bluuebunny/crossref_metadata_2025 huggingface dataset:
Degradation behavior and osseointegration of Mg–Zn–Ca screws in different bone regions of growing sheep: a pilot study
Authors: Marek Romy , Ćwieka Hanna , Donohue Nicholas , Holweg Patrick , Moosmann Julian , Beckmann Felix , Brcic Iva , Schwarze Uwe Yacine , Iskhakova Kamila , Chaabane Marwa , Sefa Sandra , Zeller-Plumhoff Berit , Weinberg Annelie-Martina , Willumeit-Römer Regine , Sommer Nicole Gabriele
Published: October 2022

Magnesium (Mg)-based implants are highly attractive for the orthopedic field and may replace titanium (Ti) as support for fracture healing. To determine the implant–bone interaction in different bony regions, we implanted Mg-based alloy ZX00 (Mg < 0.5 Zn < 0.5 Ca, in wt%) and Ti-screws into the distal epiphysis and distal metaphysis of sheep tibiae. The implant degradation and osseointegration were assessed in vivo and ex vivo after 4, 6 and 12 weeks, using a combination of clinical computed tomography, medium-resolution micro computed tomography (µCT) and high-resolution synchrotron radiation µCT (SRµCT). Implant volume loss, gas formation and bone growth were evaluated for both implantation sites and each bone region independently. Additionally, histological analysis of bone growth was performed on embedded hard-tissue samples. We demonstrate that in all cases, the degradation rate of ZX00-implants ranges between 0.23 and 0.75 mm/year. The highest degradation rates were found in the epiphysis. Bone-to-implant contact varied between the time points and bone types for both materials. Mostly, bone-volume-to-total-volume was higher around Ti-implants. However, we found an increased cortical thickness around the ZX00-screws when compared with the Ti-screws. Our results showed the suitability of ZX00-screws for implantation into the distal meta- and epiphysis.
Treatment History and Interest in Injectable Opioid Agonist Treatment With Hydromorphone Among People Who Inject Drugs
Authors: Ohlendorf Eric , Perez-Correa Andres , Riback Lindsey , Ghiroli Megan , Lopez-Castro Teresa , Fox Aaron D.
Published: October 2022

Objectives

Injectable opioid agonist treatment (iOAT) is a novel approach to treating opioid use disorder (OUD) that is typically reserved for treatment-experienced persons who inject drugs (PWID) with long-standing OUD. This study examined PWID's past OUD treatment histories and their attitudes toward iOAT with hydromorphone.

Methods

This cross-sectional study recruited syringe services program participants with OUD in New York City. Participants self-reported past OUD care episodes (detoxification; outpatient, inpatient, or medication treatment; or mutual aid groups) and current interest in iOAT with hydromorphone (assessed on a 4-point scale with 3 or 4 considered “interested”). Participants with 2 or more treatment episodes in the past 5 years were considered treatment-experienced. We examined whether the number of past care episodes was associated with interest in iOAT.

Results

Of 108 PWID, most participants were male (68.5%) and Hispanic (68.5%) with a mean age of 43 years (±10.8). Nearly all (98.1%) had severe OUD and had received past OUD care (96.3%), with the mean number of care episodes being 17.4 (SD, ±15.9). Most participants (59.8%) were treatment-experienced. Interest in iOAT with hydromorphone was high (64.8%), but there was no significant association between total past care episodes and expressing interest in iOAT (odds ratio, 1.02; 95% confidence interval, 0.99–1.05).

Conclusion

Participants were highly treatment-experienced, and iOAT interest was high regardless of prior OUD treatment. New OUD treatment options, such as iOAT with hydromorphone, would be welcomed by PWID whose OUD has not remitted with conventional treatment as well as other PWID.
Role of Delta/Notch-like epidermal growth factor-related receptor in gastric cancer patients and cells and its clinical significance
Authors: Tao Hanchuan , Wang Cheng , Zhu Yifan , Lu Chongmei , Zhou Xiaojun
Published: October 2022

Gastric cancer (GC) is a common digestive system malignancy. The aim of this study was to explore the role of Delta/Notch-like epidermal growth factor-related receptor (DNER) in GC patients and cells. Gene expression omnibus data base public databases were used to analyze the DNER expression in GC patient. A total of 30 cases of GC and adjacent tissue samples were retrospectively obtained to analyze the DNER expression. MTT assay was conducted to measure the cell viability. The apoptosis rate of GC cells was determined by flow cytometry. The migration and invasion were detected by transwell assay. Real-time polymerase chain reaction and western blot were performed to measure the DNER expression. Bioinformatics tools exhibited that DNER expression is significantly upregulated in the GC, which was also found in GC tissues and cells. The high levels of DNER were closely related the tumor size, sex and lymph node metastasis. Additionally, the survival rate of patients with high DNER expression is decreased. Furthermore, knockdown of DNER inhibits the proliferation, migration and invasion, and induces the apoptosis rate of the GC cells. DNER was upregulated in GC and knockdown of DNER inhibits the growth and metastasis of DNER. DNER may be a potential prognostic biomarker and therapeutic target of GC patients.
Impact of ABCC2 1249G>A and −24C>T Polymorphisms on Lacosamide Efficacy and Plasma Concentrations in Uygur Pediatric Patients With Epilepsy in China
Authors: Zhao Ting , Li Hong-jian , Zhang Hui-lan , Feng Jie , Yu Jing , Wang Ting-ting , Sun Yan , Yu Lu-hai
Published: October 2022

Purpose:

We aimed to evaluate the effect of the ABCC2 1249G>A (rs2273697) and −24C>T (rs717620) polymorphisms on lacosamide (LCM) plasma concentrations and the efficacy of LCM in Uygur pediatric patients with epilepsy.

Methods:

We analyzed 231 pediatric patients with epilepsy, among which 166 were considered to be LCM responsive. For drug assays, 2–3 mL of venous blood was collected from each patient just before the morning LCM dose was administered (approximately 12 hours after the evening dose, steady-state LCM concentrations). The remaining samples after routine therapeutic drug monitoring were used for genotyping analysis. The χ2 test and Fisher exact test were utilized for comparative analysis of the allelic and genotypic distribution of ABCC2 polymorphisms between the LCM-resistant and LCM-responsive groups. The Student t test or Mann–Whitney U test was conducted to analyze differences in plasma LCM concentration among pediatric patients with epilepsy with different genotypes.

Results:

Patients with the ABCC2 1249G>A GA genotype (0.7 ± 0.3 mcg/mL per kg/mg) and AA genotype (0.5 ± 0.3 mcg/mL per kg/mg) showed significantly (P < 0.001) lower LCM concentration-to-dose (CD) ratios than patients with the GG genotype (1.0 ± 0.4 mcg/mL per kg/mg). Moreover, patients with the ABCC2 −24C>T CT genotype (0.6 ± 0.2 mcg/mL per kg/mg) and TT genotype (0.6 ± 0.3 mcg/mL per kg/mg) presented a significantly (P < 0.001) lower LCM CD ratio than patients with the CC genotype (1.1 ± 0.4 mcg/mL per kg/mg).

Conclusions:

The ABCC2 1249G>A (rs2273697) and ABCC2 −24C>T (rs717620) polymorphisms can affect plasma LCM concentrations and treatment efficacy among a population of Uygur pediatric patients with epilepsy, causing these patients to become resistant to LCM. In clinical practice, ABCC2 polymorphisms should be identified before LCM treatment, and then, the dosage should be adjusted for pediatric patients with epilepsy accordingly.
Relationship between handgrip strength and endogenous hormones in postmenopausal women
Authors: García-Alfaro Pascual , García Sandra , Rodriguez Ignacio , Bergamaschi Luciana , Pérez-López Faustino R.
Published: October 2022

Objectives

This study aimed to evaluate the endogenous hormonal factors related to dominant handgrip strength (HGS) in postmenopausal women.

Methods

A cross-sectional study was performed on 402 postmenopausal women aged 47 to 83 years. The following variables were recorded: age, age at menopause, smoking status, adiposity, HGS, and physical activity. Hormonal parameters (follicle-stimulating hormone, estradiol, testosterone, cortisol, dehydroepiandrosterone sulfate, Δ4 androstenedione, insulin-like growth factor-1 [IGF-1], vitamin D, and parathormone levels) were measured and results reported as odds ratios (ORs), β coefficients and 95% confidence interval (95% CI). A directed acyclic graph was used to identify potential confounding variables and was adjusted in the regression model to assess associations between endogenous hormones and HGS.

Results

The mean dominant HGS was 22.8 ± 3.7 kg, and 25.6% of women had dynapenia. There were significant differences in plasma levels of follicle-stimulating hormone (OR, 0.99; 95% CI, 0.98-1.00), cortisol (OR, 1.07; 95% CI, 1.02-1.12), and dehydroepiandrosterone sulfate (OR, 0.99; 95% CI, 0.98-1.00) between women with normal HGS and those who presented with dynapenia. After adjusting for confounding variables, no significant association was found between endogenous hormones and HGS.

Conclusions

Our results showed that studied ovarian steroids, adrenal hormones, IGF-1, parathormone, and vitamin D were not associated with HGS.
Postoperative vault prediction for phakic implantable collamer lens surgery: LASSO formulas
Authors: Rocamora Leandro , Orlando José I. , Lwowski Christoph , Kohnen Thomas , Mertens Erik , Van Keer Karel
Published: October 2022

Purpose:

To develop and evaluate reliable formulas for predicting postoperative vault more accurately after implantable collamer lens (ICL) surgery in a White patient population with varying degrees of ametropia.

Setting:

Private clinical practice.

Design:

Retrospective analysis on dataset split into a separate training and test set.

Methods:

115 eyes of 59 patients were used to train regression models predicting postoperative vault based on anterior segment optical coherence tomography (OCT) parameters (Least Absolute Shrinkage and Selection Operator [LASSO]-OCT formula), ocular biometry data (LASSO-Biometry formula), or data from both devices (LASSO-Full formula). The performance of these models was evaluated against the manufacturer's nomogram (Online Calculation and Ordering System [OCOS]) and Nakamura 1 (NK1) and 2 (NK2) formulas on a matched separate test set of 37 eyes of 19 patients.

Results:

The mean preoperative spherical equivalent was −5.32 ± 3.37 (range: +3.75 to −17.375 diopters). The mean absolute errors of the estimated vs achieved postoperative vault for the LASSO-Biometry, LASSO-OCT, and LASSO-Full formulas were 144.1 ± 107.9 μm, 145.6 ± 100.6 μm, and 132.0 ± 86.6 μm, respectively. These results were significantly lower compared with the OCOS, NK1, and NK2 formulas (P < .006). Postoperative vault could be estimated within 500 μm in 97.3% (LASSO-Biometry) to 100% of cases (LASSO-OCT and LASSO-Full).

Conclusions:

The LASSO suite provided a set of powerful, reproducible yet convenient ICL sizing formulas with state-of-the-art performance in White patients, including those with low to moderate degrees of myopia. The calculator can be accessed at http://icl.emmetropia.be.
Association Between Skeletal Muscle Mass and Cardiovascular Risk Factors in Occupational Sedentary Population
Authors: Lu Yaru , Wang Xiao-He , Li Jing , Wang Wenhong , Zhang Shi , Huang Yaping , Wang Yi , Li Chun-Jun
Published: October 2022

Objective

The aims of this study were to determine the association of skeletal muscle mass with three cardiovascular risk factors and explore a simple and clinically feasible indicator for identifying high-risk groups of cardiovascular diseases in occupational sedentary population.

Methods

We recruited 7316 occupational sedentary participants older than 18 years from the Health Management Center of Tianjin Union Medical Center. Age-adjusted logistic regression was used to analyze the association between skeletal muscle mass index (SMI) and cardiovascular risk factors.

Results

There were significant positive associations between SMI, especially arm SMI, and cardiovascular risk factors in both male and female subjects (odds ratio, 1.28 to 5.02; P < 0.001).

Conclusions

Our findings suggest that measurements of skeletal muscle mass, particularly in the arms, may help identify individuals at high risk for cardiovascular disease in an occupationally sedentary population.
Assessment of Mobile Health Applications for Management of Knee and/or Hip Osteoarthritis Using the Mobile Application Rating Scale
Authors: Hensley Craig P. , Witte Maria M. , Cai Jiayi , Gruenke Amy , Pecze Jaclyn , Mangefrida Abigail , Chang Alison H.
Published: October 2022

Background

Mobile health applications (apps) can help individuals with knee and/or hip osteoarthritis (OA) learn about, monitor, and manage their condition. These apps have not been formally evaluated.

Objective

The aim of this study was to evaluate the publicly available mobile health apps for individuals with knee and/or hip OA using a systematic review.

Methods

We searched the Apple App Store, Android Google Play, and Amazon Appstore using the terms “arthritis,” “osteoarthritis,” “hip OA,” “knee OA,” “hip,” “knee,” “rehabilitation,” “rehab,” and “physical therapy” in December of 2021. Applications that met the inclusion/exclusion criteria were reviewed using the Mobile Application Rating Scale (MARS; 29 items across 6 sections, each rated at 1–5).

Results

Among 1104 identified apps, 94 met the inclusion/exclusion criteria for MARS appraisal. Fourteen apps met the predetermined score thresholds for final summary. Of the 14 apps appraised, the total overall mean app score on the MARS ranged from 3.12 to 4.20 (mean, 3.51 ± 0.37). Although app features varied, common features were symptom tracking, exercise recommendations, education, goal setting, and improving well-being. Many apps allowed for sharing with health care providers and included some measures to protect privacy. Jointfully Osteoarthritis was the top-rated app in both the Apple App Store and Android Google Play.

Conclusions

The majority of the apps we identified for knee and/or hip OA did not meet predetermined score thresholds for final summary. Many failed to provide comprehensive education and deliver management plans and lacked scientific testing. Future research should focus on apps that fit the needs of health care providers and patients including quality information, structured exercise programs tailored to individual needs, secure communication methods, and health information protection.
LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS
Authors: Fan Min , Yang Kun , Wang Xiaohui , Zhang Xia , Xu Jingjing , Tu Fei , Gill P. Spencer , Ha Tuanzhu , Williams David L. , Li Chuanfu
Published: October 2022

Introduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis. Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Lactic acid was injected i.p. (pH 6.8, 0.5 g/kg body weight) 6 h after CLP or sham surgery. To elucidate the role of heat shock protein A12B (HSPA12B), wild-type, HSPA12B-transgenic, and endothelial HSPA12B-deficient mice were subjected to CLP or sham surgery. To suppress lactate signaling, 3OBA (120 μM) was injected i.p. 3 h before surgery. Vascular permeability was evaluated with the Evans blue dye penetration assay. Results: We found that administration of lactate elevated CLP-induced vascular permeability. Vascular endothelial cadherin (VE-cadherin), claudin 5, and zonula occluden 1 (ZO-1) play a crucial role in the maintenance of endothelial cell junction and vascular integrity. Lactate administration significantly decreased VE-cadherin, claudin 5, and ZO-1 expression in the heart of septic mice. Our in vitro data showed that lactate (10 mM) treatment disrupted VE-cadherin, claudin 5, and ZO-1 in endothelial cells. Mechanistically, we observed that lactate promoted VE-cadherin endocytosis by reducing the expression of HSPA12B. Overexpression of HSPA12B prevented lactate-induced VE-cadherin disorganization. G protein–coupled receptor 81 (GPR81) is a specific receptor for lactate. Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice. Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.
EFFECTS OF 2-METHYL-2-THIAZOLINE ON CIRCULATORY DYNAMICS AND INTESTINAL VASCULAR SYSTEM IN RABBITS WITH ENDOTOXIC SHOCK
Authors: Onoe Atsunori , Muroya Takashi , Nakamura Fumiko , Ikegawa Hitoshi , Kuwagata Yasuyuki , Kobayakawa Reiko , Kobayakawa Ko
Published: October 2022

We hypothesized that circulatory and jejunal mucosal blood flow would improve after 2-methyl-2thiazoline (2MT) administration in endotoxic shock. This study aimed to evaluate changes in systemic circulation and in superior mesenteric venous (SMV) blood flow and jejunal mucosal tissue blood flow of the intestinal vascular system over time after administration of 2MT in rabbits with endotoxic shock. We created four groups (n = 6 each): control group, LPS (1 mg/kg) group, 2MT (80 mg/kg) group, and LPS-2MT group. As indicators of circulation, we measured MAP, heart rate, cardiac index, lactic acid level, SMV blood flow, and jejunal mucosal tissue blood flow every 30 min from 0 to 240 min. The drop in MAP observed in the LPS group was suppressed by 2MT administration. Superior mesenteric venous blood flow dropped temporarily with LPS administration but then rose thereafter. After administration of 2MT to the LPS group, SMV blood flow began to rise earlier than that in the LPS group and did not decline below that of the control group thereafter. In the LPS group, jejunal mucosal tissue blood flow transiently decreased and then increased but at a lower level than that in the control group. However, in the LPS-2MT group, although a transient decrease in jejunal mucosal tissue blood flow was observed, its flow then improved to the level of the control group. An interaction between 2MT and LPS was observed for jejunal mucosal tissue blood flow from 90 to 180 min and at 240 min (P < 0.05). We showed that 2MT maintained MAP and improved SMV blood flow and jejunal mucosal tissue blood flow. In a rabbit model of endotoxic shock, 2MT had a positive effect on MAP and jejunal mucosal tissue blood flow.
IMPACT OF TIME TO EMERGENCY DEPARTMENT RESUSCITATIVE AORTIC OCCLUSION AFTER NONCOMPRESSIBLE TORSO HEMORRHAGE
Authors: Broome Jacob M. , Ali Ayman , Simpson John T. , Tran Sherman , Tatum Danielle , Taghavi Sharven , DuBose Joseph , Duchesne Juan ,   the AORTA Study Group
Published: October 2022

Introduction: Time is an essential element in outcomes of trauma patients. The relationship of time to treatment in management of noncompressible torso hemorrhage (NCTH) with resuscitative endovascular balloon occlusion of the aorta (REBOA) or resuscitative thoracotomy (RT) has not been previously described. We hypothesized that shorter times to intervention would reduce mortality. Methods: A review of the Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery registry from 2013 to 2022 was performed to identify patients who underwent emergency department aortic occlusion (AO). Multivariate logistic regression was used to examine the impact of time to treatment on mortality. Results: A total of 1,853 patients (1,245 [67%] RT, 608 [33%] REBOA) were included. Most patients were male (82%) with a median age of 34 years (interquartile range, 30). Median time from injury to admission and admission to successful AO were 31 versus 11 minutes, respectively. Patients who died had shorter median times from injury to successful AO (44 vs. 72 minutes, P < 0.001) and admission to successful AO (10 vs. 22 minutes, P < 0.001). Multivariate logistic regression demonstrated that receiving RT was the strongest predictor of mortality (odds ratio [OR], 6.6; 95% confidence interval [CI], 4.4–9.9; P < 0.001). Time from injury to admission and admission to successful AO were not significant. This finding was consistent in subgroup analysis of RT-only and REBOA-only populations. Conclusions: Despite expedited interventions, time to aortic occlusion did not significantly impact mortality. This may suggest that rapid in-hospital intervention was often insufficient to compensate for severe exsanguination and hypovolemia that had already occurred before emergency department presentation. Selective prehospital advanced resuscitative care closer to the point of injury with “scoop and control” efforts including hemostatic resuscitation warrants special consideration.
Luteolibacter marinus sp. nov., a novel bacterium in the family Verrucomicrobiaceae, isolated from marine sediment
Authors: Xie Feilu , Zhu Suting , Guo Chaobo , Liu Xinyu , He Shan , Zhang Weiyan
Published: October 2022

A Gram-negative, rod-shaped, non-motile and strictly aerobic bacterium, designated NBU1238T, was isolated from marine sediment sampled on Meishan Island located in the East China Sea. Strain NBU1238T was able to grow optimally at 28–32 °C, at pH 7.5 and with no NaCl. Catalase and oxidase activities, H2S production and hydrolysis of Tweens 40 and 60 were positive. Methyl red reaction, Voges–Proskauer test and hydrolysis of starch, casein and Tweens 20 and 80 were negative. The major cellular fatty acids were iso-C14 : 0, C16 : 0, C16 : 1
 ω9c and C14 : 0. The only respiratory quinone was menaquinone-9. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylmethylethanolamine. The 16S rRNA gene sequence of strain NBU1238T showed 95.6, 95.6, 94.8 and 93.8% sequence similarity to

Luteolibacter flavescens

GKXT,

Luteolibacter luteus

G-1-1-1T,

Luteolibacter arcticus

MC 3726T and

Luteolibacter pohnpeiensis

A4T-83T, respectively. Phylogenetic analyses indicated that strain NBU1238T clustered with the genus

Luteolibacter

and was closely related to strains

L. flavescens

GKXT,

L. arcticus

MC 3726T and

L. luteus

G-1-1-1T. The average nucleotide identity and digital DNA–DNA hybridization values between strain NBU1238T and related species of genus

Luteolibacter

were well below the threshold limit for prokaryotic species delineation. The DNA G+C content of the genomic DNA was 65.0 mol%. Based on its phenotypic, chemotaxonomic and genotypic data, strain NBU1238T is considered to be a representative of a novel species in the genus

Luteolibacter

, for which the name Luteolibacter marinus sp. nov. is proposed. The type strain is NBU1238T (=KCTC 82227T=MCCC 1K04772T).
Gordonia pseudamarae sp. nov., a home for novel actinobacteria isolated from stable foams on activated sludge wastewater treatment plants
Authors: Riesco Raúl , Rose Jayson J. A. , Batinovic Steven , Petrovski Steve , Sánchez-Juanes Fernando , Seviour Robert J. , Goodfellow Michael , Trujillo Martha E.
Published: October 2022

The taxonomic status of two

Gordonia

strains, designated BEN371 and CON9T, isolated from stable foams on activated sludge plants was the subject of a polyphasic study which also included the type strains of

Gordonia

species and three authenticated

Gordonia amarae

strains recovered from such foams. Phylogenetic analyses of 16S rRNA gene sequences showed that these isolates formed a compact cluster suggesting a well-supported lineage together with a second branch containing the

G. amarae

strains. A phylogenomic tree based on sequences of 92 core genes extracted from whole genome sequences of the isolates, the

G. amarae

strains and

Gordonia

type strains confirmed the assignment of the isolates and the

G. amarae

strains to separate but closely associated lineages. Average nucleotide index (ANI) and digital DNA–DNA hybridisation (dDDH) similarities showed that BEN371 and CON9T belonged to the same species and had chemotaxonomic and morphological features consistent with their assignment to the genus

Gordonia

. The isolates and the

G. amarae

strains were distinguished using a range of phenotypic features and by low ANI and dDDH values of 84.2 and 27.0 %, respectively. These data supplemented with associated genome characteristics show that BEN371 and CON9T represent a novel species of the genus

Gordonia

. The name proposed for members of this taxon is Gordonia pseudamarae sp. nov. with isolate CON9T (=DSM 43602T=JCM 35249T) as the type strain.
streammd: fast low-memory duplicate marking using a Bloom filter
Authors: Leonard Conrad
Published: October 2022

The identification of duplicate reads is an essential pre-processing step in short-read sequencing analysis. For large sequencing libraries this step is typically time-consuming and resource-intensive. Here we presentstreammd: a fast, memory-efficient, single-pass duplicate marking tool operating on the principle of a Bloom filter. We show thatstreammdclosely reproduces the outputs of PicardMarkDuplicates, a widely-used duplicate marking program, while being substantially faster and suitable for pipelined applications, and that it requires much less memory thanSAMBLASTER, another single-pass duplicate marking tool.

Availability and Implementation

streammdis a C++ program available from GitHub (https://github.com/delocalizer/streammd) under the MIT license. Install instructions are in theREADME.mdfile. Unit tests are runnable withmake check. Open issues are listed athttps://github.com/delocalizer/streammd/issues.

Contact

conrad.leonard@qimrberghofer.eu.au

Supplementary information

Supplemenatary_figures.zip

Supplementary_tables.zip
Endothelial FABP4 constitutes the majority of basal circulating hormone levels and regulates lipolysis-driven insulin secretion
Authors: Inouye Karen E. , Prentice Kacey J. , Lee Alexandra , Dominguez-Gonzalez Carla , Chen Mu Xian , Lee Grace Yankun , Hotamışlıgil Gökhan S.
Published: October 2022

Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with body mass index and obesity-related pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitivelyin vivo. We generated mice with FABP4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was only reduced by ∼25% in Adipo-KO mice, whereas Endo-KO mice showed ∼75% decreases compared to wildtype controls. In contrast, Adipo-KO mice exhibited ∼62% reduction in FABP4 responses to lipolysis, while there was minimal reduction in Endo-KO mice, indicating that adipocytes are the main FABP4 source in lipolysis. We did not detect any myeloid cell contribution to circulating FABP4. Surprisingly, despite the nearly intact FABP4 responses, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis.
Are under-studied proteins under-represented? How to fairly evaluate link prediction algorithms in network biology
Authors: Yılmaz Serhan , Yorgancioglu Kaan , Koyutürk Mehmet
Published: October 2022

For biomedical applications, new link prediction algorithms are continuously being developed and these algorithms are typically evaluated computationally, using test sets generated by sampling the edges uniformly at random. However, as we demonstrate, this evaluation approach introduces a bias towards “rich nodes”, i.e., those with higher degrees in the network. More concerningly, this bias persists even when different network snapshots are used for evaluation, as recommended in the machine learning community. This creates a cycle in research where newly developed algorithms generate more knowledge on well-studied biological entities while under-studied entities are commonly overlooked. To overcome this issue, we propose a weighted validation setting specifically focusing on under-studied entities and present AWARE strategies to facilitate bias-aware training and evaluation of link prediction algorithms. These strategies can help researchers gain better insights from computational evaluations and promote the development of new algorithms focusing on novel findings and under-studied proteins.

Teaser

Systematically characterizes and mitigates bias toward well-studied proteins in the evaluation pipeline for machine learning.

Code and data availability

All materials (code and data) to reproduce the analyses and figures in the paper is available in figshare (doi:10.6084/m9.figshare.21330429). The code for the evaluation framework implementing the proposed strategies is available at github†. We provide a web tool‡to assess the bias in benchmarking data and to generate bias-adjusted test sets.
Decoding Fear or Safety and Approach or Avoidance by Brain-Wide Network Dynamics
Authors: Marques Danilo Benette , Rossignoli Matheus Teixeira , Mesquita Bruno de Avó , Prizon Tamiris , Zacharias Leonardo Rakauskas , Ruggiero Rafael Naime , Leite João Pereira
Published: October 2022

Discerning safety from threat and positive or negative outcomes of adversity are fundamental for mental health. Many brain structures have been implicated in both adaptive and maladaptive stress coping, however, how multiple regions function together as a network in the processing of this information is unclear. Here, we recorded local field potentials from seven regions of the mesolimbic-hippocampal-prefrontal cortical network (MLHFC) of male rats during the conditioning of a stimulus (CS) to the absence (safety) and then to the anticipation (fear) of footshocks, and during an approach-avoidance task. We developed a machine learning pipeline to investigate the relevance of specific features of oscillatory activity in the decoding of fear versus safety and approach versus avoidance. We found that decoding performance increased as a function of the number of brain regions included, reaching the best classification if all regions were considered. In addition, the best decoding was obtained from frequencies within the theta range (4-10 Hz). Remarkably, decoder models showed robust generalization within but not between individuals. Nevertheless, we were also able to identify patterns of MLHFC activity that decoded stress coping states from all rats. These patterns were characterized by increased brain-wide theta synchrony during fear and preceding approach. Our results indicate that stress coping information is encoded at the brain-wide level and highlight individual variability in this neural processing. Our findings also suggest that MLHFC network theta activity underlies active stress coping with both aversive and positive motivational valences.

SIGNIFICANCE STATEMENT

The appraisal of safety versus threat and positive versus negative valence of adversity are core dimensions of emotional experience and stress coping. We developed a new behavioral protocol that discriminates states of fear, safety, approach, and avoidance in a single subject and a machine learning-based method to investigate how neural oscillations can decode such states. Our work provides evidence that stress coping is processed at multiple regions on a brain-wide level involving network oscillations at the theta frequencies, which especially synchronizes during fear and approach. We highlight the potentials of combining artificial intelligence and multi-site electroencephalography to guide therapeutic decisions in precision psychiatry and theta-boosting stimulation therapies for stress-related disorders, especially related to cognitive and motivational deficits.
Disparate patterns of genetic divergence in three widespread corals across a pan-Pacific environmental gradient highlights species-specific adaptation trajectories
Authors: Hume Benjamin C C , Voolstra Christian R , Armstrong Eric , Mitushasi Guinther , Porro Barbara , Oury Nicolas , Agostini Sylvain , Boissin Emilie , Poulain Julie , Carradec Quentin , Paz-García David A. , Zoccola Didier , Magalon Hélène , Moulin Clémentine , Bourdin Guillaume , Iwankow Guillaume , Romac Sarah , Banaigs Bernard , Boss Emmanuel , Bowler Chris , de Vargas Colomban , Douville Eric , Flores Michel , Furla Paola , Galand Pierre E , Gilson Eric , Lombard Fabien , Pesant Stéphane , Reynaud Stéphanie , Sullivan Matthew B. , Sunagawa Shinichi , Thomas Olivier , Troublé Romain , Thurber Rebecca Vega , Wincker Patrick , Planes Serge , Allemand Denis , Forcioli Didier
Published: October 2022

Tropical coral reefs are among the worst affected ecosystems by climate change with predictions ranging between a 70-90% loss of reefs in the coming decades. Effective conservation strategies that maximize ecosystem resilience, and potential for recovery, must be informed by the accurate characterization of extant genetic diversity and population structure together with an understanding of the adaptive potential of keystone species. Here, we analyzed samples from theTaraPacific Expedition (2016 to 2018) that completed an 18,000 km longitudinal transect of the Pacific Ocean sampling three widespread corals –Pocillopora meandrina, Porites lobata, andMilleporacf.platyphylla– across 33 sites from 11 islands. Using deep metagenomic sequencing of 269 colonies in conjunction with morphological analyses and climate variability data we can show that the sampled transect encompasses multiple morphologically cryptic species that exhibit disparate biogeographic patterns, and most importantly, distinct evolutionary patterns, despite exposure to identical environmental regimes. Our findings demonstrate on a basin-scale that evolutionary trajectories are species-specific and complex, and can only in part be predicted from the environment. This highlights that conservation strategies must integrate multi-species investigations to consider the distinct genomic footprints shaped by selection as well as the genetic potential for adaptive change.
In silicocomparative RNA-seq analysis reveals varietal-specific intergenic small open reading frames inCucumis sativusL.
Authors: Chieng Gabrielle Shiao Wei , Tan Boon Chin , Teo Chee How
Published: October 2022

Small open reading frames (sORFs) have been reported to play important roles in growth, regulation of morphogenesis, and abiotic stress responses in various plant species. However, their sequences and functions remain poorly understood in many plant species includingCucumis sativus. Cucumis sativus(commonly known as cucumber) is Asia’s fourth most important vegetable and the second most important crop in Western Europe. The breeding of climate-resilient cucumbers is of great importance to ensure their sustainability under extreme climate conditions. In this study, we aim to isolate the intergenic sORFs fromC. sativusvar.hardwickiigenome and determine their sequence diversity and expression profiles inC. sativusvar.hardwickiiand different cultivars ofC. sativusvar.sativususing bioinformatics tools. We identified a total of 50,191 coding sORFs with coding potential (coding sORFs) fromC. sativusvar.hardwickiigenome. In addition, 1,311 transcribed sORFs were detected in RNA-seq datasets ofC. sativusvar.hardwickiiand shared homology to sequences deposited in the cucumber EST database, and among these, 91 transcribed sORFs with translation potential were detected. A total of 629 high-confidentC. sativus-specific sORFs were identified in both varieties. Varietal-specific transcribed sORFs were also identified inC. sativusvar.hardwickii(87) andC. sativusvar.sativus(2,906). Furthermore, cultivar- and tissue-specific transcribed sORFs were identified in different cultivars and tissue samples. The findings of this study provide insight into sequence diversity and expression patterns of sORFs inC. sativus, which could help in developing climate-resilient cucumbers.
Tamoxifen, associated to the conservative CKD treatment, promoted additional antifibrotic effect on experimental hypertensive nephrosclerosis
Authors: Fanelli Camilla , Ornellas Felipe M , Celestrino Giovanna A , Carmagnani Danielly N , Francini Ana LR , Noronha Irene L
Published: October 2022

CKD progression depends on the activation of an intricate set of hemodynamic and inflammatory mechanisms, promoting renal leukocyte infiltration, inflammation and fibrosis, leading to renal function loss. There are currently no specific drugs to detain fibrogenesis, which is a common end-point for different nephropathies. Clinical therapy for CKD is mostly based on the management of hypertension and proteinuria, partially achieved with renin-angiotensin-aldosterone system (RAAS) blockers, and the control of inflammation by immunosuppressive drugs. The aim of the present study was to verify if the administration of tamoxifen (TAM), an estrogen receptor modulator, clinically employed in the treatment of breast cancer and predicted to exert antifibrotic effects, would promote additional benefits when associated to a currently used therapeutic scheme for the conservative management of experimental CKD. Wistar rats underwent the NAME model of hypertensive nephrosclerosis, obtained by daily oral administration of a nitric oxide synthesis inhibitor, associated to dietary sodium overload. The therapeutic association of TAM to losartan (LOS), and mofetil mycophenolate (MMF) effectively reduced the severe hypertension, marked albuminuria and glomerular damage exhibited by NAME animals. Moreover, the association also succeeded in limiting renal inflammation in this model, and promoted further reduction of ECM interstitial accumulation and renal fibrosis, compared to the monotherapies. According to our results, the association of TAM to the currently used conservative treatment of CKD added significant antifibrotic effects bothin vivoandin vitro, and may represent an alternative to slow the progression of chronic nephropathy.
Modulation of implicitly perceived hand size by visuotactile recalibration
Authors: Fuchs Xaver , Heed Tobias
Published: October 2022

When concurrent visual and tactile stimuli are repeatedly presented with a spatial offset, even unisensory tactile stimuli are afterwards perceived with a spatial bias towards the previously presented visual stimuli. This so-called visuotactile ventriloquism aftereffect reflects visuotactile recalibration. It is unknown whether this recalibration occurs within a bodily map and interacts with perceived features like shape and size of body parts.

Here, we applied tactile stimuli to participants’ hidden left hand and simultaneously presented visual stimuli with spatial offsets that – if integrated with the tactile stimuli – implied an enlarged hand size. We either used a fixed spatial mapping between tactile and visual positions (“congruent”), or a scrambled (“incongruent”) mapping. We assessed implicitly perceived hand size via two independent behavioral assessments: pointing movements to unisensory tactile stimuli and tactile distance judgments. Moreover, we assessed explicitly perceived change in hand size with perceptual self-reports.

Especially after congruent recalibration, participants localized unimodal tactile stimuli as if they were aiming at an enlarged hand. They also reported tactile distance as shorter after congruent than incongruent recalibration. These modulations resemble those obtained after using tools that prolong the arm and extend reaching space; they suggest that recalibration affected a common, implicit hand representation that underlies both tasks. In contrast, explicit perceptual self-reports did not differ significantly between congruent and incongruent recalibration.

Thus, simple visuotactile stimuli are sufficient to modify implicitly perceived body size, indicating a tight link of low-level multisensory processes such as the visuotactile ventriloquism aftereffect and body representation.
Single and multi-analyte deep learning-based analysis framework for class prediction in biological images
Authors: Krishnan Neeraja M , Kumar Saroj , Kumar Ujjwal , Panda Binay
Published: October 2022

Measurement of biological analytes, characterizing flavor in fruits, is a cumbersome, expensive and time-consuming process. Fruits with higher concentration of analytes have greater commercial or nutritional values. Here, we tested a deep learning-based framework with fruit images to predict the class (sweet or sour and high or low) of analytes using images from two types of trees in a single and multi-analyte mode. We used fruit images from kinnow (n= 3,451), an edible hybrid mandarin and neem (n= 1,045), a tree with agrochemical and pharmaceutical properties. We measured sweetness in kinnows and five secondary metabolites in neem fruits (azadirachtin or A, deacetyl-salannin or D, salannin or S, nimbin or N and nimbolide or E) using a refractometer and high-performance liquid chromatography, respectively. We trained the models for 300 epochs, before and after hyper-parameters’ evolution, using 300 generations with 50 epochs/generation, estimated the best models and evaluated their performance on 10% of independent images. The validation F1score and test accuracies were 0.79 and 0.77, and 82.55% and 60.8%, respectively for kinnow and neem A analyte. A multi-analyte model enhanced the neem A model’s prediction to ‘high’ class when the D:N:S’s combined class predictions were high:low:high and to ‘low’ class when D:N’s combined class predictions were low:high respectively. The test accuracy increased further to ~70% with a 10-fold cross-validation error of 0.257 across ten randomly split train:validation:test sets proving the potential of a multi-analyte model to enhance the prediction accuracy, especially when the numbers of images are limiting.
Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult
Authors: Hellberg Sanna , Ahmed Osman , Zhang Yuyang , Di Nunzio Giada , Björck Hanna M , Francis Roy , Fagerberg Linn , Gisterå Anton , Zhang Xueming , Metso Jari , Manfé Valentina , Soto Yosdel , Franco-Cereceda Anders , Eriksson Per , Jauhiainen Matti , Olofsson Peder S. , Malin Stephen G.
Published: October 2022

Apolipoprotein-B (APOB) containing lipoproteins are causative for atherosclerotic cardiovascular disease. Whether the vasculature is the initial responding site or if atherogenic-dyslipidemia effects other organs simultaneously is unknown. We set out to discover how the liver responds to a dyslipidemic insult through the creation of inducible mouse models based on human familial hypercholesterolemia mutations andin vivotracing of APOB. An acute transition to atherogenic APOB-lipoprotein plasma levels resulted in rapid accumulation of triglycerides and cholesterol in the liver. Single cell RNA-seq and flow cytometry disclosed that multiple immune cells have the ability to engulf APOB-lipoproteins. However bulk RNA-seq of the liver revealed an inflammatory Kupffer cell-specific transcriptional program that could not be activated by a western diet alone. Depletion of Kupffer cells through clodronate liposomes or CD8 T cell targeting rapidly raised plasma lipoprotein levels, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting pro-atherosclerotic factors into plasma. Our results place Kupffer cells as a key gateway in organizing systemic responses at the initiation of atherosclerosis.
Arabidopsis Nicotianamine Synthases (NAS) comprise a common core-NAS domain fused to a variable auto-inhibitory C-terminus
Authors: Seebach Hiroyuki , Radow Gabriel , Brunek Michael , Schulz Frank , Piotrowski Markus , Krämer Ute
Published: October 2022

Nicotianamine Synthase (NAS) catalyzes the biosynthesis of nicotianamine (NA) from the 2-aminobutyrate moieties of threeS-adenosylmethionine molecules. NA has central roles in metal nutrition and metal homeostasis of flowering plants. Despite the availability of crystal structures of archaeal and bacterial NAS-like proteins that carry out simpler aminobutanoyltransferase reactions, the enzymatic function of NAS remains poorly understood. Here we report amino acids essential for the activity of AtNAS1 based on structural modeling and site-directed mutagenesis. An enzyme-coupled continuous activity assay allowed us to compare differing NAS proteins identified through multiple sequence alignments and phylogenetic analyses. In most class Ia and b NAS proteins of dicotyledonous and monocotyledonous angiosperm plants, respectively, the core-NAS domain is fused to a variable C-terminal domain. Compared to fungal and moss NAS (class III) that consist merely of the core-NAS domain, NA biosynthetic activities of the four paralogous Arabidopsis NAS proteins were far lower. Yet their C-terminally trimmed core-NAS variants exhibited strongly elevated activities. Out of 320 amino acids of AtNAS1, twelve, 287-TRGCMFMPCNCS-298, accounted for the auto-inhibitory effect of the C-terminus, with approximately one third contributed by N296 within a CNCS motif that is conserved in Arabidopsis. No detectable NA biosynthesis was mediated by two representatives of groups of plant NAS proteins that naturally lack the C-terminal domain, class IaArabidopsis halleriNAS5, andMedicago truncatulaNAS2 of class II which is found in dicots and diverged early during the evolution of flowering plants. Our results suggest that NAS activity is under stringent post-translational control in plants.
Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion
Authors: Ko Kyung-Pil , Huang Yuanjian , Zhang Shengzhe , Zou Gengyi , Kim Bongjun , Zhang Jie , Jun Sohee , Martin Cecilia , Dunbar Karen J. , Efe Gizem , Rustgi Anil K. , Nakagawa Hiroshi , Park Jae-Il
Published: October 2022

Background and aims

Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown.

Methods

Using CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53,CDKN2A,NOTCH1,NOTCH3,KMT2D,KMT2C,FAT1,FAT4, andAJUBA) in murine esophageal organoids (EOs). Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing (scRNA-seq). Tumorigenicity and immune evasion of organoids were monitored by allograft transplantation. Human ESCC scRNA-seq datasets were analyzed to classify patients and find subsets relevant to organoid models and immune evasion.

Results

We established 32 genetically engineered EOs and identified key genetic determinants that drive ESCC initiation. A single-cell transcriptomic analysis uncovered thatTrp53,Cdkn2a, andNotch1(PCN) triple-knockout (KO) induces neoplastic features of ESCC by generating cell lineage heterogeneity and high cell plasticity.PCNKO also generates an immunosuppressive niche enriched with exhausted T cells and M2 macrophages via the CCL2-CCR2 axis. Mechanistically,CDKN2Ainactivation transactivatesCCL2via NF-κB. Moreover, comparative single-cell transcriptomic analyses stratified ESCC patients and identified a specific subtype recapitulating the PCN-type ESCC signatures, including the high expression of CCL2 and CD274/PD-L1.

Conclusions

Our study unveils that loss ofTP53,CDKN2A, andNOTCH1induces esophageal neoplasia and immune evasion for ESCC initiation and proposes the CCL2 blockade as a viable option for targeting PCN-type ESCC.