bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of high affinity monoclonal antibodies against SARS-CoV-2 variant infection using a DNA prime-protein boost strategy
Authors: Chiang Chen-Yi , Chen Mei-Yu , Hsu Chia-Wei , Liu Chia-Yeh , Tsai Yu-Wen , Liao Hung-Chun , Yan Jia-Ying , Chuang Zih-Shiuan , Wang Hsin-I. , Pan Chien-Hsiung , Yu Chia-Yi , Yu Guann-Yi , Liao Ching-Len , Liu Shih-Jen , Chen Hsin-Wei
Published: June 2022

Background

Calls for the coronavirus to be treated as an endemic illness, such as the flu, are increasing. After achieving high coverage of COVID-19 vaccination, therapeutic drugs have become important for future SARS-CoV-2 variant outbreaks. Although many monoclonal antibodies have been approved for emergency use as treatments for SARS-CoV-2 infection, some monoclonal antibodies are not authorized for variant treatment. Broad-spectrum monoclonal antibodies are unmet medical needs.

Methods

We used a DNA prime-protein boost approach to generate high-quality monoclonal antibodies. A standard ELISA was employed for the primary screen, and spike protein-human angiotensin-converting enzyme 2 blocking assays were used for the secondary screen. The top 5 blocking clones were selected for further characterization, including binding ability, neutralization potency, and epitope mapping. The therapeutic effects of the best monoclonal antibody against SARS-CoV-2 infection were evaluated in a hamster infection model.

Results

Several monoclonal antibodies were selected that neutralize different SARS-CoV-2 variants of concern (VOCs). These VOCs include Alpha, Beta, Gamma, Delta, Kappa and Lambda variants. The high neutralizing antibody titers against the Beta variant would be important to treat Beta-like variants. Among these monoclonal antibodies, mAb-S5 displays the best potency in terms of binding affinity and neutralizing capacity. Importantly, mAb-S5 protects animals from SARS-CoV-2 challenge, including the Wuhan strain, D614G, Alpha and Delta variants, although mAb-S5 exhibits decreased neutralization potency against the Delta variant. Furthermore, the identified neutralizing epitopes of monoclonal antibodies are all located in the receptor-binding domain (RBD) of the spike protein but in different regions.

Conclusions

Our approach generates high-potency monoclonal antibodies against a broad spectrum of VOCs. Multiple monoclonal antibody combinations may be the best strategy to treat future SARS-CoV-2 variant outbreaks.
Associations of the vasoactive peptides CT-proET-1 and MR-proADM with incident type 2 diabetes: results from the BiomarCaRE Consortium
Authors: Sujana Chaterina , Salomaa Veikko , Kee Frank , Seissler Jochen , Jousilahti Pekka , Neville Charlotte , Then Cornelia , Koenig Wolfgang , Kuulasmaa Kari , Reinikainen Jaakko , Blankenberg Stefan , Zeller Tanja , Herder Christian , Mansmann Ulrich , Peters Annette , Thorand Barbara ,   for the BiomarCaRE Consortium
Published: June 2022

Background

Endothelin-1 (ET-1) and adrenomedullin (ADM) are commonly known as vasoactive peptides that regulate vascular homeostasis. Less recognised is the fact that both peptides could affect glucose metabolism. Here, we investigated whether ET-1 and ADM, measured as C-terminal-proET-1 (CT-proET-1) and mid-regional-proADM (MR-proADM), respectively, were associated with incident type 2 diabetes.

Methods

Based on the population-based Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium data, we performed a prospective cohort study to examine associations of CT-proET-1 and MR-proADM with incident type 2 diabetes in 12,006 participants. During a median follow-up time of 13.8 years, 862 participants developed type 2 diabetes. The associations were examined in Cox proportional hazard models. Additionally, we performed two-sample Mendelian randomisation analyses using published data.

Results

CT-proET-1 and MR-proADM were positively associated with incident type 2 diabetes. The multivariable hazard ratios (HRs) [95% confidence intervals (CI)] were 1.10 [1.03; 1.18], P = 0.008 per 1-SD increase of CT-proET-1 and 1.11 [1.02; 1.21], P = 0.016 per 1-SD increase of log MR-proADM, respectively. We observed a stronger association of MR-proADM with incident type 2 diabetes in obese than in non-obese individuals (P-interaction with BMI < 0.001). The HRs [95%CIs] were 1.19 [1.05; 1.34], P = 0.005 and 1.02 [0.90; 1.15], P = 0.741 in obese and non-obese individuals, respectively. Our Mendelian randomisation analyses yielded a significant association of CT-proET-1, but not of MR-proADM with type 2 diabetes risk.

Conclusions

Higher concentrations of CT-proET-1 and MR-proADM are associated with incident type 2 diabetes, but our Mendelian randomisation analysis suggests a probable causal link for CT-proET-1 only. The association of MR-proADM seems to be modified by body composition.
Elevated plasma triglyceride concentration and risk of adverse clinical outcomes in 1.5 million people: a CALIBER linked electronic health record study
Authors: Patel Riyaz S. , Pasea Laura , Soran Handrean , Downie Paul , Jones Richard , Hingorani Aroon D. , Neely Dermot , Denaxas Spiros , Hemingway Harry
Published: June 2022

Background

Assessing the spectrum of disease risk associated with hypertriglyceridemia is needed to inform potential benefits from emerging triglyceride lowering treatments. We sought to examine the associations between a full range of plasma triglyceride concentration with five clinical outcomes.

Methods

We used linked data from primary and secondary care for 15 M people, to explore the association between triglyceride concentration and risk of acute pancreatitis, chronic pancreatitis, new onset diabetes, myocardial infarction and all-cause mortality, over a median of 6–7 years follow up.

Results

Triglyceride concentration was available for 1,530,411 individuals (mean age 56·6 ± 15·6 years, 51·4% female), with a median of 1·3 mmol/L (IQR: 0.9.to 1.9). Severe hypertriglyceridemia, defined as > 10 mmol/L, was identified in 3289 (0·21%) individuals including 620 with > 20 mmol/L. In multivariable analyses, a triglyceride concentration > 20 mmol/L was associated with very high risk for acute pancreatitis (Hazard ratio (HR) 13·55 (95% CI 9·15–20·06)); chronic pancreatitis (HR 25·19 (14·91–42·55)); and high risk for diabetes (HR 5·28 (4·51–6·18)) and all-cause mortality (HR 3·62 (2·82–4·65)) when compared to the reference category of ≤ 1·7 mmol/L. An association with myocardial infarction, however, was only observed for more moderate hypertriglyceridaemia between 1.7 and 10 mmol/L. We found a risk interaction with age, with higher risks for all outcomes including mortality among those ≤ 40 years compared to > 40 years.

Conclusions

We highlight an exponential association between severe hypertriglyceridaemia and risk of incident acute and chronic pancreatitis, new diabetes, and mortality, especially at younger ages, but not for myocardial infarction for which only moderate hypertriglyceridemia conferred risk.
Atrioventricular coupling and left atrial abnormality in type 2 diabetes mellitus with functional mitral regurgitation patients verified by cardiac magnetic resonance imaging
Authors: Zhang Yi , Li Xue-Ming , Shen Meng-Ting , Huang Shan , Li Yuan , Yang Zhi-Gang
Published: June 2022

Background

Functional mitral regurgitation (FMR) in type 2 diabetes mellitus (T2DM) patients induced by left ventricular (LV) enlargement and mitral valve abnormality may aggravated the impairment in left atrial (LA) compliance. Thus, this study aimed to depict how FMR and LV dysfunction affect LA compliance in T2DM patients with FMR.

Materials and methods

A total of 148 patients with T2DM and 49 age- and sex-matched normal controls underwent cardiac magnetic resonance examination. LA longitudinal strain and LA and LV functional indices were compared among controls and different T2DM patients. The multivariate analysis was used to identify the independent indicators of LA longitudinal strain.

Results

T2DM Patients without FMR had a lower total LA empty fraction (LAEF) compared with the controls (all P < 0.05). T2DM patients with mild and moderate FMR showed increased LA volume (LAV) and LV volume while decreased LAEF, LA strain, and LV ejection fraction (P < 0.05). T2DM patients with severe FMR showed markedly increased LAV and LV volume while decreased LAEF, LA strain, and LVEF (P < 0.05). In T2DM patients with FMR, reservoir strain (εs) was independently correlated with LV end-diastolic volume (LVEDV) (β = − 0.334) and regurgitation degree (β = − 0.256). The passive strain (εe) was independently correlated with regurgitation degree (β = − 0.297), whereas the active strain (εa) was independently correlated with LVESV (β = − 0.352) and glycated haemoglobin (β = − 0.279).

Conclusion

FMR may aggravate LA and LV dysfunction in T2DM patients. Regurgitation degree was an independent determinant of the εs and the εe, LVEDV was an independent determinant of the εs, and LVESV was an independent determinant of the εa in T2DM patients with FMR.
Arterial stiffness in patients with type 1 diabetes and its comparison to cardiovascular risk evaluation tools
Authors: Helleputte Simon , Van Bortel Luc , Verbeke Francis , Op ‘t Roodt Jos , Calders Patrick , Lapauw Bruno , De Backer Tine
Published: June 2022

Background

Arterial stiffness is a potential biomarker for cardiovascular disease (CVD) risk in patients with type 1 diabetes (T1D). However, its relation with other CV risk evaluation tools in T1D has not been elucidated yet. This study aimed to evaluate arterial stiffness in T1D patients free from known CVD, and compare it to other CV risk evaluation tools used in T1D.

Methods

Cross-sectional study in adults with a T1D duration of at least 10 years and without established CVD. Patients were categorized in CVD risk groups based on2019 European Society of Cardiology (ESC) guidelines, and the STENO T1D risk engine was used to estimate 10-year risk for CV events. Arterial stiffness was evaluated with carotid-femoral pulse wave velocity (cf-PWV). Coronary artery calcium (CAC) score was assessed and carotid ultrasound was performed. Ambulatory 24-h blood pressure and central hemodynamic parameters were evaluated. Data on renal function and diabetic kidney disease was retrieved.

Results

54 patients (age: 46 ± 9.5 years; T1D duration: 27 ± 8.8 years) were included. One-fourth of patients showed prematurely increased aortic stiffness based on cf-PWV (24%). Cf-PWV was significantly associated with CAC score, carotid intima-media thickness, central hemodynamic parameters and diabetic kidney disease. Based on STENO, 20 patients (37%) were at low, 20 patients (37%) at moderate, and 14 patients (26%) at high 10-year risk for CV event. Cf-PWV was strongly associated with the STENO score (rs = + 0.81; R2 = 0.566, p < 0.001), increasing with each higher STENO group (p < 0.01). However, cf-PWV was not significantly different between the two CV risk groups (high versus very high) based on ESC criteria, and ESC criteria compared to STENO classified 10 patients more as having > 10% 10-year risk for CV events (n = 44/54; 81.5% versus n = 34/54; 63%).

Conclusions

This study demonstrated that a substantial proportion of long-standing T1D patients free from known CVD show premature arterial stiffening. Cf-PWV strongly associates with the STENO risk score for future CV events and with cardiovascular imaging and function outcomes, thereby illustrating the clinical importance of arterial stiffness. The data, however, also show considerable heterogeneity in CV risk and differences in risk categorisation between the STENO tool and ESC criteria.There is a need for refinement of CV risk classification in T1D, and future studies should investigate if evaluation of arterial stiffness should be implemented in T1D clinical practice and which patients benefit the most from its assessment.
CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway
Authors: Del Gaudio Nunzio , Di Costanzo Antonella , Liu Ning Qing , Conte Lidio , Dell’Aversana Carmela , Bove Guglielmo , Benedetti Rosaria , Montella Liliana , Ciardiello Fortunato , Carafa Vincenzo , Ambrosino Concetta , Tucci Valeria , Conte Mariarosaria , Martens Joost H. A. , Stunnenberg Hendrik G. , Nebbioso Angela , Altucci Lucia
Published: June 2022

Background

The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear.

Methods

We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype.

Results

We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression.

Conclusions

Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.
Multiple roles for Bcl-3 in mammary gland branching, stromal collagen invasion, involution and tumor pathology
Authors: Carr David , Zein Aiman , Coulombe Josée , Jiang Tianqi , Cabrita Miguel A. , Ward Gwendoline , Daneshmand Manijeh , Sau Andrea , Pratt M. A. Christine
Published: June 2022

Background

The Bcl-3 protein is an atypical member of the inhibitor of -κB family that has dual roles as a transcriptional repressor and a coactivator for dimers of NF-κB p50 and p52. Bcl-3 is expressed in mammary adenocarcinomas and can promote tumorigenesis and survival signaling and has a key role in tumor metastasis. In this study, we have investigated the role of Bcl-3 in the normal mammary gland and impact on tumor pathology.

Methods

We utilized bcl-3−/− mice to study mammary gland structure in virgins and during gestation, lactation and early involution. Expression of involution-associated genes and proteins and putative Bcl-3 target genes was examined by qRT-PCR and immunoblot analysis. Cell autonomous branching morphogenesis and collagen I invasion properties of bcl-3−/− organoids were tested in 3D hydrogel cultures. The role of Bcl-3 in tumorigenesis and tumor pathology was also assessed using a stochastic carcinogen-induced mammary tumor model.

Results

Bcl-3−/− mammary glands demonstrated reduced branching complexity in virgin and pregnant mice. This defect was recapitulated in vitro where significant defects in bud formation were observed in bcl-3−/− mammary organoid cultures. Bcl-3−/− organoids showed a striking defect in protrusive collective fibrillary collagen I invasion associated with reduced expression of Fzd1 and Twist2. Virgin and pregnant bcl-3−/− glands showed increased apoptosis and rapid increases in lysosomal cell death and apoptosis after forced weaning compared to WT mice. Bcl-2 and Id3 are strongly induced in WT but not bcl-3−/− glands in early involution. Tumors in WT mice were predominately adenocarcinomas with NF-κB activation, while bcl-3−/− lesions were largely squamous lacking NF-κB and with low Bcl-2 expression.

Conclusions

Collectively, our results demonstrate that Bcl-3 has a key function in mammary gland branching morphogenesis, in part by regulation of genes involved in extracellular matrix invasion. Markedly reduced levels of pro-survival proteins expression in bcl-3 null compared to WT glands 24 h post-weaning indicate that Bcl-3 has a role in moderating the rate of early phase involution. Lastly, a reduced incidence of bcl-3−/− mammary adenocarcinomas versus squamous lesions indicates that Bcl-3 supports the progression of epithelial but not metaplastic cancers.
An epigenome-wide study of DNA methylation profiles and lung function among American Indians in the Strong Heart Study
Authors: Domingo-Relloso Arce , Riffo-Campos Angela L. , Powers Martha , Tellez-Plaza Maria , Haack Karin , Brown Robert H. , Umans Jason G. , Fallin M. Daniele , Cole Shelley A. , Navas-Acien Ana , Sanchez Tiffany R.
Published: June 2022

Background

Epigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45–74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989–1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993–1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings.

Results

Among 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein–protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases.

Conclusion

We found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.
Molecular mechanism of interaction between fatty acid delta 6 desaturase and acyl-CoA by computational prediction
Authors: Cui Jie , Chen Haiqin , Tang Xin , Zhang Hao , Chen Yong Q. , Chen Wei
Published: June 2022

Enzyme catalyzed desaturation of intracellular fatty acids plays an important role in various physiological and pathological processes related to lipids. Limited to the multiple transmembrane domains, it is difficult to obtain their three-dimensional structure of fatty acid desaturases. So how they interact with their substrates is unclear. Here, we predicted the complex of Micromonas pusilla delta 6 desaturase (MpFADS6) with the substrate linoleinyl-CoA (ALA-CoA) by trRosetta software and docking poses by Dock 6 software. The potential enzyme–substrate binding sites were anchored by analysis of the complex. Then, site-directed mutagenesis and activity verification clarified that W290, W224, and F352 were critical residues of the substrate tunnel and directly bonded to ALA-CoA. H94 and H69 were indispensable for transporting electrons with heme. H452, N445, and H358 significantly influenced the recognition and attraction of MpFADS6 to the substrate. These findings provide new insights and methods to determine the structure, mechanisms and directed transformation of membrane-bound desaturases.

Graphical Abstract
Influence of parity and reproductive stage on the prevalence of Mycoplasma hyopneumoniae in breeding animals in belgian farrow-to-finish pig herds
Authors: Biebaut Evelien , Chantziaras Ilias , Boyen Filip , Devriendt Bert , Haesebrouck Freddy , Gomez-Duran Charles-Oliver , Maes Dominiek
Published: June 2022

Background

Dam-to-piglet transmission plays an important role in the epidemiology of enzootic pneumonia on farms. AlthoughMycoplasma hyopneumoniae(M. hyopneumoniae) infections in breeding animals are often subclinical, their control could have a positive effect onM. hyopneumoniaeinfection levels in fattening pigs. This study investigated the presence ofM. hyopneumoniaein the breeding population of ten Belgian farrow-to-finish farms suspected by the herd veterinarian to beM. hyopneumoniaeinfected. Gilt vaccination againstM. hyopneumoniaeprior to first insemination was practiced on nine of the ten farms. At four different time points in the reproductive cycle 20 animals were sampled on each farm, namely 30–40 days of gestation, 75–85 days of gestation, 3–5 days after farrowing, and 1–3 days after weaning. In total, tracheobronchial swabs and blood samples were collected from 344 gilts and 456 sows (n = 80/farm). Swabs were analysed for the presence ofM. hyopneumoniaeDNA using nested PCR andM. hyopneumoniae-specific antibodies were detected in serum with a commercial ELISA. Generalized linear mixed models with farm as random factor were used to test the effect of time point in the reproductive cycle and parity onM. hyopneumoniaePCR prevalence and seroprevalence.

Results

M. hyopneumoniaePCR prevalence ranged between 0% and 43.8% at the farm level and the seroprevalence between 32.5% and 93.8%. Gilts were significantly moreM. hyopneumoniaePCR positive than sows at the 2-4th parity (P = 0.02) and > 4th parity (P = 0.02). At 30–40 days of gestation, significantly more breeding animals were PCR positive as compared to 75–85 days of gestation (P = 0.04), 3–5 days after farrowing (P = 0.02) and 1–3 days after weaning (P = 0.02). Gilts had significantly more oftenM. hyopneumoniae-specific antibodies than sows (P = 0.03).

Conclusions

M. hyopneumoniaePCR prevalence varied a lot between farms and due to gilt vaccination the number of animals withM. hyopneumoniae-specific antibodies was high on most farms. Gilts were more oftenM. hyopneumoniaePCR positive than sows and positive animals were mostly found at 30–40 days of gestation. This emphasizes the importance of a sufficiently long quarantine period and proper gilt acclimation practices before introducing gilts to the sow herd.
Co-creation of HIVST delivery approaches for improving urban men’s engagement with HIV services in eThekwini District, KwaZulu-Natal: nominal group technique in intervention development
Authors: Mashamba-Thompson Tivani , Lessells Richard , Dzinamarira Tafadzwa , Drain Paul , Thabane Lehana
Published: June 2022

Background

HIV self-testing (HIVST) is one of the recommended approaches for HIV testing services, particularly for helping reach populations who would not normally access facility-based HIV testing. Key stakeholder engagement is paramount in tailoring health interventions to ensure uptake by target populations.

Objective

The main objective of this study was to collaborate with key stakeholder in the co-creation of an acceptable HIVST delivery strategies to help improve urban men’s engagement with HIV services.

Methods

We invited key stakeholders for urban men’s HIV services to participate in a co-creation workshop aimed at developing HIVST delivery approaches for urban men, using eThekwini municipality as a study setting. We conducted purposive sampling to include health care users and health care providers, representing a range of views across the public sector and voluntary sector. We employed the nominal group technique (NGT) method for data collection. The NGT workshop was conducted in two consecutives: phase 1 was focused on determining barriers for men’s engagement with the current/facility-based HIV testing services; phase 2 was aimed at determining HIVST delivery strategies.

Results

Participants identified the following factors as the most important barriers to uptake of HIV testing services by urban men: stigma, ignorance about the importance of testing, and testing process as well as fear of positive test results. Key stakeholders suggested internal motivation strategies as a potentially effective approach to support HIVST delivery strategy. Guided by the NGT results, we designed a HIVST delivery strategy that is supported by a risk communication approach.

Conclusion

The NGT enabled successful collaboration with key stakeholders in the co-creation of HIVST delivery strategies to guide implementation and strategy improve urban men’s engagement with HIV services. A follow-up study to evaluate the feasibility of implementing these approaches is recommended.
Shared meta-aperture system for the frequency-induced reconfigurable multiple beams
Authors: Gao P. F. , Yang R. , Gu C. G. , Zhu Y. Z.
Published: June 2022

We demonstrate the perfect synthesis of multiple beams with different radiating states at dual frequencies through a shared meta-aperture system, consisting of a checkerboard meta-lens with two kinds of gradient meta-atoms distributed in a diagonally staggered manner and a polarization converting meta-mirror possessing periodic skew double-headed arrow array. The co-linearly polarized (co-LP) waves reflected by the inner surface of the checkerboard meta-lens would be twisted into the cross-LP counterparts by the meta-mirror and then penetrate the checkerboard meta-lens to form the high-purity cross-LP directive multi-beams at one frequency. Meanwhile, the other polarization orthogonal meta-array over the outer surface of the checkerboard meta-lens would also be capable of transforming the released cross-LP fields back and create the co-LP multi-beams at another frequency. Especially, the frequency sensitivity of such shared meta-aperture system is discussed through comparing different sets of the synthesized multiple beams, and the multi-functional meta-surface coating over the checkerboard meta-lens will fundamentally determine the overall radiating patterns and the operating bandwidth. In addition, the proposed design through integrating composite functional meta-surfaces also possesses the merits of generating high-polarization purity multiple beams at different frequencies, thus should pave the way for building up more advanced shared-aperture meta-radiators with highly efficient connections in the contemporary wireless communications.
Health Disparities in Dementia
Authors: Balls-Berry Joyce (Joy) E. , Babulal Ganesh M.
Published: June 2022

PURPOSE OF REVIEW

Causes of health disparities in Alzheimer disease and related dementias (ADRD) in the United States are multifactorial. This article contextualizes health disparities as they relate to the neurodegenerative processes of ADRD.

RECENT FINDINGS

Older adults’ life expectancy has increased such that a 65-year-old is expected to live 19 or more years and an 85-year-old can expect to live, on average, 6 to 7 years longer. Individuals of certain ethnoracial groups (Black, Hispanic/Latino, American Indian/Alaska Native, and Native Hawaiian/Pacific Islander) may be at a higher risk of incident ADRD compared to non-Hispanic/Latino White people. These differences in a higher risk of ADRD across ethnoracial groups persist despite no statistically significant differences in the rate of cognitive decline over time. The intersectionality of social determinants of health, experiences with discrimination and oppression, and access to care are related to the issue of justice and the risk for and expression of ADRD. The theoretical frameworks of various health disparities provide organized approaches to tracking the progression of health disparities for diverse patients.

ADRD health disparities are complex. Neurologists and their care teams must consider the main reasons for clinical ADRD evaluations of members of ethnoracial groups and the factors that may impact patient adherence and compliance with diagnostic and management recommendations.
Rapidly Progressive Dementia
Authors: Day Gregory S.
Published: June 2022

PURPOSE OF REVIEW

This article presents a practical approach to the evaluation of patients with rapidly progressive dementia.

RECENT FINDINGS

The approach presented in this article builds upon the standard dementia evaluation, leveraging widely available tests and emergent specific markers of disease to narrow the differential diagnosis and determine the cause(s) of rapid progressive decline. The discovery of treatment-responsive causes of rapidly progressive dementia underscores the need to determine the cause early in the symptomatic course when treatments are most likely to halt or reverse cognitive decline.

A pragmatic and organized approach to patients with rapidly progressive dementia is essential to mitigate diagnostic and therapeutic challenges and optimize patient outcomes.
Genetics of Alzheimer Disease
Authors: Jayadev Suman
Published: June 2022

PURPOSE OF REVIEW

This article discusses the spectrum of genetic risk in familial and sporadic forms of early- and late-onset Alzheimer disease (AD). Recent work illuminating the complex genetic architecture of AD is discussed in the context of high and low risk and what is known in different populations.

RECENT FINDINGS

A small proportion of AD is autosomal dominant familial AD caused by variants in PSEN1, PSEN2, or APP, although more recently described rare genetic changes can also increase risk substantially over the general population, with odds ratios estimated at 2 to 4. APOE remains the strongest genetic risk factor for late-onset AD, and understanding the biology of APOE has yielded mechanistic insights and leads for therapeutic interventions. Genome-wide studies enabled by rapidly developing technologic advances in sequencing have identified numerous risk factors that have a low impact on risk but are widely shared throughout the population and involve a repertoire of cell pathways, again shining light on potential paths to intervention. Population studies aimed at defining and stratifying genetic AD risk have been informative, although they are not yet widely applicable clinically because the studies were not performed in people with diverse ancestry and ethnicity and thus population-wide data are lacking.

The value of genetic information to practitioners in the clinic is distinct from information sought by researchers looking to identify novel therapeutic targets. It is possible to envision a future in which genetic stratification joins other biomarkers to facilitate therapeutic choices and inform prognosis. Genetics already has transformed our understanding of AD pathogenesis and will, no doubt, continue to reveal the complexity of brain biology in health and disease.
Cognitive Syndromes Associated With Movement Disorders
Authors: Goldman Jennifer G. , Holden Samantha K.
Published: June 2022

PURPOSE OF REVIEW

This article reviews the recognition and management of cognitive syndromes in movement disorders, including those with parkinsonism, chorea, ataxia, dystonia, and tremor.

RECENT FINDINGS

Cognitive and motor syndromes are often intertwined in neurologic disorders, including neurodegenerative diseases such as Parkinson disease, atypical parkinsonian syndromes, Huntington disease, and other movement disorders. Cognitive symptoms often affect attention, working memory, and executive and visuospatial functions preferentially, rather than language and memory, but heterogeneity can be seen in the various movement disorders. A distinct cognitive syndrome has been recognized in patients with cerebellar syndromes. Appropriate recognition and screening for cognitive changes in movement disorders may play a role in achieving accurate diagnoses and guiding patients and their families regarding progression and management decisions.

In the comprehensive care of patients with movement disorders, recognition of cognitive syndromes is important. Pharmacologic treatments for the cognitive syndromes, including mild cognitive impairment and dementia, in these movement disorders lag behind the therapeutics available for motor symptoms, and more research is needed. Patient evaluation and management require a comprehensive team approach, often linking neurologists as well as neuropsychologists, psychologists, psychiatrists, social workers, and other professionals.
The Medicolegal and Ethical Dimensions of Physician Prescription Reluctance
Authors: Rose Rachel V. , Kass Joseph S.
Published: June 2022

This article addresses the potential legal ramifications for neurologists caring for patients with Alzheimer disease (AD) who elect neither to prescribe aducanumab nor to refer patients with AD for treatment with aducanumab. To prevail against a neurologist for failing to prescribe aducanumab or refer for aducanumab treatment, the plaintiff would have to establish that the neurologist’s failure to prescribe the medication or refer for treatment was a breach of the standard of care. The standard of care is conceptualized as the generally accepted approach to diagnosing or treating a condition. However, the controversy surrounding the US Food and Drug Administration’s (FDA’s) approval process for aducanumab (which was based on the drug’s efficacy at reducing brain amyloidosis rather than on clinically meaningful efficacy) as well as the American Academy of Neurology (AAN) position statement on aducanumab and the recent decision by the Centers for Medicare & Medicaid Services (CMS) to limit Medicare coverage of the drug and its associated costs to patients enrolled in qualifying clinical trials indicate that aducanumab cannot yet be considered the standard of care for the treatment of AD. Although deciding not to prescribe aducanumab does not violate the standard of care, neurologists treating patients with AD and not recommending this treatment should explain to their patients and their patients’ surrogate decision makers why they are not recommending the treatment.
Indian Ocean Narratives, Tidalectics, and Perth’s Centre for Stories
Authors: Gui Weihsin
Published: June 2022

This essay argues that contemporary literary anthologies of Indian Ocean narratives offer a distinctive way of representing the diversity of voices and experiences that traverse the ocean and connect the different countries and cultures along its rim. Whereas the single-author historical or historiographical novel is often the focus of Indian Ocean literary scholarship, this essay examines Ways of Being Here and Wave after Wave, anthologies produced under the rubric of Indian Ocean mentorship and writing projects by the Centre for Stories located in Perth, Western Australia. While the anthologies do share some thematic similarities with Indian Ocean novels, this essay draws on Kamau Brathwaite’s thinking to argue that the anthologies have a tidalectical aesthetic connecting their different individual pieces, which unfolds as readers move through their pages. This tidalectical aesthetic, in which there is no resolving synthesis but rather a series of interconnected and overlapping lived experiences and emotional struggles produced by multiple authors, may be a better way of representing contemporary Indian Ocean narratives that circles back to issues of migration, racism, and resistance at the very southeastern edge of the Indian Ocean.
Photography and Diaspora: A roundtable with Pok Chi Lau, Surendra Lawoti, and Wei Leng Tay
Authors: Lee Anthony W.
Published: June 2022

The classic features of diaspora are a history of dispersion among a people (whether forced or voluntary); a strong sense of a homeland from which those people have been dispersed; a desire to return to a place of origin (however fantastical, impractical, or impossible that wish might be); and a lack of full assimilation in a host country. In today’s world, in which the coming and going of peoples is extraordinarily fluid, in which “home” can be fractured or multiple, and in which, in a few countries, including those in the throes of postcolonialism, the goal of assimilation competes with the recognition (occasionally the celebration) of cultural difference, is diaspora still useful as a description? Does it help us to understand contemporary photographic practices that pursue the experiences and longings of a migrated people?

Following is a brief roundtable among three photographers who address these and other questions. In a sense, the photographers’ own movements reflect aspects of diaspora. Each was born in one country, moved to another, and return frequently to photograph the peoples and lands of their birth. They interpret their practices extraordinarily differently from one another, however, and use their cameras to different purposes and effects. In their hands, the features we associate with diaspora are often put into relationship with other ways of describing the movements of people, the forces of “home,” and the dynamics of assimilation.

Pok Chi Lau was born in Hong Kong and now lives in the United States; Surendra Lawoti was born in Nepal and now lives in Canada; and Wei Leng Tay was born in Singapore and now lives in Hong Kong. Our conversation moved fluidly between the photographers as themselves diasporic and their interest in people who might be said to belong to a diaspora.
Before the End of Everything: Masuyama Tazuko and “Another Tokuyama Village”
Authors: Kohara Masashi
Published: June 2022

(Translators’ Note: This is a translation of a Japanese-language article published in Kohara Masashi and Nobe Hiroko, eds., Masuyama Tazuko: subete shashin ni naru hi made [Masuyama Tazuko: Until Everything Becomes a Photograph](Shizuoka: Izu Photo Museum, 2014), a book accompanying the exhibition of the same title, held at the Izu Photo Museum in Shizuoka, Japan from October 6, 2013 through July 27, 2014. The article was originally published in “photographers’ gallery press”, no. 7 (Tokyo: photographers’ gallery, 2008), and then revised and expanded for the 2014 book. Although the names of the author and translator are in Western order, Japanese names that appear in the article and the bibliography are in Japanese order, with the family name first.)
Genetic analysis of Caenorhabditis elegans Haspin-like genes shows that hasp-1 plays multiple roles in the germline
Authors: Macaraeg Jommel , Reinhard Isaac , Ward Matthew , Carmeci Danielle , Stanaway Madison , Moore Amy , Hagmann Ethan , Brown Katherine , Wynne David J.
Published: June 2022

Haspin is a histone kinase that promotes error-free chromosome segregation by recruiting the chromosomal passenger complex (CPC) to mitotic and meiotic chromosomes. Haspin remains less well studied than other M-phase kinases, and the models explaining Haspin function have been developed primarily in mitotic cells. Here, we generate strains containing new conditional or nonsense mutations in the Caenorhabditis elegans Haspin homologs hasp-1 and hasp-2 and characterize their phenotypes. We show that hasp-1 is responsible for all predicted functions of Haspin and that loss of function of hasp-1 using classical and conditional alleles produces defects in germline stem cell proliferation and spermatogenesis, and confirms its role in oocyte meiosis. Genetic analysis suggests that hasp-1 acts downstream of the Polo-like kinase plk-2 and shows synthetic interactions between hasp-1 and two genes expected to promote recruitment of the CPC by a parallel pathway that depends on the kinase Bub1. This work adds to the growing understanding of Haspin function by characterizing a variety of roles in an intact animal.
The trunk–tail junctional region in Ciona larvae autonomously expresses tail-beating bursts at ∼20 second intervals
Authors: Hara Takashi , Hasegawa Shuya , Iwatani Yasushi , Nishino Atsuo S.
Published: June 2022

Swimming locomotion in aquatic vertebrates, such as fish and tadpoles, is expressed through neuron networks in the spinal cord. These networks are arranged in parallel, ubiquitously distributed and mutually coupled along the spinal cord to express undulation patterns accommodated to various inputs into the networks. While these systems have been widely studied in vertebrate swimmers, their evolutionary origin along the chordate phylogeny remains unclear. Ascidians, representing a sister group of vertebrates, give rise to tadpole larvae that swim freely in seawater. In the present study, we examined the locomotor ability of the anterior and posterior body fragments of larvae of the ascidian Ciona that had been cut at an arbitrary position. Examination of more than 200 fragments revealed a necessary and sufficient body region that spanned only ∼10% of the body length and included the trunk–tail junction. ‘Mid-piece’ body fragments, which included the trunk–tail junctional region, but excluded most of the anterior trunk and posterior tail, autonomously expressed periodic tail-beating bursts at ∼20 s intervals. We compared the durations and intervals of tail-beating bursts expressed by mid-piece fragments, and also by whole larvae under different sensory conditions. The results suggest that body parts outside the mid-piece effect shortening of swimming intervals, particularly in the dark, and vary the burst duration. We propose that Ciona larvae express swimming behaviors by modifying autonomous and periodic locomotor drives that operate locally in the trunk–tail junctional region.
RNase H-based analysis of synthetic mRNA 5′ cap incorporation
Authors: Chan S. Hong , Whipple Joseph M. , Dai Nan , Kelley Theresa M. , Withers Kathryn , Tzertzinis George , Corrêa Ivan R. , Robb G. Brett
Published: June 2022

Advances in mRNA synthesis and lipid nanoparticles technologies have helped make mRNA therapeutics and vaccines a reality. The 5′ cap structure is a crucial modification required to functionalize synthetic mRNA for efficient protein translation in vivo and evasion of cellular innate immune responses. The extent of 5′ cap incorporation is one of the critical quality attributes in mRNA manufacturing. RNA cap analysis involves multiple steps: generation of predefined short fragments from the 5′ end of the kilobase-long synthetic mRNA molecules using RNase H, a ribozyme or a DNAzyme, enrichment of the 5′ cleavage products, and LC-MS intact mass analysis. In this paper, we describe (1) a framework to design site-specific RNA cleavage using RNase H; (2) a method to fluorescently label the RNase H cleavage fragments for more accessible readout methods such as gel electrophoresis or high-throughput capillary electrophoresis; (3) a simplified method for post-RNase H purification using desthiobiotinylated oligonucleotides and streptavidin magnetic beads followed by elution using water. By providing a design framework for RNase H-based RNA 5′ cap analysis using less resource-intensive analytical methods, we hope to make RNA cap analysis more accessible to the scientific community.
Η επίδραση της νοσταλγίας στη δημιουργικότητα
Authors: Πετράτου Ειρήνη
Published: June 2022

Σκοπός της παρούσας διατριβής είναι η μελέτη της επίδρασης της νοσταλγίας που προκαλείται από τη μυρωδιά στη δημιουργικότητα. Για να επιτευχθεί ο σκοπός αυτός, πραγματοποιήθηκαν τρεις μελέτες. H πρώτη μελέτη είχε ως στόχο τη μετάφραση, προσαρμογή και στάθμιση στο ελληνικό πολιτισμικό πλαίσιο του ερωτηματολογίου Southampton Nostalgia Scale (SNS), το οποίο μετρά την Προδιάθεση για Νοσταλγία (Routledge, Arndt, Sedikides, & Wildschut, 2008). Η δεύτερη μελέτη είχε ως στόχο την διερεύνηση μυρωδιών της παιδικής ηλικίας που προκαλούν νοσταλγία και των ψυχολογικών τους λειτουργιών. Συγκεκριμένα, μελετήθηκαν πέντε μυρωδιές των παιδικών χρόνων και οι ψυχολογικές τους επιπτώσεις (Chelsea, Reid, Jeffrey, Green, Wildschut & Sedikides, 2015· Chrea, Delplanque, Grandjean, Cayeux, Le Calvé, Margot, Velazco, Sander & Scherer, 2007)· η μυρωδιά που προκάλεσε περισσότερη νοσταλγία χρησιμοποιήθηκε στην τρίτη μελέτη.Τέλος, η τρίτη μελέτη είχε ως στόχο τη διερεύνηση του κατά πόσο η όσφρηση μυρωδιάς που προκαλεί νοσταλγία (μυρωδιά που επιλέχθηκε στη δεύτερη μελέτη) σε συνάρτηση με τη νοσταλγική μνήμη μπορεί να επιδράσει στη δημιουργικότητα του ατόμου και συγκεκριμένα στη ροή ιδεών και την πρωτοτυπία (Reid, Green, Wildschut, & Sedikides, 2015· Chu & Downes, 2002, 2000). Η δημιουργικότητα ενός ατόμου μπορεί να επηρεαστεί από συναισθήματα, αναμνήσεις και εμπειρίες (Sedikides, Wildschut, Arndt, & Routledge, 2006, 2008). Αυτή η μελέτη εξετάζει τις επιδράσεις της νοσταλγίας που προκαλείται από τη μυρωδιά και της ανάκλησης στη μνήμη νοσταλγικών αναμνήσεων που προκαλούνται από τη μυρωδιά στη δημιουργικότητα· γενικότερα ποια είναι η επίδραση της οσφρητικής νοσταλγίας στη δημιουργικότητα .Συνολικά τα ευρήματα της παρούσας διατριβής έδειξαν, ότι το ερωτηματολόγιο Southampton Nostalgia Scale (SNS) του οποίου οι ψυχομετρικές ιδιότητες ελέγχθηκαν, παρουσιάζει υψηλή εγκυρότητα κι αξιοπιστία και μπορεί να χρησιμοποιηθεί αποτελεσματικά στο ελληνικό πολιτισμικό πλαίσιο. Επιπλέον, η μελέτη διερεύνησης μυρωδιών της παιδικής ηλικίας που προκαλούν νοσταλγία επιβεβαιώνει ότι η μυρωδιά που προκαλεί νοσταλγία σχετίζεται θετικά με ην αυτοεκτίμηση, την αισιοδοξία, την κοινωνική σύνδεση και την έμπνευση. Τέλος, μέσω της μελέτης επίδρασης της νοσταλγίας στη δημιουργικότητα φάνηκε ότι ο συνδυασμός της μυρωδιάς που προκαλεί νοσταλγία με την ανάκληση νοσταλγικών αναμνήσεων επηρεάζει σημαντικά στην ενίσχυση της δημιουργικότητας. Επίσης, τα αποτελέσματα έδειξαν ότι η σχέση αυτή σχετίζεται με τα θετικά συναισθήματα και την έμπνευση
HGNChelper: identification and correction of invalid gene symbols for human and mouse
Authors: Oh Sehyun , Abdelnabi Jasmine , Al-Dulaimi Ragheed , Aggarwal Ayush , Ramos Marcel , Davis Sean , Riester Markus , Waldron Levi
Published: June 2022

Gene symbols are recognizable identifiers for gene names but are unstable and error-prone due to aliasing, manual entry, and unintentional conversion by spreadsheets to date format. Official gene symbol resources such as HUGO Gene Nomenclature Committee (HGNC) for human genes and the Mouse Genome Informatics project (MGI) for mouse genes provide authoritative sources of valid, aliased, and outdated symbols, but lack a programmatic interface and correction of symbols converted by spreadsheets. We present HGNChelper, an R package that identifies known aliases and outdated gene symbols based on the HGNC human and MGI mouse gene symbol databases, in addition to common mislabeling introduced by spreadsheets, and provides corrections where possible. HGNChelper identified invalid gene symbols in the most recent Molecular Signatures Database (MSigDB 7.0) and in platform annotation files of the Gene Expression Omnibus, with prevalence ranging from ~3% in recent platforms to 30-40% in the earliest platforms from 2002-03. HGNChelper is installable from CRAN.