bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel hyperpigmentation pathophysiology following a prolonged course of imipramine therapy
Authors: McKenna Brian , Wold Lynne , Noland Mary‐Margaret , Schenck Olivia
Published: October 2023

Imipramine is a tricyclic antidepressant typically reserved for patients with treatment‐resistant mood disorders. A rare side effect of long‐term use of imipramine is a slowly progressive melanin‐associated, slate gray‐blue hyperpigmentation of the skin in a photo‐distributed pattern. We report a case of imipramine‐induced hyperpigmentation developing 50 years after initiating imipramine therapy, whose lesions were essentially devoid of melanin on histopathological exam. This differs from all other reported cases of imipramine‐induced hyperpigmentation in two notable respects. First, the time between initiating imipramine therapy and the onset of pigmentation changes was nearly 30 years longer than prior case reports. Second, the lack of melanin in our samples suggests a divergence from the hypothesized melanin‐imipramine complex mechanism of hyperpigmentation. Instead, we propose a novel pathogenesis of imipramine‐induced hyperpigmentation that is unrelated to melanin.
1069. Berberis ludingensis Harber, a new species in section Wallichianae from Sichuan, China: Berberidaceae
Authors: Harber Julian , Liang Ke
Published: October 2023

A new species of Berberis in section Wallichianae, B. ludingensis Harber is described from Luding Xian in Sichuan. Several collections of this compact, spiny species have been made in recent years.
Effect of different loading rates on the fracture behavior of FRP‐reinforced concrete
Authors: Liu Jueding , Fan Xiangqian , Wang Tao , Qu Chiyu
Published: October 2023

In order to study the effect of different loading rates on the fracture behavior of fiber‐reinforced polymer (FRP) reinforced concrete, the fracture experiments of FRP‐reinforced concrete beams under different loading rates were carried out. The calculation method of fracture toughness was given by analytic deduction, and the effects of different loading rates on the fracture parameters were analyzed. The experimental results show that there are three critical points in the fracture process of FRP‐reinforced concrete beam, which are the crack initiation load, crack resistance load, and ultimate load points. The effective crack length at the crack resistance load point increases with the increase of loading rate, and the effective crack length at the ultimate load point does not vary as the loading rate. With the increase of loading rate, the elastic modulus and fracture toughness increase gradually, and there is a logarithmic relationship with the loading rate, which has obvious rate correlation. The fracture process zone (FPZ) length of FRP‐reinforced concrete beams gradually decreases with the increase of loading rate.
Daily ritonavir‐boosted darunavir for viral suppression in pregnancy (DRV‐P)
Authors: Gacic Nikolina , Tulloch Karen , Money Deborah , Tkachuk Stacey
Published: October 2023

Background

Ritonavir‐boosted darunavir (DRV/r) is a preferred protease inhibitor in pregnant women living with HIV. Current practice at British Columbia's referral centre (the Oak Tree Clinic) is to dose DRV/r as 800/100 mg daily throughout pregnancy, although some guidelines recommend DRV/r 600/100 mg twice daily due to altered pharmacokinetics with once‐daily dosing.

Objectives

We describe the effect of once‐daily DRV/r on viral suppression, vertical transmission, adverse drug effects and adherence in pregnant women living with HIV.

Methods

This was a retrospective analysis of pregnant women living with HIV in British Columbia. Eligible women gave birth between January 2015 and August 2021, and took DRV/r 800/100 mg daily at any time during pregnancy.

Results

Thirty‐four women were included in this study. The mean (SD) age was 33 (5) years. Thirty (88%) women were diagnosed with HIV prior to pregnancy, with 22 (73%) having viral suppression at baseline. Four (12%) were diagnosed in pregnancy, with a median baseline viral load of 9616 copies/mL (range 8370–165 000). Viral suppression was achieved by 16 (100%), 24 (75%) and 26 (74%) women in the first, second and third trimesters, respectively. No vertical transmission occurred. This combination was well tolerated, with adverse drug effects that did not result in discontinuation or change in therapy. Most women maintained >75% adherence to once‐daily DRV/r at all times during pregnancy.

Conclusions

Ritonavir‐boosted darunavir 800/100 mg daily appears to be an appropriate dosing strategy for pregnant women living with HIV who are able to maintain optimal adherence.
YSZ–Al2O3 thermal barrier nanocomposites coatings: Electrophoretic deposition and characterization
Authors: Noroozpour Mina , Akbari Alireza
Published: October 2023

This paper presents the development of yttria‐stabilized zirconia–alumina (YSZ–Al2O3) nanocomposite coatings deposited on Inconel 738LC superalloy substrates using the electrophoretic deposition technique. To prepare stable suspensions of YSZ and Al2O3 nanoparticles, a mixture of 75 mL acetone and 25 mL ethanol was used as a medium with .4 g/L iodine as a dispersant. The effects of Al2O3 concentration on suspension stability, electrical conductivity, and pH were studied in detail to optimize the suspension chemistry. The deposition kinetics were systematically investigated as a function of suspension concentration, deposition voltage, deposition time, and iodine concentration () to optimize the process parameters. The as‐dried coatings deposited at Vd = 10 V for 90 s were uniform, crack‐free, and sintered at 1150°C for 4 h. The microstructure, phase composition, hardness, and adhesion strength of the coatings were analyzed using scanning electron microscopy, X‐ray diffraction, Vickers microhardness measurements, and conducting shear loading tests, respectively. The results showed that adding Al2O3 to YSZ reduces porosity, crack density, and sintering temperature while stabilizing the tetragonal phase and retarding the martensitic transformation and crack formation. Among the studied coatings, the YSZ–20 wt.% Al2O3 nanocomposite coating deposited at Vd = 10 V for 90 s exhibited the most improved microstructural features, hardness, and adhesion strength.
Quality of life and stigmatization in people with skin diseases in Europe: A large survey from the ‘burden of skin diseases’ EADV project
Authors: Gisondi Paolo , Puig Luis , Richard Marie Aleth , Paul Carle , Nijsten Tamar , Taieb Charles , Stratigos Alex , Trakatelli Myrto , Salavastru Carmen ,   the EADV Burden of Skin Diseases Project Team
Published: October 2023

Background

Several large studies on the burden of skin diseases have been performed in patients recruited in hospitals or clinical centres, thus missing people with skin diseases who do not undergo a clinical consultation.

Objectives

To evaluate the burden of the most common dermatological diseases in adult patients across Europe, in terms of quality of life, work life, and stigmatization.

Methods

Population‐based survey on a representative sample of the European general population aged 18 years or older. Participants who declared to have had one or more skin problem or disease during the previous 12 months completed the Dermatology Life Quality Index questionnaire, and answered questions regarding the impact of their skin disease on daily and work life, anxiety/depression, and stigmatization.

Results

The study population included 19,915 individuals, 44.7% of whom were men. Quality of life was particularly impaired in people with hidradenitis suppurativa (HS), and sexually transmitted diseases. About a half of participants with acne, alopecia, or chronic urticaria, and about 40% of those with atopic dermatitis (AD), skin cancers, or psoriasis reported a modest to extremely large effect of the disease on their quality of life. Overall, 88.1% of participants considered their skin disease as embarrassing in personal life and 83% in work life. About half of the respondents reported sleeping difficulty, feeling tired, and impact of the disease on taking care of themselves. Concerning stigmatization, 14.5% felt to have been rejected by others because of the skin disease, and 19.2% to have been looked at with disgust. Anxiety and depression were frequently reported by patients with all the diseases.

Conclusions

Skin diseases may heavily affect patients' daily and work life, and cause feelings of stigmatization. An early intervention is needed to avoid consequences on the patients' life course.
Patient prioritisation of impact items to develop the patient‐reported impact of dermatological diseases (PRIDD) measure: European Delphi data
Authors: Trialonis‐Suthakharan N. , Pattinson R. , Tahmasebi Gandomkari N. , Austin J. , Janus C. , Courtier N. , Hewitt R. M. , Bundy C. , Augustin M.
Published: October 2023

Background

The Global Research on the Impact of Dermatological Diseases (GRIDD) project is developing a patient‐reported measure of the impact of dermatological disease on the patient's life called Patient Reported Impact of Dermatological Diseases (PRIDD). We developed a list of 263 potential impact items through a global qualitative interview study with 68 patients. We next conducted a Delphi study to seek consensus on which of these items to prioritize for inclusion in PRIDD. This study aims to explore patterns in demographic (e.g. country) and clinical variables (e.g. disease group) across the impacts ranked as most important to European dermatology patients.

Methods

We conducted a modified, two rounds Delphi study, testing the outcomes from the previous qualitative interview study. Adults (≥18 years) living with a dermatological disease were recruited through the International Alliance of Dermatology Patient Organizations' (GlobalSkin) membership network. The survey consisted of a demographic questionnaire and 263 impact items and was available in six languages. Quantitative data were collected using ranking scales and analysed against a priori consensus criteria. Qualitative data were collected using free‐text responses and a Framework Analysis was conducted. European data were obtained, and descriptive statistics, including multiple subgroup analyses, were performed.

Results

Out of 1154 participants, 441 Europeans representing 46 dermatological disease from 25 countries participated. The results produced a list of the top 20 impacts reported by European patients, with psychological impacts accounting for the greatest proportion.

Conclusion

This study identified what patients consider to be the most important issues impacting their lives as a result of their dermatological disease. The data support previous evidence that patients experience profound psychological impacts and require psychological support. The findings can inform research, clinical practice and policy by indicating research questions and initiatives that are of most benefit to patients.
Polyubiquitin protein of Aedes aegypti as an interacting partner of dengue virus envelope protein
Authors: Yadav Karuna , Saurav Gunjan Kumar , Rana Vipin Singh , Rawat Nitish , Anjali  , Jamwal Rohit , Singh Om Prakash , Bandyopadhyay Anannya , Rajagopal Raman
Published: October 2023

Dengue virus (DENV) is an arbovirus that comprises four antigenically different serotypes. Aedes aegypti (Diptera: Culicidae) acts as the principal vector for DENV transmission, and vector control is crucial for dengue fever epidemic management. To design effective vector control strategies, a comprehensive understanding of the insect vector and virus interaction is required. Female Ae. aegypti ingests DENV during the acquisition of a blood meal from an infected human. DENV enters the insect midgut, replicates inside it and reaches the salivary gland for transmitting DENV to healthy humans during the subsequent feeding cycles. DENV must interact with the proteins present in the midgut and salivary glands to gain entry and accomplish successful replication and transmission. Ae. aegypti midgut cDNA library was prepared, and yeast two‐hybrid screening was performed against the envelope protein domain III (EDIII) protein of DENV‐2. The polyubiquitin protein was selected from the various candidate proteins for subsequent analysis. Polyubiquitin gene was amplified, and the protein was purified in a heterologous expression system for in vitro interaction studies. In vitro pull‐down assay presented a clear interaction between polyubiquitin protein and EDIII. To further confirm this interaction, a dot blot assay was employed, and polyubiquitin protein was found to interact with DENV particles. Our results enable us to suggest that polyubiquitin plays an important role in DENV infection within mosquitoes.
RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: Considerations for biomarker discovery
Authors: Grima Natalie , Liu Sidong , Southwood Dean , Henden Lyndal , Smith Andrew , Lee Albert , Rowe Dominic B. , D'Silva Susan , Blair Ian P. , Williams Kelly L.
Published: October 2023

Aim

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA‐seq) of ALS patient peripheral blood.

Methods

Whole blood RNA‐seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS–control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co‐expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected.

Results

Two hundred and forty‐five differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress‐related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS patients from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects.

Conclusions

Our findings suggest that peripheral blood RNA‐seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.
Rediscovery of Thottea philippinensis(Aristolochiaceae) from Naga‐Kabasalan Protected Landscape, Zamboanga Sibugay including the confirmation on the occurrence ofT. tomentosain the Philippines
Authors: Arcebal K. Naive Mark , Ancheta Donnafe J. , Yongco Jannah E. , Katrina R. Fulgencio Bea
Published: October 2023

Collecting expeditions carried out in the Zamboanga Peninsula of western Mindanao (Philippines) led to the rediscovery of Thottea philippinensis, previously known only by a single collection made 93 years ago. Here we provide an extended description, comments on the affinities among closely related species, an updated geographical distribution, habitat information, conservation assessment, and the first‐ever published photos of living T. philippinensis in the wild. Additionally, the occurrence of T. tomentosa in the Philippine archipelago is confirmed.
An examination of the growth of Airbnb in New Zealand and its impact on the private rental housing market: 2016–2021
Authors: Fyfe Caroline , Telfar Barnard Lucy , Howden‐Chapman Philippa , Bennett Julie
Published: October 2023

Airbnb is an online platform connecting private hosts with visitors looking for short‐term accommodation. The aim of this paper is to examine the impact of Airbnb on long‐term rental housing availability and cost in Aotearoa New Zealand before and during the COVID‐19 pandemic. Regional growth patterns in Airbnb properties were measured and their impact on the private rental market investigated. An increasing proportion of new rental housing was offered through Airbnb over the study period, particularly in popular tourist locations. Increasing occupancy rates pre‐pandemic suggest that there remains room for growth, putting further pressure on the private rental housing stock.
Virtual reality and noise canceling headphone distraction during pediatric dermatologic procedures
Authors: Jaquez Sasha D. , Haller Courtney N. , England Maryann E. , Bruinsma Raquel L. , Arbet Gregory , Croce Emily A. , Ruth Jennifer , Levy Moise L. , Diaz Lucia Z.
Published: October 2023

Pain and anxiety related to medical procedures have long been recognized as a significant healthcare concern. If a patient's procedural pain and anxiety are not addressed, long‐term physical and psychological sequelae including increased perceived pain, anxiety, disruptive behavior, trauma reactions, or refusal of future procedures can occur. The objective of our study was to assess the utility of a virtual reality (VR) headset or noise‐canceling headphones (HP) compared to treatment as usual (TAU) in reducing pain and anxiety during pediatric dermatology procedures. Results indicated a significant difference between pre‐ versus post‐procedure anxiety in the VR and HP groups but not the TAU group suggesting non‐pharmacologic technology‐based interventions such as VR and headphones may reduce patients' anxiety during pediatric dermatology procedures.
Self‐management skills in a UK sample of young people with chronic liver disease
Authors: Day Jemma , Hames Anna , Earl Megan , Simpson Anna , Joshi Deepak , Pissas Eleanna , Samyn Marianne
Published: October 2023

Background

We aimed to assess self‐management skills and adherence behaviors in young people post‐liver transplant and compare these with those of young people with autoimmune liver disease and other forms of chronic liver disease.

Method

As part of our specialist multidisciplinary clinic, n = 156 young people (aged 16–25 years) completed the Liver Self‐Management Questionnaire (an adaptation of the Developmentally Based Skills Checklist for adolescents post‐liver transplant and modified for us across liver disease type and within the United Kingdom). Those taking medication (n = 128) also completed a service‐designed questionnaire regarding adherence. The statistical significance of group differences was assessed with non‐parametric analyses.

Results

Young people post‐liver transplant were less likely to report managing their condition independently than those with autoimmune liver disease or those with other forms of chronic liver disease. They also reported higher adherence (93%) compared to those with autoimmune liver disease (77%) and those with other forms of chronic liver disease (85%). However, the vast majority of self‐management and adherence behaviors were comparable between young people post‐transplant and those with autoimmune liver disease/other forms of chronic liver disease.

Conclusion

Our data are in line with existing data from US samples and also extend these findings to include those with other forms of chronic liver disease. These data highlight the importance of individualized care for young adults, regardless of condition type or healthcare setting, and of clinicians managing their expectations regarding what is considered appropriate condition management in early adulthood.
Street‐level discretion, personal motives, and social embeddedness within public service ecosystems
Authors: Knox Stephen , Arshed Norin
Published: October 2023

Drawing on the sense of community responsibility concept, we explore the enterprise policy ecosystem in an extensive qualitative study of Scotland. We present a processual model which explains how policies are shaped in an on‐going dynamic through street‐level managers' individual agency. Our findings reveal that driving the process is an interplay between personal motives (compassion, relational strength, esteem, coherence) with a social frame of reference (policy group, locality, public organization) which is based on embeddedness within specific policy contexts. This interplay guides how managers translate policy as either an opportunity or a threat which then directs how they enact their discretion to adapt, advocate change, or resist implementation. This process offers an explanation as to how situated value is created for specific policy areas within public service ecosystems. The implications are discussed in relation to the existing literature on policy implementation.
Two novel HLA‐B variants identified in Russian individuals, HLA‐B*37:108 and ‐B*38:108
Authors: Ananeva Anastasiia , Osipova Nailia , Elagina Elmira , Andryushkina Anna V. , Shagimardanova Elena I.
Published: October 2023

HLA‐B*37:108 and ‐B*38:108, two novel alleles detected in Russian individuals by next generation sequencing.
Integrated Control Design for a Partially Turboelectric Aircraft Propulsion System
Authors: Simon Donald L. , Bianco Santino J. , Horning Marcus A.
Published: October 2023

Electrified Aircraft Propulsion (EAP) holds great potential for reducing aviation emissions and fuel burn. A variety of EAP architectures have been proposed including partially turbo-electric configurations that combine turbofan engines with motor-driven propulsors. Such architectures exhibit coupling between subsystems and thus require an integrated control solution. To address this need, this paper presents an integrated control design strategy for a commercial single-aisle partially turbo-electric aircraft concept consisting of two wing-mounted turbofan engines and an electric motor driven tailfan propulsor. Within this architecture the turbofans serve the dual purpose of generating thrust and supplying mechanical offtake power used to generate electricity for the tailfan motor. The propulsion control system is tasked with coordinating turbofan and tailfan operation under both steady-state and transient scenarios. The paper introduces a linear state-space representation of the architecture reflecting the coupling between the turbofan and tailfan subsystems along with loop transfer functions reflecting open- and closed-loop system dynamics. Also discussed is an applied strategy for scheduling the tailfan setpoint command based on the average sensed fan speed of the two turbofans. This approach ensures synchronized operation of the turbofan and tailfan subsystems while also allowing the turbofan fuel control design to be simplified. Performance of the integrated control design is assessed through a real-time hardware-in-the-loop test conducted at the NASA Electric Aircraft Testbed. During this test a scaled version of the electrical system and turbomachinery shaft dynamics were implemented in electrical machine hardware and evaluated under closed-loop control. Results from this facility test are presented to illustrate the efficacy of the applied integrated control design approach under steady-state and transient scenarios including a full-flight mission profile.
A Numerical Test Rig for Turbomachinery Flows Based on Large Eddy Simulations With a High-Order Discontinuous Galerkin Scheme—Part I: Sliding Interfaces and Unsteady Row Interactions
Authors: Bergmann Michael , Morsbach Christian , Klose Bjoern F. , Ashcroft Graham , Kügeler Edmund
Published: October 2023

In this first paper of a three-part series, we present the extension and validation of the high-order discontinuous Galerkin scheme in DLR’s CFD-solver trace for scale-resolving simulations of unsteady row interactions. The translational movement of rows in linear cascade experiments is represented in the numerical model by solving the equations in the relative frame of reference. To couple rows in different frames of reference, a sliding interface approach based on the mortar technique for non-conforming meshes has been developed. The verification of the approach is exemplified by three canonical test cases. First, the experimental order of convergence is verified for the isentropic vortex convection. Subsequently, the suitability of the sliding interface approach for scale-resolving simulations is tested on the Taylor–Green vortex flow and a turbulent cylinder flow. Finally, the LES solver is applied to the T106D cascade with upstream moving bars at an exit Reynolds number of 200,000 and exit Mach number of 0.4. The flow physics with and without bars is discussed in terms of the instantaneous flow field, and time- and phase-averaged quantities. The comparison with experimental data shows overall a good agreement, especially for the total pressure losses in the wake, but also reveals uncertainties related to the reproduction of an experiment in the numerical model.
Confronting deep uncertainty in the forest carbon industry
Authors: Wells Geoff , Pascual Unai , Stephenson Chris , Ryan Casey M.
Published: October 2023

Resilience-based and service-focused approaches could reduce contentions and injustices
Going local with ancient DNA: A review of human histories from regional perspectives
Authors: Ávila-Arcos María C. , Raghavan Maanasa , Schlebusch Carina
Published: October 2023

Ancient DNA (aDNA) has added a wealth of information about our species’ history, including insights on genetic origins, migrations and gene flow, genetic admixture, and health and disease. Much early work has focused on continental-level questions, leaving many regional questions, especially those relevant to the Global South, comparatively underexplored. A few success stories of aDNA studies from smaller laboratories involve more local aspects of human histories and health in the Americas, Africa, Asia, and Oceania. In this Review, we cover some of these contributions by synthesizing finer-scale questions of importance to the archaeogenetics field, as well as to Indigenous and Descendant communities. We further highlight the potential of aDNA to uncover past histories in regions where colonialism has neglected the oral histories of oppressed peoples.
Modern government and science advice
Authors: Vallance Patrick
Published: October 2023

Governments need to understand science. This is obvious when thinking about defense and security, health, or the challenges of climate change and biodiversity loss, but it is true for all areas of government activity. Science has something to offer in developing policy for town planning, education, transportation, food, environmental management, the administration of justice, communication systems, the use of artificial intelligence to improve public services, and much more. Seven out of the 10 largest companies in the world are based on science and technology, and there is a correlation between spending on R&D and productivity at a national level. Yet in most democracies, scientists make up a tiny fraction of politicians, and recently there have been questions about the overextension of scientific authority (so-called “scientism”) or the inappropriate empowerment of scientists. What, then, is the role of a science adviser to modern government?
In Science Journals
Authors: Funk Michael A. , Wong Wei , Vignieri Sacha , Stajic Jelena , Ash Caroline , Malo Courtney S. , Isles Hannah M. , Hurtley Stella M. , Grocholski Brent , Stern Peter , Szuromi Phil
Published: October 2023

Highlights from the
Science
family of journals
In Other Journals
Authors: Nusinovich Yevgeniya , Hurtley Stella M. , Ross Sarah H. , Yeston Jake S. , Jiang Di , Smith Keith T. , Funk Michael A.
Published: October 2023

Editors’ selections from the current scientific literature
Plantar somatosensory restoration enhances gait, speed perception, and motor adaptation
Authors: Kim Daekyoo , Triolo Ronald , Charkhkar Hamid
Published: October 2023

Lower limb loss is a major insult to the body’s nervous and musculoskeletal systems. Despite technological advances in prosthesis design, artificial limbs are not yet integrated into the body’s physiological systems. Therefore, lower limb amputees (LLAs) experience lower balance confidence, higher fear of falls, and impaired gait compared with their able-bodied peers (ABs). Previous studies have demonstrated that restored sensations perceived as originating directly from the missing limb via neural interfaces improve balance and performance in certain ambulatory tasks; however, the effects of such evoked sensations on neural circuitries involved in the locomotor activity are not well understood. In this work, we investigated the effects of plantar sensation elicited by peripheral nerve stimulation delivered by multicontact nerve cuff electrodes on gait symmetry and stability, speed perception, and motor adaptation. We found that restored plantar sensation increased stance time and propulsive force on the prosthetic side, improved gait symmetry, and yielded an enhanced perception of prosthetic limb movement. Our results show that the locomotor adaptation among LLAs with plantar sensation became similar to that of ABs. These findings suggest that our peripheral nerve–based approach to elicit plantar sensation directly affects central nervous pathways involved in locomotion and motor adaptation during walking. Our neuroprosthesis provided a unique model to investigate the role of somatosensation in the lower limb during walking and its effects on perceptual recalibration after a locomotor adaptation task. Furthermore, we demonstrated how plantar sensation in LLAs could effectively increase mobility, improve walking dynamics, and possibly reduce fall risks.
Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma
Authors: Sarin Kavita Y. , Kincaid John , Sell Brittney , Shahryari Jahanbanoo , Duncton Matthew A. J. , Morefield Elaine , Sun Wenchao , Prieto Karol , Chavez-Chiang Omar , de Moran Segura Carlos , Nguyen Jonathan , Bronson Roderick T. , Plotkin Scott R. , Kochendoerfer Gerd G. , Fenn Peter , Wootton Michael A. , Powala Christopher , de Souza Mark P. , Tsai Kenneth Y.
Published: October 2023

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.
Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase
Authors: Bakooshli Mohsen A. , Wang Yu Xin , Monti Elena , Su Shiqi , Kraft Peggy , Nalbandian Minas , Alexandrova Ludmila , Wheeler Joshua R. , Vogel Hannes , Blau Helen M.
Published: October 2023

To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal muscle in mice, providing evidence that injury drives early expression of this aging-associated enzyme or gerozyme. Treating mice with a small-molecule inhibitor of 15-PGDH promoted regeneration of motor axons and formation of neuromuscular synapses leading to an acceleration in recovery of force after an acute nerve crush injury. In aged mice with chronic denervation of muscles, treatment with the 15-PGDH inhibitor increased motor neuron viability and restored neuromuscular junctions and function. These presynaptic changes synergized with previously reported muscle tissue remodeling to result in a marked increase in the strength of aged muscles. We further found that 15-PGDH aggregates defined the target fibers that are histopathologic hallmarks of human neurogenic myopathies, suggesting that the gerozyme may be involved in their etiology. Our data suggest that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease, or aging.
Enterovirus D68 capsid formation and stability requires acidic compartments
Authors: Galitska Ganna , Jassey Alagie , Wagner Michael A. , Pollack Noah , Miller Katelyn , Jackson William T.
Published: October 2023

Enterovirus D68 (EV-D68), a picornavirus traditionally associated with respiratory infections, has recently been linked to a polio-like paralytic condition known as acute flaccid myelitis. EV-D68 is understudied, and much of the field’s understanding of this virus is based on studies of poliovirus. For poliovirus, we previously showed that low pH promotes virus capsid maturation, but here we show that, for EV-D68, inhibition of compartment acidification during a specific window of infection causes a defect in capsid formation and maintenance. These phenotypes are accompanied by radical changes in the infected cell, with viral replication organelles clustering in a tight juxtanuclear grouping. Organelle acidification is critical during a narrow window from 3 to 4 hpi, which we have termed the “transition point,” separating translation and peak RNA replication from capsid formation, maturation, and egress. Our findings highlight that acidification is crucial only when vesicles convert from RNA factories to virion crucibles.

IMPORTANCE

The respiratory picornavirus enterovirus D68 is a causative agent of acute flaccid myelitis, a childhood paralysis disease identified in the last decade. Poliovirus, another picornavirus associated with paralytic disease, is a fecal-oral virus that survives acidic environments when passing from host to host. Here, we follow up on our previous work showing a requirement for acidic intracellular compartments for maturation cleavage of poliovirus particles. Enterovirus D68 requires acidic vesicles for an earlier step, assembly, and maintenance of viral particles themselves. These data have strong implications for the use of acidification blocking treatments to combat enterovirus diseases.
Cytochrome
c
-peroxidase modulates ROS homeostasis to regulate the sexual mating of
Sporisorium scitamineum
Authors: Cai Enping , Jia Huan , Feng Ruqing , Zheng Wenqiang , Li Lei , Zhang Li , Jiang Zide , Chang Changqing
Published: October 2023

Sugarcane smut, caused by the basidiomycetous fungus
Sporisorium scitamineum,
is a global fungal disease resulting in substantial economic losses. Our previous research has highlighted the significant role of reactive oxide species (ROS) in the sexual reproduction of
S. scitamineum
, yet the underlying mechanisms remain unclear. In this study, we identified the cytochrome
c
-peroxidase encoding gene, Ss
CCP1
, as crucial for oxidative stress resistance. We further found that absence of SsCcp1 leads to defects in mating/filamentation and disrupts intracellular ROS homeostasis. However, restoration of mating/filamentation of
SsCCP1
deletion mutants was partially achieved with exogenous antioxidants (vitamin C or vitamin E). Notably, transcription of the pheromone response factor
SsPRF1
, pivotal for mating/filamentation of
S. scitamineum
, is significantly reduced in the Ss
CCP1
deletion mutants or under exogenous hydrogen peroxide (H
2
O
2
) conditions. Nevertheless, the addition of exogenous vitamin C for 60 min significantly up-regulated the
SsPRF1
gene in the Ss
CCP1
deletion mutants. Moreover, the constitutive expression of
SsPRF1
essentially reinstated the mating/filamentation of Ss
CCP1
deletion mutants, suggesting that SsCcp1 mediates the transcriptional activity of
SsPRF1
by maintaining ROS homeostasis to regulate the mating/filamentation of
S. scitamineum
. Further investigations revealed that SsCcp1 is necessary for ROS detoxification and full pathogenicity
in planta
. Overall, this study not only unveils the importance of SsCcp1 in
S. scitamineum
mating/filamentation, ROS detoxification, and virulence but also provides insights into the role of SsCcp1-regulated ROS homeostasis in sexual reproduction of
S. scitamineum
.

IMPORTANCE

Reactive oxygen species play an important role in pathogen-plant interactions. In fungi, cytochrome
c
-peroxidase maintains intracellular ROS homeostasis by utilizing H
2
O
2
as an electron acceptor to oxidize ferrocytochrome
c
, thereby contributing to disease pathogenesis. In this study, our investigation reveals that the cytochrome
c
-peroxidase encoding gene,
SsCCP1
, not only plays a key role in resisting H
2
O
2
toxicity but is also essential for the mating/filamentation and pathogenicity of
S. scitamineum
. We further uncover that SsCcp1 mediates the expression of SsPrf1 by maintaining intracellular ROS homeostasis to regulate
S. scitamineum
mating/filamentation. Our findings provide novel insights into how cytochrome
c
-peroxidase regulates sexual reproduction in phytopathogenic fungi, presenting a theoretical foundation for designing new disease control strategies.
Increase CO
2
recycling of
Escherichia coli
containing CBB genes by enhancing solubility of multiple expressed proteins from an operon through temperature reduction
Authors: Yu Jaeyoung , Shin Woo-Ri , Kim Ji Hun , Lee Soo Youn , Cho Byung-Kwan , Kim Yang-Hoon , Min Jiho
Published: October 2023

One of the current promising solutions to address problems of CO
2
emissions is the development of biological carbon fixation strategies. This strategy leads to higher chemical biosynthetic productivity through improved biological CO
2
fixation. In a previous study, we introduced the Calvin-Benson Bassham (CBB) genes of the photosynthetic bacterium
Cereibacter sphaeroides
into
Escherichia coli
to develop a strain capable of endogenous CO
2
recycling by heterologous expression of the CBB genes. However, the heterologous expression of recombinant proteins in
E. coli
is often hampered by inclusion bodies (IB), which are protein aggregates. Various factors contribute to IB formation, including host cell metabolism, protein synthesis, transformation machinery, and target protein properties. In this study, we investigated the influence of environmental conditions, particularly culture temperature, on IB formation and CO
2
recycling in the CBB strain. As a result, by reducing the culture temperature from 37°C to 30°C, a significant suppression of IB formation was achieved, resulting in a remarkable decrease in CO
2
release by approximately 5.76 times. In addition, interestingly, an enhancement in the accumulation of pyruvate by approximately 2.3 times was observed at the same time. These results demonstrate the simultaneous improvements in CO
2
recycling and the synthesis of organic acids achieved through temperature control. Based on the findings of this study, we believe that temperature control would be a promising approach to increasing chemical biosynthetic productivity as well as biological CO
2
fixation activity in integrated autotrophic biorefinery strategies.

IMPORTANCE

In a previous study, we successfully engineered
Escherichia coli
capable of endogenous CO
2
recycling through the heterologous expression of the Calvin-Benson Bassham genes. Establishing an efficient gene expression environment for recombinant strains is crucial, on par with the importance of metabolic engineering design. Therefore, the primary objective of this study was to further mitigate greenhouse gas emissions by investigating the effects of culture temperature on the formation of inclusion bodies (IB) and CO
2
fixation activity in the engineered bacterial strain. The findings demonstrate that lowering the culture temperature effectively suppresses IB formation, enhances CO
2
recycling, and concurrently increases the accumulation of organic acids. This temperature control approach, without adding or modifying compounds, is both convenient and efficient for enhancing CO
2
recycling. As such, additional optimization of various environmental parameters holds promise for further enhancing the performance of recombinant strains efficiently.
Kilometer-scale recumbent folding, tectonic attenuation, and rotational shear in the western Anaconda Range, southwestern Montana, USA
Authors: Neal Bryce A. , Laskowski Andrew K. , Lonn Jeffrey D. , Burrell William B.
Published: October 2023

The Eocene Anaconda metamorphic core complex is the most recently documented metamorphic core complex in the North American Cordillera. While much work has focused on constraining the nature and timing of core complex extension, earlier deformation preserved in its footwall is not as well understood. The Anaconda metamorphic core complex footwall contains an anomalously thin, lower- to uppermost-amphibolite-facies section of Mesoproterozoic Belt Supergroup and Paleozoic metasedimentary strata. While the tectonic nature of this thinning is generally accepted, the mechanisms behind it remain enigmatic. Previous workers have hypothesized that footwall strata were attenuated along the upper limb of the Late Cretaceous Fishtrap recumbent anticline, a kilometer-scale, NW-vergent, recumbent fold exposed throughout the west-central metamorphic core complex footwall. New geologic mapping in the west-central Anaconda Range better constrains the nature and timing of tectonic attenuation in this structurally complex area. Two generations of folds were recognized: (1) F1 recumbent isoclines associated with the Fishtrap recumbent anticline and (2) F2 W-vergent asymmetric folds associated with map-scale N-plunging folds. F1 folds, axial planar S1 transposition fabrics, and bedding-parallel faults and shear zones boudinage, transpose, and omit strata of the Belt Supergroup. We suggest that the Fishtrap recumbent anticline tectonically attenuated the Belt Supergroup through Paleozoic section of the west-central Anaconda metamorphic core complex footwall, and we propose that it is a kilometer-scale, regionally significant structure. We further propose that the fold may have developed in response to rotational shear and sinistral transpression along the Lewis and Clark Line, which was further driven by accretion of outboard terranes along the western margin of North America during Late Cretaceous time.
Association between depression and pain, functional disability, disease activity and health-related quality of life in patients with systemic lupus erythematosus: a meta-analysis
Authors: Zhao Qian , Li Xin , Chen Haoyang , Wang Lili , Wu Ning , Ma Ji , Shen Biyu
Published: October 2023

Objective

The aim of this study was to explore the effect of depression on pain, disease activity, functional disability and health-related quality of life measured by Visual Analogue Scale, Systemic Lupus Erythematosus Disease Activity Index, Health Assessment Questionnaire and Short Form-36 in patients with systemic lupus erythematosus.

Design

Meta-analysis.

Data sources

The PubMed, EMBASE, Cochrane Library and Web of Science were searched for obtaining available studies from inception to 7 March 2023.

Eligibility criteria for selecting studies

Studies evaluating the impact of depression on pain, disease activity, functional disability and quality of life were included.

Data extraction and synthesis

Two authors independently screened publications and extracted data according to set inclusion and exclusion criteria. Statistical analyses were conducted with RevMan V.5.3.0. Data were pooled using a fixed-effects or random-effects model according to heterogeneity.

Results

A total of 13 identified studies met the inclusion criteria, reporting on a total of 1911 patients with systemic lupus erythematosus. The Visual Analogue Scale score was significantly higher in patients with depression than those without depression (standardised mean difference (SMD)=0.84 (95% CI 0.27 to 1.42), p=0.004). The Health Assessment Questionnaire score was significantly higher in patients with depression than those without depression (SMD=1.05 (95% CI 0.14 to 1.95), p<0.05). The Systemic Lupus Erythematosus Disease Activity Index score was significantly higher in patients with depression than those without depression (SMD=0.46 (95% CI 0.27 to 0.64), p<0.00001). Scores in most Short Form-36 dimensions (physical function, role physical function, emotional role function, vitality, mental health, social function, general health, physical component scale, mental component scale) were lower in patients with depression than those without depression.

Conclusion

This meta-analysis showed that depression was associated with increased in pain, functional disability and disease activity, and decline in health-related quality of life in patients with systemic lupus erythematosus. Awareness of the importance of the relationship between depression in systemic lupus erythematosus patients and pain, functional disability and the quality of life might assist rheumatology physicians and nurses in assessing and preventing these symptoms.

PROSPERO registration number

CRD42021265694.