bluuebunny/crossref_metadata_2025 huggingface dataset:
Flowering time genes branching out
Authors: Colleoni Pierangela E , van Es Sam W , Winkelmolen Ton , Immink Richard G H , van Esse G Wilma
Published: March 2024

Plants are sessile by nature, and as such they have evolved to sense changes in seasonality and their surrounding environment, and adapt to these changes. One prime example of this is the regulation of flowering time in angiosperms, which is precisely timed by the coordinated action of two proteins: FLOWERING LOCUS T (FT) and TERMINAL FLOWER 1 (TFL1). Both of these regulators are members of the PHOSPHATIDYLETHANOLAMINE BINDING PROTEIN (PEBP) family of proteins. These regulatory proteins do not interact with DNA themselves, but instead interact with transcriptional regulators, such as FLOWERING LOCUS D (FD). FT and TFL1 were initially identified as key regulators of flowering time, acting through binding with FD; however, PEBP family members are also involved in shaping plant architecture and development. In addition, PEBPs can interact with TCP transcriptional regulators, such as TEOSINTE BRANCHED 1 (TB1), a well-known regulator of plant architecture, and key domestication-related genes in many crops. Here, we review the role of PEBPs in flowering time, plant architecture, and development. As these are also key yield-related traits, we highlight examples from the model plant Arabidopsis as well as important food and feed crops such as, rice, barley, wheat, tomato, and potato.
Particle initialization effects on Lyman-α forest statistics in cosmological SPH simulations
Authors: Khan Nabendu Kumar , Kulkarni Girish , Bolton James S , Haehnelt Martin G , Iršič Vid , Puchwein Ewald , Asthana Shikhar
Published: March 2024

Confronting measurements of the Lyman-α forest with cosmological hydrodynamical simulations has produced stringent constraints on models of particle dark matter and the thermal and ionization state of the intergalactic medium. We investigate the robustness of such models of the Lyman-α forest, focusing on the effect of particle initial conditions on the Lyman-α forest statistics in cosmological SPH simulations. We study multiple particle initialization algorithms in simulations that are designed to be identical in other respects. In agreement with the literature, we find that the correct linear theory evolution is obtained when a glass-like configuration is used for initial unperturbed gas particle positions alongside a regular grid configuration for dark matter particles and the use of non-identical initial density perturbations for gas and dark matter. However, we report that this introduces a large scale-dependent distortion in the 1D Lyman-α transmission power spectrum at small scales (k > 0.05 s km−1). The effect is close to 50  per cent at k ∼ 0.1 s km−1, and persists at higher resolution. This can severely bias inferences in parameters such as the dark matter particle mass. By considering multiple initial conditions codes and their variations, we also study the impact of a variety of other assumptions and algorithmic choices, such as adaptive softening, background radiation density, particle staggering, and perturbation theory accuracy, on the matter power spectrum, the Lyman-α flux power spectrum, and the Lyman-α flux PDF. This work reveals possible pathways towards more accurate theoretical models of the Lyman-α forest to match the quality of upcoming measurements.
Local models of two-temperature accretion disc coronae – II. Ion thermal conduction and the absence of disc evaporation
Authors: Bambic Christopher J , Quataert Eliot , Kunz Matthew W , Jiang Yan-Fei
Published: March 2024

We use local stratified shearing-box simulations with magnetic field-aligned thermal conduction to study an idealized model of the coupling between a cold, radiatively efficient accretion disc, and an overlying, hot, two-temperature corona. Evaporation of a cold disc by conduction from the hot corona has been proposed as a means of mediating the soft-to-hard state transitions observed in X-ray binary systems. We model the coronal plasma in our local disc patch as an MHD fluid subject to both free-streaming ion conduction and a parametrized cooling function that captures the collisional transfer of energy from hot ions to colder, rapidly cooling leptons. In all of our models, independent of the initial net vertical magnetic flux (NF) threading the disc, we find no evidence of disc evaporation. The ion heat flux into the disc is radiated away before conduction can heat the disc’s surface layers. When an initial NF is present, steady-state temperature, density, and outflow velocities in our model coronae are unaffected by conduction. Instead of facilitating disc evaporation, thermal conduction is more likely to feed the disc with plasma condensing out of the corona, particularly in flows without NF. Our work indicates that uncertainties in the amount of NF threading the disc hold far greater influence over whether or not the disc will evaporate into a radiatively inefficient accretion flow compared to thermal conduction. We speculate that a change in net flux mediates disc truncation/evaporation.
Long-term double synchronization in close-in gas giant planets
Authors: Guo Shuaishuai , Guo Jianheng , Su Jie , Yan Dongdong
Published: March 2024

Hot Jupiters, orbiting their host stars at extremely close distances, undergo tidal evolution, with some being engulfed by their stars due to angular momentum exchanges induced by tidal forces. However, achieving double synchronization can prolong their survival. Using the mesa stellar evolution code, combined with the magnetic braking model of Matt et al. (2015), we calculate 25 000 models with different metallicity and study how to attain the conditions that trigger the long-term double synchronization. Our results indicate that massive planets orbiting stars with lower convective turnover time are easier to achieve long-term double synchronization. The rotation angular velocity at the equilibrium point (Ωsta) is almost equal to orbital angular velocity of planet (n) for the majority of the main sequence lifetime if a system has undergone a long-term double synchronization, regardless of their state at this moment. We further compared our results with known parameters of giant planetary systems and found that those systems with larger planetary masses and lower convective turnover time seem to be less sensitive to changes in the tidal quality factor $Q^{\prime }_{_*}$. We suggest that for systems that fall on the state of Ωsta ≈ n, regardless of their current state, the synchronization will persist for a long time if orbital synchronization occurs at any stage of their evolution. Our results can be applied to estimate whether a system has experienced long-term double synchronization in the past or may experience it in the future.
White dwarf pollution: one star or two?
Authors: Noor Hiba Tu , Farihi Jay , Hollands Mark , Toonen Silvia
Published: March 2024

The accretion of tidally disrupted planetary bodies is the current consensus model for the presence of photospheric metals commonly detected in white dwarfs. While most dynamical studies have considered a single star and associated planetary instabilities, several investigations have instead considered the influence of widely bound stellar companions as potential drivers of white dwarf pollution. This study examines the prevalence of wide binaries among polluted white dwarfs using Gaia Data Release 3 astrometry, where three samples are investigated: 71 DAZ stars with metals detected in the ultraviolet using Hubble Space Telescope, and two groups of DZ stars identified via Sloan Digital Sky Survey spectroscopy, comprised of 116 warmer and 101 cooler sources. Each sample was searched for spatially resolved, comoving companions, and compared to the same analysis of thousands of field white dwarfs within overlapping regions of the Gaia Hertzsprung–Russell diagram. The wide binary fraction of the DAZ sample is $10.6_{-3.2}^{+3.9}$ per cent, and within $1\sigma$ of the corresponding field. However, the search yields wide binary fractions of less than 1.8 per cent for the two independent DZ star catalogues, which are each distinct from their fields by more than $3\sigma$. Both sets of results support that pollution in white dwarfs is not the result of stellar companions, and the delivery of metals to white dwarf surfaces is caused by major planets. The discrepancy between the DAZ and DZ star wide binary fractions cannot be caused by white dwarf spectral evolution, suggesting these two populations may have distinct planetary architectures.
Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma
Authors: Moreira Daniel C , Qaddoumi Ibrahim , Spiller Susan , Bouldin Thomas W , Davidson Alan , Saba-Silva Nasjla , Sullivan Daniel V , Tanaka Ryuma , Wagner Aaron S , Wood Matthew , Klimo Paul , Job Godwin , Devidas Meenakshi , Li Xiaoyu , Gajjar Amar , Robinson Giles W , Chiang Jason
Published: March 2024

Background

Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies.

Methods

We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children’s Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated.

Results

Thirty-three patients (18 male; median age, 5 years) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n = 10, 30%). Most tumors were in the cerebral hemispheres (n = 22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3% ± 8.3%; the 5-year overall survival (OS) rate was 96.4% ± 4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6% ± 15.2% (P < .01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways.

Conclusions

pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.
Tunneling nanotubes and tumor microtubes—Emerging data on their roles in intercellular communication and pathophysiology: Summary of an International FASEB Catalyst Conference October 2023
Authors: Lou Emil , Vérollet Christel , Winkler Frank , Zurzolo Chiara , Valdebenito‐Silva Silvana , Eugenin Eliseo
Published: March 2024

In the past decade, there has been a steady rise in interest in studying novel cellular extensions and their potential roles in facilitating human diseases, including neurologic diseases, viral infectious diseases, cancer, and others. One of the exciting new aspects of this field is improved characterization and understanding of the functions and potential mechanisms of tunneling nanotubes (TNTs), which are actin‐based filamentous protrusions that are structurally distinct from filopodia. TNTs form and connect cells at long distance and serve as direct conduits for intercellular communication in a wide range of cell types in vitro and in vivo. More researchers are entering this field and investigating the role of TNTs in mediating cancer cell invasion and drug resistance, cellular transfer of proteins, RNA or organelles, and intercellular spread of infectious agents, such as viruses, bacteria, and prions. Even further, the elucidation of highly functional membrane tubes called “tumor microtubes” (TMs) in incurable gliomas has further paved a new path for understanding how and why the tumor type is highly invasive at the cellular level and also resistant to standard therapies. Due to the wide‐ranging and rapidly growing applicability of TNTs and TMs in pathophysiology across the spectrum of biology, it has become vital to bring researchers in the field together to discuss advances and the future of research in this important niche of protrusion biology.
Adjusting Incidence Estimates with Laboratory Test Performances: A Pragmatic Maximum Likelihood Estimation-Based Approach
Authors: Weng Yingjie , Tian Lu , Boothroyd Derek , Lee Justin , Zhang Kenny , Lu Di , Lindan Christina P. , Bollyky Jenna , Huang Beatrice , Rutherford George W. , Maldonado Yvonne , Desai Manisha ,   on behalf of the California Pandemic Consortium
Published: March 2024

Understanding the incidence of disease is often crucial for public policy decision-making, as observed during the COVID-19 pandemic. Estimating incidence is challenging, however, when the definition of incidence relies on tests that imperfectly measure disease, as in the case when assays with variable performance are used to detect the SARS-CoV-2 virus. To our knowledge, there are no pragmatic methods to address the bias introduced by the performance of labs in testing for the virus. In the setting of a longitudinal study, we developed a maximum likelihood estimation-based approach to estimate laboratory performance-adjusted incidence using the expectation-maximization algorithm. We constructed confidence intervals (CIs) using both bootstrapped-based and large-sample interval estimator approaches. We evaluated our methods through extensive simulation and applied them to a real-world study (TrackCOVID), where the primary goal was to determine the incidence of and risk factors for SARS-CoV-2 infection in the San Francisco Bay Area from July 2020 to March 2021. Our simulations demonstrated that our method converged rapidly with accurate estimates under a variety of scenarios. Bootstrapped-based CIs were comparable to the large-sample estimator CIs with a reasonable number of incident cases, shown via a simulation scenario based on the real TrackCOVID study. In more extreme simulated scenarios, the coverage of large-sample interval estimation outperformed the bootstrapped-based approach. Results from the application to the TrackCOVID study suggested that assuming perfect laboratory test performance can lead to an inaccurate inference of the incidence. Our flexible, pragmatic method can be extended to a variety of disease and study settings.
Evaluation of Work–Life Integration, Social Isolation, and the Impact of Work on Personal Relationships Among Healthcare CEOs and Administrative Leaders
Authors: Shanafelt Tait , Trockel Mickey , Mayer Thom , Wang Hanhan , Athey Leslie
Published: March 2024

Goal:

The objective of this study was to evaluate satisfaction with work–life integration (WLI), social isolation, and the impact of work on personal relationships (IWPR) among senior healthcare operational leaders.

Methods:

Between June 7 and June 30, 2021, we performed a national survey of CEOs and other senior healthcare operational leaders in the United States to evaluate their personal work experience. Satisfaction with WLI, social isolation, and IWPR were assessed using standardized instruments. Burnout and professional fulfillment were also assessed using standardized scales.

Principal Findings:

The mean IWPR score on the 0–10 scale was 4.39 (standard deviation was 2.36; higher scores were unfavorable). On multivariable analysis to identify demographic and professional factors associated with the IWPR score, each additional hour worked per week decreased the likelihood of a favorable IWPR score. The IWPR, feeling isolated, and satisfaction with WLI were independently associated with burnout after adjusting for other personal and professional factors. On multivariable analysis, healthcare administrators were more likely than U.S. workers in other fields to indicate work had adversely impacted personal relationships in response to the item “In the past year, my job has contributed to me feeling more isolated and detached from the people who are most important to me.”

Practical Applications:

Experiencing an adverse IWPR is common among U.S. healthcare administrators, who are more likely than the general U.S. working population to indicate their job contributes to isolation and detachment from the people most important to them. Problems with WLI, isolation, and an adverse IWPR are associated with increased burnout and lower professional fulfillment. Intentional efforts by both organizations and administrative leaders are necessary to address the work characteristics and professional norms that erode WLI and result in work adversely impacting personal relationships.
Awareness Level of Cervical Cancer Patients Referred to Radiation Oncology Outpatient Clinics—A Multicenter Study
Authors: Altinok Pelin , Ergen Şefika Arzu , Güzelöz Çapar Zeliha , Canyilmaz Emine , Akgün Züleyha , Serin Meltem , Akbaş Canan , Aktan Meryem , Erdiş Eda , Özmen Hilal Kiziltunç , Özyar Enis , Çağlar Ahmetcan , Munzuroğlu Ak Filiz , Akyüz Mehmet Fatih , Altinok Ayşe
Published: March 2024

Objective

The study aimed to assess the level of knowledge of patients with cervical cancer referred to radiation oncology outpatient clinics in Turkey regarding screening methods and human papillomavirus (HPV) vaccination and increase social awareness based on the findings.

Methods

A descriptive cross-sectional survey was conducted from January to June 2022 involving 300 patients in various regions. Data on demographics, cervical cancer screening and HPV vaccination knowledge, and recommendations to relatives were collected through a questionnaire-based interview. Univariate logistic regression analyzed the impact of independent variables on knowledge levels.

Results

Among the participants, 57% were unaware of cervical cancer screening, and 66% had no knowledge of the HPV vaccine. Higher knowledge levels were associated with higher education, older age at marriage and first birth, and previous gynecological checkups. Lower knowledge levels were observed in patients treated at state institutions, with no formal education, and diagnosed with cervical cancer at age 60 or older. A significant inverse correlation was found between knowledge levels and the stage of cancer at diagnosis, with higher awareness in earlier stages.

Conclusion

The study revealed limited awareness among cervical cancer patients in Turkey regarding screening and HPV vaccination. Lower knowledge levels were associated with specific demographic factors, emphasizing the importance of targeted educational campaigns to reduce the burden of cervical cancer and promote early detection. Efforts to enhance vaccination coverage and encourage early screening can significantly improve outcomes. Comprehensive awareness surveys are essential in guiding policymaking and implementing effective early detection and prevention strategies for cervical cancer.
Risk of heart disease and stroke among individuals with prehypertension or blood pressure progression: a national population-based cohort study
Authors: Jin Qingdong , Chen Yanqing
Published: March 2024

Objective

The purpose of our study was to analyze the association of blood pressure and blood pressure progression with heart disease and stroke among Chinese population.

Method

We included a total of 10 122 adults aged 45 years and above free of heart disease or stroke at baseline from the China Health and Retirement Longitudinal Study cohort. We used Cox proportional hazards models to analyze the relationship between cardiovascular risk and prehypertension in subjects with or without progression to hypertension.

Result

During a mean follow-up of 6.5 years, 1972 subjects were either diagnosed with heart disease or had a stroke (composite outcome). Compared with individuals with normotension at baseline, the fully adjusted hazard ratio (HR) [95% confidence interval (CI)] was 1.25 (1.10–1.42) and 1.52 (1.34–1.74) for composite outcome in individuals with prehypertension and hypertension at baseline, respectively. The subjects who progressed to hypertension had higher risk of cardiovascular outcomes than those who remained at normal blood pressure or prehypertension in a fully adjusted model. The subjects who progressed from prehypertension to hypertension had 1.72 times higher risk [HR (95% CI): 1.72 (1.37–2.16)] of cardiovascular outcomes than those who remained at normal blood pressure or prehypertension in a fully adjusted model.

Conclusion

The cardiovascular risk of subjects with prehypertension is higher than that of subjects with normal blood pressure. After a diagnosis of hypertension, subjects who progressed from normal blood pressure to hypertension had an increased risk of heart disease and stroke.
Adjacent object distorts the organ-of-interest in filtered back-projection tomographic image reconstruction: ‘ramp filter’ or ‘reconstruction’ artifact revisited
Authors: Qutbi Mohsen
Published: March 2024

Objective

To simulate the artifact caused by an adjacent object on organ-of-interest during filtered back-projection (FBP) tomographic reconstruction (the so-called “ramp filter” artifact) and to demonstrate the extent to which an organ-of-interest is influenced by such adjacent hot spot or attenuating object.

Methods and Materials

Two simulations are conducted with two simplified phantoms: “hot spot” and “cardiac.” First one is used to visualize effect of hot spot on its periphery. Second one is used to evaluate effect of nearby object (liver) on left ventricle (LV) as organ-of-interest. To generate sinograms, forward projection process is done with and without modeling radiation attenuation. FBP using windowed ramp filter is done. All slices are analyzed by plotting intensity profiles.

Results

In tomographic slices, there is a hypo-intense halo around presumed edge of object when compared to background intensity, more noticeable in phantoms with less blurring. Even with ramp filter applied, no halo is visible in FBP without attenuation for cardiac phantom. In contrast, in slices with considering attenuation, zones with different levels of count suppression on both sides of object are visualized instead. The most prominent one is between liver and LV in simulation with higher-attenuating object and higher activity.

Conclusion

A single hot spot with sufficient amount of blurring does not distort its surroundings. Hot spots and attenuating objects near organ-of-interest, however, distort myocardial perfusion imaging. Artifactual defects are thus only created when attenuation is modeled during FBP, producing zones of count suppression between organ-of-interest and nearby object or hot spot.
Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism
Authors: Liu Jing , Ginsberg Henry N. , Reyes-Soffer Gissette
Published: March 2024

Purpose of review

Transmembrane 6 superfamily member 2 (TM6SF2) gene was identified through exome-wide studies in 2014. A genetic variant from glutamic acid to lysine substitution at amino acid position 167 (NM_001001524.3:c.499G> A) (p.Gln167Lys/p.E167K, rs58542926) was discovered (p.E167K) to be highly associated with increased hepatic fat content and reduced levels of plasma triglycerides and LDL cholesterol. In this review, we focus on the discovery of TM6SF2 and its role in VLDL secretion pathways. Human data suggest TM6SF2 is linked to hepatic steatosis and cardiovascular disease (CVD), hence understanding its metabolic pathways is of high scientific interest.

Recent findings

Since its discovery, completed research studies in cell, rodent and human models have defined the role of TM6SF2 and its links to human disease. TM6SF2 resides in the endoplasmic reticulum (ER) and the ER-Golgi interface and helps with the lipidation of nascent VLDL, the main carrier of triglycerides from the liver to the periphery. Consistent results from cells and rodents indicated that the secretion of triglycerides is reduced in carriers of the p.E167K variant or when hepatic TM6SF2 is deleted. However, data for secretion of APOB, the main protein of VLDL particles responsible for triglycerides transport, are inconsistent.

The identification of genetic variants that are highly associated with human disease presentation should be followed by the validation and investigation into the pathways that regulate disease mechanisms. In this review, we highlight the role of TM6SF2 and its role in processing of liver triglycerides.
Sensorimotor training improves gait, ankle joint proprioception, and quality of life in patients with diabetic peripheral neuropathy: A single-blinded randomized controlled trial
Authors: Saleh Marwa Shafiek Mustafa , Elbanna Rana Hesham Mohamed , Abdelhakiem Nadia Mohamed , Abdalla Ghada Abd Elmoniem
Published: March 2024

Objective

To investigate the effect of Sensorimotor Training (SMT) on gait, ankle joint proprioception, and quality of life in Diabetic Peripheral Neuropathy (DPN) patients.

Design

A prospective, single-blind, randomized controlled experiment was performed. Forty patients with DPN aged 50 to 65 yrs were distributed randomly into two groups, the SMT group (n = 20) and the control group (n = 20). Both groups attended awareness sessions about diabetes and foot care for 30 minutes, every two weeks. Moreover, the SMT group received 6wk (3 days/week) of SMT. Spatiotemporal gait parameters, proprioception accuracy of the ankle joint, and quality of life were measured before and after 6 weeks of intervention.

Results

Regarding baseline data, no significant differences were identified among groups (p > 0.05). After 6wk intervention, the SMT group exhibited significant improvements in all outcome variables (p < 0.001), while the control group showed significant changes in quality of life only (p = 0.03). Comparing groups after intervention reveals statistically significant differences in all measured variables in favor of the SMT group (p < 0.001).

Conclusions

Sensorimotor training may improve spatiotemporal gait parameters, ankle joint proprioception, and quality of life of patients with DPN.
Different Ectopic Endocrine Tumors on Renal Hilum Detected by 68Ga-DOTATATE PET
Authors: Lv Yuhu , Lan Xiaoli , Qin Chunxia
Published: March 2024

Renal hilum is a very rare location for primary adrenocortical adenoma or pheochromocytoma. We report 68Ga-DOTATATE PET/CT findings of primary renal hilar adrenocortical adenoma in one patient and 68Ga-DOTATATE PET/MR findings of pheochromocytoma in another patient.
Efficacy of ScopeGuide-Assisted Training in Enhancing Colonoscopy Competence and Reducing Patient Discomfort
Authors: Ma Hui-Min , Gao Li-Ping , Wang Peng-Fei , Wang Fang , Feng Yan-Hu , Yang Li-Hong , Yu Yi , Wang Xiang
Published: March 2024

Objective:

In this study, we aimed to evaluate the efficacy of the Magnetic Scope Guide Assist (ScopeGuide) in enhancing the procedural competence of endoscopists and reducing patient discomfort during colonoscopy.

Methods:

This was a retrospective study with 88 trainee participants. The study participants were trained on patients who underwent colonoscopy without anesthesia. Both ScopeGuide-assisted training and conventional training (without ScopeGuide) were utilized for colonoscopy instruction. The outcomes of training were compared, with a particular emphasis on the competency of looping resolution.

Results:

ScopeGuide-assisted training was superior to conventional training in multiple aspects, including looping resolution (Z=−3.681, P<0.001), pain scores (Z=−4.211, P<0.001), time to reach the cecum (Z=−4.06, P<0.001), willingness to undergo repeat colonoscopy (Z=−4.748, P<0.001), competence of positional changes (Z=−4.079, P<0.001), and the effectiveness of assisted compression (Z=−3.001, P=0.003). Further stratified analysis revealed that the ScopeGuide-assisted training mode was more beneficial for junior endoscopists (P<0.05 in all parameters) but not for intermediate endoscopists (P>0.05) and partially beneficial for senior endoscopists (P<0.05 for all parameters except looping resolution).

Conclusion:

ScopeGuide-assisted training can significantly facilitate endoscopists in resolving loops and reducing patient pain, thereby enhancing their colonoscopy abilities.
Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer’s Disease
Authors: Raj Ashish , Torok Justin , Ranasinghe Kamalini
Published: March 2024

INTRODUCTION

The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success.

METHODS

We tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI.

RESULTS

Although network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best.

DISCUSSION

This mathematical exposition of the “pas de deux” of co-evolving proteins provides quantitative, whole-brain support to the concept of amyloid-facilitated-tauopathy rather than the classic amyloid-cascade or pure-tau hypotheses, and helps explain certain known but poorly understood aspects of AD.
EnhancerBD identifing sequence feature
Authors: Wang Yi
Published: March 2024

Deciphering the non-coding language of DNA is one of the fundamental questions in genomic research. Previous bioinformatics methods often struggled to capture this complexity, especially in cases of limited data availability. Enhancers are short DNA segments that play a crucial role in biological processes, such as enhancing the transcription of target genes. Due to their ability to be located at any position within the genome sequence, accurately identifying enhancers can be challenging. We presented a deep learning method (enhancerBD) for enhancer recognition. We extensively compared the enhancerBD with previous 18 state-of-the-art methods by independent test. Enhancer-BD achieved competitive performances. All detection results on the validation set have achieved remarkable scores for each metric. It is a solid state-of-the-art enhancer recognition software. In this paper, I extended the BERT combined DenseNet121 models by sequentially adding the layers GlobalAveragePooling2D, Dropout, and a ReLU activation function. This modification aims to enhance the convergence of the model’s loss function and improve its ability to predict sequence features. The improved model is not only applicable for enhancer identification but also for distinguishing enhancer strength. Moreover, it holds the potential for recognizing sequence features such as lncRNA, microRNA, insultor, and silencer.
Dopamine dynamics in chronic pain: music-induced sex-dependent behavioral effects in mice
Authors: Flores-García Montse , Flores de los Heros África , Aso Ester , Grau-Sánchez Jennifer , Videla Sebastià , Rodríguez-Fornells Antoni , Bonaventura Jordi , Fernández-Dueñas Víctor
Published: March 2024

1

Chronic pain is a debilitating disease that is usually comorbid to anxiety and depression. Current treatment approaches primarily rely on analgesics, but they often neglect emotional aspects. Non-pharmacological interventions have been incorporated into clinics to provide a more comprehensive management of chronic pain. Among these interventions, listening to music is a well-accepted and cost-effective option. However, the underlying mechanisms of music-mediated pain relief remain insufficiently understood. Here, our aim was to evaluate the effects of music exposure in an animal model of chronic pain. First, we injected mice with the inflammatory agent complete Freund’s adjuvant (CFA) into the hind paw and housed them for 14 days with background music during their active period (Mozart K.205, overnight), or silence. The impact of music exposure on nociception and anxiety-like and depression-like behaviors was evaluated through different paradigms, including the hot plate, Von Frey, elevated plus maze, splash, and tail suspension tests. Additionally, we investigated whether music influences dopamine dynamics in the nucleus accumbens (NAcc), a pivotal region involved in pain processing, anhedonia, and reward. Our findings indicate that music exposure prevents the decreased NAcc activity observed in CFA-injected mice, linking with a sex-dependent reduction of allodynia, anxiety- and depression-like behaviors. Thus, females were more sensitive to music exposure. Collectively, our findings provide compelling evidence for the integration of music listening as a non-pharmacological intervention in chronic pain conditions. Moreover, the observed impact on the NAcc suggests its potential as a therapeutic target for addressing chronic pain and its associated symptoms.
Molecular Genomic Insights into Melanoma Associated Proteins PRAME and BAP1
Authors: Nawn Debaleena , Hassan Sk. Sarif , Hromić-Jahjefendić Altijana , Bhattacharya Tanishta , Basu Pallab , Redwan Elrashdy M. , Barh Debmalya , Andrade Bruno Silva , Aljabali Alaa A. , Serrano-Aroca Ángel , Lundstrom Kenneth , Tambuwala Murtaza M. , Uversky Vladimir N.
Published: March 2024

Background

Melanoma, a worldwide widespread skin cancer with over 325,000 yearly incidences, demands a thorough understanding of its molecular components to create effective therapeutics. This study looks at the PRAME (cutaneous melanoma-associated antigen) and BAP1 (gene controlling gene-environment interactions) proteins, which are important in melanoma development and are important for understanding the molecular landscape of melanoma.

Introduction

While playing a crucial role in melanoma, the structural and functional characteristics of PRAME and BAP1 remain unidentified. This work tries to unravel their complexities by investigating conserved residues, sequence invariance, and other molecular characteristics that contribute to their importance in melanoma. Promising therapeutic targets for melanoma therapy are identified by analyzing these proteins at the molecular level.

Methods

The study makes extensive use of bioinformatics methods to analyze PRAME and BAP1, including sequence conservation, inherent disorder, polyglutamic acid presence, and polarity alterations. Established approaches are used to investigate residue changes and their effects on protein folding, aggregation, and interactions.

Results

PRAME and BAP1 conserved residues highlight their critical roles in protein function and interaction. Sequence invariance indicates the possibility of functional relevance and evolutionary conservation. In intrinsically disordered proteins (IDPRs), PRAME has enhanced intrinsic disorder and flexibility, whereas BAP1 has changed disorder-promoting residue sequences. Polyglutamic acid strings are found in both proteins, emphasizing their modulatory involvement in protein interactions. Protein folding and aggregation are influenced by polarity shifts, with a balanced distribution of acidic and basic residues preserving native structures. The ratios and distributions of amino acids, particularly neutral residues, have a profound influence on interactions and gene dysregulation.

Conclusion

PRAME and BAP1 structural and functional understanding pave the way for diagnostic and tailored treatment options in melanoma. Differences in residue alterations, polarity distributions, and amino acid ratios provide intriguing drug design options. This research contributes to a better knowledge of melanoma-associated two proteins, opening the path for novel diagnostic and therapy techniques in skin cancer and beyond.
TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer’s disease models
Authors: Wilson Edward N. , Wang Congcong , Swarovski Michelle S. , Zera Kristy A. , Ennerfelt Hannah E. , Wang Qian , Chaney Aisling , Gauba Esha , Ramos Benitez Javier A. , Le Guen Yann , Minhas Paras S. , Panchal Maharshi , Tan Yuting J. , Blacher Eran , Iweka Chinyere A. , Cropper Haley , Jain Poorva , Liu Qingkun , Mehta Swapnil S. , Zuckerman Abigail J. , Xin Matthew , Umans Jacob , Huang Jolie , Durairaj Aarooran S. , Serrano Geidy E. , Beach Thomas G. , Greicius Michael D. , James Michelle L. , Buckwalter Marion S. , McReynolds Melanie R. , Rabinowitz Joshua D. , Andreasson Katrin I.
Published: March 2024

Human genetics implicate defective myeloid responses in the development of late onset, age-associated Alzheimer’s disease (AD). Aging is characterized by a decline in myeloid metabolism that triggers maladaptive, neurotoxic immune responses. TREM1 is an amplifier of pro-inflammatory myeloid responses, and here we find thatTrem1deficiency prevents age-dependent changes in myeloid metabolism, inflammation, and hippocampal memory function.Trem1deficiency rescues age-associated declines in ribose-5P, a glycolytic intermediate and the precursor for purine, pyrimidine, and NAD+biosynthesis. In vitro,Trem1deficient microglia are resistant to bioenergetic changes induced by amyloid-ß42oligomers (Aß42), suggesting that Aß42stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD model of amyloid accumulation,Trem1haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy independent of amyloid accumulation or changes in the disease-associated microglial transcriptomic signature. In agingAPPSwemice,Trem1deficiency restores synaptic mitochondrial function and cerebral glucose uptake and prevents hippocampal memory decline. In post-mortem human brain, microglial TREM1 expression increases with clinical and neuropathological severity. Thus, TREM1-mediated disruption of myeloid metabolism, both in the periphery and brain, promotes cognitive decline in aging and amyloid accumulation, two major risk factors for AD development.
Single molecule fingerprinting reveals different growth mechanisms in seed amplification assays for different polymorphs of αSynuclein fibrils
Authors: Lau Derrick , Tang Yuan , Kenche Vijaya , Copie Thomas , Kempe Daryan , Jary Eve , Graves Noah J. , Biro Maté , Masters Colin L. , Dzamko Nicolas , Gambin Yann , Sierecki Emma
Published: March 2024

Alpha-synuclein (αSyn) aggregates, detected in the biofluids of patients with Parkinson’s disease, have the ability to catalyze their own aggregation, leading to an increase in the number and size of aggregates. This self-templated amplification is used by newly developed assays to diagnose Parkinson’s disease and turned the presence of αSyn aggregates into a biomarker of the disease. It has become evident that αSyn can form fibrils with slightly different structures, called “strains” or polymorphs, but little is known about their differential reactivity in diagnostic assays. Here we compared the properties of two well-described αSyn polymorphs. Using single molecule techniques, we observed that one of the polymorphs had an increased tendency to undergo secondary nucleation and we showed that this could explain the differences of reactivity observed inin vitroseed amplification assay and cellular assays. Simulations and high-resolution microscopy suggest that a 100-fold difference in apparent rate of growth can be generated by a surprisingly low number of secondary nucleation “points” (1 every 2,000 monomers added by elongation). When both strains are present in the same seeded reaction, secondary nucleation displaces proportions dramatically and causes a single strain to dominate the reaction as the major end-product.
Identifying effective evolutionary strategies for uncovering reaction kinetic parameters under the effect of measurement noises
Authors: Yeo Hock Chuan , Varsheni Vijay , Selvarajoo Kumar
Published: March 2024

The transition from explanative modelling of fitted data to the predictive modelling of unseen data for systems biology endeavors necessitates the effective recovery of reaction parameters. Yet, the relative efficacy of optimization algorithms in doing so remains under-studied, as to the specific reaction kinetics and the effect of measurement noises. To this end, we simulate the reactions of an artificial pathway using 4 kinetic formulations: generalized mass action (GMA), Michaelis-Menten, linear-logarithmic, and convenience kinetics. We then compare the effectiveness of 5 evolutionary algorithms (CMAES, DE, SRES, ISRES, G3PCX) for objective function optimization in kinetic parameter hyperspace to determine the corresponding estimated parameters. We quickly dropped the DE algorithm due to its poor performance. Baring measurement noise, we find CMAES algorithm to only require a fraction of the computational cost incurred by other EAs for both GMA and linear-logarithmic kinetics yet performing as well by other criteria. However, with increasing noise, SRES and ISRES perform more reliably for GMA kinetics, but at considerably higher computational cost. Conversely, G3PCX is among the most efficacious for estimating Michaelis-Menten parameters regardless of noise, while achieving numerous folds saving in computational cost. Cost aside, we find SRES to be versatilely applicable across GMA, Michaelis-Menten, and linear-logarithmic kinetics, with good resilience to noise. On the other hand, we could not identify the parameters of convenience kinetics using any algorithm. Together, we find algorithms that are effective under marked measurement noise for specific reaction kinetics, as a step towards predictive modelling for systems biology endeavors.
The Rhizobial effector NopT targets Nod factor receptors to regulate symbiosis inLotus japonicus
Authors: Bao Hanbin , Wang Yanan , Li Haoxing , Wang Qiang , Lei Yutao , Ye Ying , Wadood Syed F. , Zhu Hui , Stahelin Christian , Stacey Gary , Xu Shutong , Cao Yangrong
Published: March 2024

It is well-documented that type-III effectors are required by Gram-negative pathogens to directly target different host cellular pathways to promote bacterial infection. However, in the context of legume-rhizobium symbiosis, the role of rhizobial effectors in regulating plant symbiotic pathways remains largely unexplored. Here, we show that NopT, a YopT-type cysteine protease ofSinorhizobium frediiNGR234 directly targets the plant’s symbiotic signaling pathway by associating with two Nod factor receptors (NFR1 and NFR5 ofLotus japonicus). NopT inhibits cell death triggered by co-expression of NFR1/NFR5 inNicotiana benthamiana. Full-length NopT physically interacts with NFR1 and NFR5. NopT proteolytically cleaves NFR5 bothin vitroandin vivo, but can be inactivated by NFR1 as a result of phosphorylation. NopT plays an essential role in mediating rhizobial infection inL. japonicus. Autocleaved NopT retains the ability to cleave NFR5 but no longer interacts with NFR1. Interestingly, genomes of certainSinorhizobiumspecies only harbornopTgenes encoding truncated proteins without the autocleavage site. These results reveal an intricate interplay between rhizobia and legumes, in which a rhizobial effector protease targets NFR5 to dampen symbiotic signaling. NFR1 appears to counteract this process by phosphorylating the effector. This discovery highlights the role of a bacterial effector in regulating a signaling pathway in plants and opens up the perspective of developing kinase-interacting proteases to fine-tune cellular signaling processes in general.

One-sentence summary

The rhizobial effector NopT and two Nod factor receptors ofLotus japonicus, NFR1 and NFR5, mutually interact to precisely regulate rhizobial symbiosis.
Transcriptional repression ofGTL1under water-deficit stress promotes anthocyanin biosynthesis to enhance drought tolerance
Authors: Mano Noel Anthony , Shaikh Mearaj A. , Widhalm Joshua R. , Yoo Chan Yul , Mickelbart Michael V.
Published: March 2024

The transcription factor GT2-LIKE 1 (GTL1) has been implicated in orchestrating a transcriptional network of diverse physiological, biochemical, and developmental processes. In response to water-limiting conditions, GTL1 is a negative regulator of stomatal development, but its potential role in other water-deficit responses is unknown. We hypothesized that GTL1 regulates transcriptome changes associated with drought tolerance over leaf developmental stages. To test the hypothesis, gene expression was profiled by RNA-seq analysis in emerging and expanding leaves of wild-type and a drought-tolerantgtl1-4knockout mutant under well-watered and water-deficit conditions. Our comparative analysis of genotype-treatment combinations within leaf developmental age identified 459 and 1073 differentially expressed genes in emerging and expanding leaves, respectively, as water-deficit responsive GTL1-regulated genes. Transcriptional profiling identified a potential role of GTL1 in two important pathways previously linked to drought tolerance: flavonoid and polyamine biosynthesis. In expanding leaves, negative regulation ofGTL1under water-deficit conditions promotes biosynthesis of flavonoids and anthocyanins that may contribute to drought tolerance. Quantification of polyamines did not support a role for GTL1 in these drought-responsive pathways, but this is likely due to the complex nature of synthesis and turnover. Our global transcriptome analysis suggests that transcriptional repression of GTL1 by water deficit allows plants to activate diverse pathways that collectively contribute to drought tolerance.
Sex-specific sub-lethal effects of low virulence entomopathogenic fungi may boost the Sterile Insect Technique
Authors: Duneau David , Gallet Romain , Adhiambo Maureen , Delétré Emilie , Chailleux Anais , Khamis Fathiya , Subramanian Sevgan , Brévault Thierry , Fellous Simon
Published: March 2024

BACKGROUND

The Sterile Insect Technique (SIT) is a species-specific method for controlling insect pests. Recent studies have explored the combination of SIT with entomopathogenic microorganisms, known as boosted-SIT, to enhance its effectiveness. This study aimed to evaluate the potential of the entomopathogenic fungi,Metarhizium anisopliae, in boosting the SIT for managing the oriental fruit fly,Bactrocera dorsalis.

METHODS

Adult flies from a laboratory population ofB. dorsaliswere inoculated with one of eight strains ofM. anisopliaeto assess fungus virulence in each sex. Ideally, boosted-SIT should minimally impact sterile males and reduce female fecundity maximally. A brief exposure to fungal spores was efficient to infect males, and for them to transmit the fungus to females when hosted together for 24 hours.

RESULTS

Our results showed significant variations in the mortality induced by the strains in males, but not in females that exhibited low mortality. Strains varied in their sub-lethal effects on female fecundity, with almost a two-fold variation among strains. Furthermore, strains that had the lowest virulence on males tended to reduce female fecundity the most.

CONCLUSION

Our study brings a proof of concept that it is possible to leverage boosted- SIT using carefully selected pathogen strains and their sub-lethal effects on both the male and female fruit fly.