bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-Institutional Stereotactic Body Radiation Therapy Incident Learning: Evaluation of Safety Barriers Using a Human Factors Analysis and Classification System
Authors: McGurk Ross , Woch Naheedy Katherine , Kosak Tara , Hobbs Amy , Mullins Brandon T. , Paradis Kelly C. , Kearney Meghan , Roback Donald , Durney Jeffrey , Adapa Karthik , Chera Bhishamjit S. , Marks Lawrence B. , Moran Jean M. , Mak Raymond H. , Mazur Lukasz M.
Published: August 2022

Objectives

Stereotactic body radiation therapy (SBRT) can improve therapeutic ratios and patient convenience, but delivering higher doses per fraction increases the potential for patient harm. Incident learning systems (ILSs) are being increasingly adopted in radiation oncology to analyze reported events. This study used an ILS coupled with a Human Factor Analysis and Classification System (HFACS) and barriers management to investigate the origin and detection of SBRT events and to elucidate how safeguards can fail allowing errors to propagate through the treatment process.

Methods

Reported SBRT events were reviewed using an in-house ILS at 4 institutions over 2014–2019. Each institution used a customized care path describing their SBRT processes, including designated safeguards to prevent error propagation. Incidents were assigned a severity score based on the American Association of Physicists in Medicine Task Group Report 275. An HFACS system analyzed failing safeguards.

Results

One hundred sixty events were analyzed with 106 near misses (66.2%) and 54 incidents (33.8%). Fifty incidents were designated as low severity, with 4 considered medium severity. Incidents most often originated in the treatment planning stage (38.1%) and were caught during the pretreatment review and verification stage (37.5%) and treatment delivery stage (31.2%). An HFACS revealed that safeguard failures were attributed to human error (95.2%), routine violation (4.2%), and exceptional violation (0.5%) and driven by personnel factors 32.1% of the time, and operator condition also 32.1% of the time.

Conclusions

Improving communication and documentation, reducing time pressures, distractions, and high workload should guide proposed improvements to safeguards in radiation oncology.
Trans women have worse cardiovascular biomarker profiles than cisgender men independent of hormone use and HIV serostatus
Authors: Lake Jordan E. , Wang Ruibin , Barrett Benjamin W. , Bowman Emily , Hyatt Ana N. , Debroy Paula , Candelario Jury , Teplin Linda , Bodnar Kaitlin , McKay Heather , Plankey Michael , Brown Todd T. , Funderburg Nicholas , Currier Judith S.
Published: August 2022

Background:

Feminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW).

Methods:

TW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations.

Results:

TW (HIV+ n = 75, HIV− n = 47) and CM (HIV+ n = 40, HIV− n = 40) had mean age 43-45 years; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P < 0.05). In multivariable analysis, TW had higher EN-RAGE, IL-6, IL-8, P selectin, PAI-1, oxLDL and sTNFRI/II concentrations, and lower vWF, independent of HIV serostatus and current FHT use. Both being a TW and a PWH were associated with lower ET-1.

Conclusions:

Compared to matched cisgender men, trans women have altered profiles of biomarkers associated with systemic inflammation and CVD. Further work is needed to decipher the contributions of FHT to CVD risk in TW with HIV.
A randomized study of intensified antiretroviral treatment monitoring versus standard-of-care for prevention of drug resistance and antiretroviral treatment switch
Authors: Hermans Lucas E. , Ter Heine Rob , Schuurman Rob , Tempelman Hugo A. , Burger David M. , Vervoort Sigrid C.J.M. , Deville Walter L.J.M. , De Jong Dorien , Venter Willem D.F. , Nijhuis Monique , Wensing Annemarie M.J.
Published: August 2022

Introduction:

Standard-of-care antiretroviral treatment (ART) monitoring in low and middle-income countries consists of annual determination of HIV-RNA viral load with confirmatory viral load testing in case of viral rebound. We evaluated an intensified monitoring strategy of three-monthly viral load testing with additional drug exposure and drug resistance testing in case of viral rebound.

Methods:

We performed an open-label randomized controlled trial (RCT) at a rural South African healthcare clinic, enrolling adults already receiving or newly initiating first-line ART. During 96 weeks follow-up, intervention participants received three-monthly viral load testing and sequential point-of-care drug exposure testing and DBS-based drug resistance testing in case of rebound above 1000 copies/ml. Control participants received standard-of-care monitoring according to the WHO guidelines.

Results:

Five hundred one participants were included, of whom 416 (83.0%) were randomized at 24 weeks. Four hundred one participants were available for intention-to-treat analysis. Viral rebound occurred in 9.0% (18/199) of intervention participants and in 11.9% (24/202) of controls (P = 0.445). Time to detection of rebound was 375 days [interquartile range (IQR): 348–515] in intervention participants and 360 days [IQR: 338–464] in controls [hazard ratio: 0.88 (95% confidence interval (95% CI): 0.46–1.66]; P = 0.683]. Duration of viral rebound was 87 days [IQR: 70–110] in intervention participants and 101 days [IQR: 78–213] in controls (P = 0.423). In the control arm, three patients with confirmed failure were switched to second-line ART. In the intervention arm, of three patients with confirmed failure, switch could initially be avoided in two cases.

Conclusion:

Three-monthly viral load testing did not significantly reduce the duration of viraemia when compared with standard-of-care annual viral load testing, providing randomized trial evidence in support of annual viral load monitoring.
A Patient of Venous Hemangioma of the Inferior Turbinate
Authors: Sim Soohyun , Yeon Eung Rok , Jung Soo Jin , Park Seong Kook
Published: August 2022

Sinonasal hemangiomas are relatively rare among the hemangiomas that occur from the head and neck parts. According to their histopathologic findings, they are classified as capillary, cavernous, or venous type. Some cases of capillary or cavernous hemangioma that occur from the inferior turbinate have been reported. However, there was no reported case of venous hemangioma arising from the inferior turbinate. We present a case of 67-year-old male who has venous hemangioma of the left inferior turbinate whose initial symptoms were watery rhinorrhea and postnasal drip. With this study, although uncommon, venous hemangioma should be considered as a differential diagnosis in patient with mass lesion of the inferior turbinate.
A Rare Instance of Pterygopalatine Fossa Tumor With Hearing Loss as the Main Complaint
Authors: Liu Yue , Zhao Xue , Yu Dan
Published: August 2022

Pterygopalatine schwannomas are rare tumors which usually cause the symptoms of the traffic area by the tumors in the pterygopalatine fossa which is difficult to resection. This paper presents 1 rare case of pterygopalatine fossa tumor with hearing loss as the main complaint treated by total resection through the endoscopic endonasal approach.
Early Recurrence After Resection of Locally Advanced Pancreatic Cancer Following Induction Therapy
Authors: Seelen Leonard W.F. , Floortje van Oosten Anne , Brada Lilly J.H. , Groot Vincent P. , Daamen Lois A. , Walma Marieke S. , van der Lek Bastiaan F. , Liem Mike S.L. , Patijn Gijs A. , Stommel Martijn W.J. , van Dam Ronald M. , Koerkamp Bas Groot , Busch Olivier R. , de Hingh Ignace H.J.T. , van Eijck Casper H.J. , Besselink Marc G. , Burkhart Richard A. , Borel Rinkes Inne H.M. , Wolfgang Christopher L. , Molenaar Izaak Quintus , He Jin , van Santvoort Hjalmar C.
Published: August 2022

Objective:

To establish an evidence-based cutoff and predictors for early recurrence in patients with resected locally advanced pancreatic cancer (LAPC).

Background:

It is unclear how many and which patients develop early recurrence after LAPC resection. Surgery in these patients is probably of little benefit.

Methods:

We analyzed all consecutive patients undergoing resection of LAPC after induction chemotherapy who were included in prospective databases in The Netherlands (2015–2019) and the Johns Hopkins Hospital (2016–2018). The optimal definition for “early recurrence” was determined by the post-recurrence survival (PRS). Patients were compared for overall survival (OS). Predictors for early recurrence were evaluated using logistic regression analysis.

Results:

Overall, 168 patients were included. After a median follow-up of 28 months, recurrence was observed in 118 patients (70.2%). The optimal cutoff for recurrence-free survival to differentiate between early (n=52) and late recurrence (n=66) was 6 months (P<0.001). OS was 8.4 months [95% confidence interval (CI): 7.3–9.6] in the early recurrence group (n=52) versus 31.1 months (95% CI: 25.7–36.4) in the late/no recurrence group (n=116) (P<0.001). A preoperative predictor for early recurrence was postinduction therapy carbohydrate antigen (CA) 19-9≥100 U/mL [odds ratio (OR)=4.15, 95% CI: 1.75–9.84, P=0.001]. Postoperative predictors were poor tumor differentiation (OR=4.67, 95% CI: 1.83–11.90, P=0.001) and no adjuvant chemotherapy (OR=6.04, 95% CI: 2.43–16.55, P<0.001).

Conclusions:

Early recurrence was observed in one third of patients after LAPC resection and was associated with poor survival. Patients with post-induction therapy CA 19-9 ≥100 U/mL, poor tumor differentiation and no adjuvant therapy were especially at risk. This information is valuable for patient counseling before and after resection of LAPC.
Racial and Ethnic Differences in Elective Versus Emergency Surgery for Colorectal Cancer
Authors: Howard Ryan , Hendren Samantha , Patel Minal , Gunaseelan Vidhya , Wixson Matthew , Waljee Jennifer , Englesbe Michael , Bicket Mark C.
Published: August 2022

Objective:

To evaluate differences in presentation and outcomes of surgery for colorectal cancer.

Background:

Although racial and socioeconomic disparities in colorectal cancer outcomes are well documented, disparities in access affecting disease presentation are less clear.

Methods:

We conducted a statewide retrospective study of patients who underwent resection for colorectal cancer between January 1, 2015, and April 30, 2021. The primary outcome was undergoing emergency surgery. Secondary outcomes included preoperative evaluation and postoperative outcomes. Covariates of interest included race/ethnicity, social deprivation index, and insurance type.

Results:

A total of 4869 patients underwent surgery for colorectal cancer, of whom 1122 (23.0%) underwent emergency surgery. Overall, 28.1% of Black non-Hispanic patients and 22.5% of White non-Hispanic patients underwent emergency surgery. On multivariable logistic regression, Black non-Hispanic race was independently associated with a 5.8 (95% CI, 0.3–11.3) percentage point increased risk of emergency surgery compared with White non-Hispanic race. Patients who underwent emergency surgery were significantly less likely to have preoperative carcinoembryonic antigen measurement, staging for rectal cancer, and wound/ostomy consultation. Patients who underwent emergency surgery had a higher incidence of 30-day mortality (5.5% vs 1.0%, P<0.001), positive surgical margins (11.1% vs 4.9%, P<0.001), complications (29.2% vs 16.0%, P<0.001), readmissions (12.5% vs 9.6%, P=0.005), and reoperations (12.2% vs 8.2%, P<0.001).

Conclusions:

Among patients with colorectal cancer, Black non-Hispanic patients were more likely to undergo emergency surgery than White non-Hispanic patients, suggesting they may face barriers to timely screening and evaluation. Undergoing emergency surgery was associated with incomplete oncologic evaluation, increased incidence of postoperative complications including mortality, and increased surgical margin positivity. These results suggest that racial and ethnic differences in the diagnosis and treatment of colorectal cancer impact near-term and long-term outcomes.
Segmental Versus Diffuse Main Duct Intraductal Papillary Mucinous Neoplasm
Authors: Ecker Brett L. , Dickinson Shannan M. , Saadat Lily V. , Tao Alice J. , Pulvirenti Alessandra , Balachandran Vinod P. , D’Angelica Michael I. , Drebin Jeffrey A. , Kingham T.P. , Jarnagin William R. , Wei Alice C. , Gonen Mithat , Soares Kevin C.
Published: August 2022

Objective:

To determine whether the morphologic features of the main pancreatic duct (MPD) of main-duct-involved-intraductal papillary mucinous neoplasm (IPMN) (ie, main duct or mixed main duct/side branch) have implications for the risk of malignancy and extent of resection.

Background:

International consensus guidelines acknowledge the presence of various MPD morphologies (ie, diffuse vs segmental main-duct-involved-IPMN) without a precise definition of each entity and with limited data to guide treatment strategy.

Methods:

All consecutive main-duct-involved-IPMN patients (2005–2019) with a MPD diameter ≥5 mm by cross-sectional imaging were reviewed from a prospective institutional database. Morphologic features of the MPD were correlated with the identification of high-grade dysplasia or pancreatic ductal adenocarcinoma (HGD/PDAC) by logistic regression modeling. In patients who underwent partial pancreatectomy, preoperative MPD morphologic features were correlated with the future development of HGD/PDAC in the pancreatic remnant by Cox hazards modeling.

Results:

In a cohort of 214 main-duct-involved-IPMN patients, the overall rate of HGD/PDAC was 54.2%. MPD morphologic characteristics associated with HGD/PDAC included: maximal MPD diameter (5–10 mm: 29.8%; 10–14 mm: 59.0%; 15–19 mm: 78.6%; ≥20 mm: 95.8%; P<0.001), segmental extent of maximal dilation (<25%: 28.2%; 25%–49%: 54.9%; 50%–74%: 63.1%; ≥75%: 67.9%; P=0.002), and nonsegmental MPD diameter (<5 mm: 21.5% vs ≥5 mm: 78.5%, P<0.001). Diffuse MPD dilation involving ≥90% extent was rare (5.6%). After a median follow-up of 50 months, 7 (7.2%) patients who underwent partial pancreatectomy for IPMN without associated PDAC developed HGD/PDAC in the pancreatic remnant. Maximal MPD diameter, segmental extent of maximal dilation, or nonsegmental MPD diameter were not associated with the development of HGD/PDAC in the pancreatic remnant. However, a mural nodule on preoperative imaging was associated with the development of HGD/PDAC in the pancreatic remnant.

Conclusions:

“Diffuse” involvement with homogenous dilation of the MPD was rare. For the majority of patients with segmental main-duct-involved-IPMN, the MPD morphology conferred malignancy risk. Duct morphology was not predictive for the development of HGD or invasive disease in the pancreatic remnant, implying the safety of limited pancreatic resection for initial surgical management.
Novel Double-Stranded RNA Viruses Discovered within Saccharomyces cerevisiae
Authors: Crabtree Angela , Taggart Nathan , Doering Camden , Li Shunji , Fredericks Lance , Boyer Josephine , van Leuven James , Rowley Paul
Published: August 2022

Saccharomyces yeasts harbor many different viruses and parasitic genetic elements, including double-stranded RNA (dsRNA) viruses from the family Totiviridae. The identification of novel dsRNA viruses in yeasts has been constrained by the lack of effective protocols for the unbiased preparation and sequencing of dsRNAs. We have developed a next-generation sequencing method that enables the amplification and sequencing of yeast dsRNAs. Using this method, we have performed a metagenomic screen of more than 600 strains of Saccharomyces cerevisiae for the presence of novel dsRNA viruses. Surprisingly, we have identified several novel bipartite dsRNA viruses from the family Partitiviridae within different strains of S. cerevisiae. Partitiviruses have never been described within Saccharomyces yeasts or within the wider Saccharomycotina taxonomic subdivision of the Ascomycota phylum. We confirmed the presence of these partitivirus dsRNAs using reverse transcriptase-PCR and have been successful in purifying viral particles from infected yeasts. After deep sequencing of purified dsRNAs, we have identified three species of virus that have weak homology (20-35% amino acid identity) to viruses of the genus Cryspovirus, which replicate within the protozoan pathogen Cryptosporidium parvum. Partitiviruses can modulate the virulence and fecundity of plant and human pathogens, respectively. The discovery of partitiviruses in S. cerevisiae will enable the study of how partitiviruses interact with the host cell environment and alter cellular physiology.
Cloud-controlled microscopy enables remote project-based biology education in Latinx communities in the United States and Latin America
Authors: Baudin Pierre V. , Sacksteder Raina E. , Worthington Atesh K. , Voitiuk Kateryna , Ly Victoria T. , Hoffman Ryan N. , Elliott Matthew A.T. , Parks David F. , Ward Rebecca , Torres-Montoya Sebastian , Amend Finn , Montellano Duran Natalia , Vargas Paola A. , Martinez Guadalupe , Alvarado-Arnez Lucia Elena , Ehrlich Drew , Rosen Yohei M. , Breevoort Arnar , Schouten Tallulah , Kurniawan Sri , Haussler David , Teodorescu Mircea , Mostajo-Radji Mohammed A.
Published: August 2022

Project-based learning (PBL) has long been recognized as an effective way to teach complex biology concepts. However, not all institutions have the resources to facilitate effective project-based coursework for students. We have developed a framework for facilitating PBL using remote-controlled internet-connected microscopes. Through this approach, one lab facility can host an experiment allowing simultaneous interaction by many students worldwide. Experiments on this platform can be run on long timescales and with materials that are typically unavailable to high school classrooms. This allows students to perform novel research projects rather than just repeat standard classroom experiments. To investigate the impact of this program, we designed and ran six user studies with students worldwide. All experiments were executed in Santa Cruz and San Francisco, California, with observations and decisions made remotely by the students using their personal computers and cellphones. In surveys gathered after the experiments’ conclusion, students reported increased excitement for science and a greater desire to pursue a career in STEM. This framework represents a novel, scalable, and effective PBL approach that has the potential to democratize biology and STEM education around the world.
The Impact of Population Stratification on the Analysis of Multimodal Neuroimaging Derived Measures
Authors: Huang Tzu Hsuan , Loughnan Robert , Thompson Wesley K , Fan Chun Chieh
Published: August 2022

Magnetic resonance imaging (MRI) studies of the human brain are now attaining larger sample sizes with more diverse samples. However, population stratification, a key factor driving heterogeneity and confounding of associations, is seldom accounted for in neuroimaging analyses. To investigate this issue, we assessed the impact of population stratification on multimodal imaging measures using baseline data from the Adolescent Brain Cognitive Development (ABCD) StudySM (n = 10,748). Given this sociodemographically diverse sample, which broadly reflects the population composition of the United States, we performed a thorough evaluation of the impact of population stratification on derived neuroimaging metrics across five different imaging modalities: task functional MRI (task fMRI), resting state functional MRI (rsMRI), diffusion tensor images (DTI), restricted spectrum images (RSI), and structural T1 MRI (sMRI). We used parental income level as an example to highlight the impact of population stratification in confounding brain-wide associations. We show that derived metrics from structural images have up to three times more signal related to population stratification than do functional images. Controlling for population stratification in statistical models leads to a substantial reduction in the association strength between variables of interests and imaging measures, indicating the scale of potential bias. Moreover, because of unequal access to resources (such as income) across ancestral groups in United States, population stratification effects on imaging features may bias associations between parental income levels and imaging features, as we demonstrate. Our results provide a guide for researchers to critically examine the impact of population stratification and to assist in avoiding spurious brain-behavior associations.

Highlights

Here, we conduct a comprehensive survey of the confounding impact of population stratification in large-scale imaging studies.

Morphological features from structural imaging appear to be more susceptible to the confounding effects of population stratification than do functional imaging features.

The population stratification tends to inflates the association strengths between the variable of interest and imaging features.

When the variable of interest is highly colinear with the population stratification, such as income levels, brain associations cannot be differentiated and may be misattributed as mediating effects.

It is critical to account for population stratification in imaging analyses.
“METAVIR score Ultrasound” – Pictorial Essay of Anatomy / Ultrasound / Elastography / Histology
Authors: de Oliveira Andrade Luís Jesuino , de Oliveira Luís Matos , Matos de Oliveira Gabriela Correia
Published: August 2022

The METAVIR score was specifically elaborated and evaluated in chronic hepatitis C, is scoring system for evaluation the inflammatory activity and fibrosis on liver biopsies, although it ultrasound may indicate the fibrosis degree.

Objective

To present a pictorial essay by composing histological, ultrasound and elastography images of the METAVIR score of fibrosis.

Method

Using software for image composition, based on the sonographic image of the liver with degrees of fibrosis, secondary to hepatitis C, we adapted the corresponding histological image (METAVIR) and presented a pictorial essay.

Results

The correlation of the anatomical image with the sonographic image and of the histological image with the corresponding sonographic image and elastography image are demonstrated.

Conclusion

Ultrasonographic features and elastography in evaluation hepatic fibrosis present in hepatitis C can correlate with histological features METAVIR score.
HSPA8 chaperone complex drives chaperone-mediated autophagy regulation in acute promyelocytic leukemia differentiation
Authors: Rafiq Sreoshee , Mungure Irene , Niklaus Nicolas J. , Müller Stefan , Jacquel Arnaud , Robert Guillaume , Auberger Patrick , Torbett Bruce E. , Muller Sylviane , Tschan Mario P. , Humbert Magali
Published: August 2022

Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by the hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapy are focusing on tumor debulking, all-trans retinoic acid (ATRA) induces differentiation in acute promeylocytic leukemia (APL) a particular subtype. Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects. On the contrary, the implications of chaperone-mediated autophagy (CMA) on the pathophysiology of diseases are still being explored and its role in AML has remained elusive. To answer our questions we took advantages of human AML primary samples and databases. Furthermore, we used ATRA-sensitive (NB4) and –resistant (NB4-R1) cells to further dissect a potential function for CMA in ATRA-mediated neutrophil differentiation. NB4-R1 cells are unique in that they do respond to retinoic acid transcriptionally, but do not mature in response to retinoid signaling alone unless maturation is triggered by adding cAMP. Here, we report that CMA related mRNA transcripts are higher expressed in immature hematopoietic cells as compared to neutrophils. In line, lysosomal degradation of mCherry-KFERQ CMA reporter decreases during ATRA-induced differentiation of APL cells. On the other hand, using NB4-R1 cells we found that macroautophagy flux primed the ATRA resistant NB4-R1 cells to differentiate upon ATRA treatment, but reduced association of LAMP-2A and HSPA8 is necessary for complete neutrophil maturation. Accordingly, depletion of HSPA8 attenuated CMA activity and facilitated APL differentiation. In contrast, maintaining high CMA activity by ectopic expression of LAMP-2A impeded APL differentiation. Overall, our findings demonstrate that both normal and APL neutrophil differentiation require CMA downregulation and this pathway is predominantly dependent on HSPA8 assisted by other co-chaperones.
Fusarium oxysporum Effector Clustering version 2 (FoEC2): an updated pipeline to infer host range
Authors: Brenes Guallar Megan A. , Fokkens Like , Rep Martijn , Berke Lidija , van Dam Peter
Published: August 2022

1

The fungus Fusarium oxysporum is infamous for its devastating effects on economically important crops worldwide. F. oxysporum isolates are grouped into formae speciales based on their ability to cause disease on different hosts. Assigning F. oxysporum strains to formae speciales using non-experimental procedures has proven to be challenging due to their genetic heterogeneity and polyphyletic nature. However, genetically diverse isolates of the same forma specialis encode similar repertoires of effectors, proteins that are secreted by the fungus and contribute to the establishment of compatibility with the host. Based on this observation, we previously designed the F. oxysporum Effector Clustering (FoEC) pipeline which is able to classify F. oxysporum strains by forma specialis based on hierarchical clustering of the presence of predicted putative effector sequences, solely using genome assemblies as input. Here we present the updated FoEC2 pipeline which is more user friendly, customizable and, due to multithreading, has improved scalability. It is designed as a Snakemake pipeline and incorporates a new interactive visualization app. We showcase FoEC2 by clustering 537 publicly available F. oxysporum genomes and further analysis of putative effector families as multiple sequence alignments. We confirm classification of isolates into formae speciales and are able to further identify their subtypes. The pipeline is available on github: https://github.com/pvdam3/FoEC2.
The effects of ethnoracial-related stressors during pregnancy on the developing offspring brain
Authors: Spann Marisa N. , Alleyne Kiarra , Holland Cristin M. , Davids Antonette , Pierre-Louis Arline , Bang Claire , Oyeneye Victoria , Kiflom Rebecca , Shea Eileen , Cheng Bin , Peterson Bradley S. , Monk Catherine , Scheinost Dustin
Published: August 2022

We are increasingly aware of the effects of ethnoracial stress on health, with emerging interest in the potential for intergenerational transmission before birth. Here, we investigate the effect of maternal prenatal discrimination and acculturation experiences on fetal growth, birth outcomes, and functional connectivity in the infant brain. In pregnant adolescent women, we collected self-report measures of acculturation (tailored to an adolescent and Latinx population), discrimination, and maternal distress (i.e., stress and depressive symptoms; n=165). Fetal growth were obtained via electronic health records (n=92), and infant amygdala seed connectivity was assessed using functional magnetic resonance imaging (n=38). We found that greater maternal prenatal assimilation to the host culture was associated with slower fetal growth, lower gestational age at birth, and weaker amygdala-fusiform connectivity. Maternal prenatal discrimination was associated with weaker amygdala-prefrontal connectivity. Together, these results suggest intergenerational effects of ethnoracial stressors on the growth and neural development of future generations.
The Impact of Brief Monocular Retinal Inactivation on the Central Visual System During Postnatal Development
Authors: Duffy Kevin R. , Crowder Nathan A. , Heynen Arnold J. , Bear Mark F.
Published: August 2022

During a critical period of postnatal life, monocular deprivation (MD) of kittens by eyelid closure reduces the size of neurons in layers of the dorsal lateral geniculate nucleus (dLGN) connected to the deprived eye, and shifts cortical ocular dominance in favor of the non-deprived eye, modeling deprivation amblyopia in humans. Following long-term MD, temporary retinal inactivation of the non-deprived eye with microinjection of tetrodotoxin can promote superior recovery from MD, and at older ages, in comparison to conventional occlusion therapy. This suggests that monocular inactivation (MI) is a more potent approach to producing neural plasticity than occlusion. In the current study we assessed the modification of neuron size in the dLGN as a means of measuring the impact of a brief period of MI imposed at different ages during postnatal development. The biggest impact of inactivation was observed when it occurred at the peak of the critical period for ocular dominance plasticity. The effect of MI was evident in both the binocular and monocular segments of the dLGN, distinguishing it from MD that produces changes only within the binocular segment. With increasing age, the capacity for inactivation to alter postsynaptic cell size diminished but was still significant beyond the classic critical period. In comparison to MD, inactivation consistently produced effects that were about double in magnitude, and inactivation exhibited efficacy to produce neural modifications at older ages than MD. Notwithstanding the large neural alterations precipitated by inactivation, its anatomical effects were remediated with a short period of binocular visual experience, and vision through the previously inactivated eye fully recovered after washout of TTX. Our results demonstrate that MI is a potent means of modifying the visual pathway, and does so beyond the age at which occlusion is effective. The magnitude and longevity of inactivation to evoke neural modification highlights its potential to ameliorate disorders of the visual system such as amblyopia.
Incorporating sampling bias into permutation tests for niche and distribution models
Authors: Warren Dan L. , Kass Jamie M. , Casadei-Ferreira Alexandre , Economo Evan P.
Published: August 2022

Randomization tests are often used with species niche and distribution models to estimate model performance, test hypotheses, and measure methodological biases. Many of these tests involve building null models representing the hypothesis that there is no association between the species’ occurrences and the environmental predictors, then comparing the empirical model to null distributions built from these models. These null models are commonly based on points randomly selected with a uniform probability from the study area. However, spatial sampling bias, a near-universal feature of the occurrence data used to build niche and distribution models, results in a non-uniform probability of observing species in different areas even when species occurrences are unrelated to environmental predictors. Failing to account for this bias in randomization tests results in null distributions that do not accurately represent the null hypothesis, potentially leading to incorrect conclusions. In this study, we use simulations to demonstrate that uniform sampling in randomization tests can lead to unacceptable rates of type I error and poor estimates of methodological bias when spatial sampling bias is present in the occurrence data. We present a new method that incorporates a bias estimate into replicate simulations for these randomization tests, and show that this adjustment can reduce type I error rates to an acceptable level.
Development of a Scoring Function for Comparing Simulated and Experimental Tumor Spheroids
Authors: Herold Julian , Behle Eric , Rosenbauer Jakob , Ferruzzi Jacopo , Schug Alexander
Published: August 2022

Enormous progress continues in the field of cancer biology, yet much remains to be unveiled regarding the mechanisms of cancer invasion. In particular, complex biophysical mechanisms enable a tumor to remodel the surrounding extracellular matrix (ECM), thus allowing cells to escape and invade alone or as multicellular collectives. Tumor spheroids cultured in collagen represent a simplified, reproducible 3D model system, which is sufficiently complex to recapitulate the evolving internal organization of cells and external interaction with the ECM that occur during invasion. Recent experimental approaches enable high resolution imaging and quantification of the internal structure of invading tumor spheroids. Concurrently, computational modeling enables simulations of complex multicellular aggregates based on first principles. The comparison between real and simulated spheroids represents a way to fully exploit both data sources, but remains a challenging task. We hypothesize that comparing any two spheroids requires first the extraction of basic features from the raw data, and second the definition of key metrics to match such features. Here, we present a novel data-agnostic method to compare spatial features of spheroids in 3D. To do so, we define and extract features from spheroid point cloud data, which we simulated using Cells in Silico (CiS), a high-performance framework for large-scale tissue modeling previously developed by our group. We then define metrics to compare features between individual spheroids, and combine all metrics into an overall deviation score. Finally, we use our features to compare experimental data on invading spheroids in increasing collagen densities. We propose that our approach represents the basis for defining improved metrics to compare large 3D data sets. Moving forward, this approach will enable informingin silicospheroids based on theirin vitrocounterparts, and vice versa, thus enabling both basic and applied researchers to close the loop between modeling and experiments in cancer research.

Author summary

Cells within a tumor use various methods to escape and thereby invade into healthy parts of the body. These methods are studied experimentally by examining tumor spheroids, spherical aggregates of hundreds to thousands of individual cells. Such spheroids can also be simulated, and the comparison of simulation and experiment is desirable. Here, we present an analysis strategy for the comparison of tumor spheroids, a widely used workhorse of cancer research. Using this strategy, we aim to improve the collaborative potential between experimentalists and theorists.
Ancient DNA reveals interstadials as a driver of the common vole population dynamics during the last glacial period
Authors: Baca Mateusz , Popović Danijela , Lemanik Anna , Bañuls-Cardona Sandra , Conard Nicholas J. , Cuenca-Bescós Gloria , Desclaux Emmanuel , Fewlass Helen , Garcia Jesus T. , Hadravova Tereza , Heckel Gerald , Horáček Ivan , Knul Monika Vlasta , Lebreton Loïc , López-García Juan Manuel , Luzi Eliza , Marković Zoran , Lenardić Jadranka Mauch , Murelaga Xabier , Noiret Pierre , Petculescu Alexandru , Popov Vasil , Rhodes Sara E. , Ridush Bogdan , Royer Aurélien , Stewart John R. , Stojak Joanna , Talamo Sahra , Wang Xuejing , Wójcik Jan M. , Nadachowski Adam
Published: August 2022

1

Aim

The common vole is a temperate rodent widespread across Europe. It was also one of the most abundant small mammal species throughout the Late Pleistocene. Phylogeographic studies of its extant populations suggested the Last Glacial Maximum (LGM, 26.5–19 ka ago) as one of the main drivers of the species’ population dynamics. However, analyses based solely on extant genetic diversity may not recover the full complexity of past population history. The main aim of this study was to investigate the evolutionary history and identify the main drivers of the common vole population dynamics during the Late Pleistocene.

Location

Europe

Taxon

Common vole (Microtus arvalis)

Methods

We generated a dataset comprising 4.2 kb-long fragment of mitochondrial DNA from 148 ancient and 51 modern specimens sampled from multiple localities across Europe and covering the last 60 thousand years (ka). We used Bayesian inference to reconstruct their phylogenetic relationships and to estimate the age of specimens that were not directly dated.

Results

We estimate the time to the most recent common ancestor of all Last Glacial and extant common vole lineages to 90 ka ago and the divergence of the main mtDNA lineages present in extant populations to between 55 and 40 ka ago, earlier than previous estimates. We find multiple lineage turnovers in Europe in the period of high climate variability at the end of Marine Isotope Stage 3 (MIS 3; 57–29 ka ago) in addition to those found previously around the Pleistocene/Holocene transition. Conversely, data from the Western Carpathians suggest continuity throughout the LGM even at high latitudes.

Main conclusions

Our results suggest that the main factor affecting the common vole populations during the last glacial period was the reduction of open habitats during the interstadial periods while the climate deterioration during the LGM had little impact on species’ population dynamics.
The genetic and environmental etiology of blood-based biomarkers related to risk of Alzheimer’s Disease in a population-based sample of early old-age men
Authors: Gillespie Nathan A. , Rissman Robert A. , Elman Jeremy A. , McKenzie Ruth E. , Tu Xin M. , Xian Hong , Reynolds Chandra A. , Panizzon Matthew S. , Lyons Michael J. , Eglit Graham M.L. , Neale Michael C. , Franz Carol , Kremen William S.
Published: August 2022

The amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood-based biomarkers has never been explored. We therefore, analyzed plasma beta-amyloid (Aβ40, Aβ42, Aβ42/40), total tautau (t-tautau), and neurofilament light (NFL) biomarkers in a sample of 1,050 men aged 60 to 73 years (m=68.2, SD=2.5) from the Vietnam Era Twin Study of Aging (VETSA). Unlike Aβ and tautau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework. Univariate estimates suggest that familial aggregation in Aβ42, Aβ42/40, t-tau, and NFL is entirely explained by additive genetic influences accounting for 40%-58% of the total variance. All remaining variance is associated with unshared or unique environmental influences. For Aβ40, a additive genetic (31%), shared environmental (44%), and unshared environmental (25%) influences contribute to the total variance. In the more powerful multivariate analysis of Aβ42, Aβ40, t-tau, and NFL, heritability estimates range from 32% to 58%. Aβ40 and Aβ42 are statistically genetically identical (rg = 1.00, 95%CI = 0.92,1.00) and are also moderately environmentally correlated (re = 0.66, 95%CI = 0.59, 0.73). All other genetic and environmental associations were non-significant or small. Our results suggest that plasma biomarkers are heritable and that Aβ40 and Aβ42 share the same genetic influences, whereas the genetic influences on plasma t-tau and NFL are mostly unique and uncorrelated with plasma Aβ in early old-age men.
Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer
Authors: Khan Imran , Gril Brunilde , Paranjape Anurag , Robinson Christina , Difilippantonio Simone , Biernat Wojciech , Bieńkowski Michał , Pęksa Rafał , Duchnowska Renata , Jassem Jacek , Brastianos Priscilla K. , Metellus Philippe , Bialecki Emilie , Woodroofe Carolyn C. , Wu Haitao , Swenson Rolf , Steeg Patricia S.
Published: August 2022

Advances in drug treatments for brain metastases of breast cancer have improved progression free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that to systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: Transferrin receptor (TfR) peptide, Low density lipoprotein receptor 1 (LRP1) peptide, Albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patternsin vivo.Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P <0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor (FcRn), galectin-3 (Gal-3) and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other CNS cancers.

Statement of Significance

Drug therapy for brain metastasis needs improvements. We surveyed transcytotic pathways as potential delivery systems in brain-tropic models and found that albumin has optimal properties. Albumin used a novel mechanism for endocytosis.
‘High-Density-SleepCleaner’: An open-source, semi-automatic artifact removal routine tailored to high-density sleep EEG
Authors: Leach Sven , Sousouri Georgia , Huber Reto
Published: August 2022

Background

With up to 256 channels, high-density electroencephalography (hd-EEG) has become essential to the sleep research field. The vast amount of data resulting from this magnitude of channels in overnight EEG recordings complicates the removal of artifacts.

New Method

We present a new, semi-automatic artifact removal routine specifically designed for sleep hd-EEG recordings. By employing a graphical user interface (GUI), the user assesses epochs in regard to four sleep quality markers (SQMs). Based on their topography and underlying EEG signal, the user eventually removes artifactual values. To identify artifacts, the user is required to have basic knowledge of the typical (patho-)physiological EEG they are interested in, as well as artifactual EEG. The final output consists of a binary matrix (channels x epochs). Channels affected by artifacts can be restored in afflicted epochs using epoch-wise interpolation, a function included in the online repository.

Results

The routine was applied in 54 overnight sleep hd-EEG recordings. The proportion of bad epochs highly depends on the number of channels required to be artifact-free. Between 95% and 100% of bad epochs could be restored using epoch-wise interpolation. We furthermore present a detailed examination of two extreme cases (with few and many artifacts). For both nights, the topography and cyclic pattern of delta power look as expected after artifact removal.

Comparison with Existing Methods

Numerous artifact removal methods exist, yet their scope of application usually targets short wake EEG recordings. The proposed routine provides a transparent, practical, and efficient approach to identify artifacts in overnight sleep hd-EEG recordings.

Conclusions

This method reliably identifies artifacts simultaneously in all channels and epochs.
The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain
Authors: Becker Léa J , Fillinger Clémentine , Waegaert Robin , Hener Pierre , Ayazgok Beyza , Humo Muris , Journée Sarah H , Karatas Meltem , Degiorgis Laetitia , des Neiges Santin Marie , Mondino Mary , Barrot Michel , Ibrahim El Chérif , Turecki Gustavo , Belzeaux Raoul , Veinante Pierre , Harsan Laura A , Hugel Sylvain , Lutz Pierre-Eric , Yalcin Ipek
Published: August 2022

While depression and chronic pain are frequently comorbid, underlying neuronal circuits, and their relevance for the understanding of psychopathology, remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. In naive animals, we demonstrate that activation of this pathway is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, a hub gene significantly upregulated in both mice and humans in the context of altered mood, is necessary for the emergence of depressive-like behaviors. Overall, these results place the BLA-ACC pathway at the core of pain and depression comorbidity, and unravel the role of impaired myelination and Sema4a in mood control.