bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of Ghost Introgression Requires Exploiting Topological and Branch Length Information
Authors: Pang Xiao-Xu , Zhang Da-Yong
Published: January 2024

In recent years, the study of hybridization and introgression has made significant progress, with ghost introgression—the transfer of genetic material from extinct or unsampled lineages to extant species—emerging as a key area for research. Accurately identifying ghost introgression, however, presents a challenge. To address this issue, we focused on simple cases involving 3 species with a known phylogenetic tree. Using mathematical analyses and simulations, we evaluated the performance of popular phylogenetic methods, including HyDe and PhyloNet/MPL, and the full-likelihood method, Bayesian Phylogenetics and Phylogeography (BPP), in detecting ghost introgression. Our findings suggest that heuristic approaches relying on site-pattern counts or gene-tree topologies struggle to differentiate ghost introgression from introgression between sampled non-sister species, frequently leading to incorrect identification of donor and recipient species. The full-likelihood method BPP uses multilocus sequence alignments directly—hence taking into account both gene-tree topologies and branch lengths, by contrast, is capable of detecting ghost introgression in phylogenomic datasets. We analyzed a real-world phylogenomic dataset of 14 species of Jaltomata (Solanaceae) to showcase the potential of full-likelihood methods for accurate inference of introgression.
Melatonin alleviates cadmium toxicity by regulating root endophytic bacteria community structure and metabolite composition in apple
Authors: Cao Yang , Zhang Jiran , Du Peihua , Ji Jiahao , Zhang Xue , Xu Jizhong , Ma Changqing , Liang Bowen
Published: January 2024

The level of cadmium (Cd) accumulation in orchard soils is increasing, and excess Cd will cause serious damage to plants. Melatonin is a potent natural antioxidant and has a potential role in alleviating Cd stress. This study aimed to investigate the effects of exogenous melatonin on a root endophyte bacteria community and metabolite composition under Cd stress. The results showed that melatonin significantly scavenged the reactive oxygen species and restored the photosynthetic system (manifested by the improved photosynthetic parameters, total chlorophyll content and the chlorophyll fluorescence parameters (Fv/Fm)), increased the activity of antioxidant enzymes (the activities of catalase, superoxide dismutase, peroxidase and ascorbate oxidase) and reduced the concentration of Cd in the roots and leaves of apple plants. High-throughput sequencing showed that melatonin increased the endophytic bacterial community richness significantly and changed the community structure under Cd stress. The abundance of some potentially beneficial endophytic bacteria (Ohtaekwangia, Streptomyces, Tabrizicola and Azovibrio) increased significantly, indicating that the plants may absorb potentially beneficial microorganisms to resist Cd stress. The metabolomics results showed that melatonin significantly changed the composition of root metabolites, and the relative abundance of some metabolites decreased, suggesting that melatonin may resist Cd stress by depleting root metabolites. In addition, co-occurrence network analysis indicated that some potentially beneficial endophytes may be influenced by specific metabolites. These results provide a theoretical basis for studying the effects of melatonin on the endophytic bacterial community and metabolic composition in apple plants.
Molecular monitoring of treatment efficacy in human visceral leishmaniasis
Authors: Roy Sutopa , Moulik Srija , Chaudhuri Surya Jyati , Ghosh Manab K , Goswami R P , Saha Bibhuti , Chatterjee Mitali
Published: January 2024

Background

Focused efforts of the visceral leishmaniasis elimination program have led to a drastic decline in cases, and the present challenge is disease monitoring, which this study aimed to assess.

Methods

A Leishmania kinetoplastid-targeted qPCR quantified parasite load at disease presentation, and following treatment completion (n=49); an additional 80 cases were monitored after completion of treatment.

Results

The parasite load at disease presentation was 13 461.00 (2560.00–37764.00)/µg gDNA, which upon completion of treatment reduced in 47 of 49 cases to 1(1–1)/µg gDNA, p<0.0001. In 80 cases that presented >2 months post-treatment, their parasite burden similarly decreased to 1(1–1)/µg gDNA except in 6 of 80 cases, which were qPCR positive.

Conclusion

In 129 cases of visceral leishmaniasis, qPCR by quantification of parasite burden proved effective for monitoring treatment.
Assessing Neurological Complications in Thoracic Three-Column Osteotomy
Authors: Lo Yuan-Shun , Shi Ben-Long , Lin Erh-Ti Ernest , Yeh Chen-Wei , Tsai Chun-Hao , Chen Hsien-Te , Zhu Ze-Zhang , Qiu Yong
Published: January 2024

Study Design.

Retrospective comparative study.

Objective.

To investigate the occurrence of neurological complications in patients undergoing thoracic three-column osteotomy (3CO) utilizing an magnetic resonance imaging (MRI)-based classification that assesses spinal cord shape and the presence of cerebrospinal fluid at the curve apex and evaluate its prognostic capacity for postoperative neurological deficits.

Summary of Background Data.

Recent advancements in correction techniques have improved outcomes for severe spinal deformity patients undergoing 3CO. A novel MRI-based spinal cord classification system was introduced, but its validation and association with postoperative complications remain unexplored.

Materials and Methods.

Between September 2012 and September 2018, a retrospective analysis was conducted on 158 adult patients with spinal deformities undergoing 3CO. Radiographic parameters were measured. T2-weighted axial MRI was used to describe spinal cord morphology at the apex. Intraoperative neurophysiological monitoring alerts were recorded, and preoperative and postoperative neurological functions were assessed using the Frankel score. Categorical data were compared using the χ2 or the Fisher exact test. The paired t test was utilized to assess the mean difference between preoperative and postoperative measurements, while the one-way analysis of variance and independent t test were used for comparative analyses among the different spinal cord types.

Results.

Patients were categorized into three groups: type 1, type 2, and type 3, consisting of 12, 85, and 61 patients. Patients with type 3 morphology exhibited larger Cobb angles of the main curve (P<0.001). This disparity persisted both postoperatively and during follow-up (P<0.05). Intraoperative neurophysiological monitoring alerts were triggered in 32 patients (20.3%), with a distribution of one case in type 1, six cases in type 2, and 22 cases in type 3 morphologies (P<0.001). New neurological deficits were observed in 15 patients (9.5%), with 1, 3, and 11 cases in type 1, 2, and 3 morphologies, respectively.

Conclusions.

Patients with type 3 morphology exhibited greater spinal deformity severity, a higher likelihood of preoperative neurological deficits, and an elevated risk of postoperative neurological complications. This underscores the utility of the classification as a tool for predicting postoperative neurological complications in patients undergoing thoracic 3CO.

Level of Evidence:

4.
Cotton Osteotomy: An Integral Midfoot Procedure for Forefoot Varus Correction
Authors: Hong Choon Chiet , Santini Simone , Valderrabano Victor
Published: January 2024

Forefoot varus is a component of the adult-acquired flatfoot deformity which had to be dealt with independently because isolated hindfoot procedures are insufficient to address this deformity. The dorsal opening wedge osteotomy of the medial cuneiform also known as the Cotton osteotomy is an effective and reliable procedure in the correction of forefoot varus with consistently reported good outcomes in terms of improved radiographic and functional outcomes with excellent bony union rate. Notably, it is also very versatile in that the degree of sagittal correction can be adjusted freely. The use of anatomic Cotton plates with titanium wedge integration makes the osteotomy even more robust with the prevention of early loss of correction and reduction of shear forces at the osteotomy site. Therefore, we describe our technique and experience using an anatomic Cotton plate with titanium wedge integration in Cotton osteotomy for forefoot varus.

Level of Evidence: Level V.
The effect of microRNA-9 overexpression on inhibition of melanoma cancer stem cells tumorigenicity
Authors: Parisa Sahranavardfard , Amirhossein Izadpanah , Hamed Yasavoli-Sharahi , Javad Firouzi , Masoumeh Azimi , Pardis Khosravani , Mahshad Dorraj , Faezeh Keighobadi , Ebrahimi Marzieh
Published: January 2024

Most of the studies have reported the downregulation of miR-9 in metastatic melanomas compared to primary tumors. They indicated that miR-9 negatively regulates the epithelial-to-mesenchymal transition (EMT) by inhibiting SNAIL1 expression and consequently promotes CDH1 expression. Since the process of EMT is associated to stem cell features, it could be interesting to study the effect of miR-9 on melanoma cancer stem cells. In the present study, we examined the effects of miR-9 manipulation on the stemness potential of melanoma cells. Our data demonstrated that the overexpression of miR-9 in A375 and NA8 cells significantly inhibits the ability of proliferation, self-renewal, migration, and tumorigenicity of melanoma cells which was concomitant with changes in the level of BRAF, some EMT factors, and stemness genes. Likewise, the reduction of miR-9 levels led to an increase in cell proliferation, colony and sphere formation, and the ability of cell migration and tumorigenicity. In conclusion, our results specified the role of miR-9 as a tumor suppressor miRNA to inhibit many aspects of melanoma stem cells, and therefore, it could be a potential candidate for the suppression of melanoma growth and progression.
Impact of aerobic and resistance training on fatigue, quality of life, and physical activity in prostate cancer patients: a systematic review and meta-analysis
Authors: Nader Simon , Massoud Amr , Al-Obeidat Feras , Mohamed Waleed F. , Hafez Wael , Rashid Asrar , Yousef Omar A. E. , Gador Muneir , Ahmed Sabah , Jose Mohan , Abdelrahman Ahmed , abdelshakour Mahmoud , Fathey Sherihan , Osorio María F. , Robles-Velasco Karla , Cherrez-Ojeda Iván
Published: January 2024

Background:

Prostate cancer (PCa) is a prevalent cancer with significant morbidity and mortality rates. In most cases, PCa remains asymptomatic until advanced disease manifests with symptoms, such as benign prostate hyperplasia. Timely detection and better management have improved overall survival in patients with PCa, and fatigue, reduced physical activity, and impaired quality of life (QoL) remain major challenges that impact daily life.

Objective:

This study aimed to systematically review and conduct a meta-analysis to evaluate the impact of aerobic and resistance training on fatigue, QoL, and physical activity in PCa patients undergoing treatment.

Material and methods:

A comprehensive literature search was conducted using the PubMed, Cochrane Library, and clinicaltrials.gov databases, adhering to the PRISMA guidelines. Twenty studies, involving 1393 participants, were included in the final analysis. The inclusion criteria were studies that evaluated the effects of exercise interventions relative to passive controls in patients with PCa were included. The primary outcomes of interest were fatigue, QoL, and PA. Data from eligible studies were extracted, and a meta-analysis was performed using RevMan 5.40.

Results:

Twenty studies met our inclusion criteria. Data analysis of the included studies demonstrated a significant improvement in QoL among PCa patients in the exercise group compared to the control group (SMD=0.20, 95% CI=0.07–0.34, P=0.003). However, there was no significant association between exercise and fatigue (SMD=0.07, 95% CI=−0.13–0.26, P=0.51). Sensitivity analysis did not alter these findings. Regarding physical activity outcomes, the control group exhibited superior performance in the 400 m walk test (P<0.05). No significant associations were found between exercise and the 6 m walk test or up-and-go time.

Conclusion:

This systematic review revealed that aerobic and resistance training enhance the QoL of patients with PCa, although it has a limited impact on fatigue and physical activity levels. These findings advocate a shift in clinical practice and the positioning of exercise as a core component of comprehensive cancer care. Tailoring exercise regimens according to individual patient needs and treatment stages should become the norm in treatment planning. This approach goes beyond physical wellness and addresses the psychological and emotional facets of cancer management. Moreover, there is an evident need for further research to develop holistic exercise interventions that effectively address the complex dynamics of fatigue, physical activity, and QoL in this patient group.
Integration of Intraosseous Approach Method in Georgia
Authors: Kikodze Nino , Nemsadze Ketevan
Published: January 2024

Objective

In pediatric emergencies, as in case of shock, the use of intraosseous (IO) route is recommended to get rapid vascular access as soon as possible, as it revealed better outcome. Nevertheless, the IO approach is not used at all and/or is limited because of lack of demand and lack of training on the issue of medical staff. The aim of the study was to test applicable and/or demand of IO in clinics providing pediatric critical care services and assess the opportunities to integrate IO access use in emergency care in Georgia.

Methods

A quasi-experimental study was conducted, following a training of medical staff to perform IO access procedure. Our study involved 140 children admitted to emergency department, 114 of whom underwent venous access and 26 underwent IO access. Several parameters were monitored and reported. Outcomes were compared between the 2 procedures.

Results

Use of an IO catheter has significantly altered the clinical outcome of the patient's condition; 35% of the total number of patients needed to continue their treatment in the intensive care unit, whereas 65% of the patient's continued treatment in the various general wards (compared with 99% and 1%, respectively, in intravenous access patients). None of IO patients were transferred to other clinics because of the deterioration of their clinical condition. Complications in the form of local infection were not observed in any of the patients using the IO approach (which is interesting in terms of infection control).

Conclusion

With proper training and in certain indications, the internationally approved method can be safely used in pediatric emergency management in Georgian and similar country health system contexts. Several urgent conditions with high rates of requiring hospitalization could benefit from the IO approach.
Mediation analysis of chronic kidney disease risk factors using kidney biomarkers in women living with HIV
Authors: Edrosolan Kristienne A. , Shlipak Michael G. , Scherzer Rebecca , Estrella Michelle M. , Gustafson Deborah , Karim Roksana , Fisher Molly , Cohen Mardge , Kassaye Seble , Dumond Julie , Abraham Alison , McCulloch Charles E. , Ascher Simon B.
Published: January 2024

Objective:

Novel urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in persons living with HIV. However, it is unknown whether these biomarkers provide mechanistic insight into the associations between clinical risk factors for CKD and subsequent CKD risk.

Methods:

Among 636 women living with HIV in the Women's Interagency HIV Study with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2, we used a counterfactual approach to causal mediation analysis to evaluate the extent to which systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin a1c (Hba1c) and serum albumin associations with incident CKD were mediated by eight urine proteins. These biomarkers reflect proximal tubular reabsorptive dysfunction (α1-microglobulin [a1m], β2-microglobulin, trefoil factor 3); tubular injury (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1]); kidney repair (epidermal growth factor); tubular reserve (uromodulin); and glomerular injury (urinary albumin). Incident CKD was defined as eGFR <60 ml/min/1.73 m2 measured at two consecutive 6-month visits with an average annual eGFR decline ≥3% per year.

Results:

During a median follow-up of 7 years, 11% developed CKD. Urinary albumin and KIM-1 mediated 32% (95% CI: 13.4%, 76.6%) and 23% (6.9%, 60.7%) of the association between SBP and incident CKD, respectively; and 19% (5.1%, 42.3%) and 22% (8.1%, 45.7%) of the association between DBP and incident CKD, respectively. Urinary albumin, α1m, and IL-18 were significant mediators of the association between Hba1c and incident CKD. None of the eight biomarkers mediated the association between serum albumin and incident CKD.

Conclusions:

Among women living with HIV, several urinary biomarkers reflecting distinct dimensions of kidney health may partially explain the associations between SBP, DBP, and Hba1c and subsequent CKD risk.
Addressing Current Deficits in Patient Education Materials Through Crowdsourcing
Authors: Hung Ya-Ching , Chaker Sara C. , Sigel Matthew , Saad Mariam , Yu-Hsuan Chang Monal , Slater Elizabeth D.
Published: January 2024

Background

Patient education materials are commonly reported to be difficult to understand.

Objectives

We aimed to use crowdsourcing to improve patient education materials at our institution.

Methods

This was a department-wide quality improvement project to increase organizational health literacy. There are 6 phases of this pilot study: (1) evaluating preexisting patient education materials, (2) evaluating online patient education materials at the society (the American Society of Plastic Surgeon) and government level (Medline Plus), (3) redesigning our patient education material and reevaluating the education material, (4) crowdsourcing to evaluate understandability of the new patient education material, (5) data analysis, and (6) incorporating crowdsourcing suggestions to the patient education material.

Results

Breast-related patient education materials are not easy to read at the institution level, the society level, and the government level. Our new implant-based breast reconstruction patient education material is easy to read as demonstrated by the crowdsourcing evaluation. More than 90% of the participants reported our material is “very easy to understand” or “easy to understand.” The crowdsourcing process took 1.5 days, with 700 workers responding to the survey. The total cost was $9. After incorporating participants' feedback into the finalized material, the readability of the material is at the recommended reading level. The material also had the recommended length (between 400 and 800 words).

Discussion

Our study demonstrated a pathway for clinicians to efficiently obtain a large amount of feedback to improve patient education materials. Crowdsourcing is an effective tool to improve organizational health literacy.
The Kidney Not Taken: Single-Kidney Use in Deceased Donors
Authors: McCracken Emily KE , Jay Colleen L , Garner Matthew , Webb Christopher , Farney Alan C , Orlando Giuseppe , Reeves-Daniel Amber , Mena-Gutierrez Alejandra , Sakhovskaya Natalia , Stratta Robert J
Published: January 2024

BACKGROUND:

The nonuse rate for kidneys recovered from deceased donors is increasing, rising to 27% in 2023. In 10% of these cases, 1 kidney is transplanted but the mate kidney is not.

STUDY DESIGN:

We conducted a retrospective, single-center cohort study from December 2001 to May 2023 comparing single kidneys transplanted at our center (where the contralateral kidney was not used) to kidneys where both were transplanted separately, at least 1 of which was at our center.

RESULTS:

We performed 395 single deceased-donor kidney transplants in which the mate kidney was not transplanted. Primary reasons for mate kidney nonuse were as follows: no recipient located or list exhausted (33.4%), kidney trauma or injury or anatomic abnormalities (18.7%), biopsy findings (16.7%), and poor renal function (13.7%). Mean donor and recipient ages were 51.5 ± 14.2 and 60 ± 12.6 years, respectively. Mean kidney donor profile index was 73% ± 22%, and 104 donors (26.3%) had kidney donor profile index >85%. Mean cold ischemia was 25.6 ± 7.4 hours, and 280 kidneys (70.7%) were imported. Compared with 2,303 concurrent control transplants performed at our center, primary nonfunction or thrombosis (5.1% single vs 2.8% control) and delayed graft function (35.4% single vs 30.1% control) were greater with single-kidney use (both p < 0.05). Median patient and death-censored graft survival were shorter in the single group (11.6 vs 13.5 years, p = 0.03 and 11.6 vs 19 years, p = 0.003), although the former was at least double median survival on the waiting list. In patients with functioning grafts in the single-kidney group, 1-year mean serum creatinine was 1.77 ± 0.8 mg/dL and estimated glomerular filtration rate was 44.8 ± 20 mL/min/1.73 m2.

CONCLUSIONS:

These findings suggest that many mate kidneys are being inappropriately rejected, given the acceptable outcomes that can be achieved by transplanting the single kidney in appropriately selected recipients.
Analytic and conformal scattering in general relativity
Authors: Nicolas Jean-Philippe
Published: January 2024

This paper is about two important trends of scattering theory in general relativity: time-dependent spectral analytic scattering and conformal scattering. The former was initiated by Jonathan Dimock and Bernard Kay in the mid-1980s and is based on spectral and functional analysis. The latter was proposed by Roger Penrose in 1965 and then constructed for the first time by Gerard Friedlander in 1980 by putting together Penrose’s conformal method and another analytic approach to scattering: the Lax–Phillips theory due to Peter Lax and Ralph Phillips. We shall review the history of the two approaches and explain their general principles. We shall also explore an important question: ‘can the tools of one approach be used to obtain a complete construction in the other?’

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Asymptotically de Sitter metrics from scattering data in all dimensions
Authors: Hintz Peter
Published: January 2024

In space–time dimensions

n
+
1
≥
4

, we show the existence of solutions of the Einstein vacuum equations which describe asymptotically de Sitter space–times with prescribed smooth data at the conformal boundary. This provides a short alternative proof of a special case of a result by Shlapentokh-Rothman and Rodnianski, and generalizes earlier results of Friedrich and Anderson to all dimensions.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
The case against smooth null infinity IV: Linearized gravity around Schwarzschild—an overview
Authors: Kehrberger Leonhard
Published: January 2024

This paper is the fourth in a series dedicated to the mathematically rigorous asymptotic analysis of gravitational radiation under astrophysically realistic set-ups. It provides an overview of the physical ideas involved in setting up the mathematical problem, the mathematical challenges that need to be overcome once the problem is posed, as well as the main new results we will obtain in upcoming work. From the physical perspective, this includes a discussion of how post-Newtonian theory provides a prediction on the gravitational radiation emitted by

N

infalling masses from the infinite past
in the intermediate zone
, i.e. up to some finite advanced time. From the mathematical perspective, we then take this prediction, together with the condition that there be no incoming radiation from

I

−

, as a starting point to set up a scattering problem for the linearized Einstein vacuum equations around Schwarzschild and near spacelike infinity, and we outline how to solve this scattering problem and obtain the asymptotic properties of the scattering solution near

i
0

and

I

+

. The full mathematical details will be presented in the sequel to this paper.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Safety Assessment of Five Candidate Probiotic Lactibacilli using Comparative Genome Analysis
Authors: Altavas Patrick Josemaria del Rosario , Amoranto Mia Beatriz , Kim Sang Hoon , Kang Dae-Kyung , Balolong Marilen , Dalmacio Leslie Michelle
Published: January 2024

Microorganisms belonging to the Lactobacillus genus complex (LGC) are often used for oral consumption and are generally considered safe but can exhibit pathogenicity in rare and specific cases. Therefore, screening and understanding genetic factors that may contribute to pathogenicity can yield valuable insights regarding probiotic safety. Limosilactobacillus mucosae LM1, Lactiplantibacillus plantarum SK151, Lactiplantibacillus plantarum BS25, Limosilactobacillus fermentum SK152, and Lactobacillus johnsonii PF01 are current probiotics of interest; however, their safety profiles have not been explored. The genome sequences of LM1, SK151, SK152, and PF01 were downloaded from the NCBI GenBank, while that of L. plantarum BS25 was newly sequenced. These genomes were then annotated using the Rapid Annotation using Subsystem Technology (RAST) tk pipeline. Subsequently, a command line BLAST was performed against the Virulence Factor Database (VFDB) and the Comprehensive Antibiotic Resistance Database (CARD) to identify potential virulence factors and antibiotic resistance (AR) genes. Furthermore, ResFinder was used to detect acquired AR genes. The query against the VFDB identified genes that have a role in bacterial survivability, platelet aggregation, surface adhesion, biofilm formation and immunoregulation; and no acquired AR genes were detected using CARD and ResFinder. The study shows that the query strains exhibit genes identical to those present in pathogenic bacteria with the genes matched primarily having roles related to survival and surface adherence. Our results contribute to the overall strategies that can be employed in pre-clinical safety assessments of potential probiotics. Gene mining using whole genome data, coupled with experimental validation, can be implemented in future probiotic safety assessment strategies.
Repetitive Learning Control for Body Caudal Undulation with Soft Sensory Feedback
Authors: Schwab Fabian , El Arayshi Mohamed , Rezaei Seyedreza , Sprumont Hadrien , Allione Federico , Mucignat Claudio , Lunati Ivan , Verrelli Cristiano Maria , Jusufi Ardian
Published: January 2024

Soft bio-inspired robotics is a growing field of research that seeks to close the gap with animal robustness and adaptability where conventional robots fall short. The embedding of sensors with the capability to discriminate between different body deformation modes is a key technological challenge in soft robotics to enhance robot control – a difficult task for such kinds of systems with high degrees of freedom. The recently conceived Linear Repetitive Learning Estimation Scheme (LRLES) – to be included in the traditional Proportional Integral Derivative (PID) control – is proposed here as a way to compensate for uncertain dynamics on a soft swimming robot, which is actuated with soft pneumatic actuators and equipped with soft sensors providing proprioceptive information pertaining to lateral body caudal bending akin to a goniometer. The proposed controller is derived in detail and experimentally validated, with the experiment consisting of tracking a desired trajectory for bending angle while continuously oscillating with a constant frequency. The results are compared vis a vis those achieved with the traditional PID controller, finding that the PID endowed with the LRLES outperforms the PID controller (though the latter has been separately tuned) and experimentally validating the novel controller’s effectiveness, accuracy, and matching speed.
With the leisure of time, kinetic proofreading can still perform reliable ligand discrimination
Authors: Xiao Fangzhou , Galstyan Vahe
Published: January 2024

In a recent PNAS publication, Kirby and Zilman studied kinetic proofreading for receptor signaling and argued that having more proofreading steps does not generally improve ligand discrimination when stochastic effects are taken into account. In their analysis, however, the authors made an implicit assumption about a fixed discrimination time, which is not always warranted. We show that when the discrimination time is allowed to vary in order to maintain a fixed level of signaling activity, the proofreading performance can, in fact, uniformly improve with the number of steps. We therefore call for a comprehensive study of the interplay between discrimination time, discrimination accuracy, and signaling activity, where the two seemingly contradictory results will be slices of the trade-off surface along different axes.
Decreased sarcomeric mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin action in type 2 diabetes
Authors: Rizo-Roca David , Guimarães Dimitrius SPSF. , Pendergrast Logan A. , Di Leo Nicolas , Chibalin Alexander V. , Maqdasy Salwan , Rydén Mikael , Näslund Erik , Zierath Juleen R. , Krook Anna
Published: January 2024

Plasma creatine levels are associated with risk of type 2 diabetes. Since skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. We report in men with type 2 diabetes, plasma creatine levels are increased, while intramuscular phosphocreatine content is reduced. These alterations are coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C2C12 myotubes,Ckmt2silencing reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression ofCkmt2in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Thus, beyond the canonical role of CKMT2 on creatine phosphorylation, we reveal a previously underappreciated role of CKMT2 on mitochondrial homeostasis, independent of insulin action. Collectively, our data provides functional evidence into how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.
An oomycete effector co-opts a host RabGAP protein to remodel pathogen interface and subvert defense-related secretion
Authors: Yuen Enoch Lok Him , Tumtas Yasin , Chan Lok I , Ibrahim Tarhan , Evangelisti Edouard , Tulin Frej , Skłenar Jan , Menke Frank , Kamoun Sophien , Bubeck Doryen , Schornack Sebastian , Bozkurt Tolga O.
Published: January 2024

Pathogens have evolved sophisticated mechanisms to manipulate host cell membrane dynamics, a crucial adaptation to survive in hostile environments shaped by innate immune responses. Plant- derived membrane interfaces, engulfing invasive hyphal projections of fungal and oomycete pathogens, are prominent junctures dictating infection outcomes. Understanding how pathogens transform these host-pathogen interfaces to their advantage remains a key biological question. Here, we identified a conserved effector, secreted by plant pathogenic oomycetes, that co-opts a host Rab GTPase-activating protein (RabGAP), TBC1D15L, to remodel the host-pathogen interface. The effector, PiE354, hijacks TBC1D15L as a susceptibility factor to usurp its GAP activity on Rab8a—a key Rab GTPase crucial for defense-related secretion. By hijacking TBC1D15L, PiE354 purges Rab8a from the plasma membrane, diverting Rab8a-mediated immune trafficking away from the pathogen interface. This mechanism signifies an uncanny evolutionary adaptation of a pathogen effector in co- opting a host regulatory component to subvert defense-related secretion, thereby providing unprecedented mechanistic insights into the reprogramming of host membrane dynamics by pathogens.
Logic-based modeling of biological networks with Netflux
Authors: Clark Alexander P. , Chowkwale Mukti , Paap Alexander , Dang Stephen , Saucerman Jeffrey J.
Published: January 2024

Molecular signaling networks drive a diverse range of cellular decisions, including whether to proliferate, how and when to die, and many processes in between. Such networks often connect hundreds of proteins, genes, and processes. Understanding these complex networks is aided by computational modeling, but these tools require extensive programming knowledge. In this article, we describe a user-friendly, programming-free network simulation tool called Netflux (https://github.com/saucermanlab/Netflux). Over the last decade, Netflux has been used to construct numerous predictive network models that have deepened our understanding of how complex biological networks make cell decisions. Here, we provide a Netflux tutorial that covers how to construct a network model and then simulate network responses to perturbations. Upon completion of this tutorial, you will be able to construct your own model in Netflux and simulate how perturbations to proteins and genes propagate through signaling and gene-regulatory networks.
A novel classification framework for genome-wide association study of whole brain MRI images using deep learning
Authors: Yu Shaojun , Wu Junjie , Shao Yumeng , Qiu Deqiang , Qin Zhaohui S. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2024

Genome-wide association studies (GWASs) have been widely applied in the neuroimaging field to discover genetic variants associated with brain-related traits. So far, almost all GWASs conducted in neuroimaging genetics are performed on univariate quantitative features summarized from brain images. On the other hand, powerful deep learning technologies have dramatically improved our ability to classify images. In this study, we proposed and implemented a novel machine learning strategy for systematically identifying genetic variants that lead to detectable nuances on Magnetic Resonance Images (MRI). For a specific single nucleotide polymorphism (SNP), if MRI images labeled by genotypes of this SNP can be reliably distinguished using machine learning, we then hypothesized that this SNP is likely to be associated with brain anatomy or function which is manifested in MRI brain images. We applied this strategy to a catalog of MRI image and genotype data collected by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) consortium. From the results, we identified novel variants that show strong association to brain phenotypes.
Heritable intraspecific variation among prey in size and movement interact to shape predation risk and potential natural selection
Authors: Coblentz Kyle E. , Yang Liuqingqing , Dalal Arpita , Incarnato Miyauna M. N. , Thilakarathne Dinelka D. , Shaw Cameron , Wilson Ryan , Biagioli Francis , Montooth Kristi L. , DeLong John P.
Published: January 2024

Predator and prey traits are important determinants of the outcomes of trophic interactions. In turn, the outcomes of trophic interactions shape the evolution of predator and prey traits. How species’ traits are likely to respond to selection from trophic interactions depends crucially on whether and how heritable species’ traits are and their genetic correlations. Of the many traits potentially influencing the outcomes of trophic interactions, body size and movement traits have emerged as universally key traits. Yet, how these traits shape and are shaped by trophic interactions is generally unclear, as few studies have simultaneously measured the impacts of these traits on the outcomes of trophic interactions, their heritability, and their correlations within the same system.

We used outcrossed and then clonally propagated lines of the ciliate protistParamecium caudatumfrom natural populations to examine variation in morphology and movement behavior, the extent to which this variation was heritable, and how intraspecific differences among lines alteredParameciumsusceptibility to predation by the copepodMacrocyclops albidus.

We found that theParameciumlines exhibited heritable variation in body size and movement traits. In contrast to expectations from interspecific allometric relationships, body size and movement speed showed little covariance among clonal lines. The proportion ofParameciumconsumed by copepods was positively associated withParameciumbody size and velocity, however, we also found evidence of an interaction such that greater velocities led to greater predation risk for large body-sized paramecia but did not alter predation risk for smaller body-sized paramecia. The proportion of paramecia consumed was not related to copepod body size. These patterns of predation risk and heritable trait variation in paramecia suggest that copepod predation may act as a selective force operating independently on movement and body size and generating the strongest selection against large, high-velocity paramecia.

Our results illustrate how the interactions between ecology and genetics can shape the potential natural selection on prey traits through the outcomes of trophic interactions. Further simultaneous measures of predation outcomes, traits, and their quantitative genetic characteristics will provide insights into the evolutionary ecology of species interactions and their eco-evolutionary consequences.
Aphid resistance segregates independently of cardiac glycoside and glucosinolate content in anErysimum cheiranthoides(wormseed wallflower) F2 population
Authors: Mirzaei Mahdieh , Younkin Gordon C. , Powell Adrian F. , Alani Martin L. , Strickler Susan R. , Jander Georg
Published: January 2024

Plants in the genusErysimumproduce both glucosinolates and cardiac glycosides as defense against herbivory. Two natural isolates ofErysimum cheiranthoides(wormseed wallflower) differed in their glucosinolate content, cardiac glycoside content, and resistance toMyzus persicae(green peach aphid), a broad generalist herbivore. Both classes of defensive metabolites were produced constitutively and were not induced further by aphid feeding. To investigate the relative importance of glucosinolates and cardiac glycosides inE. cheiranthoidesdefense, we generated an improved genome assembly, genetic map, and segregating F2 population. Genotypic and phenotypic analysis of the F2 plants identified quantitative trait loci affecting glucosinolates and cardiac glycosides, but not aphid resistance. The abundance of most glucosinolates and cardiac glycosides was positively correlated in the F2 population, indicating that similar processes regulate their biosynthesis and accumulation. Aphid reproduction was positively correlated with glucosinolate content. Although overall cardiac glycoside content had little effect on aphid growth and survival, there was a negative correlation between aphid reproduction and helveticoside abundance. However, this variation in defensive metabolites could not explain the differences in aphid growth on the two parental lines, suggesting that processes other than the abundance of glucosinolates and cardiac glycosides have a predominant effect on aphid resistance inE. cheiranthoides.
Concordance of whole-genome amplified embryonic DNA with the subsequently born child
Authors: Li Shenglai , Giardina Thomas , Katz Maria , Chandramohan Dhruva , Slotnick Nathan , Behr Barry , Siddiqui Noor , Xia Yuntao , Podgursky Benjamin
Published: January 2024

Before implantation subsequent to in vitro fertilization (IVF), the current options for Preimplantation Genetic Testing (PGT) are PGT for Aneuploidy (PGT-A) and, if clinically indicated, PGT for monogenic conditions (PGT-M). A more comprehensive approach involves PGT whole genome sequencing (PGT-WGS). PGT-WGS incorporates PGT-A, screens for hundreds of monogenic conditions, and can evaluate polygenic risk. Here we compare PGT-WGS results against the genome of the subsequently born child. We demonstrated high levels of concordance (both in sensitivity and precision) in exome variant calls between amplified embryonic DNA and sequenced fetal cord blood. This concordance was higher when filtering against 1300 targeted monogenic conditions implicated in birth defects, neurodevelopmental disorders, and hereditary cancer. To evaluate PGT-WGS’s ability to identify de novo variants we compared the child’s genome to parental genomes and demonstrated that PGT-WGS successfully identified 5/5 confirmed de-novo variants. We further demonstrated concordance in polygenic risk scores calculated for both the embryo and the subsequently born child. This agreement extended to both traditional polygenic scores and oligogenic scores (Type 1 diabetes, Celiac disease, and Alzheimer’s Disease), which heavily rely on accurate genotyping of HLA and APOE sites. To our knowledge, this is the first direct concordance study between a whole-genome sequencing of a trophectoderm biopsy and the DNA of the subsequently born child. By demonstrating a high degree of whole-exome concordance and adept detection of de novo variants, this approach showcases PGT-WGS’s capability to identify genetic variants not explicitly targeted for monogenic screening.
Normalized level set model for segmentation of low-contrast objects in 2- and 3- dimensional images
Authors: Baig Mirza M. Junaid , Wang Yao L. , Chung Samuel H. , Stepanyants Armen
Published: January 2024

Analyses of biomedical images often rely on accurate segmentation of structures of interest. Traditional segmentation methods based on thresholding, watershed, fast marching, and level set perform well in high-contrast images containing structures of similar intensities. However, such methods can under-segment or miss entirely low-intensity objects on noisy backgrounds. Machine learning segmentation methods promise superior performance but require large training datasets of labeled images which are difficult to create, particularly in 3D. Here, we propose an algorithm based on the Local Binary Fitting (LBF) level set method, specifically designed to improve the segmentation of low-contrast structures.
Connectivity and functional diversity of different temporo-occipital nodes for action perception
Authors: Li Baichen , Poyo Solanas Marta , Marrazzo Giuseppe , de Gelder Beatrice
Published: January 2024

The temporo-occipital cortex (TOC) plays a key role in body and action perception, but current understanding of its functions is still limited. TOC body regions are heterogeneous and their role in action perception is poorly understood. This study adopted data-driven approaches to region selectivity and investigated the connectivity of TOC nodes and the functional network sensitivity for different whole body action videos. In two human 7T fMRI experiments using independent component analysis, four adjacent body selective nodes were detected within the TOC network with distinct connectivity profiles and functional roles. Action type independent connectivity was observed for the posterior-ventral node to the visual cortex, the posterior-dorsal node to the precuneus and the anterior nodes to the frontal cortex. Action specific connectivity modulations were found in middle frontal gyrus for the aggressive condition with increased connectivity to the anterior node and decreased connectivity to the posterior-dorsal node. But for the defensive condition, node-nonspecific enhancement was found for the TOC-cingulate connectivity. By addressing the issue of multiple nodes in the temporo-occipital network we show a functional dissociation of different body selective centres related to the action type and a potential hierarchy within the TOC body network.
Dbp1 is a low performance paralog of RNA helicase Ded1 that drives impaired translation and heat stress response
Authors: Powers Emily N , Kuwayama Naohiro , Sousa Camila , Reynaud Kendra , Jovanovic Marko , Ingolia Nicholas T , Brar Gloria A
Published: January 2024

Ded1 and Dbp1 are paralogous conserved RNA helicases that enable translation initiation in yeast. Ded1 has been heavily studied but the role of Dbp1 is poorly understood. We find that the expression of these two helicases is controlled in an inverse and condition-specific manner. In meiosis and other long-term starvation states, Dbp1 expression is upregulated and Ded1 is downregulated, whereas in mitotic cells, Dbp1 expression is extremely low. Inserting theDBP1ORF in place of theDED1ORF cannot replace the function of Ded1 in supporting translation, partly due to inefficient mitotic translation of theDBP1mRNA, dependent on features of its ORF sequence but independent of codon optimality. Global measurements of translation rates and 5’ leader translation, activity of mRNA-tethered helicases, ribosome association, and low temperature growth assays show that—even at matched protein levels—Ded1 is more effective than Dbp1 at activating translation, especially for mRNAs with structured 5’ leaders. Ded1 supports halting of translation and cell growth in response to heat stress, but Dbp1 lacks this function, as well. These functional differences in the ability to efficiently mediate translation activation and braking can be ascribed to the divergent, disordered N- and C-terminal regions of these two helicases. Altogether, our data show that Dbp1 is a “low performance” version of Ded1 that cells employ in place of Ded1 under long-term conditions of nutrient deficiency.
Gadolinium-based nanoparticles AGuIX and their combination with ionizing radiation trigger AMPK-dependent proinflammatory reprogramming of tumor-associated macrophages
Authors: Muradova Zeinaf , Tannous Désirée , Mostefa-Kara Ali , Cao-Pham Thanh Trang , Lamy Constance , Broutin Sophie , Paci Angelo , Dufort Sandrine , Doussineau Tristan , Lux François , Tillement Olivier , Le Duc Géraldine , Allouch Awatef , Perfettini Jean-Luc
Published: January 2024

Background

Tumor-associated macrophages (TAMs) are essential components of the inflammatory microenvironment of tumors and are associated with poor clinical outcomes in the majority of cancers. TAMs mainly exhibit anti-inflammatory functions that promote and support the tissue remodeling, the immune suppression and the tumor growth. Regarding their plasticity, the functional reprogramming of anti-inflammatory TAMs into proinflammatory phenotype recently emerged as a therapeutic opportunity to improve the effectiveness of anticancer treatments such as radiotherapy.

Results

Here we show that gadolinium-based nanoparticles AGuIX alone and in combination with ionizing radiation (IR) induce in a dose-dependent manner, the accumulation of DNA double strand breaks, an Ataxia telangiectasia mutated (ATM)-dependent DNA-damage response, an increased expression of the Interferon regulatory factor 5 (IRF5) and the release of proinflammatory cytokines from targeted macrophages, thus directing their proinflammatory reprogramming. This process is associated with the activating phosphorylation of the Adenosine Monophosphate (AMP) activated protein kinase on threonine 172 (AMPKT172*) and the fragmentation of mitochondria. Furthermore, we demonstrate that the inactivation of AMPK reduces the mitochondrial fragmentation and the proinflammatory reprogramming of macrophages detected in response to AGuIX and their combination with IR. These results reveal that the AMPK-dependent regulation of mitochondrial fragmentation plays a central role during the proinflammatory reprogramming of macrophages. Accordingly, a positive correlation between AMPKT172* and proinflammatory activation of TAMs is detected following IR+AGuIX combination in syngeneic mouse model of colorectal cancer.

Conclusions

Altogether, our results identify a novel signaling pathway elicited by AGuIX and their combined treatment with IR, that targets macrophage polarization, skews macrophage functions toward the proinflammatory phenotype and may enhance the effectiveness of radiotherapy.