bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative cone contrast threshold testing in patients with differing pathophysiological mechanisms causing retinal diseases
Authors: White Kayla M. , Frambach Caroline , Doan John , Mehta Urmi V. , Livnat Itamar , Yuh Clara , Palma Anton M. , Jameson Kimberly A. , Kenney M. Cristina , Mehta Mitul C. , Boisvert Chantal J. , Crow Wade R. , Browne Andrew W.
Published: November 2020

Purpose

Cone contrast threshold testing (CCT) provides quantitative measurements of color and contrast function to reveal changes in vision quality that is not a standard endpoint in clinical trials. We utilize CCT to measure visual function in patients with multiple sclerosis (MS), age-related macular degeneration (AMD), epiretinal membrane (ERM), and retinal vein occlusion (RVO).

Methods

Retrospective data was gathered from 268 patients of the Gavin Herbert Eye Institute. Subjects included 17 patients with MS, 45 patients with AMD, 41 patients with ERM, 11 patients with RVO, and 123 age and visual acuity-matched healthy controls. Patients underwent the primary measurement outcome, CCT testing, as well as Sloan visual acuity test and spectral domain optical coherence tomography during normal care.

Results

Color and contrast deficits were present in MS patients regardless of history of optic neuritis. AMD with intermediate or worse disease demonstrated reduced CCT scores. All 3 stages of ERM demonstrated cone contrast deficits. Despite restoration of visual acuity, RVO-affected eyes demonstrated poorer CCT performance than unaffected fellow eyes.

Conclusions

CCT demonstrates color and contrast deficits for multiple retinal diseases with differing pathophysiology. Further prospective studies of CCT in other disease states and with larger samples sizes is warranted.

Brief Summary Statement

In a retrospective analysis of 268 adults, cone contrast threshold testing (CCT) demonstrates patterns of visual function deficits in multiple sclerosis and age-related macular degeneration and similar declines in epiretinal membranes and retinal vein occlusion beyond standard visual acuity. Across all disease states, color and contrast vision were negatively impacted.
Joint-Label Fusion Brain Atlases for Dementia Research in Down Syndrome
Authors: Queder Nazek , Phelan Michael J. , Taylor Lisa , Tustison Nicholas , Doran Eric , Hom Christy , Nguyen Dana , Lai Florence , Pulsifer Margaret , Price Julie , Kreisl William C. , Rosas Diana H. , Krinsky-McHale Sharon , Brickman Adam , Yassa Michael A. , Schupf Nicole , Silverman Wayne , Lott Ira T. , Keator David B.
Published: November 2020

Research suggests a link between Alzheimer’s Disease in Down Syndrome (DS) and the overexpression of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant’s structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable, mild cognitive impairment (MCI-DS), and dementia) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to our ground truth individual MRI-based segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the ground truth by using DS group atlases that aligns with a participant’s disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the ground truth than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using a disease-state specific atlas. All atlases are made publicly available for the research community.

Abbreviations

AD, DS, Aβ, DSG, CS-DS, CS-NT, LOOCV, ROI, MSE, MRI, PET, JLF, CS, MCI-DS, DEM.
PERCEIVED STIGMATIZATION, SOCIODEMOGRAPHIC FACTORS, AND MENTAL HEALTH HELP-SEEKING BEHAVIORS AMONG PSYCHIATRIC OUTPATIENTS ATTENDING A PSYCHIATRIC HOSPITAL IN LAGOS, NIGERIA
Authors: Ogueji Ifeanyichukwu Anthony , Ojo Taiye Emmanuel , Gidado Taiwo Nurudeen
Published: November 2020

Among the general population of patients with mental illness is a sub-population (psychiatric outpatients) who often encounter limited mental health help-seeking behaviors due to many unknown factors. Therefore, this study aimed to explore some predictors of mental health help-seeking behaviors among psychiatric outpatients. This cross-sectional study accidentally recruited 42 psychiatric outpatients receiving treatment at the Federal Neuropsychiatric Hospital, Yaba, Lagos State, Nigeria. Their mean age was 27.03±7.05 years (age range = 18-48 years). Data were collected using standardized questionnaires, and analyzed using SPSS (v. 22). Statistical significance set at p<.05. The first finding showed a positive but not significant relationship between perceived stigmatization and mental health help-seeking behavior. Second showed that gender had no significant influence on mental health help-seeking behavior. Third showed that age had a positive but not significant relationship with mental health help-seeking behavior. Last finding submitted that clinical diagnosis, religious affiliation, marital status, and educational qualification had a significant joint prediction on mental health help-seeking behaviour, with 28% variance explained. Only religious affiliation had a significant independent prediction. Our findings have practical implications for enhancing mental health help-seeking behavior and strengthening an interdisciplinary approach to mental health care.
An Examination of Sustained Versus Transient Distressing Psychotic-Like Experiences Using Adolescent Brain Cognitive Development℠ Study Data
Authors: Karcher Nicole R. , Loewy Rachel L. , Savill Mark , Avenevoli Shelli , Huber Rebekah S. , Makowski Carolina , Sher Kenneth J. , Barch Deanna M.
Published: November 2020

Objective

A potential distinguishing factor between more benign and transient psychotic-like experiences (PLEs) versus PLEs that predict risk for psychiatric disorders is whether the PLEs are sustained and distressing (sustained dPLEs). The current study examined associations of both sustained and transient dPLEs with relevant risk factors (e.g., cognition), use of mental health services, and functional correlates (e.g., school performance) in school-age children.

Method

The current study used three Adolescent Brain Cognitive Development℠ study data waves to create sustained dPLE (n=272), transient dPLE (n=244), and control (n=272) groups. Hierarchical linear models examined whether these groups differed in terms of use of mental health services, functional correlates, family history of mental disorders, other symptoms (e.g., parent-rated psychotic symptoms, internalizing, externalizing symptoms), environmental factors (e.g., adverse childhood events [ACEs]), cognitive functioning, developmental milestone delays, and neuroimaging indices.

Results

Several factors were more strongly associated with sustained versus transient dPLEs, including use of mental health services (for sustained vs. controls: d=0.38), drop in grades (d=--.30), other symptoms (i.e., parent-rated psychotic, bipolar, internalizing, externalizing, suicidality; 0.33>ds<0.88), ACEs (d=.36), and lower fluid and executive functioning cognitive scores (-0.31>ds<-0.41). For most risk factors, the sustained dPLEs group showed the greatest impairments, followed by the transient group, with the control group showing the least impairments.

Conclusions

These results have implications for understanding the pathogenesis of dPLEs, including indicating that several factors may distinguish transient from persisting dPLEs in children, including higher symptoms and ACEs, lower executive functioning scores, greater use of mental health services, and worsening school performance.
Brain growth and neurodevelopment after surgical treatment of infant post-infectious hydrocephalus in sub-Saharan Africa
Authors: Schiff Steven J. , Kulkarni Abhaya V. , Kabachelor Edith Mbabazi , Mugamba John , Ssenyonga Peter , Donnelly Ruth , Levenbach Jody , Monga Vishal , Peterson Mallory , Cherukuri Venkateswararao , Warf Benjamin C.
Published: November 2020

Importance

Post-infectious hydrocephalus in infants is a major public health burden in sub-Saharan Africa.

Objective

To determine long-term brain growth and cognitive outcome after surgical treatment of infant post-infectious hydrocephalus in Uganda.

Design

Prospective follow-up of a previously randomized cohort.

Setting

Single center in Mbale, Uganda.

Participants

Infants (<180 days old) with post-infectious hydrocephalus.

Interventions

Endoscopic or shunt surgery.

Main outcomes

Bayley Scales of Infant Development (BSID-3) and brain volume on computed tomography (raw and normalized for age and sex) at 2 years after treatment.

Results

Eighty-nine infants were assessed for 2-year outcome. There were no significant differences between the two surgical treatment arms, so they were analyzed together. Raw brain volumes increased between baseline and 24 months (median change=361 cc, IQR=293 to 443, p<0.001), but almost all of this increase was seen in the first year (median change=381 cc, IQR=310 to 442, p<0.001), with very little change between 12 and 24 months (median change=-5 cc, IQR=-52 to 42, p=0.66). The fraction of those with a normal brain volume increased from 15% at baseline to 50% at 1 year, but then declined to 18% at 2 years. Substantial normalized brain volume loss was seen in 21% between baseline and year 2 and in 77% between years 1 and 2. The extent of brain growth in the first year was not associated with extent of brain volume changes in the second year. There were significant positive correlations between 2-year brain volume and all BSID-3 scores and BSID-3 changes from baseline.

Conclusions and Relevance

In sub-Saharan Africa, even after successful surgical treatment of infant post-infectious hydrocephalus, post-treatment brain growth stagnates in the second year. While the reasons for this are unclear, this emphasizes the importance of primary infection prevention strategies along with optimizing the child’s environment to maximize brain growth potential.

Trial Registration

ClinicalTrials.gov number, NCT01936272

KEY POINTS

Question

What is the brain growth and cognitive trajectory of infants treated for post-infectious hydrocephalus in Uganda?

Findings

In this prospective follow-up of a cohort of 89 infants, early normalization of brain volume after treatment was followed by brain growth stagnation in the second year, with many falling back into the sub-normal range. Poor brain growth was associated with poor cognitive outcome.

Meaning

Successful surgical treatment of hydrocephalus is not sufficient to allow for adequate brain growth and cognitive development. Interventions aimed at primary infection prevention and reducing comorbidities are needed to improve brain growth potential.
Plasma lipidomic profiles and risk of diabetes: two prospective cohorts of HIV-infected and HIV-uninfected individuals
Authors: Zhang Eric , Chai Jin Choul , Deik Amy A. , Hua Simin , Sharma Anjali , Schneider Michael F. , Gustafson Deborah , Hanna David B. , Lake Jordan E. , Rubin Leah H. , Post Wendy S. , Anastos Kathryn , Brown Todd , Clish Clary B. , Kaplan Robert C. , Qi Qibin
Published: November 2020

Objectives

Antiretroviral therapy (ART) use is associated with disrupted lipid and glucose metabolism in people with HIV-infection. We aimed to identify plasma lipid species associated with risk of diabetes in the context of HIV infection.

Research Design and Methods

We profiled 211 plasma lipid species in 491 HIV-infected and 203 HIV-uninfected participants aged 35-55 years from the Women’s Interagency HIV study and the Multicenter AIDS Cohort Study. Cox proportional hazards model was used to examine associations between baseline lipid species and incident diabetes (166 diabetes cases were identified during a median follow-up of 12.6 years).

Results

We identified 11 lipid species, representing independent signals for 8 lipid classes/subclasses, associated with risk of diabetes (P<0.05 after FDR correction). After adjustment for multiple covariates, cholesteryl ester (CE)(22:4), lysophosphatidylcholine (LPC)(18:2), phosphatidylcholine (PC)(36:4), phosphatidylcholine-plasmalogen(34:3), and phosphatidylethanolamine (PE)(38:2) were associated with decreased risk of diabetes (HRs=0.70 to 0.82 per SD increment), while diacylglycerol(32:0), LPC(14:0), PC(38:3), PE(36:1), and triacylglycerol(50:1) were associated with increased risk of diabetes (HRs=1.26 to 1.56 per SD increment). HIV serostatus did not modify any lipid-diabetes associations; however, most of these lipid species were positively associated with HIV and/or ART use, including 3 diabetes-decreased (CE(22:4), LPC(18:2), PE(38:2)) and all 5 diabetes-increased lipid species.

Conclusions

This study identified multiple plasma lipid species associated with incident diabetes. Regardless of the directions of their associations with diabetes, most diabetes-associated lipid species were elevated in ART-treated people with HIV-infection. This suggests a complex role of lipids in the link between ART and diabetes in HIV infection.
Mental Health of Keyworkers in the UK during the COVID-19 Pandemic: a Cross-sectional Analysis of a Community Cohort
Authors: Ayling Kieran , Jia Ru , Chalder Trudie , Massey Adam , Broadbent Elizabeth , Coupland Carol , Vedhara Kavita
Published: November 2020

Objectives

Previous pandemics have resulted in high levels of psychological morbidity among frontline workers. Here we report on the early mental health impact of the COVID-19 pandemic on keyworkers in the UK, as assessed during the first six weeks of nationwide social distancing measures being introduced. Comparisons are made with non-keyworkers, and psychological factors that may be protective to keyworkers’ mental health are explored.

Design

Cross-sectional analysis of a community cohort study.

Methods

During April 2020, keyworkers (n=1559) and non-keyworkers (n=1436) completed online measures of depression, anxiety, and stress levels as well as explanatory demographic and psychological factors hypothesised to be related to these mental health outcomes.

Results

Keyworkers reported significantly higher depression, anxiety, and stress than pre-pandemic population norms. Compared to non-keyworkers, keyworkers were more likely to worry about COVID-19 and perceived they were at higher risk from the virus. This was particularly evident for health and social care keyworkers. Younger keyworkers and those in a clinically increased risk group were more likely to report poorer mental health. Lower positive mood, greater loneliness and worrying more about COVID-19 were all associated with poorer mental health outcomes amongst keyworkers.

Conclusions

The mental health impact of the COVID-19 pandemic on keyworkers in the UK has been substantial. Worry about COVID-19 and perceived risk from COVID-19 in keyworkers are understandable given potential increased exposure to the virus. Younger and clinically vulnerable keyworkers may benefit most from any interventions that seek to mitigate the negative mental health impacts of the pandemic.
Impacts of the COVID-19 Pandemic on Cardiac Rehabilitation Delivery around the World
Authors: Ghisi Gabriela Lima de Melo , Xu Zhiming , Liu Xia , Mola Ana , Gallagher Robyn , Babu Abraham Samuel , Yeung Colin , Marzolini Susan , Buckley John , Oh Paul , Contractor Aashish , Grace Sherry L
Published: November 2020

Background

To investigate impacts of COVID-19 on CR delivery around the globe, including effects on providers and patients.

Methods

In this cross-sectional study, a piloted survey was administered to CR programs globally via REDCap from April-June/2020. The 50 members of the ICCPR and personal contacts facilitated program identification.

Results

Overall, 1062(18.3% program response rate) responses were received from 70/111(63.1% country response rate) countries in the world with existent CR programs. Of these, 367(49.1%) programs reported they had stopped CR delivery, and 203(27.1%) stopped temporarily (mean=8.3±2.8weeks). Alternative models were delivered in 322(39.7%) programs, primarily through low-tech modes (n=226,19.3%). 353(30.2%) respondents were re-deployed, and 276 (37.3%) felt the need to work due to fear of losing their job, despite the perceived risk of contracting COVID-19 (mean=30.0%±27.4/100). 266(22.5%) reported anxiety, 241(20.4%) were concerned about exposing their family, 113(9.7%) reported increased workload to transition to remote delivery, and 105(9.0%) were juggling caregiving responsibilities during business hours. Patients were often contacting staff regarding grocery shopping for heart-healthy foods (n=333,28.4%), how to use technology to interact with the program (n=329,27.9%), having to stop their exercise because they have no place to exercise (n=303,25.7%), and their risk of death from COVID-19 due to pre-existing cardiovascular disease (n=249,21.2%). Respondents perceived staff (n=488,41.3%) and patient (n=453,38.6%) personal protective equipment, as well as COVID-19 screening (n=414,35.2%) and testing (n=411,35.0%) as paramount to in-person service resumption.

Conclusion

Approximately 4400 programs ceased service delivery. Those that remain open are implementing new technologies to ensure their patients receive CR safely, despite the challenges.

Highlights

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COVID-19 has impacted cardiac rehabilitation (CR) delivery around the globe.

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In this cross-sectional study, a survey was completed by 1062 (18.3%) CR programs from 70 (63.1%) countries.

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The pandemic has resulted in cessation of ∼75% of CR programs, with others ceasing initiation of new patients, reducing components delivered, and/or changing of mode delivery with little opportunity for planning and training.

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There is also significant psychosocial and economic impact on CR providers.

-

Alternative CR model (e.g. home-based, virtual) reimbursement advocacy is needed, to ensure safe, accessible secondary prevention delivery.
Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST
Authors: Chattopadhyay Subhayan , Karlsson Jenny , Valind Anders , Andersson Natalie , Gisselsson David
Published: November 2020

Clonal deconvolution of mutational landscapes is crucial to understand the evolutionary dynamics of cancer. Two limiting factors for clonal deconvolution that have remained unresolved are variation in tumor cell fraction (TCF) and chromosomal copy number across different samples of the same tumor. We developed a semi-supervised algorithm that tracks variant calls through multi-sample spatiotemporal tumor data. While normalizing allele frequencies based on TCF it also adjusts for copy number changes at clonal deconvolution. Absent à priori copy number data, it rendersin silicocopy number estimations from bulk sequences. Using published and simulated tumor sequences, we reliably segregated clonal/subclonal variants even at low sequencing depth (∼50x). Given at least one pure tumor sample (>70% TCF), we could normalize and deconvolve paired samples down to a TCF of 40%. This renders a reliable clonal reconstruction well adapted to multi-regionally sampled solid tumor, which are often aneuploid and contaminated by non-cancer cells.
A Recombinant Protein Biomarker DDA Library Increases DIA Coverage of Low Abundance Plasma Proteins
Authors: Ahn Seong Beom , Kamath Karthik S. , Mohamedali Abidali , Noor Zainab , Wu Jemma X. , Pascovici Dana , Adhikari Subash , Cheruku Harish R. , Guillemin Gilles J. , McKay Matthew J. , Nice Edouard C. , Baker Mark S.
Published: November 2020

Credible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). Here, we employed a mixture of recombinant proteins in DDA libraries to subsequently detect cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 human recombinant proteins that had been previously implicated as possible cancer biomarkers in both our own and other studies. The rPSL was then used to identify proteins from non-depleted colorectal cancer (CRC) plasmas by SWATH-MS. Most (32/36) of the proteins in the rPSL were reliably identified in plasma samples, including 8 proteins (BTC, CXCL10, IL1B, IL6, ITGB6, TGFα, TNF, TP53) not previously detected using high-stringency MS in human plasmas according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and post-digestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 were identified using DDA-MS. The 20 additional proteinsexclusivelyidentified by using the rPSL approach with SWATH were mostly lower abundance (i.e., <10ng/ml) plasma proteins. To mitigate FDR concerns, and replicating a more typical approach, the DDA rPSL was also merged into a human plasma DDA library. When SWATH identification was repeated using this merged library, the majority (33/36) of low abundance plasma proteins from the rPSL could still be identified using high-stringency HPP Guidelines v3.0 protein inference criteria.
Goblet Cell Hyperplasia Increases SARS-CoV-2 Infection in COPD
Authors: Osan Jaspreet K. , Talukdar Sattya N. , Feldmann Friederike , Ann DeMontigny Beth , Jerome Kailey , Bailey Kristina L. , Feldmann Heinz , Mehedi Masfique
Published: November 2020

SARS-CoV-2 has become a major problem across the globe, with approximately 50 million cases and more than 1 million deaths and currently no approved treatment or vaccine. Chronic obstructive pulmonary disease (COPD) is one of the underlying conditions in adults of any age that place them at risk for developing severe illness associated with COVID-19. We established an airway epithelium model to study SARS-CoV-2 infection in healthy and COPD lung cells. We found that both the entry receptor ACE2 and the co-factor transmembrane protease TMPRSS2 are expressed at higher levels on nonciliated goblet cell, a novel target for SARS-CoV-2 infection. We observed that SARS-CoV-2 infected goblet cells and induced syncytium formation and cell sloughing. We also found that SARS-CoV-2 replication was increased in the COPD airway epithelium likely due to COPD associated goblet cell hyperplasia. Our results reveal goblet cells play a critical role in SARS-CoV-2 infection in the lung.
Type 1 dopamine receptor (D1R)-independent circadian food anticipatory activity in mice
Authors: Assali Dina R. , Sidikpramana Michael , Villa Andrew P. , Falkenstein Jeffrey , Steele Andrew D.
Published: November 2020

Circadian rhythms are entrained by light and influenced by non-photic stimuli, such as feeding. The activity preceding scheduled mealtimes, food anticipatory activity (FAA), is elicited in rodents fed a limited amount at scheduled times. FAA is thought to be the output of an unidentified food entrained oscillator. Previous studies, using gene deletion and receptor pharmacology, implicated dopamine type receptor 1 (D1R) signaling in the dorsal striatum as necessary for FAA in mice. To further understand the role of D1R in promoting FAA, we utilized the Cre-lox system to create cell type-specific deletions of D1R. We were unsuccessful in obtaining conditional deletion of D1R when using transgenically drivenD1R-Cre. We then created a conditional deletion of D1R in GABA neurons usingVgat-ires-Creline, which had attenuated FAA, but the amount was higher than expected based on prior results using a constitutive knockout of D1R,D1R KODrago. This result prompted us to re-test the originalD1R KODragoline, which expressed less FAA than controls, but only moderately so. To determine if genetic drift had diminished the effect of D1R deletion on FAA, we re-established theD1R KODragoknockout line from cryopreserved samples. The reestablishedD1R KODrago-cryohad a clear impairment of FAA compared to controls, but still developed increased activity preceding mealtime across the 4 weeks of timed feeding. Finally, we tested a different deletion allele ofD1Rcreated by the Knockout Mouse Project. This line ofD1R KOKOMPmice had a significant impairment in the acquisition of FAA, but eventually reached similar levels of premeal activity compared to controls after 4 weeks of timed feeding. Taken together, our results suggest that D1R signaling promotes FAA, but other dopamine receptors likely contribute to FAA given that mice lacking the D1 receptor still retain some FAA.
Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells
Authors: Makena Monish Ram , Ko Myungjun , Dang Donna Kimberly , Rao Rajini
Published: November 2020

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+signaling, represses mesenchymal gene expression, mitigates tumor migrationin vitroand metastasisin vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+levels to activate downstream components of non-canonical Wnt/Ca2+signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+signaling pathways to reverse EMT in breast tumors.

Simple Summary

The triple receptor negative breast cancer subtype, or TNBC, currently has no tailored treatment options. TNBC is highly metastatic, associated with high patient mortality, and disproportionately occurs in Black/African American women where it contributes to racial disparities in health outcomes. Therefore, we focused on new therapeutic approaches to TNBC. We discovered that levels of the Calcium-ATPase SPCA2 are abnormally low in TNBC and that these low levels correlate with poor survival prognosis in patients. Previously, we showed that recombinant SPCA2 prevented TNBC cells from acquiring aggressive ‘mesenchymal’ properties associated with metastasis bothin vitroandin vivo. These findings motivated us to search for drugs that turn the SPCA2 gene back on in TNBC cells. In this study, we show that histone deacetylase inhibitors increase SPCA2 levels, activate Ca2+signaling and convert cancer cells to a less aggressive ‘epithelial’ state. These findings could lead to new treatment options for TNBC.

Graphical Abstract
Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
Authors: Churchill Grant C. , Strupp Michael , Bremova-Ertl Tatiana , Factor Mallory , Patterson Marc C , Platt Frances M. , Galione Antony
Published: November 2020

N-acetyl-DL-leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-leucine versus L-leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-leucine and N-acetyl-L-leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-leucine with L-leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-leucine is drug-like compared to L-leucine. Our calculations show that at physiological pH, L-leucine is a zwitterion, whereas N-acetyl-L-leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not.
Myelinating Schwann cells and Netrin-1 control intra-nervous vascularization of the developing mouse sciatic nerve
Authors: Taïb Sonia , Lamandé Noël , Martin Sabrina , Topilko Piotr , Brunet Isabelle
Published: November 2020

Peripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during postnatal period.
The receptor-like cytoplasmic kinase MAZZA and CLAVATA-family receptors interactin vivo, together mediating developmental processes inArabidopsis thaliana
Authors: Blümke Patrick , Schlegel Jenia , Becher Sabine , Pinto Karine , Simon Rüdiger
Published: November 2020

The receptor-like kinases (RLKs) CLAVATA1 (CLV1) and BARELY ANY MERISTEMs (BAM1 – 3) form the CLV-family (CLVf), which perceives peptides of the CLV3/EMBRYO SURROUNDING REGION (ESR)-related (CLE) family within various signaling pathways ofArabidopsis thaliana. CLE peptide signaling, which is required for meristem size control, vascular development, or pathogen responses, involves the formation of receptor complexes at the plasma membrane (PM). These complexes comprise RLKs and co-receptors in varying compositions depending on the signaling context and regulate target gene expression, such asWUSCHEL(WUS). How the CLE signal is transmitted intracellularly after perception at the PM is not known.

Here, we found that the membrane-associated receptor-like cytoplasmic kinase (RLCK) MAZZA (MAZ) MAZ and additional members of the Pti1-like protein family interactin vivowith CLVf receptors. MAZ, which is widely expressed throughout the plant, localizes to the PM via posttranslational palmitoylation potentially enabling stimulus-triggered protein re-localization. We identified a role for a CLV1/MAZ signaling module during stomatal and root development, and redundancy could potentially mask other phenotypes ofmaz-1mutants. We propose that RLCKs such as MAZ mediate CLVf signaling in a variety of developmental contexts, paving the way towards understanding the intracellular processes after CLE peptide perception.
Epithelial Infection withCandida albicansElicits a Multi-system Response in Planarians
Authors: Maciel Eli Isael , Arevalo Ashley Valle , Ziman Benjamin , Nobile Clarissa J. , Oviedo Néstor J.
Published: November 2020

Candida albicansis one of the most common fungal pathogens of humans. Prior work introduced the planarianSchmidtea mediterraneaas a new model system to study the host response to fungal infection at the organismal level. In the current study, we analyzed host-pathogen changes that occurredin situduring early infection withC. albicans. We found that the transcription factor Bcr1 and its downstream adhesin Als3 are required forC. albicansto adhere to and colonize the planarian epithelial surface, and that adherence ofC. albicanstriggers a multi-system host response that is mediated by the Dectin signaling pathway. This infection response is characterized by two peaks of stem cell divisions and transcriptional changes in differentiated tissues including the nervous and the excretory systems. This response bears some resemblance to a wound-like response to physical injury; however, it takes place without visible tissue damage and it engages a distinct set of progenitor cells. Overall, we identified twoC. albicansproteins that mediate epithelial infection of planarians and a comprehensive host response facilitated by diverse tissues to effectively clear the infection.
Bioinformatic and computational analysis reveals the prevalence and nature of PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases
Authors: Hatstat A. Katherine , Pupi Michael D. , McCafferty Dewey G.
Published: November 2020

The Nedd4 family contains several structurally related but functionally distinct HECT-type ubiquitin ligases. The members of the Nedd4 family are known to recognize substrates through their multiple WW domains, which recognize PY motifs (PPxY, LPxY) or phospho-threonine or phospho-serine residues. To better understand substrate specificity across the Nedd4 family, we report the development and implementation of a python-based tool, PxYFinder, to identify PY motifs in the primary sequences of previously identified interactors of Nedd4 and related ligases. Using PxYFinder, we find that, on average, half of Nedd4 family interactions are PY-motif mediated. Further, we find that PPxY motifs are more prevalent than LPxY motifs and are more likely to occur in proline-rich regions. Further, PPxY regions are more disordered on average relative to LPxY-containing regions. Informed by consensus sequences for PY motifs across the Nedd4 interactome, we rationally designed a peptide library and employed a computational screen, revealing sequence- and biomolecular interaction-dependent determinants of WW-domain/PY-motif interactions. Cumulatively, our efforts provide a new bioinformatic tool and expand our understanding of sequence and structural factors that contribute to PY-motif mediated substrate recognition across the Nedd4 family.
SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A
Authors: Scarborough Anna M. , Flaherty Juliana N. , Hunter Olga V. , Liu Kuanqing , Kumar Ashwani , Xing Chao , Tu Benjamin P. , Conrad Nicholas K.
Published: November 2020

S-adenosylmethionine (SAM) is the methyl donor for nearly all cellular methylation events. Cells regulate intracellular SAM levels through intron detention of the MAT2A RNA, which encodes only SAM synthetase expressed in most cells. The N6-adenosine methyltransferase METTL16 promotes splicing of the MAT2A detained intron by an unknown mechanism. Using an unbiased CRISPR knock-out screen, we identified CFIm25 (NUDT21) to be a regulator of MAT2A intron detention and intracellular SAM levels. CFIm25 is a component of the cleavage factor Im(CFIm) complex that regulates poly(A) site selection, but we show it promotes MAT2A splicing, independent of poly(A) site selection. CFIm25-mediated MAT2A splicing induction requires the RS domains of its binding partners, CFIm68 and CFIm59 as well as binding sites in detained intron and 3′ UTR. These studies uncover mechanisms that regulate MAT2A intron detention and reveal previously undescribed roles for CFImin splicing and SAM metabolism.
The small GTPase Arf6 functions as a membrane tether in a chemically-defined reconstitution system
Authors: Fujibayashi Kana , Mima Joji
Published: November 2020

Arf-family small GTPases are essential protein components for membrane trafficking in all eukaryotic endomembrane systems, particularly during the formation of membrane-bound, coat protein complex-coated transport carriers. In addition to their roles in the transport carrier formation, a number of Arf-family GTPases have been reported to physically associate with coiled-coil tethering proteins and multisubunit tethering complexes, which are responsible for membrane tethering, a process of the initial contact between transport carriers and their target subcellular compartments. Nevertheless, whether and how indeed Arf GTPases are involved in the tethering process remain unclear. Here, using a chemically-defined reconstitution approach with purified proteins of two representative Arf isoforms in humans (Arf1, Arf6) and synthetic liposomes for model membranes, we discovered that Arf6 can function as a bona fide membrane tether, directly and physically linking two distinct lipid bilayers even in the absence of any other tethering factors, whereas Arf1 retained little potency to trigger membrane tethering under the current experimental conditions. Arf6-mediated membrane tethering reactions requiretrans-assembly of membrane-anchored Arf6 proteins and can be reversibly controlled by the membrane attachment and detachment cycle of Arf6. The intrinsic membrane tethering activity of Arf6 was further found to be significantly inhibited by the presence of membrane-anchored Arf1, suggesting that the tethering-competent Arf6-Arf6 assembly intranscan be prevented by the heterotypic Arf1-Arf6 association in acisconfiguration. Taken together, these findings lead us to postulate that self-assemblies of Arf-family small GTPases on lipid bilayers contribute to driving and regulating the tethering events of intracellular membrane trafficking.
The road ahead: should Hong Kong develop five pillars of old age protection?
Authors: Lam Gigi
Published: November 2020

Purpose

This paper demonstrates that Hong Kong currently provides four pillars of old-age protection: a publicly managed and noncontributory social security system (zero pillar), a funded contribution scheme (the second pillar), voluntary personal savings (the third pillar) and informal support, formal social programs and other individual financial assets (the fourth pillar). This paper aims at evaluating current four pillars of old-age protection and unraveling the deep-seated causes underlying the current old-age protection model by tracing a short history from 1965 onward. This paper aims at making recommendations about the current old-age protection model.

Design/methodology/approach

The paper analyzes the current four pillars of old age protection. A comprehensive literature review was conducted covering relevant government reports, academics' journal papers and nongovernmental organizations' reports concerning the development of old age protection system from 1965 to the present.

Findings

The poverty rate of elderly residents was approximately 44.5% between 2009 and 2018, indicating that the four pillars of old-age protection had been unable to alleviate poverty in the aging population. The development of the current four pillars is attributed to a residual welfare system, the effectiveness of which is further dependent on familial dependence or welfare financialization. However, the reliability of familial dependence is affected by the declining coresidence rate and low fertility rate, whereas welfare financialization not only predominately favors financial institutions but also exacerbates income polarization. Therefore, the University of Hong Kong (2014) introduced an additional pillar of noncontributory social pension and assistance, which generated a contentious debate. The Hong Kong Special Administrative Region (HKSAR) government initiated a public engagement exercise on retirement protection in 2015 to assess public opinion on old-age protection. These consultation exercises were met with broad public disappointment because of the explicit reservations imposed by the government on the proposals.

Practical implications

Although the government's resistant attitude can be attributed to the residual welfare system, pension reform needs to be urgently implemented at three levels, namely strengthening of each pillar, emphasis on the pillar's interrelatedness and introduction of the first pillar.

Originality/value

The poverty of the elderly population is serious in Hong Kong. It is important to solve the deep-seated problems faced by the current old-age protection model. Hence, it comes a critical time to design a sustainable old-age protection model despite the heated discussion on the establishment of a central provident fund and pension system among officials since 1960s.
Family business in tourism: an international systematic review of literature with an emphasis on Latin America
Authors: López-Chávez Beatriz Adriana , Maldonado-Alcudia César , Larrañaga Núñez Ana María
Published: November 2020

Purpose

The purpose of this study is to analyze the current state of knowledge of family businesses in tourism through a systematic review of international academic literature with an emphasis on Latin America.

Design/methodology/approach

The paper opted for a systematic review involving analyzing international academic documents, articles, dissertations and papers that presented both theoretical and empirical research results. The search was conducted from January to April 2019 on online databases and search engines.

Findings

Studies are concentrated in strategic planning and competitiveness. Most of them are published since 2014 by Ibero-American countries. Some features are coincident among the varied geographical contexts, as the importance of generational succession planning; search for family welfare throughout the business; and the existence of own capacities and resources. Besides, the owner's objectives and gender involvement differ in the research results of developed countries and emerging economies; some implications for Latin America are analyzed.

Originality/value

The family business has international economic relevance, especially in tourism. Still, the studies in this field are few, even when tourism implies processes and interactions that can influence the development of the companies that integrate their industry. In this way, a compilation of the recent works is carried out, in order to identify how the complex family dynamics with tourism are integrated into the studies, main contributions to the field and knowledge gaps.
Humanistic leadership in a Chinese context
Authors: Yang Bo , Fu Pingping , Beveridge ‘Alim J. , Qu Qing
Published: November 2020

Purpose

Through three case studies, the authors aim to examine how Confucian humanistic philosophy can be applied to leadership practices and show how it is possible to practice humanistic leadership in the Chinese context.

Design/methodology/approach

The authors use case studies of three exemplary humanistic leaders and the companies they lead to describe their leadership practices and influence on others and their companies.

Findings

The authors identify three common elements that connect their observations to an emerging scholarly conceptualization of humanistic leadership and develop a framework of Confucian humanistic leadership consisting of five attributes. The cases the authors studied suggest that the five attributes should be understood as being mutually reinforcing and acting in concert, rather than each acting independently of the others. The authors found that there is inherent consistency and connection between the core values of Confucianism and humanistic leadership.

Originality/value

The research contributes to the leadership literature, specifically the emerging literature on humanistic leadership, by introducing a framework for Confucian humanistic leadership. While much of the extant literature on humanistic leadership has been conceptual, the study shows how it is possible to practice humanistic leadership in the Chinese context by drawing on the foundation provided by Confucian humanistic philosophy. The findings also contribute to humanistic leadership research by providing important insights into specific capabilities that can help put the principles of humanistic leadership into practice, but that have not been considered to date.
Does the market for corporate control influence executive risk-taking incentives? Evidence from takeover vulnerability
Authors: Ongsakul Viput , Chatjuthamard Pattanaporn , Jiraporn Napatsorn , Jiraporn Pornsit
Published: November 2020

Purpose

This study aims to investigate the role of the market for corporate control as an external governance mechanism and its effect on executive risk-taking incentives. Managers tend to be risk-averse as they are more exposed to idiosyncratic risk, resulting in sub-optimal risk-taking that does not maximize shareholders’ wealth. The takeover market alleviates this problem, inducing managers to take more risk. Therefore, risk-taking incentives inside the firm are less powerful when the outside takeover market is more active.

Design/methodology/approach

Exploiting a novel measure of takeover vulnerability recently constructed by Cain et al. (2017), the authors explore how takeover vulnerability influences executive risk-taking incentives. Using a large sample of US firms, the authors use fixed-effects regressions, propensity score matching and instrumental variable analysis.

Findings

Consistent with this study’s hypothesis, a more active takeover market results in less powerful risk-taking incentives. Specifically, a rise in takeover vulnerability by one standard deviation diminishes executive risk-taking incentives by 22.39%, which is an economically meaningful magnitude.

Originality/value

To the best of the authors’ knowledge, this study is the first to explore the effect of the takeover market on managerial risk-taking incentives, using a novel measure of takeover susceptibility. The authors’ measure of takeover vulnerability is considerably less susceptible to endogeneity, enabling the authors to draw causal inferences with more confidence.