bluuebunny/crossref_metadata_2025 huggingface dataset:
Awesome SOSS: transmission spectroscopy of WASP-96b with NIRISS/SOSS
Authors: Radica Michael , Welbanks Luis , Espinoza Néstor , Taylor Jake , Coulombe Louis-Philippe , Feinstein Adina D , Goyal Jayesh , Scarsdale Nicholas , Albert Loïc , Baghel Priyanka , Bean Jacob L , Blecic Jasmina , Lafrenière David , MacDonald Ryan J , Zamyatina Maria , Allart1 Romain , Artigau Étienne , Batalha Natasha E , Cook Neil James , Cowan Nicolas B , Dang Lisa , Doyon René , Fournier-Tondreau Marylou , Johnstone Doug , Line Michael R , Moran Sarah E , Mukherjee Sagnick , Pelletier Stefan , Roy Pierre-Alexis , Talens Geert Jan , Filippazzo Joseph , Pontoppidan Klaus , Volk Kevin
Published: June 2023

The future is now – after its long-awaited launch in 2021 December, JWST began science operations in 2022 July and is already revolutionizing exoplanet astronomy. The Early Release Observations (ERO) programme was designed to provide the first images and spectra from JWST, covering a multitude of science cases and using multiple modes of each on-board instrument. Here, we present transmission spectroscopy observations of the hot-Saturn WASP-96 b with the Single Object Slitless Spectroscopy (SOSS) mode of the Near Infrared Imager and Slitless Spectrograph, observed as part of the ERO programme. As the SOSS mode presents some unique data reduction challenges, we provide an in-depth walk-through of the major steps necessary for the reduction of SOSS data: including background subtraction, correction of 1/f noise, and treatment of the trace order overlap. We furthermore offer potential routes to correct for field star contamination, which can occur due to the SOSS mode’s slitless nature. By comparing our extracted transmission spectrum with grids of atmosphere models, we find an atmosphere metallicity between 1× and 5× solar, and a solar carbon-to-oxygen ratio. Moreover, our models indicate that no grey cloud deck is required to fit WASP-96 b’s transmission spectrum, but find evidence for a slope shortward of 0.9 μm, which could either be caused by enhanced Rayleigh scattering or the red wing of a pressure-broadened Na feature. Our work demonstrates the unique capabilities of the SOSS mode for exoplanet transmission spectroscopy and presents a step-by-step reduction guide for this new and exciting instrument.
Reanalysis of neutron-capture elements in the benchmark r-rich star CS 31082−001
Authors: Ernandes H , Castro M J , Barbuy B , Spite M , Hill V , Castilho B , Evans C J
Published: June 2023

We revisit the abundances of neutron-capture elements in the metal-poor ([Fe/H] = −2.9) r-process-rich halo star CS 31082−001. Partly motivated by the development of the new near-ultraviolet Cassegrain U-band Efficient Spectrograph for the Very Large Telescope, we compiled an expanded line list for heavy elements over the range 3000–4000 Å, including hyperfine structure for several elements. Combining archival near-ultraviolet spectra of CS 31082−001 from the Hubble Space Telescope and the Very Large Telescope, we investigate the abundances and nucleosynthesis of 35 heavy elements (Ge, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, Sn, Ba, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Os, Ir, Pt, Pb, Bi, Th, and U). Our analysis includes the first abundance estimates for tin, holmium, and ytterbium from these data, and the first for lutetium from ground-based data, enabling a more complete view of the abundance pattern of this important reference star. In general, the r-process-dominated elements are as enhanced as those in the Sun, particularly for elements with Z ≥ 56 (Ba and heavier). However, the abundances for the lighter elements in our sample, from Ge to Sn (31 ≤ Z ≤ 50), do not scale with the solar abundance pattern. Moreover, the Ge abundance is deficient relative to solar, indicating that it is dominantly an iron-peak rather than neutron-capture element. Our results (or upper limits) on Sn, Pt, Au, Pb, and Bi all pose further questions, prompting further study on the origin and evolution of the known r-rich and actinide-rich, metal-poor stars.
Spatially resolved mock observations of stellar kinematics: full radiative transfer treatment of simulated galaxies
Authors: Barrientos Acevedo Daniela , van der Wel Arjen , Baes Maarten , Grand Robert J J , Kapoor Anand Utsav , Camps Peter , de Graaff Anna , Straatman Caroline M S , Bezanson Rachel
Published: June 2023

We present a framework to build realistic mock spectroscopic observations for state-of-the-art hydrodynamical simulations, using high spectral resolution stellar population models and full radiative transfer treatment with skirt. As a first application, we generate stellar continuum mock observations for the Auriga cosmological zoom simulations emulating integral-field observations from the Sydney–AOO Multi-object Integral Field Spectrograph (SAMI) Galaxy Survey. We perform spectral fitting on our synthetic cubes and compute the resulting rotation velocity (Vrot) and velocity dispersion within 1Re (σe) for a subset of the Auriga sample. We find that the kinematics produced by Auriga are in good agreement with the observations from the SAMI galaxy survey after taking into account the effects of dust and the systematics produced by the observation limitations. We also explore the effects of seeing convolution, inclination, and attenuation on the line-of-sight velocity distribution. For highly inclined galaxies, these effects can lead to an artificial decrease in the measured V/σ by nearly a factor of two (after inclination correction). We also demonstrate the utility of our method for high-redshift galaxies by emulating spatially resolved continuum spectra from the Large Early Galaxy Census (LEGA-C) survey and, looking forward, the European Extremely Large Telescope (E-ELT) High Angular Resolution Monolithic Optical and Near-infrared Integral field spectrograph (HARMONI). Our framework represents a crucial link between the ground truth for stellar populations and kinematics in simulations and the observed stellar continuum observations at low and high redshift.
Nutrition as the foundation for successful aging: a focus on dietary protein and omega-3 polyunsaturated fatty acids
Authors: Hawley Aubree L , Baum Jamie I
Published: June 2023

Skeletal muscle plays a critical role throughout the aging process. People living with sarcopenia, a progressive and generalized loss of skeletal muscle mass and function, often experience diminished quality of life, which can be attributed to a long period of decline and disability. Therefore, it is important to identify modifiable factors that preserve skeletal muscle and promote successful aging (SA). In this review, SA was defined as (1) low cardiometabolic risk, (2) preservation of physical function, and (3) positive state of wellbeing, with nutrition as an integral component. Several studies identify nutrition, specifically high-quality protein (eg, containing all essential amino acids), and long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), as positive regulators of SA. Recently, an additive anabolic effect of protein and n-3 PUFAs has been identified in skeletal muscle of older adults. Evidence further suggests that the additive effect of protein and n-3 PUFAs may project beyond skeletal muscle anabolism and promote SA. The key mechanism(s) behind the enhanced effects of intake of protein and n-3 PUFAs needs to be defined. The first objective of this review is to evaluate skeletal muscle as a driver of cardiometabolic health, physical function, and wellbeing to promote SA. The second objective is to examine observational and interventional evidence of protein and n-3 PUFAs on skeletal muscle to promote SA. The final objective is to propose mechanisms by which combined optimal intake of high-quality protein and n-3 PUFAs likely play a key role in SA. Current evidence suggests that increased intake of protein above the Recommended Dietary Allowance and n-3 PUFAs above the Dietary Guidelines for Americans recommendations for late middle-aged and older adults is required to maintain skeletal muscle mass and to promote SA, potentially through the mechanistical target of rapamycin complex 1 (mTORC1).
Tracing the Roots of Dementia Praecox: Charles Lasègue and his 1852 Essay “Du Délire De Persécutions” (On Persecutory Delusions)
Authors: Kendler Kenneth S
Published: June 2023

While the evolution of our modern concepts of mania and melancholia over the 19th century is relatively well-understood, no such clear narrative exists for the nonaffective psychotic syndromes that culminated in Kraepelin’s concept of dementia praecox in 1899. These narratives were relatively distinct in Germany and France. An important milestone in the French literature is the 1852 essay by the alienist and polymath Charles Lasègue which contained the first detailed modern description of a persecutory delusional syndrome. Lasègue was a careful clinical observer who emphasized a symptomatic approach to psychiatric nosology and was less concerned with course and outcome. He details the evolution of persecutory delusions from increasing referential observations of real events, to the resulting anxious confusion and then the emergence of explanatory delusional beliefs. Once formed, these beliefs, he notes, are relatively impervious to correction. Lasègue was unusual for his time in emphasizing a “first-person perspective” on psychotic experiences, and quotes from his patients in his case history, of which he presents 15. Of these, 12 had auditory hallucinations and 4 passivity phenomena. While conceptualized differently than mid-19th century pre-Kraepelinian German writing on delusional syndromes, and unique on its focus on persecutory delusions, Lasègue’s important essay shared a common view on the key features of a broad nonaffective delusional-hallucinatory syndrome. It was this syndrome that Kraepelin, over multiple drafts in the first 6 editions of his textbook from 1883 to 1899, was to divide into his mature concepts of paranoia and the paranoid subtype of dementia praecox.
Safety and Efficacy Profile of Corneas Harvested From Donors of Drowning Victims
Authors: Priyadarshini Kshyanaprava , Das Sujata , Sahu Srikant Kumar , Parida Priyadarshini , Priyadarshini Smruti Rekha
Published: June 2023

Purpose:

The aim of this study was to analyze the tissue quality and outcomes of corneal transplants from donor corneal tissues harvested from drowning victims.

Methods:

This retrospective study was conducted on corneal tissues harvested from drowning victims between March 2018 and September 2022. Details of the tissue quality and outcomes after keratoplasty were collected from the eye bank and outpatient records.

Results:

Thirty-four donor corneas were collected from drowning victims during the study period. The mean age of the donors was 37.1 ± 20.3 years. The mean donor-to-preservation time was 4.9 ± 2.6 hours. The mean endothelial cell density was 3025 ± 271 cells/mm2. Twenty donor corneas (58.8%) were used at our institute, 2 were stored in glycerol for future use, and 12 were transported to other transplant centers. The overall utilization was 94.1% (32/34 corneas). Of the 20 corneas used at our institute, 17 were used for optical grafts and 3 for therapeutic indications. Of the 17 optical grafts, 10 were used for optical penetrating keratoplasty, 6 for endothelial keratoplasty, and 1 for anterior lamellar keratoplasty. The most common indication for keratoplasty was regrafting the previously failed grafts (25%). None of the transplanted eyes developed an infection in the immediate postoperative period. Eight eyes had clear grafts after 3 months. Of the 12 tissues transferred to other keratoplasty centers, 10 were used for optical grafts and 2 for therapeutic/tectonic grafts.

Conclusions:

Donor corneas retrieved from drowning victims may be considered safe for transplantation. The postoperative outcomes of the tissues obtained from these donors were satisfactory. Hence, these donor corneas can be optimally used in routine transplantation procedures.
Peripheral Ulcerative Keratitis Associated With Lichen Planus
Authors: Neo Yan Ning , Farwana Reem , Ahmoye Sarah , Vasquez-Perez Alfonso
Published: June 2023

Purpose:

The aim of this study was to report a case of peripheral ulcerative keratitis (PUK) associated with lichen planus.

Methods:

A 42-year-old woman with histological confirmation of lichen planus from an oral buccal mucosa biopsy presented with bilateral peripheral stromal thinning and an epithelial defect, in keeping with PUK.

Results:

All screening for known causes of PUK were negative, and lichen planus was presumed as the etiological factor. Oral prednisolone 1 mg/kg was initiated, alongside topical steroids and topical ciclosporin. The PUK resolved after 3 months, and a slow-tapering regimen of oral prednisolone was needed to prevent a relapse of ocular surface inflammation. Topical steroids were also tapered and discontinued after 5 months, and the ocular surface remained stable with topical ciclosporin with no relapse after 1 year.

Conclusions:

Ocular manifestations of lichen planus are rare and mostly involve the conjunctiva; however, PUK might also develop, presumably due to its similar mechanisms with other T-cell autoimmune diseases. Systemic immunosuppression is required initially but further control of the ocular surface can be achieved successfully with topical ciclosporin.
A Trauma-Informed Mentoring Framework for Forensic Nurses: An Overview of STEERR—Structure, Process, and Evaluation
Authors: Hoffman Sarah J. , Dillon Tara , Moore Kaylen M. , Frerich Ellen A. , Porta Carolyn M.
Published: June 2023

The STEERR Mentoring Framework, grounded in decolonized and feminist mentorship approaches, integrates foundational principles of mentoring with the unique and complex characteristics of the role of the forensic nurse. The primary objective of the program is to support a competent, sustainable, and resilient forensic nursing workforce. In this article, we describe the development process, framework structure, and evaluation approach implemented within a 1-year pilot initiative focused on forensic nurses in the sexual assault nurse examiner role. We reflect on strategies for broader application and replication in forensic nursing programs across the United States.
COVID-19–Related Suicides—Public Health Role of Forensic Pathologists
Authors: He Sophia D. Q. , Lee Jenelle H. , Prahlow Joseph A.
Published: June 2023

Concerns about potential increases in suicidal behavior during the coronavirus disease 2019 (COVID-19) pandemic arose in response to reported widespread mental health deterioration. Although early data did not corroborate such concerns, suicide remains a significant cause of preventable deaths worldwide and is of significant interest to public health in the setting of a pandemic. In this study, we present 17 cases of COVID-19–related suicides seen in our West Michigan Medical Examiner's office from 2020 to 2022, which exhibit the complex relationship between mental health and pandemic-related psychological, social, and economic stressors. The relationships were generally categorized as increased anxiety and/or stress due to COVID-19 (5/17 [29.4%]), the loss of social support and/or social isolation occurring as a result of COVID-19 restrictions (5/17 [29.4%]), financial concerns or loss of income as a result of COVID-19 policies (3/17 [17.6%]), grief related specifically to COVID-19 (2/17 [11.8%]), and purported neuropsychiatric sequelae of a prior COVID-19 infection (2/17 [11.8%]). By examining these cases, we highlight ways in which public health systems might prepare for and respond to mental health crises during current or future pandemics and the need for increased collaboration between forensic pathologists and epidemiologists in collating high-quality data during death investigations.
Evaluating the effect of equipping an unloading knee orthosis with local muscle vibrators on clinical parameters, muscular activation level, and medial contact force in patients with medial knee osteoarthritis: A randomized trial
Authors: Barati Kourosh , Kamyab Mojtaba , Ebrahimi Takamjani Ismail , Parnianpour Mohamad , Hosseini Nesa , Bidari Shahrbanoo
Published: June 2023

Background:

Unloading knee orthosis is prescribed for people with unicompartmental knee osteoarthritis (OA) to unload the damaged compartment. However, despite its benefits, wearing unloading knee orthoses in the long term may decrease knee muscle activity and have a side effect on knee OA progression rate.

Objectives:

Therefore, this study aimed to determine whether equipping an unloading knee orthosis with local muscle vibrators improves its effectiveness in improving clinical parameters, medial contact force (MCF), and muscular activation levels.

Methods:

The authors performed a clinical evaluation on 14 participants (7 participants wearing vibratory unloading knee orthoses and 7 participants wearing conventional unloading knee orthoses) with medial knee OA.

Results:

Wearing both orthoses (vibratory and conventional) for 6 weeks significantly improved (p < 0.05) the MCF, pain, symptoms, function, and quality of life compared with the baseline assessment. Compared with the baseline assessment, the vastus lateralis muscle activation level significantly increased (p = 0.043) in the vibratory unloading knee orthoses group. The vibratory unloading knee orthoses significantly improved the second peak MCF, vastus medialis activation level, pain, and function compared with conventional unloading knee orthoses (p < 0.05).

Conclusions:

Given the potential role of medial compartment loading in the medial knee OA progression rate, both types of unloading knee orthoses (vibratory and conventional) have a potential role in the conservative management of medial knee OA. However, equipping the unloading knee orthoses with local muscle vibrators can improve its effectiveness for clinical and biomechanical parameters and prevent the side effects of its long-term use.
A Preoperative Imaging Evaluation to Avoid Orbital Complications in Functional Endoscopic Sinus Surgery
Authors: Hemmi Tomotaka , Nomura Kazuhiro , Kobayashi Yuta , Numano Yuki , Suzuki Jun , Sugawara Mitsuru , Katori Yukio
Published: June 2023

Functional endoscopic sinus surgery has become popular worldwide. However, serious complications have been reported with it. A preoperative imaging evaluation is thus essential to avoid complications. The authors compared 0.5 mm slice computed tomography (CT) images reconstructed from sinus CT data with conventional 2 mm slice CT images. The authors evaluated patients who underwent endoscopic surgery. Data regarding age, sex, history of craniofacial trauma, diagnosis, operative procedure, and CT findings of eligible patients were extracted from medical records and retrospectively reviewed. One hundred twelve patients underwent endoscopic surgery during the study period. Six patients (5.4%) had orbital blowout fractures, and half of them could only be identified by 0.5 mm slice CT images. The authors presented the usefulness of 0.5 mm slice CT images in the preoperative imaging evaluation of functional endoscopic sinus surgery. Surgeons should also recognize that a small number of patients have “stealth” (asymptomatic and unrecognized) blowout fractures.
Biophysical evolution of the receptor binding domains of SARS-CoVs
Authors: Upadhyay Vaibhav , Panja Sudipta , Lucas Alexandra , Patrick Casey , Mallela Krishna M.G.
Published: June 2023

With hundreds of coronaviruses (CoVs) identified in bats that are capable of infecting humans, it is important to understand how CoVs that affected the human population have evolved. Seven known coronaviruses have infected humans, of which three CoVs caused severe disease with high mortality rates: SARS-CoV emerged in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019. Both SARS-CoV and SARS-CoV-2 belong to the same family, follow the same receptor pathway, and use their receptor binding domain (RBD) of spike protein to bind to the ACE2 receptor on the human epithelial cell surface. The sequence of the two RBDs is divergent, especially in the receptor binding motif (RBM) that directly interacts with ACE2. We probed the biophysical differences between the two RBDs in terms of their structure, stability, aggregation, and function. Since RBD is being explored as an antigen in protein subunit vaccines against CoVs, determining these biophysical properties will also aid in developing stable protein subunit vaccines. Our results show that despite RBDs having a similar three-dimensional structure, they differ in their thermodynamic stability. RBD of SARS-CoV-2 is significantly less stable than that of SARS-CoV. Correspondingly, SARS-CoV-2 RBD shows a higher aggregation propensity. Regarding binding to ACE2, less stable SARS-CoV-2 RBD binds with a higher affinity than more stable SARS-CoV RBD. In addition, SARS-CoV-2 RBD is more homogenous in terms of its binding stoichiometry towards ACE2, compared to SARS-CoV RBD. These results indicate that SARS-CoV-2 RBD differs from SARS-CoV RBD in terms of its stability, aggregation, and function, possibly originating from the diverse RBMs. Higher aggregation propensity and decreased stability of SARS-CoV-2 RBD warrants further optimization of protein subunit vaccines that use RBD as an antigen either by inserting stabilizing mutations or formulation screening.

Statement of Significance

This study holds significant relevance in the context of the COVID-19 pandemic and the broader understanding of coronaviruses. A comparison of the receptor binding domains (RBDs) of SARS-CoV and SARS-CoV-2 reveals significant differences in their structure, stability, aggregation, and function. Despite divergent sequences, the RBDs share a similar fold and ACE2 receptor binding capability, likely through convergent evolution. These findings are crucial for understanding coronavirus evolution, interactions with human receptors, and the spillover of coronaviruses from animals to humans. The study also has implications for vaccine design strategies for SARS-CoVs, where the RBD is used as an antigen in protein subunit vaccines. By anticipating future outbreaks and enhancing our understanding of zoonotic spillover, this research contributes to safeguarding human health.
Catch me if you can: current status and topical issues on the use of eDNA-based targeted detection of rare and endangered animal species
Authors: Duarte Sofia , Simões Luara , Costa Filipe O.
Published: June 2023

Animal detection through DNA present in environmental samples (eDNA) is a valuable tool for detecting rare species, that are difficult to observe and monitor. eDNA-based tools are underpinned by molecular evolutionary principles, which are key to devising tools to efficiently single out a targeted species from an environmental sample, using carefully chosen marker regions and customized primers. Here, we present a comprehensive review of the use of eDNA-based methods for the detection of targeted animal species, such as rare, endangered, or invasive species, through the analysis of 460 publications (2008-2022). Aquatic ecosystems have been the most surveyed, in particular, freshwaters (75%), and to a less extent marine (14%) and terrestrial systems (10%). Vertebrates, in particular, fish (38%), and endangered species, have been the most focused in these studies, and Cytb and COI are the most employed markers. Among invertebrates, assays have been mainly designed for Mollusca and Crustacea species (22%), in particular, to target invasive species, and COI has been the most employed marker. Targeted molecular approaches, in particular qPCR, have been the most adopted (73%), while eDNA metabarcoding has been rarely used to target single or few species (approx. 5%). However, less attention has been given in these studies to the effects of environmental factors on the amount of shed DNA, the differential amount of shed DNA among species, or the sensitivity of the markers developed, which may impact the design of the assays, particularly to warrant the required detection level and avoid false negatives and positives. The accuracy of the assays will also depend on the availability of genetic data from closely related species to assess both marker and primers’ specificity. In addition, eDNA-based assays developed for a particular species may have to be refined taking into account site-specific populations, as well as any intraspecific variation.

Graphical Abstract
ADAM11 a novel regulator of Wnt and BMP4 signaling in neural crest and cancer
Authors: Pandey Ankit , Cousin Hélène , Horr Brett , Alfandari Dominique
Published: June 2023

Cranial neural crest (CNC) cells are induced at the border of the neural plate by a combination of FGF, Wnt, and BMP4 signaling. CNC then migrate ventrally and invade ventral structures where they contribute to craniofacial development. Here we show that a non-proteolytic ADAM, Adam11, originally identified as a putative tumor suppressor binds to proteins of the Wnt and BMP4 signaling pathway. Mechanistic studies concerning these non-proteolytic ADAM lack almost entirely. We show that Adam11 positively regulates BMP4 signaling while negatively regulating β-catenin activity. By modulating these pathways, Adam11 controls the timing of neural tube closure and the proliferation and migration of CNC. Using both human tumor data and mouse B16 melanoma cells, we further show that ADAM11 levels similarly correlate with Wnt or BMP4 activation levels. We propose that ADAM11 preserve naïve cells by maintaining low Sox3 and Snail/Slug levels through stimulation of BMP4 and repression of Wnt signaling, while loss of ADAM11 results in increased Wnt signaling, increased proliferation and early epithelium to mesenchyme transition.
Automated clinical conversations across the cataract pathway with an artificial intelligence (AI) conversation agent: a UK regional service evaluation protocol
Authors:   Automated cataract surgery telephone consult evaluation collaboration, Higham Aisling
Published: June 2023

Introduction

Digital technologies have the potential to support clinical pathways. This study aims to evaluate the impact of using an artificial intelligence-based conversational assistant known as Dora in the cataract pathway. Dora conducts clinical conversations with patients over a telephone call both before and after cataract surgery. Through automation of routine activity, the aim is to increase efficiency of the cataract pathway and the capacity of organisations.

Method and Analysis

We will use a mixed-methods cohort-based approach across all sites using Dora in South East England. The study has 3 key objectives, to: 1) Report site-specific variation on the implementation and impact of using Dora 2) assess the impact on the triple bottom line (financial, social and environmental performance) through implementation of Dora 3) understand the real-world patient outcomes of using Dora in clinical pathways. The Dora platform prospectively records symptom and outcome information from each call. We will retrospectively collect data from the hospital record and also collect qualitative data regarding the ease of implementation and patient acceptability of the technology.

Ethics and dissemination

This will be registered as a service evaluation at each of the participating clinical sites. Research ethics is not needed as per Health Research Authority guidelines. Site-specific reports will be provided to each participant site as well as an overall report to be disseminated through NHS-England. Results will be published in a formal project report endorsed by stakeholders, and in peer-reviewed scientific reports.

Article Summary

Strengths and limitations of this study

Strengths

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This is the largest study on the use of an AI based natural language clinical assistant across multiple different hospital sites, with varied geographical locations, demographics and baseline clinical pathways.

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This is a large-scale evaluation with input from multiple independent clinicians, patients, evaluators, economists and strategists.

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Standardised data collection from autonomous clinical assistant

Limitations

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Retrospective collection of hospital level follow up data
Combination of Polymeric Micelle Formulation of TGFβ Receptor Inhibitors and Paclitaxel Produce Consistent Response Across Different Mouse Models of TNBC
Authors: Vinod Natasha , Hwang Duhyeong , Fussell Sloane Christian , Owens Tyler Cannon , Tofade Olaoluwa Christopher , Copling Sage , Ramsey Jacob D. , Rädler Patrick D. , Atkins Hannah M. , Livingston Eric E. , Ashley Ezzell J. , Papkov Marina Sokolsky- , Yuan Hong , Perou Charles M. , Kabanov Alexander V.
Published: June 2023

Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor-beta (TGFβ) family of proteins and their receptors (TGFR) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with Paclitaxel (PTX) chemotherapy. These TGFβi target TGFR-I (SB) or both TGFR-I&II (LY). Due to the poor water solubility of these drugs, we incorporated each of them in poly(2-oxazoline) (POx) high-capacity polymeric micelles (SB-POx and LY-POx). We assessed their anti-cancer effect as single agents and in combination with micellar Paclitaxel (PTX-POx) using multiple immunocompetent TNBC mouse models that mimic human subtypes (4T1, T11-Apobec and T11-UV). While either TGFβi or PTX showed a differential effect in each model as single agents, the combinations were consistently effective against all three models. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGFβ, EMT, TLR-4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGFβi and PTX combination therapy using high-capacity POx micelle delivery provides a robust anti-tumor response in multiple TNBC subtype mouse models.

Translational Impact Statement

Paclitaxel is a widely used chemotherapy in breast cancer. However, response to single-agent chemotherapy is short-lived in a metastatic setting. This study shows the broad applicability of the therapeutic combination of TGFβ inhibitors with Paclitaxel across different TNBC subtypes.
Single-tier point-of-care serodiagnosis of Lyme disease
Authors: Ghosh Rajesh , Joung Hyou-Arm , Goncharov Artem , Palanisamy Barath , Ngo Kevin , Pejcinovic Katarina , Krockenberger Nicole , Horn Elizabeth J. , Garner Omai B. , Ghazal Ezdehar , O’Kula Andrew , Arnaboldi Paul M. , Dattwyler Raymond J. , Ozcan Aydogan , Di Carlo Dino
Published: June 2023

Point-of-care (POC) serological testing provides actionable information for several difficult to diagnose illnesses, empowering distributed health systems. Accessible and adaptable diagnostic platforms that can assay the repertoire of antibodies formed against pathogens are essential to drive early detection and improve patient outcomes. Here, we report a POC serologic test for Lyme disease (LD), leveraging synthetic peptides tuned to be highly specific to the LD antibody repertoire across patients and compatible with a paper-based platform for rapid, reliable, and cost-effective diagnosis. A subset of antigenic epitopes conserved acrossBorrelia burgdorferigenospecies and targeted by IgG and IgM antibodies, were selected based on their seroreactivity to develop a multiplexed panel for a single-step measurement of combined IgM and IgG antibodies from LD patient sera. Multiple peptide epitopes, when combined synergistically using a machine learning-based diagnostic model, yielded a high sensitivity without any loss in specificity. We blindly tested the platform with samples from the U.S. Centers for Disease Control & Prevention (CDC) LD repository and achieved a sensitivity and specificity matching the lab-based two-tier results with a single POC test, correctly discriminating cross-reactive look-alike diseases. This computational LD diagnostic test can potentially replace the cumbersome two-tier testing paradigm, improving diagnosis and enabling earlier effective treatment of LD patients while also facilitating immune monitoring and surveillance of the disease in the community.
AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor
Authors: Trepte Philipp , Secker Christopher , Kostova Simona , Maseko Sibusiso B. , Choi Soon Gang , Blavier Jeremy , Minia Igor , Ramos Eduardo Silva , Cassonnet Patricia , Golusik Sabrina , Zenkner Martina , Beetz Stephanie , Liebich Mara J. , Scharek Nadine , Schütz Anja , Sperling Marcel , Lisurek Michael , Wang Yang , Spirohn Kerstin , Hao Tong , Calderwood Michael A. , Hill David E. , Landthaler Markus , Olivet Julien , Twizere Jean-Claude , Vidal Marc , Wanker Erich E.
Published: June 2023

Protein-protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays and AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways.
High-resolution mapping of cell cycle dynamics during T-cell development and regenerationin vivo
Authors: Kunze-Schumacher Heike , Verheyden Nikita A. , Grewers Zoe , Meyer-Hermann Michael , Greiff Victor , Robert Philippe A. , Krueger Andreas
Published: June 2023

Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known on how stage-specific alterations in cell cycle behavior drive proliferation dynamics during T-cell development. Here, we employedin vivodual-nucleoside pulse labeling combined with determination of DNA replication over time as well as fluorescent ubiquitination-based cell cycle indicator mice to establish a quantitative high-resolution map of cell cycle kinetics of thymocytes. We developed an agent-based mathematical model of T-cell developmental dynamics. To generate the capacity for proliferative bursts, cell cycle acceleration followed a ‘stretch model’, characterized by simultaneous and proportional contraction of both G1 and S phase. Analysis of cell cycle phase dynamics during regeneration showed tailored adjustments of cell cycle phase dynamics. Taken together, our results highlight intrathymic cell cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T-cell developmental program.
Phage predation, disease severity and pathogen genetic diversity in cholera patients
Authors: Madi Naïma , Cato Emilee T. , Sayeed Md. Abu , Creasy-Marrazzo Ashton , Cuénod Aline , Islam Kamrul , Khabir Md. Imam UL. , Bhuiyan Md. Taufiqur R. , Begum Yasmin A. , Freeman Emma , Vustepalli Anirudh , Brinkley Lindsey , Kamat Manasi , Bailey Laura S. , Basso Kari B. , Qadri Firdausi , Khan Ashraful I. , Shapiro B. Jesse , Nelson Eric J.
Published: June 2023

Despite an increasingly detailed picture of the molecular mechanisms of phage-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. Here we report a year-long, nation-wide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantifiedVibrio cholerae(prey) and its virulent phages (predators) using metagenomics and quantitative PCR, while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressedV. choleraeto varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of anti-phage defenses, predation was ‘effective,’ with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of anti-phage defenses, predation was ‘ineffective,’ with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics.

One Sentence Summary

A survey of cholera patients in Bangladesh identifies phage predation as a biomarker of disease severity and driver of coevolution within patients.
Analysis of structure-activity and structure-mechanism relationships among thyroid stimulating hormone receptor binding chemicals by leveraging ToxCast library
Authors: Sahoo Ajaya Kumar , Baskaran Shanmuga Priya , Chivukula Nikhil , Kumar Kishan , Samal Areejit
Published: June 2023

Thyroid stimulating hormone receptor (TSHR) is an integral part of the hypothalamic-pituitary-thyroid axis. Notably, dysregulation in TSHR activation in humans can lead to adverse effects such as Grave’s disease, hypothyroidism and Hashimoto’s disease. Moreover, animal studies have shown that binding of endocrine disrupting chemicals (EDCs) with TSHR can lead to developmental toxicity. Several such chemicals have also been screened for their adverse physiological effects in human cell lines through various high-throughput assays under the ToxCast project. The vast resource of data generated through ToxCast has enabled the development of different toxicity predictors, but they can be limited in their predictive ability due to the heterogeneity in structure-activity relationships among chemicals. In an attempt to explore this heterogeneity, we systematically investigated structure-activity and structure-mechanism relationships among the TSHR binding chemicals from ToxCast. By employing structure-activity similarity (SAS) map, we identified 79 activity cliffs among 509 chemicals in the TSHR agonist dataset and 69 activity cliffs among 650 chemicals in the TSHR antagonist dataset. Further, by using the matched molecular pair (MMP) approach, we find that the resultant activity cliffs (MMP-cliffs) are a subset of activity cliffs identified via the SAS map approach. Moreover, by leveraging ToxCast mechanism of action (MOA) annotations for chemicals common to both TSHR agonist and antagonist datasets, we identified 3 chemical pairs as Strong MOA-cliffs and 19 chemical pairs as Weak MOA-cliffs. In conclusion, the insights from this systematic analysis of the structure-activity as well as the structure-mechanism relationships of TSHR binding chemicals are likely to inform ongoing efforts towards development of better predictive toxicity models for characterizing the chemical exposome.
Characterizing the power spectrum dynamics of the NREM to REM sleep transition
Authors: Serantes Diego , Cavelli Matías , González Joaquín , Mondino Alejandra , Benedetto Luciana , Torterolo Pablo
Published: June 2023

The transition from NREM to REM sleep is considered a transitional or intermediate stage (IS), characterized by high amplitude spindles in the frontal cortex and theta activity in the occipital cortex. Early reports in rats showed an IS lasting from 1 to 5 s, but recent studies suggested a longer duration of this stage. To further characterize the IS, we analyzed its spectral characteristics on electrocorticogram (ECoG) recordings of the olfactory bulb (OB), motor (M1), somato-sensory (S1) and secondary visual cortex (V2) in twelve Wistar male adult rats. By comparing the IS to consolidated NREM/REM epochs, our results reveal that the IS has specific power spectral patterns that statistically differ from both NREM and REM sleep states. Specifically, the main findings were that sigma (11-16 Hz) and beta (17-30 Hz) power in OB, M1, and S1 increased during the IS compared to NREM and REM sleep and began 55 s before REM sleep onset. Additionally, low gamma (31-48 Hz) in the OB started transitioning from NREM levels to REM ones 65 s before its onset. Finally, the high-frequency oscillations (102-198 Hz) in OB, M1, and S1 showed a power increase that began 40 s before REM sleep and reached REM sleep values 10 s after its onset. Thus, we argue that the NREM to REM transition contains its own spectral profile and is more extended than previously described.
An inducible germ cell ablation chicken model for high-grade germline chimeras
Authors: Chen Yi-Chen , Saito Daisuke , Suzuki Takayuki , Takemoto Tatsuya
Published: June 2023

Chicken embryos are a powerful and widely used animal model in developmental biology studies. After the development of CRISPR technology, gene-edited chickens have been generated by transferring primordial germ cells (PGCs) after genetic modifications. However, the low inheritance caused by the competition between host germ cells and the transferred ones is the most common complication and largely reduces the production efficiency in this way. Here, we generated a gene-edited chicken, in which germ cells can be ablated in a drug-dependent manner, as recipients for gene-edited PGC transfer. We used the nitroreductase/metronidazole (NTR/Mtz) system for cell ablation, in which NTR produces cytotoxic alkylating agents from administered Mtz, causing cell apoptosis. The chicken Vasa homolog (CVH) gene locus is used to drive the expression of the NTR gene in a germ cell-specific manner. In addition, a fluorescent protein gene, mCherry, was also placed in the CVH locus to visualize the PGCs. We named this systemgerm cell-SpecificAutonoMoUsRemovAlInduction (gSAMURAI). gSAMURAI chickens will be an ideal recipient to produce offspring derived from transplanted exogenous germ cells.
Evolutionary engineering a larger porin using a loop-to-hairpin mechanism
Authors: Dhar Rik , Bowman Alexander M. , Hatungimana Brunojoel , Slusky Joanna SG
Published: June 2023

In protein evolution, diversification is generally driven by genetic duplication. The hallmarks of this mechanism are visible in the repeating topology of various proteins. In outer membrane β-barrels, duplication is visible with β-hairpins as the repeating unit of the barrel. In contrast to the overall use of duplication in diversification, a computational study hypothesized evolutionary mechanisms other than hairpin duplications leading to increases in the number of strands in outer membrane β-barrels. Specifically, the topology of some 16- and 18-stranded β-barrels appear to have evolved through a loop to β-hairpin transition. Here we test this novel evolutionary mechanism by creating a chimeric protein from an 18-stranded β-barrel and an evolutionarily related 16-stranded β-barrel. The chimeric combination of the two was created by replacing loop L3 of the 16-stranded barrel with the sequentially matched transmembrane β-hairpin region of the 18-stranded barrel. We find the resulting chimeric protein is stable and has characteristics of increased strand number. This study provides the first experimental evidence supporting the evolution through a loop to β-hairpin transition.

Highlights

We find evidence supporting a novel diversification mechanism in membrane β-barrels

The mechanism is the conversion of an extracellular loop to transmembrane β-hairpin

A chimeric protein modeling this mechanism folds stably in the membrane

The chimera has more β-structure and a larger pore, consistent with a loop-to-hairpin transition
A KDELR-mediated ER retrieval system guides the signaling pathways of UPR and AMPK to maintain cellular homeostasis
Authors: Zhu Mengdan , Fang Zheng , Wu Yifan , Dong Fenfen , Wang Yuzhou , Zheng Fan , Ma Xiaopeng , Ma Shisong , He Jiajia , Hill Donald L. , Liu Xing , Yao Xuebiao , Fu Chuanhai
Published: June 2023

KDELR (Erd2 in yeasts) mediates the retrieval of ER-resident proteins from the Golgi apparatus, yet how the KDELR-mediated ER retrieval system is involved in regulating cellular homeostasis has been unclear. Here we report that the loss of the Erd2-mediated ER retrieval system induces the unfolded protein response (UPR) and increases mitochondrial respiration and reactive oxygen species (ROS) in an UPR-dependent manner. Moreover, transcriptomic analysis revealed that expression of the genes involved in mitochondrial respiration and the tricarboxylic acid cycle is enhanced in an UPR-dependent manner in cells lacking Erd2. In cells lacking Erd2, the enhancement of mitochondrial respiration and ROS is required for maintaining cell viability. The loss of the Erd2-mediated ER retrieval system also activates AMPK, and consequently derepresses carbon catabolite repression. Hence, our work establishes a role of the KDELR/Erd2-mediated ER retrieval system in guiding the signalling pathways of AMPK and UPR and underscores the crucial role of the KDELR/Erd2-mediated ER retrieval system in the maintenance of cellular homeostasis.
LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation
Authors: Fahmy Ahmed M. , Cannon Tyler , Paredes Camberly Herdandez , Ahmadi Ali , Xu Yong Zhong , Barette Benoit , Ibrahim Maha , Lanoix Joël , Arango-Duque Guillermo , Schurr Erwin , Chevet Eric , Thibault Pierre , Gruenheid Samantha , McBride Heidi , Desjardins Michel
Published: June 2023

While the contribution of inflammation in the pathological process leading to Parkinson’s disease (PD) is well established, a growing body of evidence supports a role for the long-lasting adaptive immune system in the disease. We showed that, in inflammatory conditions, the PD-proteins PINK1 and Parkin negatively regulate the presentation of mitochondrial antigens on MHC I molecules, a process referred to as MitAP (MitochondrialAntigenPresentation). In the absence of PINK1, over-activation of this pathway in antigen-presenting cells (APCs) engages autoimmune mechanisms leading to the establishment of cytotoxic CD8+T cells. Co-culture of dopaminergic neurons (DNs) with these T cells led to neuronal cell death, suggesting that the MitAP in DNs made them susceptible to T cell-mediated destruction. In the present study, we used a pharmacological and genetic approach to characterize the MitAP pathway at the molecular level. We showed that this antigen presentation pathway is induced in APCs in response to inflammatory signals through the sequential activation of TLR4, cGAS-STING and the Unfolded Protein Response (UPR). A “UPR motif” present on a STING cytoplasmic domain was shown to specifically activate the UPR sensor IRE1. Remarkably, the PD-related protein LRRK2, acted with STING upstream of the UPR to regulate the transition from innate to adaptive immunity, thereby identifying this PD-related protein as a key player in the immune response during inflammation.