bluuebunny/crossref_metadata_2025 huggingface dataset:
Preferences for Weight Gain Compared With Other Antiretroviral Therapy Side Effects in People Living With HIV: A Discrete Choice Experiment
Authors: Tieosapjaroen Warittha , Fairley Christopher K. , Chow Eric P.F. , Aguirre Ivette , Hoy Jennifer F. , Ong Jason J.
Published: July 2022

Backgroud:

Antiretroviral (ARV) side effects are a critical determinant of adherence among people living with HIV (PLWH). Integrase strand transfer inhibitors (INSTIs), a commonly used ARV, have been reported to cause weight gain. We determined the relative importance of weight gain compared with other side effects from the perspective of PLWH.

Setting:

Melbourne Sexual Health Centre and the Alfred Hospital in Victoria, Australia.

Methods:

We conducted a discrete choice experiment survey to explore PLWH's preferences for 8 short-term side effects (eg, weight gain and depression) and 4 long-term side effects (eg, long-term weight gain and risks of heart attack). We sent an anonymous survey link through short message service (SMS) and postcards to PLWH attending both centers between July and August 2021. The choice data were analyzed using random parameter logit (RPL) and latent class (LCM) models.

Results:

Three hundred thirty-five respondents were included: most were male (88.1%). In the RPL analyses, weight gain was the second most important attribute after depression for short-term side effects and the third most important attribute after risk of heart attack and kidney problem for long-term side effects. In the LCM analyses, 23.9% were most sensitive to short-term weight gain, whereas 16.0% were most sensitive to long-term weight gain.

Conclusions:

Weight gain was the second most important short-term side effect and the third most important long-term side effect in a cohort of Australian PLWH. However, weight gain was the most important side effect of ARV for a significant minority.
FDG PET/CT in Unilateral Renal Metastasis From Colon Cancer
Authors: Ji Xia , Dong Aisheng
Published: July 2022

Renal metastasis from colon cancer is rare. We describe FDG PET/CT findings in a case with a right renal and a postcaval lymph node metastasis from colon cancer. Both the renal tumor and postcaval lymph node showed increased FDG uptake with SUVmax of 6.1 for the renal tumor and 5.5 for the postcaval lymph node. The imaging findings mimicked a primary renal cancer with postcaval lymph node metastasis.
18F-FDOPA and MRI Findings in a Case of Multiple Sclerosis
Authors: Lersy François , Kremer Stéphane , Chibbaro Salvatore , Namer Izzie Jacques , Bund Caroline
Published: July 2022

A 39-year-old woman with no significant medical history underwent a brain MRI because of headaches and dysarthria having lasted 3 weeks. A tumor lesion was suspected. PET imaging was decided. She underwent FDG and FDOPA PET, leading to the diagnosis of low-grade glioma. Three months later, a new imaging assessment was organized. It showed a decrease in the hypermetabolism of the lesion and the appearance of a second lesion questioning the diagnosis. Further assessment led to the conclusion of a multiple sclerosis. This case illustrates that FDOPA PET uptake should be interpreted with caution in patients with suspected primary brain tumors.
Elevated 68Ga-FAPI Uptake by Primary Benign Intraosseous Meningioma
Authors: Gong Weidong , Yang Xiao , Li Lanying , Ma Jiao , Zhang Chunyin
Published: July 2022

Intraosseous meningioma is an extremely rare benign tumor. We present the 68Ga–fibroblast activation protein inhibitor (FAPI) PET/CT findings of primary intraosseous meningioma in a 71-year-old woman. 68Ga-FAPI PET/CT revealed an intraosseous mass in the right parietal bone with increased FAPI activity. Primary skull malignancy was suspected. However, pathological examination after resection of the mass in the right parietal bone confirmed the diagnosis of benign meningioma (WHO I). A final diagnosis of benign intraosseous meningioma was made.
Congenital Melanocytic Nevi Syndrome With Leptomeningeal Melanoma
Authors: Mohite Ashish , Agrawal Archi , Purandare Nilendu , Shah Sneha , Puranik Ameya , Choudhury Sayak , Dev Indraja , Ghosh Suchismita , Rangarajan Venkatesh
Published: July 2022

The incidence of congenital melanocytic nevi (CMNs) is 1% to 6% for small- to intermediate-size nevi to 1 in 500,000 for giant size nevi. Large and satellite CMNs are known to be associated with neurocutaneous melanosis and central nervous system malformations such as Dandy-Walker malformation, defects of the vertebra-skull, and intraspinal lipomas. We hereby present a case of CMN syndrome in an 18-year-old girl with leptomeningeal melanoma, evaluated with MRI, adequately staged, and screened with FDG PET.
Craniofacial Fellowship Applicant Perceptions of Virtual Interviews
Authors: Yoon Joshua , Pan Judy , Major Melanie , Chang Daniel R. , Ha Michael , Rasko Yvonne , Naran Sanjay , Grant Michael P. , Yang Robin , Liang Fan , Steinberg Jordan P.
Published: July 2022

Introduction:

The 2021 interview cycle for craniofacial fellowship applicants was the first to be held virtually due to the coronavirus disease 2019 pandemic. Here, we detail the craniofacial fellowship applicant perceptions and experience on the virtual interview process.

Materials and Methods:

An institutional review board–approved 35-question survey study on the perception of the virtual interview process among craniofacial fellowship applicants was conducted. Surveys were distributed to individuals who had applied through the match, overseen by the American Society of Craniofacial Surgeons (ASCFS).

Results:

Ten surveys were fully completed with a corresponding response rate of 48%. The average number of interviews completed was 12.7±7.7 and 50% of applicants interviewed at >1 program in a single day. Overall, 90% of respondents preferred in-person interviews before the interview season, however, only 10% preferred the in-person format afterwards. Preference for a virtual-only format increased from 10% to 70%. Applicants cited cost (100%), ease of scheduling (90%), and ability to participate in more interviews (70%) as the primary strengths of the virtual platform; none reported difficulties with self-advocacy. After the interview cycle, 90% stated they would recommend virtual interviews.

Conclusions:

The greatest strengths of virtual interviews were the ability to participate in more interviews, the ease of scheduling, and the cost benefits. Most applicants reported the same or increased ability for self-advocacy with virtual interviews. Following the index interview cycle for 2021, the majority of fellowship applicants now appear to prefer a virtual-only or hybrid format and would recommend virtual interviews in the future.
Follow-up Schedule for Patients With Sentinel Node–negative Cutaneous Melanoma (The MELFO Study)
Authors: Moncrieff Marc D. , Bastiaannet Esther , Underwood Beverly , Francken Anne Brecht , Garioch Jennifer , Damude Samantha , Heaton Martin , Deckers Eric A. , Patel Nakul , Hoekstra-Weebers Josette E. , Hoekstra Harald J.
Published: July 2022

Objectives and Design:

The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines.

Background:

Evidence-based guidelines for the follow-up of sentinel node–negative melanoma patients are lacking.

Methods:

Overall, 388 adult patients diagnosed with sentinel node–negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared.

Results:

At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54–1.39, P=0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P=0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49–2.07, P=0.99).

Conclusions:

A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node–negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients’ acceptance is very high.
Executive Dysfunction, Social Cognition Impairment, and Gray Matter Pathology in Myotonic Dystrophy Type 2: A Pilot Study
Authors: Theodosiou Thomas , Christidi Foteini , Xirou Sofia , Karavasilis Efstratios , Bede Peter , Papadopoulos Constantinos , Argyropoulos Georgios D. , Kourtesis Panagiotis , Pantolewn Varvara , Ferentinos Panagiotis , Kararizou Evangelia , Velonakis Georgios , Zalonis Ioannis , Papadimas Georgios
Published: July 2022

Background:

In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized.

Objective:

To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2.

Method:

Eleven genetically confirmed individuals with DM2 and 26 age- and education-matched healthy controls were administered the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) to screen for impairment in multiple cognitive domains. MRI data were evaluated by morphometric analyses to identify disease-specific gray and white matter alterations. The following statistical thresholds were used for cognitive comparisons: P
FDR < 0.05 and Bayes factor (BF10) >10.

Results:

The DM2 group exhibited cognitive impairment (ECAS Total score; P
FDR = 0.001; BF10 = 108.887), which was dominated by executive impairment (P
FDR = 0.003; BF10 = 25.330). A trend toward verbal fluency impairment was also identified. No significant impairments in memory, language, or visuospatial function were captured. The analysis of subscores revealed severe impairments in social cognition and alternation. Voxel-based morphometry identified widespread frontal, occipital, and subcortical gray matter atrophy, including the left superior medial frontal gyrus, right medial orbitofrontal gyrus, right operculum, right precuneus, bilateral fusiform gyri, and bilateral thalami.

Conclusion:

DM2 may be associated with multifocal cortical and thalamic atrophy, which is likely to underpin the range of cognitive manifestations mostly characterized by executive impairment and specifically by impaired social cognition.
Integrating Mendelian randomization and literature-mined evidence for breast cancer risk factors
Authors: Vabistsevits Marina , Robinson Tim , Elsworth Ben , Liu Yi , Gaunt Tom R
Published: July 2022

Abstract Figure

Graphical Abstract

Objective

An increasing challenge in population health research is efficiently utilising the wealth of data available from multiple sources to investigate disease mechanisms and identify potential intervention targets. The use of biomedical data integration platforms can facilitate evidence triangulation from these different sources, improving confidence in causal relationships of interest. In this work, we aimed to integrate Mendelian randomization (MR) and literature-mined evidence from the EpiGraphDB biomedical knowledge graph to build a comprehensive overview of risk factors for developing breast cancer.

Methods

We utilised MR-EvE (“Everything-vs-Everything”) data to identify candidate risk factors for breast cancer and generate hypotheses for potential mediators of their effect. We also integrated this data with literature-mined relationships, which were extracted by overlapping literature spaces of risk factors and breast cancer. The literature-based discovery (LBD) results were followed up by validation with two-step MR to triangulate the findings from two data sources.

Results

We identified 129 novel and established lifestyle risk factors and molecular traits with evidence of an effect on breast cancer, and made the MR results available in an R/Shiny app (https://mvab.shinyapps.io/MR_heatmaps/). We developed an LBD approach for identifying potential mechanistic intermediates of identified risk factors. We present the results of MR and literature evidence integration for two case studies (childhood body size and HDL-cholesterol), demonstrating their complementary functionalities.

Conclusion

We demonstrate that MR-EvE data offers an efficient hypothesis-generating approach for identifying disease risk factors. Moreover, we show that integrating MR evidence with literature-mined data may be used to identify causal intermediates and uncover the mechanisms behind the disease.
Incorporating Algorithmic Uncertainty into a Clinical Machine Deep Learning Algorithm for Urgent Head CTs
Authors: Yoon Byung C. , Pomerantz Stuart R. , Mercaldo Nathaniel D. , Goyal Swati , L’Italien Eric , Lev Michael H. , Buch Karen , Buchbinder Bradley R. , Chen John W. , Conklin John , Gupta Rajiv , Hunter George J. , Kamalian Shahmir M. , Kelly Hillary R. , Rapalino Otto , Rincon Sandra P. , Romero Javier M. , He Julian , Schaefer Pamela W. , Do Synho , González R. Gilberto
Published: July 2022

Machine learning (ML) algorithms to detect critical findings on head CTs may expedite patient management. Most ML algorithms for diagnostic imaging analysis utilize dichotomous classifications to determine whether a specific abnormality is present. However, imaging findings may be indeterminate, and algorithmic inferences may have substantial uncertainty. We incorporated awareness of uncertainty into an ML algorithm that detects intracranial hemorrhage or other urgent intracranial abnormalities and evaluated prospectively identified, 1000 consecutive noncontrast head CTs assigned to Emergency Department Neuroradiology for interpretation. The algorithm classified the scans into high (IC+) and low (IC-) probabilities for intracranial hemorrhage or other urgent abnormalities. All other cases were designated as No Prediction (NP) by the algorithm. The positive predictive value for IC+ cases (N = 103) was 0.91 (CI: 0.84-0.96), and the negative predictive value for IC-cases (N = 729) was 0.94 (0.91-0.96). Admission, neurosurgical intervention, and 30-day mortality rates for IC+ was 75% (63-84), 35% (24-47), and 10% (4-20), compared to 43% (40-47), 4% (3-6), and 3% (2-5) for IC-. There were 168 NP cases, of which 32% had intracranial hemorrhage or other urgent abnormalities, 31% had artifacts and postoperative changes, and 29% had no abnormalities. An ML algorithm incorporating uncertainty classified most head CTs into clinically relevant groups with high predictive values and may help accelerate the management of patients with intracranial hemorrhage or other urgent intracranial abnormalities.
Computational Causal Discovery for Posttraumatic Stress and Negative Self Image in Young Maltreated Children
Authors: Saxe Glenn N. , Morales Leah J. , Ma Sisi , Urgurbil Mehmet , Aliferis Constantin
Published: July 2022

Objectives

This article features the application of computational causal discovery (CCD) methods to determine the mechanism for Posttraumatic Stress (PTS) in young, maltreated children, in order to advance knowledge for prevention. Advances in prevention require research that identifies causal factors, but the scientific literature that would inform the identification of causes are almost exclusively based on the application of correlational methods to observational data. Causal inferences from such research will frequently be in error. We conducted the present study to explore the application of CCD methods as an alternative – or a supplement – to experimental methods, which can rarely be applied in human research on causal factors for PTS.

Methods

A data processing pipeline that integrates state-of-the-art CCD algorithms was applied to an existing observational, longitudinal data set collected by the Consortium for Longitudinal Studies in Child Abuse and Neglect (LONGSCAN). This data set contains a sample of 1,354 children who were identified in infancy to early childhood as being maltreated or at risk.

Results

A causal network model of 251 variables (nodes) and 818 bivariate relations (edges) was discovered, revealing four direct causes and two direct effects for PTS at age 8, within a network containing a broad diversity of causal pathways. Specific causal factors included stress, social, family and development problems: and several of these factors point to promising approaches for prevention.

Conclusions

These results indicate that CCD methods show promise for research on the complex etiology of PTS in young, maltreated children.
Investigating causality in the association between DNA methylation and prevalent T2D using a bidirectional two-sample Mendelian Randomization
Authors: Juvinao-Quintero Diana L. , Sharp Gemma C. , Sanderson Eleanor , Relton Caroline L. , Elliott Hannah R.
Published: July 2022

Aim

Several studies have identified associations between type 2 diabetes (T2D) and DNA methylation (DNAm). However, the causal role of these associations remains unclear. This study aims to provide evidence for a causal relationship between DNA methylation and T2D.

Methods

We implemented a bidirectional two-sample Mendelian randomization (2SMR) to evaluate causality at 58 CpG sites previously detected in a meta-analysis of epigenome-wide association studies (meta-EWAS) of prevalent T2D in Europeans. We retrieved genetic proxies for T2D and DNAm from the largest GWAS available. We also used data from the Avon Longitudinal Study of Parents and Children (ALSPAC, UK) when associations of interest were not available in the larger datasets. We identified 62 independent SNPs as proxies for T2D, and 39 methylation quantitative trait loci or mQTL as proxies for 30 of the 58 T2D-related CpGs. We applied correction for multiple testing using Bonferroni and inferred causality based on a P < 1.0×10−3 or P < 2.0×10−3 for the T2D⟶ DNAm direction, and the opposing DNAm ⟶ T2D direction of the 2SMR, respectively.

Results

We found strong evidence of causality of DNAm at cg25536676 (DHCR24) on T2D, where an increase in transformed residuals of DNAm at this site were associated with 43% (OR=1.43, 95%CI=1.15-1.78, P=0.001) higher risk of T2D. We infer a likely causal direction for the remaining CpG sites assessed. In silico analyses showed that CpGs analyzed were enriched for eQTMs, and for specific traits dependent on the direction of causality predicted by 2SMR.

Conclusions

We identified one CpG mapping to a gene related with the metabolism of lipids (DHCR24), as a novel causal biomarker for the risk of T2D. CpGs within the same gene-region have previously been associated with T2D-related traits in observational studies (BMI, waist circumference, HDL-cholesterol, insulin) and in MR analyses (LDL-cholesterol). Thus, we hypothesize that our candidate CpG in DHCR24 may be a causal mediator of the association between known modifiable risk factors and T2D. Formal causal mediation analysis should be implemented to further validate this assumption.
Mixed Methods Sequential Epidemiological Protocol (MMSEP) for Evaluation of Time Utilization by the Community Health Workers and Factors Affecting its Optimization
Authors: Kalne Poonam Sanjay , Joshi Shiv Hiren , Kalne Pooja Sanjay , Mehendale Ashok Madhukar
Published: July 2022

Background

Many countries have a significant shortage of healthcare staff, resulting in a reduction in the range and quality of services. Low and middle-income countries rely heavily on Community Health Workers. Existing data suggests a lack of clarity regarding the scope of work as well as about the utilization of the working hours. The purpose of this work is to propose a protocol to evaluate the time utilization of the Community Health Workers and to identify the promoters and challenges that they come across while delivering their duties so that the workflow optimization processes can be hypothesized.

Methods

The Mixed Methods Sequential Epidemiological Protocol incorporates three phases. Phase I includes free listing to identify Community Health Workers’ workflow using a generic form with a single open-ended question for each cadre. After pile-sorting the free lists, the pile names should be used as categories for the time-motion study to be done in phase II. For each of these categories, time spent should be recorded and analyzed. Phase III includes in-depth interviews with Community Health Workers who use considerably varied times for the same category of work.

Discussion

The intended study will help in comparing the workflow of different cadres of health workers and finding out different factors promoting and inhibiting better utilization of their working hours. This approach will inform reasonable and feasible improvements to health-related planning of services and utilization of the health workforce and will help in increasing the efficiency of health workers to deliver services.

Author contributions
Temperature dependence of competitive ability differs from that of growth rate
Authors: Sunday Jennifer M. , Bernhardt Joey , Harley Christopher , O’Connor Mary I.
Published: July 2022

The effect of climate warming on future community composition is expected to be contingent on competitive outcomes, yet we currently lack mechanistic ecological understanding of how temperature affects competitive ability. Here, we combine resource competition theory with metabolic scaling theory and test hypotheses about how the temperature dependence of competitive ability changes with temperature. We find that the minimum resource requirement for growth, R* – an inverse indicator of competitive ability in phytoplankton – changes with temperature following a U-shaped pattern in all four species tested. The shape of temperature-dependence of competitive ability is systematically different from the temperature-dependence of population growth rates, both in our experiments and in collated data from previous studies. Our results suggest that exploitative competitive success is highest at temperatures that are sub-optimal for growth, and declines rapidly at both cold and warm ends of the thermal performance curve.
Two major extinction events in the evolutionary history of turtles: one caused by a meteorite, the other by hominins
Authors: Pereira Anieli G. , Antonelli Alexandre , Silvestro Daniele , Faurby Søren
Published: July 2022

We live in a time of highly accelerated extinction, which has the potential to mirror past mass extinction events. However, the rarity of these events and the restructuring of diversity that they cause complicate direct comparisons between the current extinction crisis and earlier mass extinctions. Among animals, turtles (Testudinata) are one of few groups which both have a sufficient fossil record and a sufficiently stable ecological importance to enable meaningful comparisons between the end Cretaceous mass extinction and the ongoing extinction event. In this paper we analyze the fossil record of turtles and recover three significant peaks in extinction rate. Two of these are in the Cretaceous, the second of these took place at the Cretaceous–Paleogene transition (K-Pg), reflecting the overall patterns previously reported for many other taxa. The third major extinction event started in the Pliocene and continues until now. This peak only affected terrestrial turtles and started much earlier in Eurasia and Africa lineages than elsewhere. This suggests that it may be linked to co-occurring hominins rather than having been caused by global climate change.
Genetic affinities and sub-structuring in Coorg population of Southern India
Authors: Mukhopadhyay Anirban , Kumar Lomous , Sran Kiran , Thangaraj Kumarasamy , Thelma B K
Published: July 2022

The Coorgs, also known as Kodavas, are one of the smallest religious and socio-culturally homogenous communities in the world, currently residing in the state of Karnataka, India. Due to a stark contrast with the surrounding subpopulations, their genetic architecture and population & demographic history have been a matter of debate for long. To better understand the population structure and demographic history of this caste group, we analysed the population, using high-resolution autosomal (n=70) as well uniparentally inherited markers (Y-chromosomal and mitochondrial DNA) (n=144). Our first ever findings elucidate that origin of Coorgs traces back to early or middle Bronze Age. We further found population substructure among Coorgs, which manifested as three distinct clusters in a Principal component analysis. One of these subgroups has undergone a rare and immense amount of population-specific drift but all three eventually admixed, both genetically and socio-culturally. The mtDNA analysis showed 40% South Asian-specific mitochondrial lineages among Coorgs; while the Y-chromosomal analysis revealed predominant presence of Eurasian, Middle-Eastern and Indian-specific haplogroups suggesting male-centric migration and eventual assimilation with local females. Our results for the first time identify these ancient and distinct genealogies that make up the contemporary Coorgs and may explain the socio-cultural differences with their immediate and distant neighbours in the country and the prevalent narrative history. In a wider context, the study also reveals an ancient, yet unknown, Middle Eastern source population that might have contributed to an early west to east migration into India.
Coupling of oxytocin and cholecystokinin pathways in the hypothalamus is required for gut-to-brain homeostatic feeding control
Authors: Gruber T , Lechner F , Murat C , Contreras RE , Sanchez-Quant E , Miok V , Le Thuc O , González-García I , Williams RH , Pfluger PT , Müller TD , Woods SC , Martinez-Jimenez CP , Tschöp MH , Grinevich V , García-Cáceres C
Published: July 2022

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut including cholecystokinin (CCK) to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on chow diet. Notably, exposing wildtype mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity towards CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in DIO mice via chemogenetics or polypharmacology sufficiently re-establishes CCK’s anorexigenic effects. Lastly, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under HFHS diet, which restrains their CCK-evoked activation. In sum, we here document a novel (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.
A drop-on-demand bioprinting approach to spatially arrange multiple cell types and monitor their cell-cell interactions towards vascularization based on endothelial cells and mesenchymal stem cells
Authors: Weygant Joshua , Koch Fritz , Adam Katrin , Troendle Kevin , Zengerle Roland , Finkenzeller Günter , Kartmann Sabrina , Koltay Peter , Zimmermann Stefan
Published: July 2022

Spheroids, organoids, or highly-dense cell-laden droplets are often used as building blocks for bioprinting, but so far little is known about the spatio-temporal cellular interactions post printing. We present a drop-on-demand approach to study the biological interactions of such building blocks in micrometer dimensions. Droplets (containing approximately 700 cells in 10 nl) of multiple cell types are patterned in a 3D hydrogel matrix with a precision of less than 70 μm. It is applied to investigate interactions of cell types relevant for vascularization approaches. We show that a gap of 200 μm between droplets containing endothelial cells (HUVECs) and adipose-derived mesenchymal stem cells (ASCs) leads to decreased sprouting of HUVECs towards ASCs and increased growth from ASCs towards HUVECs. For mixed aggregates containing both cell types, cellular interconnections of ASCs with up to approximately 0.8 millimeter length and inhibition of HUVEC sprouting are observed. When ASCs are differentiated into smooth muscle cells (SMCs), HUVECs display decreased sprouting towards SMCs in separate aggregates, whereas no cellular interconnections or inhibition of HUVEC sprouting are detected for mixed aggregates. These findings demonstrate that this approach acts as a new tool to investigate cell-cell interactions of different cell types in 3D bioprinted constructs.
Misaligned chromosomes that satisfy the spindle assembly checkpoint are a strong predictor of micronuclei formation in dividing cancer cells
Authors: Gomes Ana Margarida , Orr Bernardo , Novais-Cruz Marco , De Sousa Filipe , Ferrás Cristina , Maiato Helder
Published: July 2022

Chromosome alignment to the spindle equator is a hallmark of mitosis that is thought to promote chromosome segregation fidelity in metazoans. Yet, chromosome alignment is only indirectly supervised by the spindle assembly checkpoint (SAC) as a byproduct of chromosome bi-orientation, and the consequences of defective chromosome alignment remain unclear. Here we investigated how human cells respond to chromosome alignment defects of distinct molecular nature by following the fate of live HeLa cells after RNAi-mediated depletion of 120 proteins previously implicated in chromosome alignment. Surprisingly, in all cases, cells frequently entered anaphase after a delay with chronically misaligned chromosomes. Using depletion of key proteins as prototypes for defective chromosome alignment, we show that chronically misaligned chromosomes often satisfy the SAC and directly missegregate. In-depth analysis of specific molecular perturbations that prevent proper kinetochore-microtubule attachments revealed that chronically misaligned chromosomes that missegregate frequently result in micronuclei. Higher-resolution live-cell imaging indicated that, contrary to most anaphase lagging chromosomes that correct and reintegrate the main nuclei, chronically misaligned chromosomes are a strong predictor of micronuclei formation in a cancer cell model of chromosomal instability, but not in normal near-diploid cells. We provide evidence supporting that intrinsic differences in kinetochore-microtubule attachment stability on misaligned chromosomes account for this distinct outcome. Thus, chronically misaligned chromosomes that satisfy the SAC may represent a previously overlooked mechanism driving chromosomal/genomic instability during cancer cell division, and we unveil genetic conditions predisposing for these events.
Embryoid bodies facilitate comparative analysis of gene expression in humans and chimpanzees across dozens of cell types
Authors: Barr Kenneth A , Rhodes Katherine L , Gilad Yoav
Published: July 2022

Comparative gene expression studies in apes are fundamentally limited by the challenges associated with sampling across different tissues. Here, we used single-cell RNA-sequencing of embryoid bodies (EBs) to collect transcriptomic data from over 70 cell types in three humans and three chimpanzees. We found hundreds of genes whose regulation is conserved across cell types, as well as genes whose regulation likely evolves under directional selection in one or a handful of cell types. Using EBs from a human-chimpanzee fused cell line, we also inferred the proportion of inter-species regulatory differences due to changes in cis and trans elements between the species. Thus, we present the most comprehensive dataset of comparative gene expression from humans and chimpanzees to date, including a catalog of regulatory mechanisms associated with inter-species differences.
Reassessing the abundance of miRNAs in the human pancreas and rodent cell lines and its implication
Authors: Sun Guihua , Qi Meirigeng , Kim Alexis S. , Lizhar Elizabeth M. , Al-Abdullah Ismail H , Riggs Arthur D.
Published: July 2022

miRNAs are critical for pancreas development and function. However, we found that there are discrepancies of pancreatic miRNA abundance in published datasets. To obtain a more relevant profile that is close to the true profile, we profiled small RNAs from human islets cells, acini, and four rodent pancreatic cell lines routinely used in diabetes and pancreatic research using a bias reduction protocol for small RNA sequencing. In contrast to the previous notion that miR-375-3p is the sole dominant pancreatic miRNA, we found that miR-148a-3p and miR-7-5p were equally abundant in islets.In silicostudies using predicted and validated targets of these three miRNAs revealed that they possibly work in cooperation to modulate cell differentiation in endocrine and exocrine cells. Our results also suggest, compare to the well characterized miR-375, both miR-148a-3p and miR-7-5p may play more critical roles in human pancreas development and function. Moreover, according toin silicopredicted targets, we found that miR-375-3p had a much broader target spectrum by targeting the coding sequence and the 5’ untranslated region rather than the conventional 3’ untranslated region, suggesting additional unexplored roles for miR-375-3p beyond pancreas. Our study provides a valuable resource for studying miRNAs in pancreas.
PerturbNet predicts single-cell responses to unseen chemical and genetic perturbations
Authors: Yu Hengshi , Welch Joshua D.
Published: July 2022

Small molecule treatment and gene knockout or overexpression induce complex changes in the molecular states of cells, and the space of possible perturbations is too large to measure exhaustively. We present PerturbNet, a deep generative model for predicting the distribution of cell states induced by unseen chemical or genetic perturbations. Our key innovation is to use high-throughput perturbation response data such as Perturb-Seq to learn a continuous mapping between the space of possible perturbations and the space of possible cell states.

Using Sci-Plex and LINCS datasets, PerturbNet can accurately predict the distribution of gene expression changes induced by unseen small molecules given only their chemical structures. PerturbNet also accurately predicts gene expression changes induced by shRNA, CRISPRi, or CRISPRa perturbations using a perturbation network trained on gene functional annotations. Furthermore, self-supervised sequence embeddings allow PerturbNet to predict gene expression changes induced by missense mutations. We also use PerturbNet to attribute cell state shifts to specific perturbation features, including atoms and functional gene annotations. Finally, we leverage PerturbNet to design perturbations that achieve a desired cell state distribution. PerturbNet holds great promise for understanding perturbation responses and ultimately designing novel chemical and genetic interventions.
Brain-implanted conductors amplify radiofrequency fields in rodents: advantages and risks
Authors: Vöröslakos Mihály , Yaghmazadeh Omid , Alon Leeor , Sodickson Daniel K. , Buzsáki György
Published: July 2022

Over the past few decades, daily exposure to radiofrequency (RF) fields has been increasing due to the rapid development of wireless and medical imaging technologies. Under extreme circumstances, exposure to very strong RF energy can lead to heating of body tissue, even resulting in tissue injury. The presence of implanted devices, moreover, can amplify RF effects on surrounding tissue. Therefore, it is important to understand the interactions of RF fields with tissue in the presence of implants, in order to establish appropriate wireless safety protocols, and also to extend the benefits of medical imaging to increasing numbers of people with implanted medical devices. This study explored the neurological effects of RF exposure in rodents implanted with neuronal recording electrodes. We exposed freely moving and anesthetized rats and mice to 950 MHz RF energy while monitoring their brain activity, temperature, and behavior. We found that RF exposure could induce fast onset firing of single neurons without heat injury. In addition, brain implants enhanced the effect of RF stimulation resulting in reversible behavioral changes. Using an optical temperature measurement system, we found greater than tenfold increase in brain temperature in the vicinity of the implant. On the one hand, our results underline the importance of careful safety assessment for brain implanted devices, but on the other hand, we also show that metal implants may be used for neurostimulation if brain temperature can be kept within safe limits.
Pre-Germinal Center Interactions with T Cells are Natural Checkpoints to Limit Autoimmune B Cell Responses
Authors: Parham Kate A , Tan Xiu Xia Sherry , Morelli Daniel M , Chowdhury Lika , Craig Heather C , Kerfoot Steven M
Published: July 2022

Interactions with antigen-specific T cells drive B cells activation and fate choices that ultimately determine the quality of high-affinity antibody responses. As such, thse interactions, and especially the long-lived interactions that occur prior to germinal center formation, may be important checkpoints to regulate undesirable responses. We directly observed interactions between T and B cells responding to the self-antigen Myelin Oligodendrocyte Glycoprotein (MOG) and found that they are of lower quality compared to interactions between cells responding to the model foreign antigen NP-ovalbumin (NP-OVA). This was associated with reduced expression of molecules that facilitate these interactions on the B cells but not on T cells. B cell expression of these molecules was not dictated by the T cell partner, nor could the relative lack of expression on MOG-sp. B cells be reversed by a multivalent antigen. Instead, MOG-sp. B cells were inherently less responsive to B cell Receptor stimulation than MOG-non-sp. cells. However, the phenotype of MOG-sp. B cells was not consistent with previous descriptions of autoimmune B cells that had been tolerized via regular exposure to systemically-expressed self-antigen. This suggests that alternate anergy pathways may exist to limit B cell responses to tissue-restricted self-antigens.
Single nuclei analyses reveal transcriptional profiles and marker genes for diverse supraspinal populations
Authors: Beine Zachary , Wang Zimei , Tsoulfas Pantelis , Blackmore Murray G.
Published: July 2022

The mammalian brain contains numerous neurons distributed across forebrain, midbrain, and hindbrain that project axons to the lower spinal cord and work in concert to control movement and achieve homeostasis. Extensive work has mapped the anatomical location of supraspinal cell types and continues to establish specific physiological functions. The patterns of gene expression that typify and distinguish these disparate populations, however, are mostly unknown. Here we combined retrograde labeling of supraspinal cell nuclei with fluorescence activated nuclei sorting and single nuclei RNA sequencing analyses to transcriptionally profile neurons that project axons from the mouse brain to lumbar spinal cord. We identified fourteen transcriptionally distinct cell types and used a combination of established and newly identified marker genes to assign an anatomical location to each. To validate the putative marker genes, we visualized selected transcripts and confirmed selective expression within lumbar-projecting neurons in discrete supraspinal regions. Finally, we illustrate the potential utility of these data by examining the expression of transcription factors that distinguish different supraspinal cell types and by surveying the expression of receptors for growth and guidance cues that may be present in the spinal cord. Collectively these data establish transcriptional differences between anatomically defined supraspinal populations, identify a new set of marker genes of use in future experiments, and provide insight into potential differences in cellular and physiological activity across the supraspinal connectome.

SIGNIFICANCE STATEMENT

The brain communicates with the body through a wide variety of neuronal populations with distinct functions and differential sensitivity to damage and disease. We have employed single nuclei RNA sequencing technology to distinguish patterns of gene expression within a diverse set of neurons that project axons from the mouse brain to the lumbar spinal cord. The results reveal transcriptional differences between populations previously defined on the basis of anatomy, provide new marker genes to facilitate rapid identification of cell type in future work, and suggest distinct responsiveness of different supraspinal populations to external growth and guidance cues.
Drosophila cap-binding protein eiF4EHP promotes translation via a 3’UTR-dependent mechanism under hypoxia and contributes to fruit fly adaptation to oxygen variations
Authors: Liang Manfei , Hody Clara , Yammine Vanessa , Soin Romuald , Sun Yuqiu , Lin Xing , Tian Xiaoying , Meurs Romane , Perdrau Camille , Delacourt Nadège , Andris Fabienne , Conrard Louise , Kruys Véronique , Gueydan Cyril
Published: July 2022

Hypoxia induces profound modifications in gene expression program enabling eukaryotic cells to adapt to lowered ATP supply resulting from the blockade of oxidative phosphorylation. One major consequence of oxygen deprivation is the massive repression of protein synthesis, leaving a limited set of mRNAs to be translated. D. melanogaster is strongly resistant to oxygen fluctuations, however the mechanisms allowing specific mRNA to be translated in hypoxia are still unknown. Here, we show that Ldh mRNA encoding lactate dehydrogenase is highly translated in hypoxia by a mechanism involving its 3’ untranslated region. Furthermore, we identified the cap-binding protein eiF4HP as a main factor involved in 3’UTR-dependent translation under hypoxia. In accordance with this observation, we show that eiF4EHP is necessary for Drosophila development under low oxygen concentrations and contributes to Drosophila mobility after hypoxic challenge. Altogether, our data bring new insight into mechanisms contributing to Drosophila adaptation to oxygen variations.
Novel methods to identify TCM constitution of hyperlipidemic patients and predict atherosclerotic diseases
Authors: Zeng Liling , Zhang Qixin , Sun Chen , Huang Li , Yuan Jiamin , Tan Fei , Wu Yanhua , Yang Zhimin , Xu Fuping
Published: July 2022

Hyperlipidemia can accelerate the progression of atherosclerosis, ultimately leading to cardiovascular disease. TCM constitution has been widely used as an indicator of health status and susceptibility to diseases. However, there still lack of objective, credible ways to identify TCM constitution of hyperlipidemic patients, and the connection between TCM constitution and atherosclerotic diseases in individuals with hyperlipidemia is unknown. This study aims to identify differentially expressed microRNAs (DEMs) as biomarkers of the TCM constitution of hyperlipidemic patients and explore the potential connection between TCM constitution and atherosclerotic diseases. In the study, we randomly recruited 10 hyperlipidemic patients with asthenic constitution (HAC), 10 hyperlipidemic patients with strong constitution (HSC), and 10 hyperlipidemic patients with normal constitution (HNC) and collected serum miRNA. After analyzing the miRNA expression profiles, we found that hsa-miR-338-3p may be a potential blood biomarker for the identification of the TCM constitution of hyperlipidemic patients. Moreover, the HSC classification is likely a cardiocerebrovascular disease predisposition and is closely related to the inflammatory process and glucose and lipid metabolism, which contribute to the development of atherosclerotic diseases.
Biopriming of broad bean seeds with entomopathogenic fungusMetarhizium robertsiidoes not affect invertebrate communities of the agroecosystem
Authors: Lyubechanskii I.I. , Novgorodova T.A. , Panina Y. , Kryukov V.V. , Sorokina V.S. , Sadokhina T.A. , Bakshaev D.Ju. , Dudko R.Ju. , Gurina A.A. , Glupov V.V.
Published: July 2022

Biopriming, or treatment of seeds with beneficial microorganisms such as beneficial fungi, can be a promising strategy in agricultural cultivation. However, the effects of such treatment on non-target organisms living in the soil and on plants have not been sufficiently studied, and it is not known very well whether such treatment would alter invertebrate communities (e.g., harm them). Here, we addressed the effect of treating broad bean seeds (Vicia fabaL.) with the conidia of entomopathogenic ascomyceteMetarhizium robertsiion the diversity and abundance of invertebrate communities in the agroecosystem in the south part of West Siberia in 2019 and 2020. We have analyzed the effect both on the general invertebrate communities as well as on the main pests of beans. In the case of bean pests, we assessed the rate of plant infestation by aphids (Hemiptera: Aphididae) and the degree of leaf damage by leafminer fliesLiriomyza bryoniae(Diptera: Agromyzidae). In most cases, the treatment did not lead to significant changes in the total abundance of the soil invertebrates and herbivores or the abundance of predominant taxa (Coleoptera: Carabidae, Staphylinidae, Elateridae, Scarabaeidae, Curculionidae; Hemiptera: Miridae, Cicadellidae, Aphididae; larvae of Diptera). A positive effect of treatment on population density of the soil mesofauna was noted for Diptera larvae in June 2019. Regarding aphids and leafminer flies, no significant effect was observed in terms of the proportion of plants with aphids and the density of aphid colonies on individual plants throughout the season, and no significant influence was found on the proportion of plant leaves damaged by leafminer flyLiriomyza bryoniaelarvae. In summary, in Western Siberia, the treatment of broad bean seeds withM. robertsiidid not significantly affect non-target arthropods common for bean fields as well as the main pests of beans, namely aphids and miner flies.