bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs
Authors: Wehrle Chase J. , Zhang Mingyi , Khalil Mazhar , Pita Alejandro , Modaresi Esfeh Jamak , Diago-Uso Teresa , Kim Jaekeun , Aucejo Federico , Kwon David C.H. , Ali Khaled , Cazzaniga Beatrice , Miyazaki Yuki , Liu Qiang , Fares Sami , Hong Hanna , Tuul Munkhbold , Jiao Chunbao , Sun Keyue , Fairchild Robert L. , Quintini Cristiano , Fujiki Masato , Pinna Antonio D. , Miller Charles , Hashimoto Koji , Schlegel Andrea
Published: April 2024

Objective:

Assess cost and complication outcomes after liver transplantation (LT) using normothermic machine perfusion (NMP).

Background:

End-ischemic NMP is often used to aid logistics, yet its impact on outcomes after LT remains unclear, as does its true impact on costs associated with transplantation.

Methods:

Deceased donor liver recipients at 2 centers (January 1, 2019, to June 30, 2023) were included. Retransplants, splits, and combined grafts were excluded. End-ischemic NMP (OrganOx-Metra) was implemented in October 2022 for extended-criteria donation after brain death (DBDs), all donations after circulatory deaths (DCDs), and logistics. NMP cases were matched 1:2 with static cold storage controls (SCS) using the Balance-of-Risk [donation after brain death (DBD)-grafts] and UK-DCD Score (DCD-grafts).

Results:

Overall, 803 transplantations were included, 174 (21.7%) receiving NMP. Matching was achieved between 118 NMP-DBDs with 236 SCS; and 37 NMP-DCD with 74 corresponding SCS. For both graft types, median inpatient comprehensive complications index values were comparable between groups. DCD-NMP grafts experienced reduced cumulative 90-day comprehensive complications index (27.6 vs 41.9, P=0.028). NMP also reduced the need for early relaparotomy and renal replacement therapy, with subsequently less frequent major complications (Clavien-Dindo ≥IVa). This effect was more pronounced in DCD transplants. NMP had no protective effect on early biliary complications. Organ acquisition/preservation costs were higher with NMP, yet NMP-treated grafts had lower 90-day pretransplant costs in the context of shorter waiting list times. Overall costs were comparable for both cohorts.

Conclusions:

This is the first risk-adjusted outcome and cost analysis comparing NMP and SCS. In addition to logistical benefits, NMP was associated with a reduction in relaparotomy and bleeding in DBD grafts, and overall complications and post-LT renal replacement for DCDs. While organ acquisition/preservation was more costly with NMP, overall 90-day health care costs-per-transplantation were comparable.
Systemic acylcarnitine levels are affected in response to multiple injuries and hemorrhagic shock: An analysis of lipidomic changes in a standardized porcine model
Authors: Kalbas Yannik , Kumabe Yohei , Karl-Ludwig Felix , Halvachizadeh Sascha , Teuben Michel Paul Johan , Weisskopf Miriam , Cesarovic Nikola , Hülsmeier Andreas J. , Märsmann Sonja , Hierholzer Christian , Hildebrand Frank , Hornemann Thorsten , Pfeifer Roman , Cinelli Paolo , Pape Hans-Christoph
Published: April 2024

INTRODUCTION

Along with recent advances in analytical technologies, tricarboxylic acid–cycle intermediates are increasingly identified as promising makers for cellular ischemia and mitochondrial dysfunction during hemorrhagic shock. For traumatized patients, the knowledge of the role of lipid oxidation substrates is sparse. In this study, we aimed to analyze the dynamics of systemic acylcarnitine (AcCa) release in a standardized polytrauma model with hemorrhagic shock.

METHODS

Fifty-two male pigs (50 ± 5 kg) were randomized into two groups: group isolated fracture was subject to a standardized femur shaft fracture, and group polytrauma was subject to a femur fracture, followed by blunt chest trauma, liver laceration, and a pressure-controlled hemorrhagic shock for 60 minutes. Resuscitation was performed with crystalloids. Fractures were stabilized by intramedullary nailing. Venous samples were collected at six time points (baseline, trauma, resuscitation, 2 hours, 4 hours, and 6 hours). Lipidomic analysis was performed via liquid chromatography coupled mass spectrometry. Measurements were collated with clinical markers and near-infrared spectrometry measurements of tissue perfusion. Longitudinal analyses were performed with linear mixed models, and Spearman's correlations were calculated. A p value of 0.05 was defined as threshold for statistical significance.

RESULTS

From a total of 303 distinct lipids, we identified two species of long-chain AcCas. Both showed a highly significant (p < 0.001) twofold increase after hemorrhagic shock in group polytrauma that promptly normalized after resuscitation. This increase was associated with a significant decrease of the base excess (p = 0.005), but recovery after resuscitation was faster. For both AcCas, there were significant correlations with decreased muscle tissue oxygen delivery (p = 0.008, p = 0.003) and significant time-lagged correlations with the increase of creatine kinase (p < 0.001, p < 0.001).

CONCLUSION

Our results point to plasma AcCas as a possible indicator for mitochondrial dysfunction and cellular ischemia in hemorrhagic shock. The more rapid normalization after resuscitation in comparison with acid base changes may warrant further investigation.
Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study
Authors: Shoji Jun , Goggins William C. , Wellen Jason R. , Cunningham Patrick N. , Johnston Olwyn , Chang Shirley S. , Solez Kim , Santos Vicki , Larson Tami J. , Takeuchi Masahiro , Wang Xuegong
Published: April 2024

Background.

Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40−related processes in FSGS, potentially preventing rFSGS.

Methods.

A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant.

Results.

Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, −89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, −34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study.

Conclusions.

In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.
Efficacy of Newer Nucleos(t)ide Analogs After Hepatitis B Immunoglobulin Discontinuation Against Hepatitis B and D Recurrence in Liver Transplant Recipients
Authors: Cholongitas Evangelos , Oikonomou Theodora , Bafa Konstantina , Sinakos Emmanouil , Papatheodoridis George V. , Goulis Ioannis
Published: April 2024

Background.

The use of nucleos(t)ide analogs (NAs) with a high genetic barrier to resistance, namely entecavir and tenofovir, has improved the efficacy of antiviral prophylaxis against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, the optimal duration and dosage of hepatitis B immunoglobulin (HBIG) administration, particularly in patients transplanted for HBV and hepatitis D virus (HDV) coinfection, remains controversial.

Methods.

We evaluated 28 patients transplanted for HBV/HDV cirrhosis. After LT, each patient received a fixed scheme of low-dose HBIG plus NA for 6 mo post-LT and then continued with long-term NA prophylaxis (entecavir: 8, tenofovir: 20 patients).

Results.

During 72 mo of follow-up, reappearance of hepatitis B surface antigen at low titers was observed in 1 (3.6%) patient at 33 mo after HBIG discontinuation, which became negative after a single dose of HBIG 1000 IU/L, whereas both serum HBV DNA and HDV RNA remained persistently undetectable and without any clinical or biochemical evidence of HBV/HDV recurrence.

Conclusions.

We showed for the first time the efficacy of a short, fixed scheme of low-dose HBIG plus NA followed by long-term NA monoprophylaxis against HBV/HDV recurrence after LT, although careful follow-up is needed after HBIG discontinuation, whereas further larger studies are needed to confirm these findings.
Using the i-PARIHS theoretical framework to develop evidence implementation strategies for central venous catheter maintenance: a multi-site quality improvement project
Authors: Wang Wenchao , Fu Qin , Shen Weijie , Xu Yulu , Wang Linjuan , Chun Xiao , Shi Yuyun , Lin Jianping , Zhao Yaxun , Gu Ying
Published: April 2024

Introduction:

Evidence-based nursing practice can reduce complications associated with central venous catheters (CVCs). In this project, the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework was considered an ideal theoretical instrument to identify facilitators and barriers to implementing evidence-based practice.

Methods:

The project was conducted in pediatric intensive care units in six Chinese tertiary children's hospitals. Twenty-two audit criteria were obtained from best practice recommendations, and a baseline audit was conducted to assess current practice against best practice. Next, the i-PARIHS framework was used to identify facilitators and barriers to best practice and develop improvement strategies. A follow-up audit was then conducted to measure changes in compliance with best practices.

Results:

Facilitators and barriers were identified at the innovation, recipient, and context levels. A comprehensive CVC maintenance strategy was then developed to apply the best evidence to nurses’ clinical work. Of the 22 audit criteria, 17 showed significant improvement compared with the baseline audit.

Conclusions:

The i-PARIHS framework is an effective tool for developing targeted, evidence-based improvement strategies and applying these to the clinical setting. The quality of the nurses’ clinical practice improved during CVC maintenance. However, there is no certainty that these positive results can be maintained, and long-term data are needed to verify this.

Spanish abstract:

http://links.lww.com/IJEBH/A185
Deep convolutional neural network with face identity recognition experience exhibits brain-like neural representations of personality traits
Authors: Li Wenlu , Li Jin , Jiang Tianzi
Published: April 2024

Faces contain both identity and personality trait information. Previous studies have found that convolutional neural networks trained for face identity recognition spontaneously generate personality trait information. However, the successful classification of different personality traits does not necessarily mean that convolutional neural networks adopt brain-like representation mechanisms to achieve the same computational goals. Our study found that convolutional neural network with visual experience in face identity recognition (VGG-face) exhibited brain-like neural representations of personality traits, including coupling effects and confusion effects, while convolutional neural networks with the same network architecture but lacked visual experience for face identity recognition (VGG-16 and VGG-untrained) did not exhibit brain-like effects. In addition, compared to the VGG-16 and the VGG-untrained, the VGG-face exhibited higher similarity in neural representations with the human brain across all individual personality traits. In summary, these findings revealed the necessity of visual experience in face identity recognition for developing face personality traits judgment.
Protective role ofPtendownregulation in Huntington’s Disease models
Authors: Nisha  , Thapliyal Deepti , Gohil Bhavya , Modak Aninda Sundar , Ahuja Sanchi , Singh N. Tarundas , Sahu Bhavani Shankar , Singh M. Dhruba
Published: April 2024

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder that stems from the expansion of CAG repeats within the coding region of the Huntingtin gene. Currently, there exists no effective therapeutic intervention that can prevent the progression of the disease. Our investigation aims to identify a novel genetic modifier with therapeutic potential. We employ transgenic flies containingHtt93QandHtt138Q.mRFP constructs, which encode mutant pathogenic Huntingtin proteins featuring 93 and 138 polyglutamine (Q) repeats, respectively. The resultant mutant protein causes the loss of photoreceptor neurons in the eye and a progressive loss of neuronal tissues in the brain and motor neurons inDrosophila. Several findings have demonstrated the association of HD with growth factor signaling defects. Phosphatase and tensin homolog (Pten) have been implicated in the negative regulation of insulin signaling/receptor tyrosine signaling pathway which regulates the growth and survival of cells. In the present study, we downregulatedPtenand found a significant improvement in morphological phenotypes in the eye, brain, and motor neurons. These findings were further correlated with the enhancement of the functional vision and climbing ability of the flies. We also noted the reduction in both poly(Q) aggregate levels and caspase activity which are involved in the apoptotic pathway. Moreover, we elucidated the protective role of Pten inhibition through the utilization of VO-OHpic (referred to as PTENi). In alignment with the genetic modulation ofPten, pharmaceutical inhibition ofPtenimproved the climbing ability of flies and reduced the poly(Q) aggregates and apoptosis levels. A similar reduction in poly(Q) aggregates was observed in the mouse neuronal inducible HD cell line model. Our study illustrates that Pten inhibition is a potential therapeutic approach for HD.
An Open Resource: MR and light sheet microscopy stereotaxic atlas of the mouse brain
Authors: Mansour Harrison , Azrak Ryan , Cook James J. , Hornburg Kathryn J. , Qi Yi , Tian Yuqi , Williams Robert W. , Yeh Fang-Cheng , White Leonard E. , Johnson G. Allan
Published: April 2024

We have combined MR histology and light sheet microscopy (LSM) of five postmortem C57BL/6J mouse brains in a stereotaxic space based on micro-CT yielding a multimodal 3D atlas with the highest spatial and contrast resolution yet reported. Brains were imaged in situ with multi gradient echo (mGRE) and diffusion tensor imaging (DTI) at 15 μm resolution (∼ 2.4 million times that of clinical MRI). Scalar images derived from the average DTI and mGRE provide unprecedented contrast in 14 complementary 3D volumes, each highlighting distinct histologic features. The same tissues scanned with LSM and registered into the stereotaxic space provide 17 different molecular cell type stains. The common coordinate framework labels (CCFv3) complete the multimodal atlas. The atlas has been used to correct distortions in the Allen Brain Atlas and harmonize it with Franklin Paxinos. It provides a unique resource for stereotaxic labeling of mouse brain images from many sources.
Nucleic Acid Aptamers Protect Against Lead (Pb(II)) Toxicity
Authors: Anwar Afreen , De Ayreflor Reyes Solimar Ramis , John Aijaz Ahmad , Breiling Erik , O’Connor Abigail M. , Reis Stephanie , Shim Jae-Hyuck , Shah Ali Asghar , Srinivasan Jagan , Farny Natalie G.
Published: April 2024

Lead (Pb(II)) is a pervasive heavy metal toxin with many well-established negative effects on human health. Lead toxicity arises from cumulative, repeated environmental exposures. Thus, prophylactic strategies to protect against the bioaccumulation of lead could reduce lead-associated human pathologies. Here we show that DNA and RNA aptamers protectC. elegansfrom toxic phenotypes caused by lead. Reproductive toxicity, as measured by brood size assays, is prevented by co-feeding of animals with DNA or RNA aptamers. Similarly, lead-induced behavioral anomalies are also normalized by aptamer feeding. Further, cultured human HEK293 and primary murine osteoblasts are protected from lead toxicity by transfection with DNA aptamers. The osteogenic development, which is decreased by lead exposure, is maintained by prior transfection of lead-binding DNA aptamers. Aptamers may be an effective strategy for the protection of human health in the face of increasing environmental toxicants.

SYNOPSIS

Lead remains a pervasive environmental contaminant with significant human health implications. This study investigates an entirely novel intervention for the problem of lead toxicity, using nucleic acid aptamers.
An ALS Therapeutic Assembly Modulator Target in Peripheral Blood Mononuclear Cells: Implications for ALS Pathophysiology, Therapeutics, and Diagnostics
Authors: Yu Shao Feng , Michon Maya , Lingappa Anuradha F. , Paulvannan Kumar , Solas Dennis , Staats Kim , Ichida Justin , Dey Debendranath , Rosenfeld Jeffrey , Lingappa Vishwanath R.
Published: April 2024

Assembly modulators are a new class of allosteric site-targeted therapeutic small molecules, some of which are effective at restoring nuclear localization of TDP-43 in ALS cellular models, and display efficacy in a variety of ALS animal models. One of these compounds has been shown to target a small subfraction of protein disulfide isomerase, a known allosteric modulator implicated in ALS pathophysiology, within a novel, transient, and energy-dependent multi-protein complex that includes other important members of the ALS interactome, such as TDP- 43, RanGTPase, and selective autophagy receptor p62/SQSTM1. Building on earlier literature suggesting PBMC dysfunction in ALS, we demonstrate here that a similar multi-protein complex drug target is present in PBMCs with signature alterations in PBMCs from ALS patients compared to PBMCs from healthy individuals. ALS-associated changes in the drug target include increased RanGTPase and MMP9, diminished p62/SQSTM1, and most distinctively, appearance of a 17kDa post-translationally modified form of RanGTPase. Many of these changes are not readily apparent from analysis of whole cell extracts, as a number of the proteins present in the target multi-protein complex, including RanGTPase, comprise a miniscule percent of their total in cell extracts. A small subset of each of these proteins appear to come together in a transient, energy-dependent fashion, to form the drug target. Furthermore, whole blood from ALS patients shows a distinctive degradation of RanGTPase not observed in blood from healthy individuals, which appears to be rescued by treatment with either of two structurally unrelated ALS-active assembly modulators. Our findings are consistent with the hypothesis that ALS is fundamentally a disorder of homeostasis that can be both detected and treated by assembly modulators.
Characterizing medaka visual features using a high-throughput optomotor response assay
Authors: Suzuki Risa , Woo Jia Zheng , Thumberger Thomas , Hofmann Gero , Wittbrodt Joachim , Tavhelidse-Suck Tinatini
Published: April 2024

Medaka fish (Oryzias latipes) is a powerful model to study genetics underlying the developmental and functional traits of the vertebrate visual system. We established a simple and high-throughput optomotor response (OMR) assay utilizing medaka larvae to study visual functions including visual acuity and contrast sensitivity. Our assay presents multiple adjustable stripes in motion to individual fish in a linear arena. For that the OMR assay employs a tablet display and theFish Stripessoftware to adjust speed, width, color, and contrast of the stripes. Our results demonstrated that optomotor responses were robustly induced by black and white stripes presented from below in the linear-pool-arena. We detected robust strain specific differences in the OMR when comparing long established medaka inbred strains. We observed an interesting training effect upon the initial exposure of larvae to thick stripes, which allowed them to better respond to narrower stripes. The OMR setup and protocol presented here provide an efficient tool for quantitative phenotype mapping, addressing visual acuity, trainability of cortical neurons, color sensitivity, locomotor response, retinal regeneration and others. Our open-source setup presented here provides a crucial prerequisite for ultimately addressing the genetic basis of those processes.
Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome
Authors: Alvino F.G. , Gini S. , Minetti A. , Pagani M. , Sastre-Yagüe D. , Barsotti N. , De Guzman E. , Schleifer C. , Stuefer A. , Kushan L. , Montani C. , Galbusera A. , Papaleo F. , Lombardo M. V. , Pasqualetti M. , Bearden C.E. , Gozzi A.
Published: April 2024

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3β inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper-to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3β, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.
The psychedelic, DOI, increases dopamine release in nucleus accumbens to predictable rewards and reward cues
Authors: Martin David , Delgado Angel , Calu Donna
Published: April 2024

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute psychedelic administration during well learned Pavlovian tasks in which sequential cues predict rewards. We find that the psychedelic 5-HT2A/2Cagonist, DOI, increases dopamine signaling to rewards and proximal reward cues but not to the distal cues that predict these events. We determine that the elevated dopamine produced by psychedelics to reward cues occurs independently of psychedelic-induced changes in reward value. The increased dopamine associated with predictable reward cues supports psychedelic-induced increases in prediction error signaling. These findings lay a foundation for developing psychedelic strategies aimed at engaging error-driven learning mechanisms to disrupt entrenched associations or produce new associations.
Right Thoracotomy with Central Cannulation for Valve Surgery: 10 Years of Experience
Authors: Sharma Anil , Dixit Sunil , Sharma Dr.Mohit , Mittal Dr.Sourabh , Shah Dr.Apurva , Goyal Shefali
Published: April 2024

Background

The aim of this study is to report the early outcomes of valvular heart surgeries performed via the right thoracotomy approach. While thoracotomy with femoro-femoral bypass is an established method for minimally invasive open-heart surgeries, thoracotomy with conventional cannulation is still being explored. In our center, we conducted 958 valvular heart surgery cases using the right anterolateral thoracotomy approach with central cannulation and data were analyzed.

Methods

This is a retrospective observational study based on prospectively collected data from patients who underwent valvular heart surgery at our center spanning from April 2013 to April 2023. The data encompass demographics, procedures, operative techniques, post-operative morbidity, mortality, and a 1-month follow-up.

Results

Our study revealed no procedure-related mortality. No patient required conversion to median sternotomy. Smooth cannulation and satisfactory exposure were achieved in all patients. The study encompassed a wide age range, from 14 to 68 years, with 618 female patients (64.5%) and 340 male patients (35.5%).The average cross-clamp time ranged from 38 to 90 minutes, the duration of cardio-pulmonary bypass ranged from 45 to 105 minutes, post-operative extubation ranged from 3 to 8 hours, the average drain volume ranged from 100 to 350 ml, and the incision size ranged from 5 to 7 cm.

Conclusions

Our data demonstrate that conventional cannulation via the right antero-lateral thoracotomy approach for valvular heart disease is a viable alternative to reduce the side effects associated with sternotomy and femoral cannulation. This procedure is safe, reproducible, and provides the same level of treatment quality.
Estimating and predicting kidney function decline in the general population
Authors: Iwagami Masao , Odani Kazunori , Saito Tomoki
Published: April 2024

Introduction

We aimed to estimate the rate of kidney function decline over 10 years in the general population and develop a machine learning model to predict it.

Methods

We used the JMDC database from 2012 to 2021, which includes company employees and their family members in Japan, where annual health checks are mandated for people aged 40–74 years. We estimated the slope (average change) of estimated glomerular filtration rate (eGFR) over a period of 10 years. Then, using the annual health-check results and prescription claims for the first five years from 2012 to 2016 as predictor variables, we developed an XGBoost model, evaluated its prediction performance with the root mean squared error (RMSE), R2, and area under the receiver operating characteristic curve (AUROC) for rapid decliners (defined as the slope <-3 ml/min/1.73 m2/year) using 5-fold cross validation, and compared these indicators with those of the linear regression model using only eGFR data from 2012 to 2016.

Results

We included 126 424 individuals (mean age, 45.2 years; male, 82.4%; mean eGFR, 79.0 ml/min/1.73 m2in 2016). The mean slope was -0.89 (standard deviation, 0.96) ml/min/1.73 m2/year. The predictive performance of the XGBoost model (RMSE, 0.78; R2, 0.35; and AUROC, 0.89) was better than that of the linear regression model using only eGFR data (RMSE, 1.94; R2, -3.03; and AUROC, 0.79).

Conclusion

Application of machine learning to annual health-check and claims data could predict the rate of kidney function decline, whereas the linear regression model using only eGFR data did not work.
Foraging Under Uncertainty Follows the Marginal Value Theorem with Bayesian Updating of Environment Representations
Authors: Webb James , Steffan Paul , Hayden Benjamin Y. , Lee Daeyeol , Kemere Caleb , McGinley Matthew
Published: April 2024

Foraging theory has been a remarkably successful approach to understanding the behavior of animals in many contexts. In patch-based foraging contexts, the marginal value theorem (MVT) shows that the optimal strategy is to leave a patch when the marginal rate of return declines to the average for the environment. However, the MVT is only valid in deterministic environments whose statistics are known to the forager; naturalistic environments seldom meet these strict requirements. As a result, the strategies used by foragers in naturalistic environments must be empirically investigated. We developed a novel behavioral task and a corresponding computational framework for studying patch-leaving decisions in head-fixed and freely moving mice. We varied between-patch travel time, as well as within-patch reward depletion rate, both deterministically and stochastically. We found that mice adopt patch residence times in a manner consistent with the MVT and not explainable by simple ethologically motivated heuristic strategies. Critically, behavior was best accounted for by a modified form of the MVT wherein environment representations were updated based on local variations in reward timing, captured by a Bayesian estimator and dynamic prior. Thus, we show that mice can strategically attend to, learn from, and exploit task structure on multiple timescales simultaneously, thereby efficiently foraging in volatile environments. The results provide a foundation for applying the systems neuroscience toolkit in freely moving and head-fixed mice to understand the neural basis of foraging under uncertainty.
Phylogeography of the Giant Honeybees Based on Mitochondrial Gene Sequences
Authors: Bhatta Chet P. , Cluff Sarah C. , Smith Deborah R.
Published: April 2024

Abstract

We carried out a phylogenetic analysis of the giant honeybees using mitochondrial COI and COII gene sequences analyzed with maximum likelihood methods. Our goal was to resolve phylogenetic relationships amongApis laboriosa, and theApis dorsatasubspecies:A. d. dorsata, A. d. binghami, andA. d. breviligula, the last two of which have been proposed as full species by several authors. We obtained strong support for four clades withinA. dorsata: the three subspecies mentioned above, and a fourth from south India, but our analysis did not resolve the phylogenetic relationships among the four clades withinA. dorsatain the broad sense. Recognition of these distinct lineages is important for conservation planning, so that their individual ecologies and migration patterns can be taken into account.
Surface passivation and functionalization for interferometric scattering microscopy
Authors: Sülzle Jenny , Elfeky Laila , Manley Suliana
Published: April 2024

Interferometric scattering (iSCAT) microscopy enables the label-free observation of biomolecule interactions with surfaces. Consequently, single-particle imaging and tracking with iSCAT is a growing area of study. However, establishing reliable cover glass passivation and functionalization methods are crucial to reduce non-specific binding and prepare surfaces forin vitrosingle-molecule binding experiments. Existing protocols for fluorescence microscopy can contain strongly scattering or mobile components, which make them impractical for iSCAT-based microscopy. In this study, we characterize several different surface coatings using iSCAT. We present approaches for cover glass passivation using 3-aminopropyltriethoxysilane (APTES) and polyethylene glycol (PEG, 2k) along with functionalization via a maleimide-thiol linker. These coatings are compatible with water or salt buffers, and show low background scattering; thus, we are able to measure proteins as small as 60 kDa. In this technical note, we offer a surface preparation suitable forin vitroexperiments with iSCAT.
3D Printers in Hospitals: Bacterial Contamination of Common and Antimicrobial 3D-Printed Material
Authors: Jackson Katelin C. , Clancey Erin , Call Douglas R. , Lofgren Eric
Published: April 2024

COVID-19 has presented hospitals with unique challenges. A SHEA Research Network survey showed that 40% reported “limited” or worse levels of personal protective equipment (PPE), and 13% were self-producing PPE to address those deficits, including 3D-printed items. However, we do not know how efficiently, if at all, 3D-printed materials can be disinfected. Additionally, two filaments, PLACTIVE and BIOGUARD, claim to be antimicrobial; they use copper nanocomposites and silver ions to reduce bacterial populations. We assess how PLACTIVE and BIOGUARD may be contaminated and how well they reduce contamination, and how readily Polylactic Acid (PLA), a standard 3D-printed material, may be disinfected.

3D-printed materials, including PLACTIVE and BIOGUARD, are readily contaminated with bacteria that are common in hospitals and can sustain that contamination. Our findings reveal that the levels of contamination on PLACTIVE and BIOGUARD can vary under specific conditions such as layer height or bacterial contact time, sometimes surpassing or falling short of PLA. However, disinfected disks had lower overall CFU averages than those that were not, but the level of disinfection was variable, and bacterial populations recovered hours after disinfection application. Proper disinfection and using appropriate 3D-printed materials are essential to limit bacterial contamination. 3D printers and their products can be invaluable for hospitals, especially when supplies are low, and healthcare worker safety is paramount. Environmental services should be made aware of the presence of antimicrobial 3D-printed materials, and patients should be discouraged from printing their own items for use in hospital environments.

IMPORTANCE

The COVID-19 pandemic has intensified the demand for personal protective equipment (PPE) in hospitals, prompting the utilization of 3D-printed materials to address shortages. Given the role of environmental contamination in healthcare-associated infections, understanding the potential for bacterial colonization on these materials is crucial. Our findings highlight the importance of proper disinfection practices and material selection in mitigating bacterial contamination, enhancing infection prevention strategies in hospitals, and ensuring the safety of healthcare workers and patients.
Machine learning predictions improve identification of real-world cancer driver mutations
Authors: Tran Thinh N. , Fong Chris , Pichotta Karl , Luthra Anisha , Shen Ronglai , Chen Yuan , Waters Michele , Kim Susie , Berger Michael F , Riely Gregory , Ladanyi Marc , Chakravarty Debyani , Schultz Nikolaus , Jee Justin
Published: April 2024

Characterizing and validating which mutations influence development of cancer is challenging. Machine learning has delivered significant advances in protein structure prediction, but its utility for identifying cancer drivers is less explored. We evaluated multiple computational methods for identifying cancer driver alterations. For identifying known drivers, methods incorporating protein structure or functional genomic data outperformed methods trained only on evolutionary data. We further validated VUSs annotated as pathogenic by testing their association with overall survival in two cohorts of patients with non-small cell lung cancer (N=7,965 and 977). “Pathogenic” VUSs inKEAP1andSMARCA4identified by several methods were associated with worse survival, unlike “benign” VUSs. “Pathogenic” VUSs exhibited mutual exclusivity with known oncogenic alterations at the pathway level, further suggesting biological validity. Despite training primarily on germline, rather than somatic, mutation data, computational predictions contribute to a more comprehensive understanding of tumor genetics as validated by real-world data.
Assessing Heterogeneity in the N-Telopeptides of Type I Collagen by Mass Spectrometry
Authors: Darula Zsuzsanna , McCabe Maxwell C. , Barrett Alex , Schmitt Lauren R. , Maslanka Mark D. , Saviola Anthony J , Orgel Joseph , Burlingame Alma , Staab-Weijnitz Claudia A. , Stenmark Kurt , Weaver Valerie , Chalkley Robert J. , Hansen Kirk C.
Published: April 2024

Collagen cross-links created by the lysyl oxidase and lysyl hydroxylase families of enzymes are a significant contributing factor to the biomechanical strength and rigidity of tissues, which in turn influence cell signaling and ultimately cell phenotype. In the clinic, the proteolytically liberated N-terminal cross-linked peptide of collagen I (NTX) is used as a biomarker of bone and connective tissue turnover, which is altered in several disease processes. Despite the clinical utility of these collagen breakdown products, the majority of the cross-linked peptide species have not been identified in proteomic datasets. Here we evaluate several parameters for the preparation and identification of these peptides from the collagen I-rich Achilles tendon. Our refined approach involving chemical digestion for protein solubilization coupled with mass spectrometry allows for the identification of the NTX cross-links in a range of modification states. Based on the specificity of the enzymatic cross-linking reaction we utilized follow-up variable modification searches to facilitate identification with a wider range of analytical workflows. We then applied a spectral library approach to identify differences in collagen cross-links in bovine pulmonary hypertension. The presented method offers unique opportunities to understand extracellular matrix remodeling events in development, aging, wound healing, and fibrotic disease that modulate collagen architecture through lysyl-hydroxylase and lysyl-oxidase enzymes.
Essential genes forHaemophilus parainfluenzaesurvival and biofilm growth
Authors: de Palma Thais H. , Powers Chris , McPartland Morgan J. , Welch Jessica Mark , Ramsey Matthew
Published: April 2024

Haemophilus parainfluenzae(Hp) is a Gram-negative, pleomorphic rod, highly prevalent and abundant as a commensal in the human oral cavity, and an infrequent extraoral opportunistic pathogen.Hpoccupies multiple niches in the oral cavity, including the tongue dorsum, keratinized gingiva, and the supragingival plaque biofilm. As a member of the HACEK group,Hpis also known to cause infective endocarditis. Additionally, case reports have identifiedHpas the causative agent of meningitis, septic arthritis, chronic osteomyelitis, septicemia, and a variety of other infectious diseases. Little is known about howHpinteracts with its neighbors in the healthy biofilm nor about its mechanisms of pathogenesis as an extraoral opportunistic pathogen. To address these unknowns, we identified the essential genomes of twoHpstrains and the conditionally essential genes for their growth inin vitrobiofilms aerobically and anaerobically. Using transposon insertion sequencing (TnSeq) with a highly saturatedmarinertransposon library in two strains, the ATCC33392 type-strain (Hp392) and a commensal oral isolate EL1 (HpEL1), we show that the essential genome ofHp392 andHpEL1 is composed of 395 and 384 genes, respectively. The core essential genome, consisting of 341 essential genes conserved between both strains, was composed of genes associated with genetic information processing, carbohydrate, protein, and energy metabolism. We also identified conditionally essential genes for aerobic and anaerobic biofilm growth, which were associated with carbohydrate and energy metabolism in both strains ofHp. Additionally, RNAseq analysis determined that most genes upregulated during anaerobic growth are not essential forHp392 anaerobic biofilm survival. The completion of this library and analysis under these conditions gives us a foundational insight into the basic biology ofH. parainfluenzaein differing oxygen conditions, similar to itsin vivooral habitat. Further, the creation of this library presents a valuable tool for further investigation into conditionally essential genes for an organism that lives in close contact with many microbial species in the human oral habitat.
Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer’s disease mouse model
Authors: Orlowski Alex , Karippaparambil Joseph , Paumier Jean-Michel , Ghanta Shraddha , Pallares Eduardo , Chandran Rumamol , Edmison Daisy , Tandukar Jamuna , Gao Ruixuan , Gowrishankar Swetha
Published: April 2024

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer’s pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term “AP-4 dystrophies”. Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome build up resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer’s disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared to those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region-specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.

Significance Statement

A major pathological feature of Alzheimer’s disease is the accumulation of axonal lysosomes near sites of amyloid plaques. Lysosome accumulation is thought to contribute to amyloid production. In fact, a genetic perturbation that arrests lysosomes in axons exacerbates amyloid plaque pathology. The mechanisms that control axonal lysosome abundance as well the molecular composition of axonal endolysosomes that produce Abeta, however, are not fully understood. Axonal lysosome build-up is emerging as a common pathology in other neurodegenerative disorders such as Hereditary Spastic Paraplegia (HSP), but its relevance to amyloid production is unknown. We find that a model of HSP caused by loss of AP-4 adaptor complex lead to axonal lysosome buildup that differs in some of its content, but still contributes to amyloidogenesis. This demonstrates that different perturbations leading to changes in heterogeneous pool of axonal lysosomes can converge on a common pathology.
Two distinct integrin binding sites on MMP9 drive cancer invasion by mediating integrin membrane trafficking & stabilization
Authors: Dutta Sarbajeet , Sarkar Soumili , Tolani Simran , Hazari Asrafuddoza , Sen Shamik
Published: April 2024

Matrix stiffening has been established to drive cancer progression through increased activity of matrix metalloproteases (MMPs) which degrade the matrix creating paths for migration. However, the non-proteolytic functions of MMPs in cancer invasion remain relatively less understood. Here we have probed the importance of proteolytic and non-proteolytic functions of MMP9, which exhibits robust stiffness dependent expression and secretion in highly invasive cancer cells. We show that while MMP9 sustains spreading and 2D migration non-proteolytically by stabilizing focal adhesions, MMP9 proteolytic activity is essential for 3D invasion. We then establish the function of two distinct integrin β1 (ITG β1) binding sites on MMP9, with the hemopexin domain mediating co-packaging and co-transport of ITG β1/MMP9 to the cell periphery, and the RGD domain stabilizing ITG β1 on the cell membrane prior to matrix degradation. Together, our results illustrate how MMP9 optimizes cancer invasion by spatiotemporally integrating matrix remodeling with adhesion formation.
A Behavioral Assay to Quantify Odor-Guided Thermotaxis withAnopheles gambiaeunder Semi-Field Conditions
Authors: Giraldo Diego , McMeniman Conor J.
Published: April 2024

The African malaria mosquitoAnopheles gambiaeis strongly attracted to human body odor and skin temperature. Quantitative behavioral assays suitable for use in semi-field environments with this nocturnal mosquito species are essential to gain improved insights intoAn. gambiaesensory biology, the mechanistic basis of mosquito attraction to humans, and host preference. In this protocol, we describe steps for engineering equipment for a novel behavioral assay forAn. gambiae, which we have termed the odor-guided thermotaxis assay (OGTA). The OGTA uses infrared videography to quantify landings of femaleAn. gambiaeon an aluminum platform heated to human skin temperature that can be baited with volatile odorants such as carbon dioxide or human whole body odor. The OGTA facilitates high-content recordings ofAn. gambiaelanding behavior during odor-guided thermotaxis under naturalistic semi-field conditions without the requirement for domestic power.
Quantifying Mosquito Host Preference
Authors: Giraldo Diego , McMeniman Conor J.
Published: April 2024

The most dangerous mosquito species for human health are those that blood feed preferentially and frequently on humans (anthropophilic mosquitoes). These include prolific disease vectors such as the African malaria mosquitoAnopheles gambiaeand yellow fever mosquitoAedes aegypti. The chemosensory basis for anthropophilic behavior exhibited by these disease vectors, as well as the factors that drive interindividual differences in human attractiveness to mosquitoes, remain largely uncharacterized. Here, we concisely review established methods to quantify mosquito interspecific and intraspecific host preference in the laboratory, as well as semi-field and field environments. Experimental variables for investigator consideration during assays of mosquito host preference across these settings are highlighted.
Correlation between the symmetry energy slope and the deconfinement phase transition
Authors: Lopes Luiz L. , Menezes Debora P. , Pelicer Mateus R.
Published: April 2024

We study how the nuclear symmetry energy slope (L) can affect the hadron-quark phase transition and neutron star properties. We show that the main physical quantities as the critical chemical potential and pressure are strongly influenced by the symmetry energy slope. In extreme cases, the total amount of deconfined quarks can reach up to 99% of the hybrid star mass.

Published by the American Physical Society
2024
Euler fluid in
2+1
dimensions as a gauge theory and an action for the Euler fluid in any dimension
Authors: Nastase Horatiu , Sonnenschein Jacob
Published: April 2024

In this paper we parallel the construction of Tong of a gauge theory for shallow water, by writing a gauge theory for the Euler fluid in 2+1 dimensions. We then extend it to a Euler fluid coupled to an electromagnetic background. We argue that the gauge theory formulation provides a topological argument for the quantization of 2+1 dimensional Euler Hopfion solution. In the process, we find a (nongauge) action for the Euler fluid that can be extended to any dimension, including the physical 3+1 dimensions. We also discuss several aspects of the Arnold-Beltrami-Childress flow.

Published by the American Physical Society
2024
Fluctuation theorem on a Riemannian manifold
Authors: Cai Yifan , Wang Tao , Zhao Liu
Published: April 2024

Based on the covariant underdamped and overdamped Langevin equations with Stratonovich coupling to multiplicative noises and the associated Fokker-Planck equations on a Riemannian manifold, we present the first law of stochastic thermodynamics on the trajectory level. The corresponding fluctuation theorems are also established, with the total entropy production of the Brownian particle and the heat reservoir playing the role of dissipation function.

Published by the American Physical Society
2024