COVID ARDS Depend on Patient Sub-Type
Authors: Cheyne Helen , Gandomi Amir , Vajargah Shahrzad Hosseini , Catterson Victoria M. , Mackoy Travis , Mccullagh Lauren , Musso Gabriel , Hajizadeh Negin
Published: July 2022

Background

The most common cause of death in people with COVID-19 is acute respiratory distress syndrome (ARDS). ARDS is a heterogeneous syndrome, however, subgroups that have been identified among non-COVID-19 ARDS patients do not clearly apply to COVID-19 ARDS patients. Additionally, studies of COVID-19 ARDS have been limited by sample size.

Methods

We applied an iterative clustering and machine learning framework to electronic health record data from thousands of hospitalized COVID-19 ARDS patients with the goal of defining and characterizing clinically-relevant COVID-19 ARDS subgroups (phenoclusters). We then applied a supervised model to identify risk factors for hospital mortality for each phenocluster and compared these between phenoclusters and the entire cohort.

Findings

Risk factors that predict mortality in the overall cohort of COVID-19 ARDS patients do not necessarily predict mortality in phenoclusters. In fact, some risk factors increase the risk of hospital mortality in some phenoclusters, but decrease mortality in others.

Interpretation

These phenocluster-specific risk factors would not have been observed with a single predictive model. Heterogeneity in phenoclusters of COVID-19 ARDS as well as drivers of mortality may partially explain challenges in finding effective treatments when applied to all patients with ARDS.

Funding

This work was supported by philanthropic funds to the Feinstein Institutes for Medical Research. The funding source did not control any aspect of the study and did not review the results. All authors had full access to the full data in the study and accept responsibility to submit for publication.
Functional genomics for curation of variants in telomere biology disorder associated genes, a systematic review
Authors: Nelson Niles , Feurstein Simone , Niaz Aram , Truong Jia , Holien Jessica K. , Lucas Sionne , Fairfax Kirsten , Dickinson Joanne , Bryan Tracy M.
Published: July 2022

Background

Patients with an underlying telomere biology disorder (TBD) have variable clinical presentations and can be challenging to diagnose clinically. A genomic diagnosis for patients presenting with TBD is vital for optimal treatments. Unfortunately, many variants identified during diagnostic testing are variants of uncertain significance (VOUS). This complicates management decisions, delays treatment and risks non-uptake of a potentially curative therapies. Improved application of functional genomic evidence may reduce VOUS classifications.

Methods

We systematically searched the literature for published functional assays interrogating TBD gene variants. Where possible, established likely benign/benign and likely pathogenic/pathogenic variants were used to estimate the assay sensitivity, specificity, positive predictive value, negative predictive value and odds of pathogenicity.

Results

3131 articles were screened and 152 met inclusion criteria. Sufficient data to enable a PS3/BS3 recommendation was available forTERTvariants only. We recommend PS3 and BS3 can be applied at a moderate and supportive level respectively. PS3/BS3 application was limited by a lack of assay standardisation and limited inclusion of benign variants.

Conclusions

Further assay standardisation and assessment of benign variants is required for optimal use of the PS3/BS3 criterion for TBD gene variant classification.
FOXA2 controls the anti-oxidant response in FH-deficient cells
Authors: Rogerson Connor , Sciacovelli Marco , Maddalena Lucas A , Valcarcel-Jimenez Lorea , Schmidt Christina , Yang Ming , Ivanova Elena , Kent Joshua , Mora Ariane , Cheeseman Danya , Carroll Jason S , Kelsey Gavin , Frezza Christian
Published: July 2022

Hereditary Leiomyomatosis and renal cell cancer (HLRCC) is a cancer syndrome caused by inactivating germline mutations in fumarate hydratase (FH) and subsequent accumulation of fumarate. Fumarate accumulation leads to the activation of an anti-oxidant response via nuclear translocation of the transcription factor NRF2. The activation of the anti-oxidant response is key for cellular survival in FH-deficient cells, yet the extent to which chromatin remodelling shapes the anti-oxidant response is currently unknown. Here, we explored the global effects of FH loss on the chromatin landscape to identify transcription factor networks involved in the highly remodelled chromatin landscape of FH-deficient cells. We identify FOXA2 as a key transcription factor which directly regulates anti-oxidant response genes and subsequent metabolic rewiring. Moreover, we also find that FOXA2 regulates anti-oxidant genes independent of the canonical anti-oxidant regulator NRF2. The identification of FOXA2 as an anti-oxidant regulator provides new insights into the molecular mechanisms behind cell responses to fumarate accumulation, and potentially provides new avenues for therapeutic intervention for HLRCC.
On the automaticity of visual statistical learning
Authors: Himberger Kevin D. , Finn Amy S. , Honey Christopher J.
Published: July 2022

Humans can extract regularities from their environment, enabling them to recognize and predict sequences of events. The process of regularity extraction is called ‘statistical learning’ and is generally thought to occur rapidly and automatically; that is, regularities are extracted from repeated stimulus presentations, without intent or awareness, as long as the stimuli are attended. We hypothesized that visual statistical learning is not entirely automatic, even when stimuli are attended, and that the learning depends on the extent to which viewers process the relationships between stimuli. To test this, we measured statistical learning performance across seven conditions in which participants (N=774) viewed image sequences. As task instructions across conditions increasingly required participants to attend to relationships between stimuli, their learning performance increased from chance to robust levels. We conclude that the learning observed in visual statistical learning paradigms is, for the most part, not automatic and requires more than passively attending to stimuli.
Monoallelic CRMP1 gene variants cause neurodevelopmental disorder
Authors: Ravindran Ethiraj , Arashiki Nobuto , Becker Lena-Luise , Takizawa Kohtaro , Lévy Jonathan , Rambaud Thomas , Makridis Konstantin L. , Goshima Yoshio , Li Na , Vreeburg Maaike , Demeer Bénédicte , Dickmanns Achim , Stegmann Alexander P.A , Hu Hao , Nakamura Fumio , Kaindl Angela M.
Published: July 2022

Collapsing response mediator proteins (CRMPs) are key for brain development and function. Here, we link CRMP1 to a neurodevelopmental disorder. We report heterozygous de novo variants in the CRMP1 gene in three unrelated individuals with muscular hypotonia, intellectual disability and/or autism spectrum disorder. Based on in silico analysis these variants are predicted to affect the CRMP1 structure. We further analyzed the effect of the variants on the protein structure/levels and cellular processes. We showed that the human CRMP1 variants are dominant-negative and impact the oligomerization of CRMP1 proteins. Moreover, overexpression of mutant-CRMP1 variants affect neurite outgrowth of murine cortical neurons. While altered CRMP1 levels have been reported in psychiatric diseases, genetic mutation in CRMP1 gene has never been linked to human disease. We report for the first-time mutations in the CRMP1 gene and emphasize its key role in brain development and function by linking directly to a human neurodevelopmental disease.
Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation
Authors: Filipello Fabia , You Shih Feng , Mahali Sidhartha , Iyer Abhirami Kannan , Martinez Rita , Korvatska Olena , Raskind Wendy H , Bollman Bryan , Cantoni Claudia , De Feo Luca , Ghezzi Laura , Minaya Miguel , Cashikar Anil G , Satoh Jun-Ichi , Beatty Wandy , Cella Marina , Piccio Laura , Karch Celeste M
Published: July 2022

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemoral dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two siblings homozygous for the TREM2 p.Q33X mutation (termed NHD), one related non-carrier, and one unrelated non-carrier. Transcriptomic analysis and biochemical assays revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol metabolism genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation, which were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to a defect in lysosomal function. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
Knowledge, attitudes, and practices regarding COVID-19 among university students and employees in Massachusetts, USA: a qualitative study
Authors: Ravenhurst Johanna , Snyder Teah , Wallace Kate , Pennell Sheila , Goff Sarah L. , Lover Andrew A.
Published: July 2022

Background

At the time of this study, Massachusetts had recorded a total of 352,558 COVID-19 cases and 12,076 deaths. Few qualitative studies have been conducted that investigate the experiences of university students and employees during the COVID-19 pandemic. The objective of this study was to explore the knowledge, attitudes, and practices regarding COVID-19 in university affiliates to inform future COVID-19 policies.

Methods

Semi-structured focus groups and interviews were conducted via Zoom between December 14, 2020 and January 15, 2021. Twenty-two focus group participants included undergraduate students, graduate students and university employees who had not experienced isolation or quarantine during the Fall 2020 semester. Fourteen participants who had experienced quarantine or isolation were interviewed individually to protect confidentiality. Data were analyzed using Dedoose software via inductive thematic analysis, with reporting as per Consolidated Criteria for Reporting Qualitative Studies (COREQ) guidelines.

Results

Five major themes emerged from these data: COVID-19 knowledge, stress and coping, trust, decision-making, and institutional feedback. Misinformation regarding COVID-19 was common, compounding high levels of stress reported by many participants. Reported direct sources of stress included physical illness, fear of infection, and lack of access to resources while in quarantine or isolation settings. Reported indirect sources of stress included social isolation and financial constraints. Levels of trust were generally high regarding mainstream news media, scientific journals, and university-related information sources. For decision-making processes, participants described altered behaviors to socialize safely during the pandemic, which included increased testing, gathering outdoors, and limiting group sizes. Conversely, some undergraduate students reported increases in socialization behaviors after testing negative for COVID-19, while most university employees did not report altered behaviors after negative test results. While some participants described negative feedback regarding university decisions, most feedback for the institution was positive, with participants reporting appreciation for the university’s asymptomatic testing program and other on-campus health response activities.

Conclusion

The university’s investment in COVID-related resources, including the asymptomatic testing program and the on-campus quarantine and isolation spaces, were reported to greatly reduce stress and increase perceived safety. Key findings from this research could guide institutional communication, public health protocols, and support for university community members.
Efficacy and longevity of immune response to 3rd COVID-19 vaccine and effectiveness of a 4th dose in severely immunocompromised patients with cancer
Authors: Thakkar Astha , Pradhan Kith , Duva Benjamin , Carreño Juan Manuel , Sahu Srabani , Thiruthuvanathan Victor , Campbell Sean , Gallego Sonia , Bhagat Tushar D , Rivera Johanna , Choudhary Gaurav , Olea Raul , Sabalza Maite , Shapiro Lauren C. , Lee Matthew , Quinn Ryann , Mantzaris Ioannis , Chu Edward , Will Britta , Pirofski Liise-anne , Krammer Florian , Verma Amit , Halmos Balazs
Published: July 2022

Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. We demonstrate that a 3rd dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination. The immune response is durable as assessed by anti-S antibody titers, T-cell activity and neutralization activity against wild-type SARS-CoV2 and BA1.1.529 at 6 months of follow up. A subset of severely immunocompromised hematologic malignancy patients were unable to mount adequate immune response after the 3rd dose and were treated with a 4th dose in a prospective clinical trial which led to adequate immune-boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. These results indicate that vaccine booster-induced immunity is durable in cancer patients and additional doses can further stimulate immunity in a subset of hematologic malignancy patients.

Statement of significance

We demonstrate that a 3rd dose of vaccine leads to seroconversion in 57% of negative patients with durable immune responses at 6 months. A 4th dose of vaccine can seroconvert hematologic malignancy patients with higher baseline IgM and CD19 levels.
Vascular Encasement Image Defined Risk Factors Predict Surgical Complications in Neuroblastoma
Authors: Stokes Rachael , Bannon Aidan , Leung Bonnie , Alloo Jasmin , Davies-Payne David , Winstanley Mark , Wood Andrew , Evans Stephen , Hamill James
Published: July 2022

Background

Specific Image Defined Risk Factors (IDRF) may be of more relevance to the pediatric surgical oncologist than simply the presence of any IDRF. The aim of this study was to correlate IDRF with surgical complications with reference to vascular encasement IDRF and the grade of complication.

Methods

We searched the New Zealand Children’s Cancer Registry for all cases of neuroblastoma treated at a single pediatric oncology center between January 2007 – February 2021 and reviewed the pre-treatment axial imaging for IDRF status. Surgical complications were scored by Clavien-Dindo grade and correlated with the number of IDRF and with the subset of vascular encasement IDRF.

Results

Of 101 patients, 77 were IDRF positive. In total, 74 underwent surgical resection and 32 (43.2%) had a surgical complication. Complications were related to the number of IDRF (OR 1.33, 95% CI 1.05 – 1.73, p = 0.02) and the subgroup of vascular encasement IDRF (OR 1.78, 95% CI 1.12 – 3.04, p = 0.01) but were not significantly correlated with the subgroup of non-vascular encasement IDRF. We report three cases of chyle leak associated with tumor encasing the origin of the celiac axis and/or the superior mesenteric artery.

Conclusions

The vascular encasement IDRF subgroup is potentially a more useful prognostic indicator of surgical complications than non-vascular IDRF. More studies are needed to correlate specific IDRF with specific surgical complications to aid operative decision making.

Level of evidence

Level III

Highlights

Image Defined Risk Factors (IDRF) in neuroblastoma correlate with survival, completeness of resection, and surgical complications.

Complications correlate specifically with the subset of vascular encasement IDRF. Chylous ascites was a specific complication associated with encasement of the celiac and superior mesenteric vessels.
EvAM-Tools: tools for evolutionary accumulation and cancer progression models
Authors: Diaz-Uriarte Ramon , Herrera-Nieto Pablo
Published: July 2022

EvAM-Tools is an R package and web application that provides a unified interface to state-of-the-art cancer progression models (CPMs) and, more generally, evolutionary models of event accumulation. The output includes, in addition to the fitted models, the transition (and transition rate) matrices between genotypes and the probabilities of evolutionary paths. Generation of random cancer progression models is also available. Using the GUI in the web application, users can easily construct models (modifying Directed Acyclic Graphs —DAGs— of restrictions, matrices of mutual hazards, or specifying genotype composition), generate data from them (with user-specified observational/genotyping error), and analyze the data.

Availability and Implementation

Implemented in R and C; open source code available under the GNU Affero General Public License v3.0 athttps://github.com/rdiaz02/EvAM-Tools. Docker images freely available fromhttps://hub.docker.com/u/rdiaz02. Web app freely accessible athttps://iib.uam.es/evamtools.

Contact

r.diaz@uam.es
Bacterial Polyphosphates Induce CXCL4 and Synergize with Complement Anaphylatoxin C5a in Lung Injury
Authors: Roewe Julian , Walachowski Sarah , Sharma Arjun , Berthiaume Kayleigh A. , Reinhardt Christoph , Bosmann Markus
Published: July 2022

Polyphosphates are linear polymers of inorganic phosphates that exist in all living cells and serve pleiotropic functions. Bacteria produce long-chain polyphosphates, which can interfere with host defense to infection. In contrast, short-chain polyphosphates are released from platelet dense granules and bind to the chemokine, CXCL4.

Here, we report that long-chain polyphosphates induced the release of CXCL4 from mouse bone marrow-derived macrophages and peritoneal macrophages in a dose-/time-dependent fashion resulting from an induction of CXCL4 mRNA. This polyphosphate effect was lost after pre-incubation with recombinant exopolyphosphatase (PPX) Fc fusion protein, demonstrating the potency of long chains over monophosphates and ambient cations. In detail, polyphosphate chains longer than 70 inorganic phosphate residues were typically required to mediate robust CXCL4 release. Polyphosphates acted independently of the purinergic P2Y1 receptor and the MyD88 and TRIF adaptors of Toll-like receptors. On the other hand, polyphosphates augmented LPS/MyD88-induced CXCL4 release, which was explained by intracellular signaling convergence on PI3K/Akt. Polyphosphates alone induced phosphorylation of Akt at threonine-308. Pharmacologic blockade of PI3K (wortmannin, LY294002) antagonized polyphosphate-induced CXCL4 release from macrophages. Intra-tracheal polyphosphate administration to C57BL/6J mice caused histologic signs of lung injury, disruption of the endothelial-epithelial barrier, influx of Ly6G+ polymorphonuclear neutrophils, depletion of CD11c+SiglecF+ alveolar macrophages, and release of CXCL4. Long-chain polyphosphates synergized with the complement anaphylatoxin, C5a, which was partly explained by upregulation of the receptor, C5aR1, on myeloid cells. C5aR1-/- mice were protected from polyphosphate-induced lung injury. In conclusion, we demonstrate that polyphosphates govern immunomodulation in macrophages and are capable of inducing lung injury.
Optogenetic Maxwell Demon to Exploit Intrinsic Noise and Control Cell Differentiation Despite Time Delays and Extrinsic Variability
Authors: May Michael P , Munsky Brian
Published: July 2022

The field of synthetic biology focuses on creating modular components which can be used to generate complex and controllable synthetic biological systems. Unfortunately, the intrinsic noise of gene regulation can be large enough to break these systems. Noise is largely treated as a nuisance and much past effort has been spent to create robust components that are less influenced by noise. However, extensive analysis of noise combined with ‘smart’ microscopy tools and optognenetic actuators can create control opportunities that would be difficult or impossible to achieve in the deterministic setting. In previous work, we proposed an Optogenetic Maxwell’s Demons (OMD) control problem and found that deep understanding and manipulation of noise could create controllers that break symmetry between cells, even when those cells share the same optogenetic input and identical gene regulation circuitry. In this paper, we extend those results to analyze (in silico) the robustness of the OMD control under changes in system volume, with time observation/actuation delays, and subject to parametric model uncertainties.
A small molecule ligand for the novel pain target GPR171 produces minimal reward in mice
Authors: McDermott Max V. , Ram Akila , Mattoon Matt T. , Haderlie Emmaline E. , Raddatz Megan C. , Thomason Madi K. , Bobeck Erin N.
Published: July 2022

ProSAAS is one of the most abundant proteins in the brain and is processed into several smaller peptides. One of which, BigLEN, is an endogenous ligand for the G protein-coupled receptor, GPR171. Recent work in rodent models has shown that a small-molecule ligand for GPR171, MS15203, increases morphine antinociception and is effective in lessening chronic pain. While these studies provide evidence for GPR171 as a possible pain target, its abuse liability has not yet been assessed which we evaluate in the current study. We first mapped the distribution of GPR171 and ProSAAS throughout the reward circuit of the brain using immunohistochemistry and showed that GPR171 and ProSAAS are localized in the hippocampus, basolateral amygdala, nucleus accumbens, prefrontal cortex. In the major dopaminergic structure, the ventral tegmental area (VTA), GPR171 appeared to be primarily localized in dopamine neurons while ProSAAS is outside of dopamine neurons. Next, MS15203 was administered to mice with or without morphine, and VTA slices were stained for the immediate early gene c-Fos as a marker of neuronal activation. Quantification of c-Fos-positive cells revealed no statistical difference between MS15203 and saline, suggesting that MS15203 does not increase VTA activation and dopamine release. Similarly, the results of a conditioned place preference experiment showed that treatment with MS15203 or MS15203 + Morphine produced no place preference compared to Saline indicating a lack of reward-related behavior. Taken together this data provides evidence that the novel pain therapeutic, MS15203, has minimal reward liability. Therefore, GPR171 deserves further exploration as a pain target.

Significance Statement

MS15203, a drug that activates the receptor GPR171, was previously shown to increase morphine analgesia. The authors use in vivo and histological techniques to show that it fails to activate the rodent reward circuitry, providing support for the continued exploration of MS15203 as a novel pain drug, and GPR171 a novel pain target.
Communication dynamics in the human connectome shape the cortex-wide propagation of direct electrical stimulation
Authors: Seguin Caio , Jedynak Maciej , David Olivier , Mansour L Sina , Sporns Olaf , Zalesky Andrew
Published: July 2022

Communication between gray matter regions underpins all facets of brain function. To date, progress in understanding large-scale neural communication has been hampered by the inability of current neuroimaging techniques to track signaling at whole-brain, high-spatiotemporal resolution. Here, we use 2.77 million intracranial EEG recordings, acquired following 29,055 single-pulse electrical stimulations in a total of 550 individuals, to study inter-areal communication in the human brain. We found that network communication models—computed on structural connectivity inferred from diffusion MRI—can explain the propagation of direct, focal electrical stimulation through white matter, measured at millisecond time scales. Building on this finding, we show that a parsimonious statistical model comprising structural, functional and spatial factors can accurately and robustly predict cortex-wide effects of brain stimulation (out-of-sampleR2=54%). Our work contributes towards the biological validation of concepts in network neuroscience and provides insight into how white matter connectivity shapes inter-areal signaling. We anticipate that our findings will have implications for research on macroscale neural information processing and the design of brain stimulation paradigms.
Integrative modeling reveals the molecular architecture of the Intraflagellar Transport A (IFT-A) complex
Authors: McCafferty Caitlyn L. , Papoulas Ophelia , Jordan Mareike A. , Hoogerbrugge Gabriel , Nichols Candice , Pigino Gaia , Taylor David W. , Wallingford John B. , Marcotte Edward M.
Published: July 2022

Intraflagellar transport (IFT) is a conserved process of cargo transport in cilia that is essential for development and homeostasis in organisms ranging from algae to vertebrates. In humans, variants in genes encoding subunits of the cargo-adapting IFT-A and IFT-B protein complexes are a common cause of genetic diseases known as ciliopathies. While recent progress has been made in determining the atomic structure of IFT-B, little is known of the structural biology of IFT-A. Here, we combined chemical cross-linking mass spectrometry and cryo-electron tomography with AlphaFold2-based prediction of both protein structures and interaction interfaces to model the overall architecture of the monomeric six-subunit IFT-A complex, as well as its polymeric assembly within cilia. We define monomer-monomer contacts and membrane-associated regions available for association with transported cargo, and we also use this model to provide insights into the pleiotropic nature of human ciliopathy-associated genetic variants in genes encoding IFT-A subunits. Our work demonstrates the power of integration of experimental and computational strategies both for multi-protein structure determination and for understanding the etiology of human genetic disease.

The 3D structure of the six-subunit complex and its polymeric assembly gives insights into cargo transport in cilia and how specific mutations in these genes lead to ciliopathy birth defects.
Sublethal and transgenerational effects of lambda-cyhalothrin and abamectin on the development and reproduction of Cydia pomonella
Authors: Ju Di , Liu Yu-Xi , Liu Xue , Dewer Youssef , Mota-Sanchez David , Yang Xue-Qing
Published: July 2022

The codling moth Cydia pomonella (Lepidoptera: Tortricidae) is a major invasive pest of pome fruits and walnuts worldwide. Lambda-cyhalothrin (LCT) and abamectin (AM) have been frequently used in C. pomonella control, but control of this pest is very difficult because shortly after hatching, larvae of this insect bore tunnels and hide inside host plant fruit. In this study, a simulated field spray bioassay method was developed against neonate larvae of C. pomonella and concentration-response bioassays were conducted to evaluate the susceptibility of the neonate larvae to LCT and AM. Exposure of neonate larvae to sublethal concentrations (LC30) of LCT or AM significantly reduced the survival rate of larvae (4th and 5th instars), lowered the mean weight of larvae and pupae, and decreased the daily maximal number of eggs laid and the total number of eggs laid (fecundity) per female. The sublethal effects, including reduced body mass, mean fecundity and net reproductive rate, extended mean generation time, and shortened oviposition period, were also found in transgenerational offspring. Furthermore, the transgenerational maternal effects were more obvious for AM than LCT, in comparison to the control. Additionally, the estimated population size was decreased by exposure to LC30 of LCT and AM, and the observed reduction of fecundity and population size within and across generations was likely the result of the downregulation of the reproduction-related vitellogenin gene (CpVg) after exposure to LC30 of LCT and AM. These results provide a better understanding of the overall effects of LCT and AM on C. pomonella and the transgenerational effects which should be taken into consideration when using insecticides in order to control C. pomonella.
Flavor Classification/Categorization and Differential Toxicity of Oral Nicotine Pouches (ONPs) in Lung Epithelial Cells
Authors: Shaikh Sadiya , Tung Wai Cheung , Lucas Joseph , Yogeswaran Shaiesh , Li Dongmei , Rahman Irfan
Published: July 2022

The prevalence of flavored tobacco product usage amongst youth in the United States is partly due to the emergence of non-combustible nicotine-containing products (NCNPs), including oral nicotine pouches (ONPs) and smokeless tobacco products. ONPs are available in various different flavors (mint, fruity, tobacco, dessert, citrus, coffee, wintergreen, and berry) and may use either Tobacco-Derived Nicotine (TDN) or Tobacco-Free Nicotine (TFN). Currently, several brands of ONPs are sold in the U.S and comprise a significant portion of NCNP sales in the U.S. There is a growing concern that flavored ONPs may not only induce oral health effects, but may also induce systemic toxic effects due to nicotine and other ONP byproducts being absorbed into systemic circulation through the oral mucosa. These byproducts can act locally on other tissues and may potentially cause redox dysregulation and heightened inflammatory responses systemically in the respiratory, cardiovascular, and/or renal systems. Hence, we determined the effects of flavored ONPs from four of the most widely sold brands in the U.S in inducing toxicological effects on the respiratory epithelium. Prior to analyzing the effects ONPs, we first classified ONPs sold in the US based on their flavor and the flavor category to which they belong to using a wheel diagram. Subsequently, using human bronchial epithelial cells (16-HBE and BEAS-2B) exposed to extracts of flavored ONPs, we assessed the levels of ONP-induced inflammatory cytokine release (IL-6 and IL-8), cellular Reactive Oxygen Species (ROS) production, and cytotoxicity in the airway epithelium. Our data showed that cells exposed to the lowest concentration treatments showed increased cytotoxicity, differential cellular ROS production, and proinflammatory cytokine release. The most striking response was observed among cells treated with the spearmint ONP, whereas ONPs containing original tobacco and fruity flavors showed varied levels of ROS release in 16-HBE cells. Our data suggest that flavored ONPs are unsafe and likely to cause systemic and local toxicological responses during chronic usage. Our study is a part of ongoing efforts to use in vitro, ex-vivo, and in vivo systems to understand how the usage of various flavored ONPs may cause both oral and pulmonary toxicity, and impact human periodontal health.
Co-opted Genes of Algal Origin Protect C. elegans against Cyanogenic Toxins
Authors: Wang Bingying , Pandey Taruna , Long Yong , Delgado-Rodriguez Sofia E. , Daugherty Matthew D. , Ma Dengke K.
Published: July 2022

Amygdalin is a cyanogenic glycoside widely used by many plants in herbivore defense. Poisonous to most animals, amygdalin-derived cyanide is detoxified by potent enzymes commonly found in bacteria and plants but not most animals. Here we show that the nematode C. elegans can detoxify amygdalin by a genetic pathway comprising cysl-1, egl-9, hif-1 and cysl-2. Essential for amygdalin resistance, cysl-1 encodes a protein similar to cysteine synthetic enzymes in bacteria and plants, but functionally co-opted in C. elegans. We identify exclusively HIF-activating egl-9 mutations in a cysl-1 suppressor screen and show that cysl-1 confers amygdalin resistance by regulating HIF-1-dependent cysl-2 transcription to protect against amygdalin toxicity. Phylogenetic analysis suggests cysl-1 and cysl-2 were likely acquired from green algae through horizontal gene transfer (HGT) and functionally co-opted in protection against amygdalin. Our studies reveal that HGT-mediated evolutionary changes can facilitate host survival and adaptation to adverse environment stresses and biogenic toxins.
CryoEM Structures of the Human HIV-1 Restriction Factor SERINC3 and Function as a Lipid Transporter
Authors: Leonhardt Susan A. , Purdy Michael D. , Grover Jonathan R. , Yang Ziwei , Poulos Sandra , McIntire William E. , Tatham Elizabeth A. , Erramilli Satchal , Nosol Kamil , Lai Kin Kui , Ding Shilei , Lu Maolin , Uchil Pradeep D. , Finzi Andrés , Rein Alan , Kossiakoff Anthony A. , Mothes Walther , Yeager Mark
Published: July 2022

The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). CryoEM maps of full-length human SERINC3 and an ICL4 deletion construct reveal that hSERINC3 is comprised of twoα- helical bundles connected by a ∼40-residue, tilted, “crossmember” helix. The design resembles non-ATP-dependent lipid transporters. Consistently, purified hSERINCs reconstituted into proteoliposomes flip phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. SERINC3 and SERINC5 reduce infectivity and expose PS on the surface of HIV-1 and also MLV, which is counteracted by Nef and GlycoGag, respectively. Antiviral activities by SERINCs and the scramblase TMEM16F correlate with the exposure of PS and with altered conformation of the envelope glycoprotein. We conclude that SERINCs are lipid transporters, and we demonstrate that lipid flipping is directly correlated with loss of infectivity.

One Sentence Summary

The HIV-1 restriction factor SERINC3 has a molecular design similar to non-ATP dependent lipid transporters, a function supported by the observation of flipping activity in proteoliposomes and exposure of phosphatidylserine on HIV-1 and MLV particles, which is correlated with loss of infectivity.
Tracing back primed resistance in cancer via sister cells
Authors: Dai Jun , Zheng Shuyu , Falco Matías M. , Bao Jie , Eriksson Johanna , Pikkusaari Sanna , Forstén Sofia , Jiang Jing , Wang Wenyu , Gao Luping , Perez-Villatoro Fernando , Dufva Olli , Saeed Khalid , Wang Yinyin , Amiryousefi Ali , Färkkilä Anniina , Mustjoki Satu , Kauppi Liisa , Tang Jing , Vähärautio Anna
Published: July 2022

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. We developed ReSisTrace that uses shared transcriptomic features of synchronised sister cells to predict the states that prime treatment resistance. We applied ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells. The pre-resistant phenotypes were defined by cell cycle and proteostatic features, reflecting the traits enriched in the upcoming subclonal selection. Furthermore, DNA repair deficiency rendered cells susceptible to both DNA damaging agents and NK killing in a context-dependent manner. Finally, we leveraged the pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies.
PAT mRNA decapping factors function specifically and redundantly during development inArabidopsis
Authors: Zuo Zhangli , Roux Milena Edna , Dagdas Yasin F. , Rodriguez Eleazar , Petersen Morten
Published: July 2022

Evolutionarily conserved PAT1 proteins activate mRNA decay through binding mRNA and recruiting decapping enzymes and other factors hence optimize transcriptional reprogramming during development. Here, we generated multiple mutants ofpat1(Protein Associated with Topoisomerase II),path1andpath2and inspected their growth and leaf morphology phenotype.pattriple mutants exhibit extreme stunted growth and all mutants withpat1exhibit leaf serration while mutants withpat1andpath1all display short petioles. All 3 PATs can be found localized to Prossessing Bodies (PBs) upon auxin treatment and RNA-seq analysis indicate that all 3 PATs redundantly regulate auxin responses. Moreover, shade avoidance and NAC genes are misregulated inpat1path1double andpattriple mutants suggesting PAT1 and PATH1 function in petiole elongation and leaf patterning. In conclusion, PAT proteins exhibit both specific and overlapping functions during different stages of plant growth and our observations underpin the importance of the mRNA decay machinery for proper development.
Genomic diversity and molecular epidemiology of a multidrug resistantPseudomonas aeruginosaDMC30b isolated from hospitalized burn patient in Bangladesh
Authors: Hoque M. Nazmul , Jahan M. Ishrat , Hossain M. Anwar , Sultana Munawar
Published: July 2022

Objectives

Pseudomonas aeruginosais a key opportunistic pathogen causing a wide range of community- and hospital-acquired infections in immunocompromised or catheterized patients. Here, we report the complete genome sequence of a multidrug resistant (MDR)P. aeruginosaDMC30b in order to elucidate the genetic diversity, molecular epidemiology, and underlying mechanisms for antimicrobial resistance and virulence.

Methods

P. aeruginosaDMC30b was isolated from septic wound swab of a severe burn patient. Whole-genome sequencing (WGS) was performed under Ion Torrent platform. The genome was annotated using the SPAdes v. 3.12.01 in an integrated Genome Analysis Platform (IonGAP) for Ion Torrent sequence data. The genome was annotated using the NCBI Prokaryotic Genome Annotation Pipeline (PGAP).In-silicopredictions of antimicrobial resistance genes (ARGs), virulence factor genes (VFGs) and metabolic functional potentials were performed using different curated bioinformatics tools.

Results

P. aeruginosaDMC30b was classified as MDR and belongs to sequence type 244 (ST244). The complete genome size is 6,994,756 bp with a coverage of 76.76x, G+C content of 65.7% and a BUSCO (Benchmarking Universal Single-Copy Orthologs) score of 100. The genome ofP. aeruginosaDMC30b harboured two plasmids (e,g., IncP-6 plasmid p10265-KPC; 78,007 bp and ColRNAI_pkOIISD1; 9,359 bp), 35 resistomes (ARGs) conferring resistance to 18 different antibiotics (including four beta-lactam classes), and 214 VFGs. It was identified as the 167thST244 strain among ∼ 5,800 whole-genome sequences ofP. aeruginosaavailable in the NCBI database.

Conclusion

P. aeruginosaDMC30b belongs to ST244 and was identified as the 167thsuch isolate to be submitted to NCBI, and the first complete ST244 genome from Bangladesh. The complete genome data with high genetic diversity and underlying mechanisms for antimicrobial resistance and virulence ofP. aeruginosaDMC30b (ST244) will aid in understanding the evolution and phylogeny of such high-risk clones and provide a solid basis for further research on MDR or extensively drug resistant strains.
FOXP2confers oncogenic effects in prostate cancer through activating MET signalling
Authors: Zhu Xiaoquan , Chen Chao , Wei Dong , Xu Yong , Liang Siying , Jia Wenlong , Li Jian , Qu Yanchun , Zhai Jianpo , Zhang Yaoguang , Wu Pengjie , Hao Qiang , Zhang Linlin , Zhang Wei , Yang Xinyu , Pan Lin , Qi Ruomei , Li Yao , Wang Feiliang , Yi Rui , Yang Ze , Wang Jianye , Zhao Yanyang
Published: July 2022

Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found thatFOXP2is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. To date, little is known regarding the link ofFOXP2to prostate cancer. We observed that highFOXP2expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression ofFOXP2induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely,FOXP2knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression ofFOXP2in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression ofFOXP2aberrantly activates oncogenic MET signalling and inhibitors targeting MET signalling effectively reverts theFOXP2-induced oncogenic phenotype. Additionally, the novel recurrentFOXP2-CPED1fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data demonstrate for the first time thatFOXP2is an oncogene involved in tumorigenicity of prostate.