bluuebunny/crossref_metadata_2025 huggingface dataset:
High-stability spherical lanthanide nanoclusters for magnetic resonance imaging
Authors: Wang Hai-Ling , Liu Donglin , Jia Jian-Hua , Liu Jun-Liang , Ruan Ze-Yu , Deng Wei , Yang Shiping , Wu Si-Guo , Tong Ming-Liang
Published: February 2023

High-nuclear lanthanide clusters have shown great potential for the administration of high-dose mononuclear gadolinium chelates in magnetic resonance imaging (MRI). The development of high-nuclear lanthanide clusters with excellent solubility and high stability in water or solution has been challenging and is very important for expanding the performance of MRI. We used N-methylbenzimidazole-2-methanol (HL) and LnCl3·6H2O to synthesize two spherical lanthanide clusters, Ln32 (Ln = Ho, Ho32; and Ln = Gd, Gd32), which are highly stable in solution. The 24 ligands L− are all distributed on the periphery of Ln32 and tightly wrap the cluster core, ensuring that the cluster is stable. Notably, Ho32 can remain highly stable when bombarded with different ion source energies in HRESI-MS or immersed in an aqueous solution of different pH values for 24 h. The possible formation mechanism of Ho32 was proposed to be Ho(III), (L)− and H2O → Ho3(L)3/Ho3(L)4 → Ho4(L)4/Ho4(L)5 → Ho6(L)6/Ho6(L)7 → Ho16(L)19 → Ho28(L)15 → Ho32(L)24/Ho32(L)21/Ho32(L)23. To the best of our knowledge, this is the first study of the assembly mechanism of spherical high-nuclear lanthanide clusters. Spherical cluster Gd32, a form of highly aggregated Gd(III), exhibits a high longitudinal relaxation rate (1 T, r1 = 265.87 mM−1·s−1). More notably, compared with the clinically used commercial material Gd-DTPA, Gd32 has a clearer and higher-contrast T1-weighted MRI effect in mice bearing 4T1 tumors. This is the first time that high-nuclear lanthanide clusters with high water stability have been utilized for MRI. High-nuclear Gd clusters containing highly aggregated Gd(III) at the molecular level have higher imaging contrast than traditional Gd chelates; thus, using large doses of traditional gadolinium contrast agents can be avoided.
Photodegradable polar-functionalized polyethylenes
Authors: Wang Chaoqun , Xia Jian , Zhang Yuxing , Hu Xiaoqiang , Jian Zhongbao
Published: February 2023

The degradation of plastics has attracted much attention from the global community. Polyethylenes (PEs), as the most abundant synthetic plastics, are most frequently studied. PE is non-degradable and non-polar because of the sole presence of the pure hydrocarbon components. Concurrent incorporation of both in-chain cleavable and functional groups into the PE chain is an effective pathway to overcome the non-degradable and non-polar issue; however, the method for achieving this pathway remains elusive. Here, we report a strictly non-alternating (>99%) terpolymerization of ethylene with CO and fundamental polar monomers via a coordination–insertion mechanism using late transition metal catalysts, which effectively prevents the formation of undesired chelates originating from both co-monomers under a low CO concentration. High-molecular-weight linear PEs with both in-chain isolated keto (>99%) and main-chain functional groups are prepared. The incorporation of key low-content isolated keto groups makes PEs photodegradable while retaining their desirable bulk material properties, and the introduction of polar functional groups considerably improves their surface properties.
Beaver activity and red squirrel presence predict bird assemblages in boreal Canada
Authors: Feldman Mariano J , Mazerolle Marc J , Imbeau Louis , Fenton Nicole J
Published: February 2023

Wetlands and predation in boreal ecosystems play essential roles throughout the breeding season for bird assemblages. We found a positive association of beaver activity and a negative influence of American red squirrels (Tamiasciurus hudsonicus) on bird assemblages. We used a multispecies hierarchical model to investigate whether bird communities differ between two major wetland habitats in boreal Canada: beaver ponds and peatland ponds. In addition to including variables such as forest cover and latitude, we adopted a structural equation model approach to estimate the occupancy of American red squirrels and its potential influence on bird communities. Using automated recording stations deployed at 50 ponds, we detected 96 bird species in 2018 and 2019. Bird species were grouped into four taxonomic guilds according to their habitat successional requirements: early successional species, late successional species, generalists, and wetland species. Beaver ponds harbored higher species richness, a pattern driven primarily by early successional species. The occupancy of almost a quarter of the species was lower in the presence of red squirrels. Late successional species responded positively to the cover of forest surrounding the pond. Our results highlight the value of considering acoustic data of red squirrels to quantify habitat quality in boreal forests. We conclude that beaver activity shapes bird assemblages through modification of their habitat, and that some bird guilds are associated negatively with the presence of American red squirrels.
Singing on the nest is a widespread behavior in incubating Northern Mockingbirds and increases probability of nest predation
Authors: Stracey Christine M , Sanchez Karina , Brown Brishauna , Hawkins Dakota , Shepherd Tricia
Published: February 2023

In this study, we documented for the first time singing on the nest (SOTN) in 74% of 65 Northern Mockingbird (Mimus polyglottos) nests that were monitored with continuous-running video cameras (8,353.9 hr sampled). As predicted, higher rates of SOTN significantly decreased daily survival rates of nests. SOTN occurred almost exclusively by females during the egg stage and in 86% (48 of 56) of nests for which we had sampling from the egg stage. While extensive at the population level, the average rate of SOTN per individual was low (5.24 ± 1.24 s SOTN per hour of video sampled). We found mixed support for the hypothesis that SOTN functions in territory maintenance. We found no support for the hypotheses that SOTN functions to coordinate parental care, defend nests, or aid in vocal learning. Given the limited attention SOTN has received and the mostly anecdotal accounts of it, our understanding of its costs and benefits is lacking. We conclude that while individual rates of SOTN are quite low, SOTN may be more widespread in populations than previously thought and that studies specifically designed to test hypotheses regarding potential functions are critically needed.
Deriving the dilaton potential in improved holographic QCD from the chiral condensate
Authors: Hashimoto Koji , Ohashi Keisuke , Sumimoto Takayuki
Published: February 2023

We derive an explicit form of the dilaton potential in improved holographic QCD (IHQCD) from the QCD lattice data of the chiral condensate as a function of the quark mass. This establishes a data-driven holographic modeling of QCD—machine-learning holographic QCD. The modeling consists of two steps for solving inverse problems. The first inverse problem is to find the emergent bulk geometry consistent with the lattice QCD simulation data at the boundary. We solve this problem with the refinement of the neural ordinary differential equation, a machine-learning technique. The second inverse problem is to derive a bulk gravity action with a dilaton potential such that its solution is the emergent bulk geometry. We solve this problem at non-zero temperature, and derive the explicit form of the dilaton potential. The dilaton potential determines the bulk action, the Einstein-dilaton system; thus we derive holographically the bulk system from the QCD chiral condensate data. The usefulness of the model is shown in the example of the prediction of the string breaking distance, whose value is found to be consistent with other lattice QCD data.
Strategies of strengthening mechanical properties in the osteoinductive calcium phosphate bioceramics
Authors: Li Qipeng , Feng Cong , Cao Quanle , Wang Wei , Ma Zihan , Wu Yonghao , He Tinghan , Jing Yangtian , Tan Wenxuan , Liao Tongxiao , Xing Jie , Li Xiangfeng , Wang Ye , Xiao Yumei , Zhu Xiangdong , Zhang Xingdong
Published: February 2023

Calcium phosphate (CaP) bioceramics are widely applied in the bone repairing field attributing to their excellent biological properties, especially osteoinductivity. However, their applications in load-bearing or segmental bone defects are severely restricted by the poor mechanical properties. It is generally considered that it is challenging to improve mechanical and biological properties of CaP bioceramics simultaneously. Up to now, various strategies have been developed to enhance mechanical strengths of CaP ceramics, the achievements in recent researches need to be urgently summarized. In this review, the effective and current means of enhancing mechanical properties of CaP ceramics were comprehensively summarized from the perspectives of fine-grain strengthening, second phase strengthening, and sintering process optimization. What’s more, the further improvement of mechanical properties for CaP ceramics was prospectively proposed including heat treatment and biomimetic. Therefore, this review put forward the direction about how to compatibly improve mechanical properties of CaP ceramics, which can provide data and ideas for expanding the range of their clinical applications.
Host Determinants of Fungal Species Composition and Symptom Manifestation in the Sorghum Grain Mold Disease Complex
Authors: Wenndt Anthony , Boyles Richard , Ackerman Arlyn , Sapkota Sirjan , Repka Ace , Nelson Rebecca
Published: February 2023

Sorghum grain mold (SGM) is an important multifungal disease complex affecting sorghum (Sorghum bicolor) production systems worldwide. SGM-affected sorghum grain can be contaminated with potent fumonisin mycotoxins produced by Fusarium verticillioides, a prevalent SGM-associated taxon. Historically, efforts to improve resistance to SGM have achieved only limited success. Classical approaches to evaluating SGM resistance are based solely on disease severity, which offers little insight regarding the distinct symptom manifestations within the disease complex. In this study, three novel phenotypes were developed to facilitate assessment of SGM symptom manifestation. A sorghum diversity panel composed of 390 accessions was inoculated with endogenous strains of F. verticillioides and evaluated for these phenotypes, as well as for the conventional panicle grain mold severity rating phenotype, in South Carolina, U.S.A., in 2017 and 2019. Distributions of phenotype values were examined, broad-sense heritability was estimated, and relationships to botanical race were explored. A typology of SGM symptom manifestations was developed to classify accessions using principal component analysis and k-means clustering, constituting a novel option for basing breeding decisions on SGM outcomes more nuanced than disease severity. Genome-wide association studies were performed using SGM trait data, resulting in the identification of 19 significant single nucleotide polymorphisms in linkage disequilibrium with a total of 86 gene models. Our findings provide a basis of exploratory evidence regarding the genetic architecture of SGM symptom manifestation and indicate that traits other than disease severity could be tractable targets for SGM resistance breeding.
MCPyV-Negative Merkel Cell Carcinoma In Situ Associated With Immunosuppression
Authors: Mazumder Anika , Khoshnoodi Pooria , Gruber Jessica , Burkemper Nicole M.
Published: February 2023

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neoplasm that is almost always intradermal. Immunosuppression increases the risk of MCC, which is believed to be due to increased susceptibility to Merkel cell polyomavirus (MCPyV). Intraepidermal MCC, or MCC in situ (MCCis), is extremely rare and usually associated with other cutaneous lesions. Here, we describe a case of MCPyV-negative MCCis arising in an immunocompromised patient. This case adds to only 9 previously reported cases of MCCis without a coexisting neoplasm and suggests that immunosuppression can lead to MCCis by mechanisms other than MCPyV. Although previously reported cases of MCCis demonstrated excellent prognosis, local recurrence and metastasis are still possible. Prognostication, treatment, and follow-up of MCCis should be similar to MCC.
Langerhans Cell Histiocytosis Evolving into Juvenile Xanthogranuloma: Two Linked Entities
Authors: Shaker Nada , Sangueza Omar P.
Published: February 2023

Background:

Langerhans cell histiocytosis (LCH) represents a myeloid clonal proliferation that involves the skin and other organs. Occasionally, cases of LCH evolve into juvenile xanthogranuloma (JXG).

Case Presentation:

A 7-month-old boy presented with an itchy, flaky rash resembling seborrheic dermatitis affecting the scalp and eyebrows. The lesions started at 2 months old. On physical examination, there were reddish/brown lesions on the trunk, denuded areas on the groin and neck, and a large lesion behind his bottom teeth. In addition, there were thick white plaques in his mouth and thick whitish material in both ears. A skin biopsy showed features of LCH. Radiologic examination demonstrated several osteolytic lesions. Chemotherapy produced marked improvement. A few months later, the patient developed lesions with clinical and histologic features of XG.

Conclusion:

A possible association between LCH and XG is explained by lineage maturation development. Chemotherapy may play a role in modifying the production of cytokines that enhance the transformation or ‘maturation’ of Langerhans cells into multinucleated macrophages (Touton cells) characteristic of a more favorable proliferative inflammatory condition.
Variability of expert assessments of ECG time domain parameters
Authors: Böck Carl , Mörtl Christoph , Mahringer Christoph , Huemer Mario , Meier Jens
Published: February 2023

BACKGROUND

In anaesthesiology, time domain parameters of the ECG are frequently used for long QT diagnosis, determination of branch blocks and for identifying atrioventricular blocks. However, this analysis depends on several factors and therefore the time domain parameters are prone to variability.

OBJECTIVE

To determine the variability of expert assessments of ECG time domain parameters in daily clinical practice.

DESIGN

In an observational study 18 physicians labelled the onset, peak and end of the waves (P-QRS-T) for 26 preselected, distinctive beats. Based on this, clinically important durations and intervals were derived: the duration of the P wave, T wave and QRS complex, as well as the length of the PQ and QT interval. These parameters were subsequently analysed with respect to inter-expert variability (for all experts and discipline-based subgroups) and, additionally, were compared with computer-aided analysis.

SETTING

ECG recordings from participating patients were recorded in March 2015 during standard examination in the hospital and stored in the local ECG database.

PATIENTS

We did not define inclusion or exclusion criteria for the patients themselves; the ECG beats were selected by a medical expert with respect to their shapes and abnormalities.

MAIN OUTCOME MEASURES

Variability of clinically relevant ECG wave durations and intervals quantified were expressed as the interquartile range and the Q2/Q98 span for 18 investigators.

RESULTS

The resulting wave durations (Pdur, QRSdur and Tdur) and intervals (PQ and QT) showed high variability, for instance, captured by the Q2/Q98 span ranging from 39 to 99 ms.

CONCLUSION

The observed, inter-investigator variability of assessing the PQ and QT intervals, as well as the wave durations, might result in important variance regarding ECG-associated diagnoses. Whether these variances play a major role in typical clinical situations would have to be demonstrated with further clinical observational studies.
Innovations and Opportunities in Care for Black Mothers and Birthing People
Authors: Syed Gullnar , Sims Jacqueline , House Sherrell Hicklen , Bruno Beverly , Boulware Angel , Tang Kylie , Curenton Stephanie M.
Published: February 2023

In recent years, there has been increased attention given to how racism fuels health inequities, including the inadequacy of prenatal care (PNC) that Black women and Black birthing people receive. This increase of attention has brought notable advancements in research, practice, and policy that intend to better understand and address these systemic inequities within the health care system. This review aims to provide an overview of promising developments in the study of Black mothers' and birthing people's experiences in PNC and delivery, to detail current research surrounding interventions to improve quality and mitigate bias in obstetric care, and to offer ways in which legislation can support such strategies targeting the root causes of inequities in care.
Accuracy and Precision of Point-of-Care International Normalized Ratio in Patients With Liver Disease
Authors: Shadlyn Tevyn , Bauman Mary , Tandon Puneeta , Yap Jason , Kawada Patricia
Published: February 2023

Objective:

To determine if the CoaguChek XS Pro Point-of-Care (POC) device can accurately and precisely measure the international normalized ratio (INR) compared with the gold standard laboratory INR in pediatric and adult patients with liver disease.

Methods:

This prospective cohort study included 15 pediatric patients without liver disease, 13 pediatric patients with liver disease, and 17 adult patients with liver disease. The accuracy of the POC INR values was determined using the correlation and Bland-Altman limits of agreement. The accuracy of the coagulometer INR was assessed by calculating the proportion of POC INR measurements that were ≤15% of their corresponding laboratory INR.

Results:

A comparison of INR measurements showed an excellent correlation in pediatric patients without liver disease (r = 0.82), pediatric patients with liver disease (r = 0.89), and adult patients with liver disease (r = 0.96). Fourteen (93%) POC INR values were ≤15% in pediatric patients without liver disease from its paired laboratory INR. All 13 paired measurements were ≤15% in pediatric patients with liver disease. In adult patients with liver disease, 12 (71%) POC INR values were ≤15% of their paired laboratory INR.

Conclusions:

In patients with liver disease, the CoaguChek XS Pro provides an accurate measure of the INR compared to laboratory INR measurements.
Feasibility of Left Ventricle Ejection Fraction Calculation Using Electrocardiographically Gated SPECT Acquisition of 99mTc-HDP Bone Scintigraphy in Cardiac Amyloidosis
Authors: te Beek Erik T. , Lafeber Albert , Postema Jan W.A. , Constandse Jan , Ronner Eelko , ten Broek Marc R.J.
Published: February 2023

We performed bone scintigraphy in 6 patients with suspected cardiac amyloidosis. To evaluate feasibility of left ventricle function analysis, we additionally performed electrocardiographically gated SPECT acquisition. The cardiac-gated SPECT data confirmed adequate tracer uptake for automatic myocardial contour determination. LVEF estimations ranged between 24% and 54%. Comparison with LVEF estimations from prior echocardiography generally showed only small differences. In one patient, the LVEF measurements from both methods seemed discordant, probably reflecting actual LVEF worsening, which was confirmed at follow-up echocardiography. Therefore, our results may suggest that cardiac-gated SPECT acquisition at bone scintigraphy can provide meaningful estimates of LVEF.
Solitary Malignant Peripheral Nerve Sheath Tumor of Lumbar Vertebra Mimicking Metastatic Malignancy
Authors: Guo Ziyu , Liu Wei , Dong Ziqian , Yang Lan , Xie Peng
Published: February 2023

Malignant peripheral nerve sheath tumor involving solitary lumbar vertebra is extremely rare. A 72-year-old man had a chief complaint of growing lumbocrural pain for 2 months. The CT scan detected a solitary vertebral lesion, which highly supported the diagnosis of metastatic malignancy. 18F-FDG PET/CT demonstrated that the vertebral lesion had heterogeneous intense FDG accumulation with an SUVmax of 16.4. The pathological examination confirmed the diagnosis of malignant peripheral nerve sheath tumor. This case highlights that MPNST should be considered when there is solitary vertebra invasion with increased FDG uptake.
Male-killer symbiont screening reveals novel associations in Adalia ladybirds
Authors: Archer Jack , Hurst Gregory D D , Hornett Emily
Published: February 2023

While male-killing bacteria are known to infect across arthropods, ladybird beetles represent a known hotspot. In some host species, there are multiple different symbionts that vary in presence and frequency between populations. To further our understanding of spatial and frequency variation, we tested for the presence of three male-killing bacteria: Wolbachia, Rickettsia and Spiroplasma, in two Adalia ladybird species from a previously unexplored UK population. The two-spot ladybird, A. bipunctata is known to harbour all three male-killers, and we identified Spiroplasma infection in the Merseyside population for the first time. However, in contrast to previous studies on ladybirds from continental Europe, evidence from egg hatch rates indicates this Spiroplasma strain does not cause embryonic male-killing in the Merseyside population. In the related ten-spot ladybird, A. decempunctata, there is only one previous record of a male-killing symbiont, a Rickettsia, which we did not detect in the Merseyside sample. However, PCR assays indicated the presence of a Spiroplasma in a single A. decempunctata. Marker sequence indicated that this Spiroplasma was divergent from that found in sympatric A. bipunctata. Genome sequencing of the Spiroplasma-infected A. decempunctata additionally revealed the presence of cobionts in the form of a Centistes parasitoid wasp and the parasitic fungi Beauveria. Further study of A. decempunctata from this population is needed to resolve whether it is the ladybird or wasp cobiont that harbours Spiroplasma, and to establish the phenotype of this strain. These data indicate first that microbial symbiont phenotype should not be assumed from past studies conducted in different locations, and second that cobiont presence may confound screening studies aimed to detect the frequency of a symbiont in field collected material from a focal host species.
Identification of cell type-specific gene targets underlying thousands of rare diseases and subtraits
Authors: Murphy Kitty B. , Gordon-Smith Robert , Chapman Jai , Otani Momoko , Schilder Brian M. , Skene Nathan G.
Published: February 2023

Rare diseases (RDs) are uncommon as individual diagnoses, but as a group contribute to an enormous disease burden globally. However, partly due the low prevalence and high diversity of individual RDs, this category of diseases is understudied and under-resourced. The advent of large, standardised genetics databases has enabled high-throughput, comprehensive approaches that uncover new insights into the multi-scale aetiology of thousands of diseases. Here, using the Human Phenotype Ontology (9,677 annotated phenotypes) and multiple single-cell transcriptomic atlases (77 human cell types and 38 mouse cell types), we conducted >688,000 enrichment tests (x100,000 bootstrap iterations each) to identify >13,888 genetically supported cell type-phenotype associations. Our results recapitulate well-known cell type-phenotype relationships, and extend our understanding of these diseases by pinpointing the genes linking phenotypes to specific cell (sub)types. We also reveal novel cell type-phenotype relationships across disparate branches of clinical disease (e.g. the nervous, cardiovascular, and immune systems). Next, we introduce a computational pipeline to prioritise gene targets with high cell type-specificity to minimise off-target effects and maximise therapeutic potential. To broaden the impact of our study, we have released two R packages to fully replicate our analyses, as well as a series of interactive web apps so that stakeholders from a variety of backgrounds may further explore and utilise our findings. Together, we present a promising avenue for systematically and robustly uncovering the multi-scale aetiology of RDs at scale.
Lives and Livelihood, Not Quite a Trade-Off: A Cross-Country Analysis of the Short-Term Impact of COVID-19 Mortality on Real GDP
Authors: Suah Jing Lian
Published: February 2023

Introduction

A supposed lives-livelihood trade-off (LLTO) has been at the centre stage of the COVID-19 pandemic, where policymakers often attempt to balance the health cost of COVID-19, including deaths, and the economic cost of lockdowns.

Methodology

This paper uses country-level panel (longitudinal) data on real GDP, stringency of non-pharmaceutical interventions (NPIs), economic policy support, COVID-19 deaths, and vaccination to quantify the short-run LLTO. Beyond descriptive analysis, adjustments were made — (1) two-stage least squares instrumental variables in a cross-sectional setting using pre-pandemic institutional quality as the excluded instrument, and (2) two-way fixed effects in a panel data setting.

Findings

Real GDP is negatively associated with COVID-19 deaths, as does more stringent containment measures. However, the offsetting positive association of real GDP with economic policy support is substantial. A historical decomposition of average real GDP that the positive attribution of fiscal support roughly equates the negative attribution of lockdown stringency and COVID-19 mortality.

Conclusion

Cross-country empirical evidence suggests no direct tradeoff between the economy, and public health. A change in policy thinking from a LLTO paradigm to a ‘no trade-off’ entails economic policy treating public health goals as invariant in supporting incomes through adequate, direct, and timely means.
Altered glutamate signaling in Parkinson’s disease patients with REM sleep behavior disorder
Authors: Doppler Christopher E.J. , Seger Aline , Farrher Ezequiel , Brambilla Cláudia Régio , Hensel Lukas , Filss Christian P. , Gogishvili Ana , Shah N. Jon , Lerche Christoph W. , Neumaier Bernd , Langen Karl-Josef , Fink Gereon R. , Sommerauer Michael
Published: February 2023

Background and Objectives

Clinical heterogeneity of patients with Parkinson’s disease is well recognized. Parkinson’s disease with rapid eye movement (REM) sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher non-motor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning disbalances in neurotransmitter systems remain elusive.

Methods

Combining magnetic resonance (MR) spectroscopy and11C-ABP688 positron emission tomography (PET) on PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with Parkinson’s disease. Thirty-three patients were grouped according to their RBD status in overnight video-polysomnography and compared to 15 age- and sex-matched healthy control (HC) subjects. Total volumes of distribution (VT) of11C-ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between minutes 45 to 60 of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single voxel STEAM MR spectroscopy of the left putamen.

Results

We measured globally elevated VTof11C-ABP688 in patients with Parkinson’s disease and RBD compared to patients without RBD and HC subjects (F(2,45) = 5.579,p= 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VTof11C-ABP688. VTof11C-ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600,p= 0.023), and with dopaminergic treatment response in Parkinson’s disease patients (F(1,30) = 5.823,p= 0.022).

Conclusion

Our results suggest that patients with Parkinson’s disease and RBD exhibit altered glutamatergic signaling indicated by higher VTof11C-ABP688 despite unaffected glutamate metabolism. The disbalance of glutamate receptors and neurotransmitter might indicate a novel mechanism contributing to the heterogeneity of Parkinson’s disease and warrants further investigation of drugs targeting mGluR5.
Mapping Sleep’s Oscillatory Events as a Biomarker of Alzheimer’s Disease
Authors: Pulver Rachelle L. , Kronberg Eugene , Medenblik Lindsey M. , Kheyfets Vitaly O. , Ramos Alberto R. , Holtzman David M. , Morris John C. , Toedebusch Cristina D. , Sillau Stefan H. , Bettcher Brianne M. , Lucey Brendan P. , McConnell Brice V.
Published: February 2023

Objective

Memory-associated neural circuits produce oscillatory events within single-channel sleep electroencephalography (EEG), including theta bursts (TBs), sleep spindles (SPs) and multiple subtypes of slow waves (SWs). Changes in the temporal “coupling” of these events are proposed to serve as a biomarker for early stages of Alzheimer’s disease (AD) pathogenesis.

Methods

We analyzed data from 205 aging adults, including single-channel sleep EEG, cerebrospinal fluid (CSF) AD-associated biomarkers, and Clinical Dementia Rating® (CDR®) scale. Individual SW events were sorted into high and low transition frequencies (TF) subtypes. We utilized time-frequency spectrogram locations within sleep EEG to “map” the precision of SW-TB and SW-SP neural circuit coupling in relation to amyloid positivity (by CSF Aβ42/Aβ40threshold), cognitive impairment (by CDR), and CSF levels of AD-associated biomarkers.

Results

Cognitive impairment was associated with lower TB spectral power in both high and low TF SW-TB coupling (p<0.001, p=0.001). Cognitively unimpaired, amyloid positive aging adults demonstrated lower precision of the neural circuits propagating high TF SW-TB (p<0.05) and low TF SW-SP (p<0.005) event coupling, compared to cognitively unimpaired amyloid negative individuals. Biomarker correlations were significant for high TF SW-TB coupling with CSF Aβ42/Aβ40(p=0.005), phosphorylated-tau181(p<0.005), and total-tau (p<0.05). Low TF SW-SP coupling was also correlated with CSF Aβ42/Aβ40(p<0.01).

Interpretation

Loss of integrity in neural circuits underlying sleep-dependent memory processing can be measured for both SW-TB and SW-SP coupling in spectral time-frequency space. Breakdown of sleep’s memory circuit integrity is associated with amyloid positivity, higher levels of AD-associated pathology, and cognitive impairment.
BCM PDX Portal: An Intuitive Web-based Tool for Patient-Derived Xenograft Collection Management, as well as Visual Integration of Clinical and Omics Data
Authors: Dowst Heidi , McOwiti Apollo , Zheng Fei , Rajaram Srinivasan Ramakrishnan , Hernandez-Herrera Anadulce , Rainusso Nino , Brubaker Lisa , Yao Qizhi Cathy , Redell Michelle , Stevens Alexandra , Lerner Seth , Woodfield Sarah , Espinoza Andres F. , Landua John D. , Hilsenbeck Susan G. , Dobrolecki Lacey E. , Lewis Michael T.
Published: February 2023

Objective

Mouse Patient-Derived Xenograft (PDX) models are essential tools for evaluating experimental therapeutics. Baylor College of Medicine (BCM) established a PDX Core to provide technical support and infrastructure for PDX-based research. To manage PDX collections effectively, de-identified patient clinical and omics data, as well as PDX-related information and omics data, must be curated and stored. Data must then be analyzed and visualized for each case. To enhance PDX collection management and data dissemination, the BCM Biomedical Informatics Core created the BCM PDX Portal (https://pdxportal.research.bcm.edu/).

Materials and Methods

Patient clinical data are abstracted from medical records for each PDX and stored in a central database. Annotations are reviewed by a clinician and de-identified. PDX development method and biomarker expression are annotated. DNAseq, RNAseq, and proteomics data are processed through standardized pipelines and stored. PDX gene expression (mRNA/protein), copy number alterations, and mutations can be searched in combination with clinical markers to identify models potentially useful as a PDX cohort.

Results

PDX collection management and PDX selection of models for drug evaluation are facilitated using the PDX Portal.

Discussion

To improve the translational effectiveness of PDX models, it is beneficial to use a tool that captures and displays multiple features of the patient clinical and molecular data. Selection of models for studies should be representative of the patient cohort from which they originated.

Conclusion

The BCM PDX Portal is a highly effective PDX collection management tool allowing data access in a visual, intuitive manner thereby enhancing the utility of PDX collections.
Changes of sociobehavioural characteristics and HIV in 29 Sub-Saharan African countries, 2000-2018
Authors: Post Jeffrey , Ng’ambi Wingston , Keiser Olivia , Merzouki Aziza
Published: February 2023

Introduction

HIV epidemics and associated sociobehavioural characteristics vary widely across Sub-Saharan African (SSA) countries. In this study, we investigated how national changes on sociobehavioural characteristics may be associated with trajectories in HIV epidemics.

Methods

We analyzed aggregated data from 80 DHS surveys of 29 SSA countries between 2000 and 2018. We described each national survey by 46 pre-selected demographic, socio- economic, behavioural and HIV-related variables. Using Principal Component Analysis, we reduced the dimensionality of surveys and visualized them on a 2-dimensional space. We used consensus clustering to identify groups of countries with similar sociobehavioural characteristics over time, and identified the main drivers of change. We used k-means clustering with dynamic time warping to group countries based on the evolution of their national HIV effective contact rates since 1990 (computed based on UNAIDS estimates of yearly HIV incidence and prevalence).

Results

We identified three groups of countries with similar sociobehavioural and HIV-related characteristics that persisted from 2000 to 2018. While countries within groups remained similar since 2000, differences between the groups increased over time. The most important characteristics that explained the change in the sociobehavioural space since 2000 were: ART coverage, HIV testing, increase in accepting attitudes towards People Living with HIV/AIDS and increasing knowledge about AIDS. We also identified two groups of countries with characteristic evolutions of HIV effective contact rates since 1990. The first group of countries was characterized by a rapid decrease of effective contact rate since the early 1990. The second group experienced a slow decrease of the effective contact rate in the early 1990, followed by a faster decrease after 1995. While the three clusters based on sociobehavioural characteristics were associated with different peak levels of HIV incidence, the two clusters based on the progression of the effective contact rate were associated with the timing when peak HIV incidence levels were reached.

Conclusions

Our findings suggest that the initial conditions of nascent epidemics, likely determined by sociobehavioural characteristics, are crucial in determining the long-term progression of HIV epidemics. Our methods can help to predict the effects of behavioural change on the HIV epidemic and design targeted interventions to reach epidemic control.
“We had to put ourselves in their shoes”: Experiences of Medical Students and ObGyn Residents with a Values Clarification Workshop on Abortion
Authors: Valley Taryn M. , Cowley Elise S. , Farooque Alma , Shultz Zoey B. , Williams Margaret , Askins Jacquelyn , Godecker Amy , Jacques Laura
Published: February 2023

Purpose

Values clarification workshops on abortion have been shown to increase support for abortion among healthcare workers. However, few studies have examined the impact of values clarification workshops on abortion among medical trainees. This study aimed to understand medical student and obstetrics and gynecology (ObGyn) residents’ experiences with a virtual values clarification workshop on abortion.

Methods

Clerkship year medical students and ObGyn residents at four midwestern teaching hospitals were invited to be interviewed about their experiences in a virtual values clarification workshop on abortion from January 2021 through December 2021. A single interviewer conducted interviews via Zoom using a standardized interview guide. Participants were asked to provide feedback and discuss their experiences in the workshop. Four qualitatively trained evaluators coded the interview transcripts in NVivo, using an inductive approach to establish consensus codes then themes.

Results

This study interviewed 37 trainees, including 24 medical students and 13 ObGyn residents, as well as five facilitators, between November 2021 and February 2022. Three themes emerged in both trainee groups. First, participants found the workshopshelped trainees clarify and understand their own views on abortionthrough thought exploration, peer validation, and reflection on their views’ potential societal impacts. Second, through the workshop,participants reflected on others’ opinions on abortionand better understood the spectrum of beliefs their peers held. Finally, participants found the workshopshelped them explore and develop their professional identity as physicians-in-training, through practicing communication skills and building trust and mutual respect among peers.

Conclusions

Medical trainees found values clarification workshops on abortion to be valuable, helping them establish their own beliefs about abortion, contextualize these beliefs among their peers’, and practice professionalism. These findings indicate that values clarification workshops can play a key role in helping medical trainees discuss abortion and prepare for their professional future.

One in four people capable of pregnancy will have an abortion during their lifetime; abortions are one of the most common medical procedures in the United States1. Given this ubiquity, abortion education is recommended for medical students and required for Obstetrics and Gynecology (ObGyn) residents2–4. However, abortion education is increasingly sparse for both groups of trainees5,6. In addition, abortion is highly stigmatized and polarizing, including within healthcare7–9.
Development and evaluation of a novel educational program for providers on the use of polygenic risk scores
Authors: Yanes T. , Wallingford C. , Young MA. , McInerney-Leo A.M. , Willis A. , McKnight L. , Terrill B. , McInerny S. , Forrest L. , Cicciarelli L. , Williams R. , Keane H. , James PA
Published: February 2023

Background

Polygenic risk scores (PRS) for breast and ovarian cancer risk are increasingly available to the public through clinical research and commercial genetic testing companies. Healthcare providers frequently report limited knowledge and confidence using PRS, representing a significant barrier to evaluation and uptake of this technology. We aimed to develop and evaluate the impact of a novel online educational program on genetic healthcare providers (GHP) attitudes, confidence and knowledge using PRS for breast and ovarian cancer risk.

Methods

The educational program was informed by adult learning theory and the Kolb experiential learning model. The program was comprised of two phases: i) an online module covering the theoretical aspects of PRS and ii) a facilitated virtual workshop with pre-recorded role plays and case discussions. A pre-and post-education survey was administered to evaluate the impact of the educational program on GHP attitudes, confidence, knowledge, and preparedness for using PRS. Eligible participants were GHP working in one of 12 familial cancer in Australia registered to recruit patients for a breast and ovarian cancer PRS clinical trial and completed the education program.

Results

124 GHP completed the PRS education, of whom 80 (64%) and 67 (41%) completed the pre- and post-evaluation survey, respectively. Pre-education, GHP reported limited experience, confidence and preparedness using PRS. GHP frequently recognized potential benefits to PRS, most commonly that this information could improve access to tailored screening (rated as beneficial/very beneficial by 92% of GHP pre-education). Completion of the education program was associated with significantly improved attitudes (p=<0.001), confidence (p=<0.001), knowledge of (p=<0.001) and preparedness (p=<0.001) using PRS. Most GHP indicated the education program entirely met their learning needs (73%) and felt the content was entirely relevant to their clinical practice (88%). GHP identified further PRS implementation issues including limited funding models, diversity issues, need for clinical guidelines and ongoing updates given the rapid pace of PRS research.

Conclusions

Delivery of a novel education program can improve GHP attitudes, confidence, knowledge, and preparedness using PRS. Careful consideration of healthcare providers’ learning needs is required to support PRS research and clinical translation.
Prediction and Design of Protease Enzyme Specificity Using a Structure-Aware Graph Convolutional Network
Authors: Lu Changpeng , Lubin Joseph H. , Sarma Vidur V. , Stentz Samuel Z. , Wang Guanyang , Wang Sijian , Khare Sagar D.
Published: February 2023

Site-specific proteolysis by the enzymatic cleavage of small linear sequence motifs is a key post-translational modification involved in physiology and disease. The ability to robustly and rapidly predict protease substrate specificity would also enable targeted proteolytic cleavage – editing – of a target protein by designed proteases. Current methods for predicting protease specificity are limited to sequence pattern recognition in experimentally-derived cleavage data obtained for libraries of potential substrates and generated separately for each protease variant. We reasoned that a more semantically rich and robust model of protease specificity could be developed by incorporating the three-dimensional structure and energetics of molecular interactions between protease and substrates into machine learning workflows. We present Protein Graph Convolutional Network (PGCN), which develops a physically-grounded, structure-based molecular interaction graph representation that describes molecular topology and interaction energetics to predict enzyme specificity. We show that PGCN accurately predicts the specificity landscapes of several variants of two model proteases: the NS3/4 protease from the Hepatitis C virus (HCV) and the Tobacco Etch Virus (TEV) proteases. Node and edge ablation tests identified key graph elements for specificity prediction, some of which are consistent with known biochemical constraints for protease:substrate recognition. We used a pre-trained PGCN model to guide the design of TEV protease libraries for cleaving two non-canonical substrates, and found good agreement with experimental cleavage results. Importantly, the model can accurately assess designs featuring diversity at positions not present in the training data. The described methodology should enable the structure-based prediction of specificity landscapes of a wide variety of proteases and the construction of tailor-made protease editors for site-selectively and irreversibly modifying chosen target proteins.
Functional organization of visual responses in the octopus optic lobe
Authors: Pungor Judit R. , Allen V. Angelique , Songco-Casey Jeremea O. , Niell Cristopher M.
Published: February 2023

Cephalopods are highly visual animals with camera-type eyes, large brains, and a rich repertoire of visually guided behaviors. However, the cephalopod brain evolved independently from that of other highly visual species, such as vertebrates, and therefore the neural circuits that process sensory information are profoundly different. It is largely unknown how their powerful but unique visual system functions, since there have been no direct neural measurements of visual responses in the cephalopod brain. In this study, we used two-photon calcium imaging to record visually evoked responses in the primary visual processing center of the octopus central brain, the optic lobe, to determine how basic features of the visual scene are represented and organized. We found spatially localized receptive fields for light (ON) and dark (OFF) stimuli, which were retinotopically organized across the optic lobe, demonstrating a hallmark of visual system organization shared across many species. Examination of these responses revealed transformations of the visual representation across the layers of the optic lobe, including the emergence of the OFF pathway and increased size selectivity. We also identified asymmetries in the spatial processing of ON and OFF stimuli, which suggest unique circuit mechanisms for form processing that may have evolved to suit the specific demands of processing an underwater visual scene. This study provides insight into the neural processing and functional organization of the octopus visual system, highlighting both shared and unique aspects, and lays a foundation for future studies of the neural circuits that mediate visual processing and behavior in cephalopods.

Highlights

The functional organization and visual response properties of the cephalopod visual system are largely unknown

Using calcium imaging, we performed mapping of visual responses in the octopus optic lobe

Visual responses demonstrate localized ON and OFF receptive fields with retinotopic organization

ON/OFF pathways and size selectivity emerge across layers of the optic lobe and have distinct properties relative to other species
Hemi Manganese Exchangers 1 and 2 enable manganese import at the plasma membrane in cyanobacteria
Authors: Reis Mara , Brandenburg Fabian , Knopp Michael , Flachbart Samantha , Bräutigam Andrea , Metzger Sabine , Gould Sven B. , Eisenhut Marion
Published: February 2023

Manganese (Mn) is key to oxygenic photosynthesis as it catalyzes the splitting of water in photosystem II and functions as cofactor of multiple enzymes. A single ABC-type transporter, MntCAB, is so far established for the uptake of the metal under limiting conditions in cyanobacteria. It is unknown how Mn is imported under replete conditions. We identified two proteins in the cyanobacteriumSynechocystissp. PCC 6803, which are homologous to the unknown protein family 0016 (UPF0016) member manganese exporter (Mnx). In contrast to Mnx, which consists of six transmembrane domains, the new candidate proteins contain three transmembrane domains. Hence, we named them hemi manganese exchangers (Hmx) 1 and 2. Knock-out mutants inhmx1and/orhmx2showed sensitivity toward low Mn supplementation, and reduced intracellular Mn pools. Additional deletion ofmntChindered the cells to thrive unless the medium was supplemented with Mn to compensate for the depletion of their intracellular Mn pool. In accordance with the observed localization of Hmx1 and Hmx2 in the plasma membrane, we postulate a Mn uptake function for heteromeric Hmx1/2 across the plasma membrane under a wide range of Mn concentrations and a supporting role for the MntCAB system under Mn-limiting conditions. On the basis of their phylogenies, we propose that Hmx1 and Hmx2 are the ancestral progenitors of eukaryote-type UPF0016 proteins with six transmembrane domains. The Mn transport function of Hmx1/2 underscores this as a fundamental and ancient feature of the UPF0016 family. Potentially, Hmx1 and Hmx2 coevolved with the internalization of the oxygen-evolving complex.