bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of carvedilol posology timing on clinically significant portal hypertension: insights from elastography measurements
Authors: Besteiro Bruno , Marques da Cruz Manuel , Alves Cláudia , Costa Fátima , Nunes Mariana , Dias Daniel Martinho , Barreira Ana , Calvão Joana , Mesquita Mónica , Carvalho Sónia , Pinho Inês , Carrola Paulo , Ramos José Presa
Published: March 2024

Background and aims

Carvedilol has emerged as the preferred β-blocker for treating portal hypertension. However, there is still a debate in dosing regimen, with a potential lower bioavailability in once-daily regimens. The aim of this study is to assess the acute effects of carvedilol posology in patients with clinically significant portal hypertension (CSPH), as a surrogate marker of bioavailability.

Methods

In this experimental study, 34 patients with CSPH receiving carvedilol twice daily were asked to suppress the night dose of carvedilol, creating a standardized 24-hour dose interval. Spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) by transient elastography (TE) were performed, with the exact interval between the last carvedilol administration and TE measurements consistently maintained at 24 hours and compared with values prior and under treatment.

Results

Thirty-four patients were included, predominantly male (82.9%). SSM after suspending carvedilol for 24 hours [mean, 73.9kPa (SD, 17.0)] was significantly higher (P < 0.001) than under treatment [mean, 56.3kPa (SD, 13.2)] and was not significantly different (P = 0.908) from SSM prior to introduction of carvedilol [mean, 74.5kPa (SD, 12.4)]. Differences were also found in stratified analysis for carvedilol dosage, D’Amico classification stages, MELDNa scores, MELD3.0 scores, Child-Pugh class A and CSPH due to alcoholic cirrhosis. LSM after suspension was not significantly different from both under treatment and prior to treatment.

Conclusion

The differences in SSM after skipping one dose of carvedilol show both the importance of strict adherence to the prescribed dosing regimen to achieve the expected therapeutic benefits and the impact of twice daily prescription in bioavailability throughout the day.
Efficacy and safety of naldemedine for opioid-induced constipation in older patients with cancer: a retrospective study
Authors: Imai Hisao , Fujita Yukiyoshi , Hiruta Eriko , Masuno Takashi , Yamazaki Shigeki , Tanaka Hajime , Kamiya Teruhiko , Sandoh Mitsuru , Takei Satoshi , Arai Kazuya , Nishiba Hiromi , Mogi Junnosuke , Koizuka Shiro , Saito Taeko , Obayashi Kyoko , Kaira Kyoichi , Minato Koichi
Published: March 2024

Background

Opioids are pain relievers that are often associated with opioid-induced constipation (OIC) that worsens with age. We performed a multicenter, retrospective analysis on the efficacy and safety of naldemedine, an opioid receptor antagonist, in treating OIC in patients with cancer (age >75 years).

Methods

The electronic medical records of cancer patients who received naldemedine at 10 Japanese institutions between 7 June 2017 and August 31, 2019, were retrieved. Patients aged ≥75 years who were treated with naldemedine for the first time and hospitalized for at least 7 days before and after initiating naldemedine therapy were included in this analysis.

Results

Sixty patients were observed for at least 7 days before and after starting naldemedine. The response rate was 68.3%, and the frequency of bowel movements increased significantly after naldemedine administration in the overall population (P < 0.0001) and among those who defecated <3 times/week before naldemedine administration (P < 0.0001). Diarrhea was the most frequent adverse event in all grades, observed in 45% of patients, of which 92.6% were Grade 1 or 2. Grade 4 or higher adverse events, including death, were not observed.

Conclusion

Naldemedine exhibits significant efficacy and safety in OIC treatment in older patients with cancer.
Expression of Early Growth Response 3 in Skin Cancers
Authors: Zhou Kai-Yi , Deng Li-Jia , Luo Si-Yu , Wang Qin-Xiao , Fang Sheng
Published: March 2024

Objective:

To assess the expression of early growth response 3 (EGR3) in normal skin and different types of skin tumors: cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), melanoma (MM), and cutaneous adnexal tumors containing sebaceous carcinoma (SC), trichoepithelioma (TE) and clear cell hidradenoma (CCH).

Background:

EGR3, expressed in multiple organs, including skin, plays an important role in cell differentiation and tumor growth. Previous studies have shown that EGR3 suppresses tumor growth and is downregulated in various malignancies. However, its distribution in normal skin and its expression especially in skin tumors have not been studied.

Materials and Methods:

Samples of normal cases (n = 4), cSCC (n = 12), BCC (n = 12), MM (n = 12), SC (n = 4), TE (n = 4), and CCH (n = 4) were collected from patients treated in our department between 2018 and 2023. Immunohistochemistry was used to investigate the expression of EGR3. The results were analyzed with the description of the staining pattern and the histochemical score.

Results:

Immunohistochemical staining showed that EGR3 was uniquely expressed in normal skin in the granular layer and upper part of the stratum spinosum, as well as in sebaceous glands and hair follicles, but not in sweat glands. In skin cancers, BCC, SC, and TE showed positive EGR3 staining, whereas cSCC, MM, and CCH were negative.

Conclusions:

EGR3 has a specific expression pattern in normal skin and in skin tumors, which is important for the differential diagnosis of skin tumors, in particular for cSCC and sebaceous gland carcinoma.
Methylene Blue in Metformin Intoxication
Authors: Katlan Banu
Published: March 2024

Metformin (MTF) is a widely used oral antidiabetic medication. Regardless the reason, high doses of MTF cause lactic acidosis as a result of its effects on mitochondrial ATP production and no-mediated vascular smooth muscle relaxation. Metformin-associated lactic acidosis can be life-threatening despite all treatments. Methylene blue (MB) has the potential to reverse the toxic effects of MTF through its effects on both the mitochondrial respiratory chain and nitric oxide production. The use of MB in MTF intoxication has only been reported in a limited number of cases. Herein, we present a 16-year-old female patient who attempted suicide by ingesting high doses of MTF. Supportive treatments, such as vasopressor, inotropic treatments, and sodium bicarbonate, were started in the patient who developed fluid-resistant hypotension after pediatric intensive care unit admission. Because of rising lactate levels, Continuous renal replacement therapy (CRRT) was started immediately. Despite all treatments, hypotension and hyperlactatemia persisted; MB was given as a rescue therapy. Noticeable hemodynamic improvement was observed within 30 minutes of initiating MB infusion, allowing a gradual decrease in the doses of inotropic infusions within the first hour of therapy. Patient's cardiovascular support was discontinued on the second day, and she was discharged on the fifth day. We speculate that, considering the mechanisms of MTF toxicity and the mechanisms of action of MB, it is suggested that early administration of MB, not only as a rescue treatment but as the initial approach to MTF poisoning in combination with other treatments, may result in improved outcomes.
Characteristics and Risk Factors of Central Nervous System Infection in Children With Febrile Seizures
Authors: do Valle Daniel Almeida , Costa Luisa Carolina Vinhal , Fregonese Amanda Perin , da Silva Dannyelle Heloize Leite , Maldonado Giovana Kellen Souza , da Silva Letícia Tozzini Tavares , Couto Mylena da Silva
Published: March 2024

Objective

The aim of the present study is to evaluate the necessity of performing lumbar puncture in patients experiencing febrile seizures, considering the epidemiology specific to Brazil.

Methods

A retrospective cross-sectional study was performed from January 2017 to December 2021.

Results

A total of 469 children with seizure and fever were analyzed. The identified event was the first in 65.9% (n = 309). A total of 54.2% (n = 254) of patients had a simple febrile seizure. Infectious focus, excluding previous central nervous system (CNS) infection, was identified in 35.6% (n = 167) patients. Meningitis was identified in 7.7% (n = 36) patients, all of them were viral. Patients with CNS infection had a higher frequency of symptoms such as nausea and vomiting, drowsiness, headache, and higher level of leukocytosis. A longer duration of fever was found to be more strongly associated with CNS infection.

Conclusions

When considering the use of lumbar puncture in febrile seizure, it is important to conduct a comprehensive evaluation that considers multiple factors, including clinical signs, symptoms, and the overall clinical context. Meningeal signs may be less prominent, and other symptoms such as lethargy, irritability, and vomiting may serve as more reliable indicators. Although clinical examination suggestive of meningitis remains an important factor, the recurrence of febrile seizures and a longer length of fever can provide additional insights and aid in decision-making regarding lumbar puncture.
Use of Donor-derived Cell-free DNA to Inform Tapering of Immunosuppression Therapy in Kidney Transplant Recipients: An Observational Study
Authors: Osuchukwu George , Trevino Alexa , McCormick Sarah , Kaur Navchetan , Prigmore Brittany , Al Haj Baddar Nour , Bloom Michelle S. , Demko Zachary , Gauthier Philippe
Published: March 2024

Background.

Immunosuppression therapy (IST) is required for allograft survival but can cause significant adverse effects. Donor-derived cell-free DNA (dd-cfDNA) is a validated noninvasive biomarker for active rejection in kidney transplant (KTx). Evidence supporting dd-cfDNA testing use in IST management is limited.

Methods.

In this single-center observational study, dd-cfDNA testing was performed in 21 KTx patients considered good candidates for mycophenolic acid (MPA) reduction. Patients with dd-cfDNA <1% at the first visit (enrollment) had their MPA dosage reduced; those with dd-cfDNA ≥1% had their MPA dosage maintained. Patients were monitored with dd-cfDNA for 6 additional visits.

Results.

Of 21 patients enrolled in the study, 17 were considered low risk for rejection by dd-cfDNA and underwent MPA reduction; 4 patients were considered high risk for rejection by dd-cfDNA and had their initial MPA dosage maintained. Of the 4 patients considered high risk for rejection by dd-cfDNA, 1 experienced chronic allograft nephropathy and graft loss, and another received an indication biopsy that showed no evidence of rejection. Of the 17 patients considered low risk for rejection by dd-cfDNA, none experienced allograft rejection. dd-cfDNA was used for surveillance in a 6-mo period following MPA reduction; no untoward results were noted.

Conclusions.

This proof-of-concept study reports the use of dd-cfDNA to directly inform IST management in a cohort of KTx who were candidates for IST reduction.
Recent updates on treatment patterns in patients with treated attention-deficit/hyperactivity disorders from a nationwide real-world database in South Korea
Authors: Cho Yoon , Kim Ah-Young , Lee Sukhyang , Lee Hankil
Published: March 2024

The prevalence of attention-deficit/hyperactivity disorder (ADHD) is steadily increasing across Korea. We analyzed ADHD patients with ADHD medications (Rx) characteristics and treatment patterns compared to patients without Rx and identified the differences between pediatric-/adult- and active-/transient-patients with Rx. Using a nationwide claims dataset from 2020 to 2021, we conducted a prevalence-based cross-sectional study and analyzed the recent patients’ characteristics and patterns among ADHD patients. Among 132 017 ADHD patients with Rx, differences from 20 312 without Rx across all characteristics except sex. We found significant differences in characteristics and treatment patterns between pediatric-/adult- and active-/transient-patients with Rx. Age-specific sex ratios notably diverged in pediatric patients (61.2%), but remained similar in adults, revealing significant psychiatric comorbidities differences. Active-patients peaked at 6–11 years (41.4%), while transient-patients at 18–30 years (36.1%). Predominantly, methylphenidate (89.7%), atomoxetine (27.8%), and clonidine (2.8%) were prescribed, with 85% experiencing treatment changes within methylphenidate formulations. In pediatric patients, extended-release methylphenidate was preferred (56.1%), adults favored oral delivery system methylphenidate (71.5%), and active-patients had higher treatment rates than transient-patients across all patterns, with low monotherapy rates. This study provides epidemiologic insights into recent characteristics and treatment patterns of ADHD patients with Rx in Korea, providing valuable evidence for identifying those actively receiving ADHD treatment in future healthcare policy decisions.
Composite material in the sea urchin
Cidaris
rugosa
: ordered and disordered micrometre-scale bicontinuous geometries
Authors: Jessop Anna-Lee , Millsteed Allan J. , Kirkensgaard Jacob J. K. , Shaw Jeremy , Clode Peta L. , Schröder-Turk Gerd E.
Published: March 2024

The sponge-like biomineralized calcite materials found in echinoderm skeletons are of interest in terms of both structure formation and biological function. Despite their crystalline atomic structure, they exhibit curved interfaces that have been related to known triply periodic minimal surfaces. Here, we investigate the endoskeleton of the sea urchin
Cidaris rugosa
that has long been known to form a microstructure related to the Primitive surface. Using X-ray tomography, we find that the endoskeleton is organized as a composite material consisting of domains of bicontinuous microstructures with different structural properties. We describe, for the first time, the co-occurrence of ordered single Primitive and single Diamond structures and of a disordered structure within a single skeletal plate. We show that these structures can be distinguished by structural properties including solid volume fraction, trabeculae width and, to a lesser extent, interface area and mean curvature. In doing so, we present a robust method that extracts interface areas and curvature integrals from voxelized datasets using the Steiner polynomial for parallel body volumes. We discuss these very large-scale bicontinuous structures in the context of their function, formation and evolution.
Cooperation among unequal players with aspiration-driven learning
Authors: Chen Fang , Zhou Lei , Wang Long
Published: March 2024

Direct reciprocity promotes the evolution of cooperation when players are sufficiently equal, such that they have similar influence on each other. In the light of ubiquitous inequality, this raises the question of how reciprocity evolves among unequal players. Existing studies on inequality mainly focus on payoff-driven learning rules, which rely on the knowledge of others’ strategies. However, inferring one’s strategy is a difficult task even if the whole interaction history is known. Here, we consider aspiration-driven learning rules, where players seek strategies that satisfy their aspirations based on their own information. Under aspiration-driven learning rules, we explore the evolutionary dynamics among players with inequality in endowments and productivity. We model the interactions among unequal players with asymmetric games and characterize the condition where cooperation is feasible. Remarkably, we find that aspiration-driven learning rules lead to a higher level of cooperation than payoff-driven ones over a wide range of inequality. Moreover, our results show that high aspiration levels are conducive to the evolution of cooperation when more productive players are equipped with higher endowments. Our work highlights the advantages of aspiration-driven learning for promoting cooperation among unequal players and suggests that aspiration-based decision-making may be more beneficial for the collective.
Interaction of MLE with CLAMP zinc finger is involved in proper MSL proteins binding to chromosomes in
Drosophila
Authors: Tikhonova Evgeniya , Revel-Muroz Anastasia , Georgiev Pavel , Maksimenko Oksana
Published: March 2024

The
Drosophila
male-specific lethal (MSL) complex binds to the male X chromosome to activate transcription. It comprises five proteins (MSL1, MSL2, MSL3, male absent on the first (MOF), and maleless (MLE)) and two long noncoding RNAs (lncRNAs; roX1 and roX2). The MLE helicase remodels the roX lncRNAs, enabling the lncRNA-mediated assembly of the
Drosophila
dosage compensation complex. MSL2 is expressed only in males and interacts with the N-terminal zinc finger of the transcription factor chromatin-linked adapter for MSL proteins (CLAMP), which is important for the specific recruitment of the MSL complex to the male X chromosome. Here, we found that MLE's unstructured C-terminal region interacts with the sixth zinc-finger domain of CLAMP.
In vitro
, 4–5 zinc fingers are critical for the specific DNA-binding of CLAMP with GA repeats, which constitute the core motif at the high affinity binding sites for MSL proteins. Deleting the CLAMP binding region in MLE decreases the association of MSL proteins with the male X chromosome and increases male lethality. These results suggest that interactions of unstructured regions in MSL2 and MLE with CLAMP zinc finger domains are important for the specific recruitment of the MSL complex to the male X chromosome.
Response of flexible structures to air-blast: nonlinear compressibility effects in fluid–structure interaction
Authors: Pal Aninda , Ghoshal Ritwik
Published: March 2024

This paper presents a coupled model that considers the nonlinear compressibility effect in fluid–structure interaction (FSI) during air-blast loading on flexible structures. In this coupled model, structural behaviour is idealized as a linear single-degree-of-freedom mass-spring-damper system whereas nonlinear fluid compressibility is considered by applying Rankine–Hugoniot jump conditions across a moving plate. The surrounding fluid medium is modelled with an ideal gas equation and hence, this model can be applied for FSI analysis with relatively strong shocks (reflection coefficient of up to 8). The nonlinear compressibility of the fluid medium at the backside of the plate is also considered in this coupled formulation and its effects on the structural responses are examined. Moreover, the negative/underpressure phase of the reflected wave profile, which is typically neglected in a decoupled model, is also considered in the proposed model and its influence on the structural response is also investigated. The study reveals that the nonlinear compressibility of fluid medium significantly influences the coupled FSI phenomena, especially in flexible lightweight structures. Numerical examples are presented to highlight the implications of the nonlinear compressibility effect in FSI on the reflected pressure profile and the response of flexible structures. Parametric dependencies of response on structural mass and natural frequency are examined thoroughly and a response spectrum is obtained. It is envisaged that the lightweight protective structure design under higher blast intensity may benefit from this study.
Harmonic wave scattered by an inclusion in an elastic plane: The complete Gurtin-Murdoch model
Authors: Dai Ming , Schiavone Peter
Published: March 2024

We consider the propagation of a harmonic elastic wave in a composite inclusion–matrix structure subjected to plane deformation. The interface between the inclusion and matrix is described by the
complete
Gurtin-Murdoch model with non-vanishing interface tension and interface stretching rigidity. We consider an inclusion of general shape and formulate the corresponding boundary value problem for the wave functions in the inclusion and matrix when a harmonic compressional or shear wave is incident on the edge of the matrix. The problem is then solved by series expansion methods for the case of a circular inclusion embedded in an infinite matrix. The series solution obtained is validated by checking its convergence and via comparisons with existing static and dynamic solutions for certain reduced cases. Numerical examples are presented for the case of a small-sized circular hole embedded in a soft matrix demonstrating the influence of surface tension on the incident wave-induced dynamic stress concentration in the matrix. We find that the presence of surface tension relieves the peak stress around the circular hole when the frequency of the incident wave is below a certain critical value, while it tends to intensify the peak stress for a high-frequency incident wave.
Inertia-gravity waves in geophysical vortices
Authors: Vidal Jérémie , Colin de Verdière Yves
Published: March 2024

Pancake-like vortices are often generated by turbulence in geophysical flows. Here, we study the inertia-gravity oscillations that can exist within such geophysical vortices, due to the combined action of rotation and gravity. We consider a fluid enclosed within a triaxial ellipsoid, which is stratified in density with a constant Brunt–Väisälä frequency (using the Boussinesq approximation) and uniformly rotating along a (possibly) tilted axis with respect to gravity. The wave problem is then governed by a mixed hyperbolic-elliptic equation for the velocity. As in the rotating non-stratified case considered by Vantieghem (2014,Proc. R. Soc. A,470, 20140093. (doi:10.1098/rspa.2014.0093)), we find that the spectrum is pure point in ellipsoids (i.e. only consists of eigenvalues) with polynomial eigenvectors. Then, we characterize the spectrum using numerical computations (obtained with a bespoke Galerkin method) and asymptotic spectral theory. Finally, the results are discussed in light of natural applications (e.g. for Mediterranean eddies or Jupiter’s vortices).
Building pyramids against the evolutionary emergence of pathogens
Authors: Gandon Sylvain , Guillemet Martin , Gatchitch François , Nicot Antoine , Renaud Ariane C. , Tremblay Denise M. , Moineau Sylvain
Published: March 2024

Mutations allowing pathogens to escape host immunity promote the spread of infectious diseases in heterogeneous host populations and can lead to major epidemics. Understanding the conditions that slow down this evolution is key for the development of durable control strategies against pathogens. Here, we use theory and experiments to compare the efficacy of three strategies for the deployment of resistance: (i) amixingstrategy where the host population contains two single-resistant genotypes, (ii) apyramidingstrategy where the host carries a double-resistant genotype, (iii) acombiningstrategy where the host population is a mix of a single-resistant genotype and a double-resistant genotype. First, we use evolutionary epidemiology theory to clarify the interplay between demographic stochasticity and evolutionary dynamics to show that thepyramidingstrategy always yields lower probability of evolutionary emergence. Second, we test experimentally these predictions with the introduction of bacteriophages into bacterial populations where we manipulated the diversity and the depth of immunity using a Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated (CRISPR-Cas) system. These biological assays confirm that pyramiding multiple defences into the same host genotype and avoiding combination with single-defence genotypes is a robust way to reduce pathogen evolutionary emergence. The experimental validation of these theoretical recommendations has practical implications in various areas, including for the optimal deployment of resistance varieties in agriculture and for the design of durable vaccination strategies.
Cultural traits operating in senders are driving forces of cultural evolution
Authors: Enquist Magnus , Jansson Fredrik , Ghirlanda Stefano , Michaud Jérôme
Published: March 2024

We introduce a mathematical model of cultural evolution to study cultural traits that shape how individuals exchange information. Current theory focuses on traits that influence the reception of information (receiver traits), such as evaluating whether information represents the majority or stems from a trusted source. Our model shifts the focus from the receiver to the sender of cultural information and emphasizes the role of sender traits, such as communicability or persuasiveness. Here, we show that sender traits are probably a stronger driving force in cultural evolution than receiver traits. While receiver traits evolve to curb cultural transmission, sender traits can amplify it and fuel the self-organization of systems of mutually supporting cultural traits, including traits that cannot be maintained on their own. Such systems can reach arbitrary complexity, potentially explaining uniquely human practical and mental skills, goals, knowledge and creativity, independent of innate factors. Our model incorporates social and individual learning throughout the lifespan, thus connecting cultural evolutionary theory with developmental psychology. This approach provides fresh insights into the trait-individual duality, that is, how cultural transmission of single traits is influenced by individuals, who are each represented as an acquired system of cultural traits.
Mechanistic models for West Nile virus transmission: a systematic review of features, aims and parametrization
Authors: de Wit Mariken M. , Dimas Martins Afonso , Delecroix Clara , Heesterbeek Hans , ten Bosch Quirine A.
Published: March 2024

Mathematical models within the Ross–Macdonald framework increasingly play a role in our understanding of vector-borne disease dynamics and as tools for assessing scenarios to respond to emerging threats. These threats are typically characterized by a high degree of heterogeneity, introducing a range of possible complexities in models and challenges to maintain the link with empirical evidence. We systematically identified and analysed a total of 77 published papers presenting compartmental West Nile virus (WNV) models that use parameter values derived from empirical studies. Using a set of 15 criteria, we measured the dissimilarity compared with the Ross–Macdonald framework. We also retrieved the purpose and type of models and traced the empirical sources of their parameters. Our review highlights the increasing refinements in WNV models. Models for prediction included the highest number of refinements. We found uneven distributions of refinements and of evidence for parameter values. We identified several challenges in parametrizing such increasingly complex models. For parameters common to most models, we also synthesize the empirical evidence for their values and ranges. The study highlights the potential to improve the quality of WNV models and their applicability for policy by establishing closer collaboration between mathematical modelling and empirical work.
Insights into adaptive behavioural plasticity from the guppy model system
Authors: Fox Janay A. , Toure M. Wyatt , Heckley Alexis , Fan Raina , Reader Simon M. , Barrett Rowan D. H.
Published: March 2024

Behavioural plasticity allows organisms to respond to environmental challenges on short time scales. But what are the ecological and evolutionary processes that underlie behavioural plasticity? The answer to this question is complex and requires experimental dissection of the physiological, neural and molecular mechanisms contributing to behavioural plasticity as well as an understanding of the ecological and evolutionary contexts under which behavioural plasticity is adaptive. Here, we discuss key insights that research with Trinidadian guppies has provided on the underpinnings of adaptive behavioural plasticity. First, we present evidence that guppies exhibit contextual, developmental and transgenerational behavioural plasticity. Next, we review work on behavioural plasticity in guppies spanning three ecological contexts (predation, parasitism and turbidity) and three underlying mechanisms (endocrinological, neurobiological and genetic). Finally, we provide three outstanding questions that could leverage guppies further as a study system and give suggestions for how this research could be done. Research on behavioural plasticity in guppies has provided, and will continue to provide, a valuable opportunity to improve understanding of the ecological and evolutionary causes and consequences of behavioural plasticity.
Reduction in activity and abundance of mitochondrial electron transport chain supercomplexes in pulmonary hypertension-induced right ventricular dysfunction
Authors: Ma Wenzhuo , Zhang Peng , Vang Alexander , Zimmer Alexsandra , Huck Scarlett , Nicely Preston , Wang Eric , Mancini Thomas J , Owusu-Sarfo Joseph , Cavarsan Clarissa F. , Belyvech Andriy E. , Campbell Kenneth S. , Terentyev Dmitry , Choudhary Gaurav , Clements Richard T.
Published: March 2024

Pulmonary hypertension (PH) results in RV hypertrophy, fibrosis and dysfunction resulting in RV failure which is associated with impaired RV metabolism and mitochondrial respiration. Mitochondrial supercomplexes (mSC) are assemblies of multiple electron transport chain (ETC) complexes that consist of physically associated complex I, III and IV that may enhance respiration and lower ROS generation. The goal of this study was to determine if mSCs are reduced in RV dysfunction associated with PH. We induced PH in Sprague-Dawley rats by Sugen/Hypoxia (3 weeks) followed by normoxia (4 weeks). Control and PH rats were subjected to echocardiography, blue and clear native-PAGE to assess mSC abundance and activity, and cardiomyocyte isolation to assess mitochondrial reactive oxygen species (ROS). mSC formation was also assessed in explanted human hearts with and without RV dysfunction. RV activity of CI and CIV and abundance of CI, CIII and CIV in mitochondrial mSCs was severely reduced in PH rats compared to control. There were no differences in total CI or CIV activity or abundance in smaller ETC assemblies. There were no changes in both RV and LV of expression of representative ETC complex subunits. PAT, TAPSE and RV Wall thickness significantly correlated with CIV and CI activity in mSC, but not total CI and CIV activity in the RV. Consistent with reduced mSC activity, isolated PH RV myocytes had increased mitochondrial ROS generation compared to control. Reduced mSC activity was also demonstrated in explanted human RV tissue from patients undergoing cardiac transplant with RV dysfunction. The right atrial pressure/pulmonary capillary wedge pressure ratio (RAP/PCWP, an indicator of RV dysfunction) negatively correlated with RV mSC activity level. In conclusion, reduced assembly and activity of mitochondrial mSC is correlated with RV dysfunction in PH rats and humans with RV dysfunction.
GABAergic amacrine cells balance biased chromatic information in the mouse retina
Authors: Korympidou Maria M. , Strauss Sarah , Schubert Timm , Franke Katrin , Berens Philipp , Euler Thomas , Vlasits Anna
Published: March 2024

The retina extracts chromatic information present in an animal’s environment. In the mouse, the feed-forward, excitatory pathway through the retina is dominated by a chromatic gradient, with green and UV signals primarily processed in the dorsal and ventral retina, respectively. However, at the output of the retina, chromatic tuning is more mixed, suggesting that amacrine cells alter spectral tuning. We genetically targeted the population of 40+ GABAergic amacrine cell types and used two-photon calcium imaging to systematically survey chromatic responses in their dendritic processes. We found that amacrine cells show diverse chromatic responses in different spatial regions of their receptive fields and across the dorso-ventral axis of the retina. Compared to their excitatory inputs from bipolar cells, amacrine cells are less chromatically tuned and less likely to be colour-opponent. We identified 25 functional amacrine cell types that, in addition to their chromatic properties, exhibit distinctive achromatic receptive field properties. A combination of pharmacological interventions and a biologically-inspired deep learning model revealed how lateral inhibition and recurrent excitatory inputs shape chromatic properties of amacrine cells. Our data suggest that amacrine cells balance the strongly biased spectral tuning of excitation in the mouse retina and thereby support increased diversity in chromatic information of the retinal output.
Activation of the mPFC-NAc pathway reduces motor impulsivity but does not affect risk-related decision-making in innately high-impulsive rats
Authors: Arrondeau Chloé , Urueña-Méndez Ginna , Marchessaux Florian , Goutaudier Raphaël , Ginovart Nathalie
Published: March 2024

Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) are characterized by exacerbated motor and risk-related impulsivities, which are associated with decreased cortical activity. In rodents, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been separately implicated in impulsive behaviors, but studies on the specific role of the mPFC-NAc pathway in these behaviors are limited. Here, we investigated whether heightened impulsive behaviors are associated with reduced mPFC activity in rodents, and determined the involvement of the mPFC-NAc pathway in motor and risk-related impulsivities. We used the Roman High- (RHA) and Low-Avoidance (RLA) rat lines, which display divergent phenotypes in impulsivity. To investigate alterations in cortical activity in relation to impulsivity, regional brain glucose metabolism was measured using positron emission tomography and [18F]-fluorodeoxyglucose ([18F]FDG). Using chemogenetics, the activity of the mPFC-NAc pathway was either selectively activated in high-impulsive RHA rats or inhibited in low-impulsive RLA rats, and the effects of these manipulations on motor and risk-related impulsivity were concurrently assessed using the rat gambling task. We showed that basal [18F]FDG uptake was lower in the mPFC and NAc of RHA compared to RLA rats. Activation of the mPFC-NAc pathway in RHA rats reduced motor impulsivity, without affecting risk-related decision-making. Conversely, inhibition of the mPFC-NAc pathway had no effect in RLA rats. Our results suggest that the mPFC-NAc pathway controls motor impulsivity, but has limited involvement in risk-related decision-making. Our findings suggest that reducing fronto-striatal activity may help attenuate motor impulsivity in patients with impulse control dysregulation like ADHD or SUD.
Functions ofC. elegansneurons from synaptic connectivity
Authors: Emmons Scott W.
Published: March 2024

Despite decades of research on theC. elegansnervous system based on an anatomical description of synaptic connectivity, the circuits underlying behavior remain incompletely described and the functions of many neurons are still unknown. Updated and more complete chemical and gap junction connectomes of both adult sexes covering the entire animal including the muscle end organ have become available recently. Here these are analyzed to gain insight into the overall structure of the connectivity network and to suggest functions of individual neuron classes. Modularity analysis divides the connectome graph into ten communities that can be correlated with broad categories of behavior. A significant role of the body wall musculature end organ is emphasized as both a site of significant information convergence and as a source of sensory input in a feedback loop. Convergence of pathways for multisensory integration occurs throughout the network — most interneurons have similar indegrees and outdegrees and hence disperse information as much as they aggregate it. New insights include description of a set of high degree interneurons connected by many gap junctions running through the ventral cord that may represent a previously unrecognized locus of information processing. There is an apparent mechanosensory and proprioceptive field covering the entire body formed by connectivity of the many mechanosensory neurons of multiple types to two interneurons with output connections across the nervous system. Several additional significant, previously unrecognized circuits and pathways are uncovered, some involving unstudied neurons. The insights are valuable for guiding theoretical investigation of network properties as well as experimental studies of the functions of individual neurons, groups of neurons, and circuits.
Transcriptional bursting, gene activation, and roles of SAGA and Mediator Tail measured using nucleotide recoding single cell RNA-seq
Authors: Schofield Jeremy A , Hahn Steven
Published: March 2024

A time resolved nascent single-cell RNA-seq approach was developed to dissect gene-specific transcriptional bursting and the roles of SAGA and Mediator Tail (the activator-binding module). Most yeast genes show near-constitutive behavior while only a subset of genes show high mRNA variance suggestive of transcription bursting. Bursting behavior is highest in the coactivator redundant (CR) gene class (dependent on both SAGA and TFIID) and is strongest in TATA-containing CR genes. Applying this approach to analyze gene activation, we found that basal histone gene transcription is in a low level, low-noise constitutive mode while the activated state unexpectedly shows an increase in both the fraction of active promoters and a switch to a noisy and bursty transcription mode. Rapid depletion of either SAGA or Mediator Tail suggests that both factors play an important role in stimulating the fraction of active promoters at CR genes, with a variable gene-specific role in transcriptional bursting.
An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning
Authors: Lv Mingyue , Cai Ruyi , Zhang Renzimo , Xia Xiju , Li Xuelin , Wang Yipan , Wang Huan , Zeng Jianzhi , Xue Yifei , Mao Lanqun , Li Yulong
Published: March 2024

Octopamine (OA), analogous to norepinephrine in vertebrates, is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions, including olfactory associative learning. However, the spatial and temporal dynamics of OAin vivoremain poorly understood due to limitations associated with the currently available methods used to detect it. To overcome these limitations, we developed a genetically encodedGPCRactivation-based (GRAB) OA sensor called GRABOA1.0. This sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular OA. Using GRABOA1.0, we monitored OA release in theDrosophilamushroom body (MB), the fly’s learning center, and found that OA is released in response to both odor and shock stimuli in an aversive learning model. This OA release requires acetylcholine (ACh) released from Kenyon cells, signaling via nicotinic ACh receptors. Finally, we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octβ1R in dopaminergic neurons, leading to alterations in synaptic plasticity within the MB. Thus, our new GRABOA1.0sensor can be used to monitor OA release in real-time under physiological conditions, providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.
Advancements in Cardiovascular Disease Detection: Leveraging Data Mining and Machine Learning
Authors: Hossain Md. Sahadat , Talukder Md. Alamin , Mahmud Md. Zulfiker
Published: March 2024

Cardiovascular disease (CVD) is a significant global health concern, requiring early detection and accurate prediction for effective intervention. Machine learning (ML) offers a data-driven approach to analyzing patient data, identifying complex patterns and predicting CVD risk factors like blood pressure (BP), cholesterol levels, and genetic predispositions. Our research aims to predict CVD presence using ML algorithms, leveraging the Heart Disease UCI dataset with 14 attributes and 303 instances. Extensive feature engineering enhanced model performance. We developed five models using Logistic Regression, K-Nearest Neighbors (KNN), Decision Tree Classifier, Support Vector Machine (SVM), and Random Forest Classifier, refining them with hyperparameter tuning. Results show substantial accuracy improvements post-tuning and feature engineering. ‘Logistic Regression’ achieved the highest accuracy at 93.44%, closely followed by ‘Support Vector Machine’ at 91.80%. Our findings emphasize the potential of ML in early CVD prediction, underlining its value in healthcare and proactive risk management. ML’s utilization for CVD risk assessment promises personalized healthcare, benefiting both patients and healthcare providers. This research showcases the practicality and effectiveness of ML-based CVD risk assessment, enabling early intervention, improving patient outcomes, and optimizing healthcare resource allocation.
Forest and Biodiversity 2: a tree diversity experiment to understand the consequences of multiple dimensions of diversity and composition for long-term ecosystem function and resilience
Authors: Cavender-Bares Jeannine , Grossman Jake J. , Guzmán Q. J. Antonio , Hobbie Sarah E. , Kaproth Matthew A. , Kothari Shan , Lapadat Cathleen , Montgomery Rebecca , Park Maria
Published: March 2024

We introduce a new “low-density” tree diversity experiment at the Cedar Creek Ecosystem Science Reserve in central Minnesota, USA aimed at testing long-term ecosystem consequences of tree diversity and composition. The experiment was designed to provide guidance on forest restoration efforts that will simultaneously advance carbon sequestration goals and contribute to biodiversity conservation and sustainability.

The new Forest and Biodiversity (FAB2) experiment uses native tree species in varying levels of species richness, phylogenetic diversity, and functional diversity to test the mechanisms and processes that contribute to forest stability and ecosystem productivity in the face of global change. FAB2 was designed and established in conjunction with a prior experiment (FAB1) in which the same set of twelve species was planted in 16 m2plots at high density (0.5 m spacing). In addition to lower density plantings (1 m spacing), FAB2 also has larger plots (100 m2and 400 m2) appropriate for testing long-term ecosystem consequences of species composition and diversity.

Within the first six years, mortality in the 400 m2monoculture plots was significantly higher than in the 100 m2plots. The highest mortality among any treatments occurred inTilia americanaandAcer negundomonocultures, but mortality for both species decreased with increasing plot diversity. These results highlight the importance of forest diversity in reducing mortality in some species and point to potential mechanisms, including light and drought stress, that cause tree mortality in vulnerable monocultures. The experiment highlights challenges to maintaining monoculture and low-diversity treatments in tree mixture experiments of large extent.

The FAB2 experiment provides a long-term platform for discerning the importance of species and lineage effects and of multiple dimensions of diversity in restoring ecosystem functions and services provided by forests. It also provides a platform for improving remote sensing approaches, including Uncrewed Aerial Vehicles (UAVs) equipped with LiDAR, multispectral, and hyperspectral sensors, to complement ground-based monitoring of forest function and diversity. We aim for the experiment to contribute to international efforts to monitor and manage forests in the face of global change.
Analysis of meiotic recombination inDrosophila simulansshows heterozygous inversions do not cause an interchromosomal effect
Authors: Man Bowen , Kim Elizabeth , Vadlakonda Alekhya , Stern David L. , Crown K. Nicole
Published: March 2024

Chromosome inversions are of unique importance in the evolution of genomes and species because when heterozygous with a standard arrangement chromosome, they suppress meiotic crossovers within the inversion. In Drosophila species, heterozygous inversions also cause the interchromosomal effect, whereby the presence of a heterozygous inversion induces a dramatic increase in crossover frequencies in the remainder of the genome within a single meiosis. To date, the interchromosomal effect has been studied exclusively in species that also have high frequencies of inversions in wild populations. We took advantage of a recently developed approach for generating inversions inDrosophila simulans, a species that does not have inversions in wild populations, to ask if there is an interchromosomal effect. We used the existing chromosome 3R balancer and generated a new chromosome 2L balancer to assay for the interchromosomal effect genetically and cytologically. We found no evidence of an interchromosomal effect inD. simulans. To gain insight into the underlying mechanistic reasons, we qualitatively analyzed the relationship between meiotic double-strand break formation and synaptonemal complex assembly. We find that the synaptonemal complex is assembled prior to double-strand break formation as inD. melanogaster; however, we show that the synaptonemal complex is assembled prior to localization of the oocyte determination factor Orb, whereas inD. melanogaster, synaptonemal complex formation does not begin until Orb is localized. Together, our data show heterozygous inversions inD. simulansdo not induce an interchromosomal effect and that there are differences in the developmental programming of the early stages of meiosis.
RESTandRCORgenes display distinct expression profiles in neurons and astrocytes using 2D and 3D human pluripotent stem cell models
Authors: Maksour Simon , Ng Neville , Hulme Amy J. , Miellet Sara , Engel Martin , Muñoz Sonia Sanz , Balez Rachelle , Rollo Ben , Finol-Urdaneta Rocio K. , Ooi Lezanne , Dottori Mirella
Published: March 2024

Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor involved in neurodevelopment and neuroprotection. REST forms a complex with the REST corepressors, CoREST1, CoREST2, or CoREST3 (encoded byRCOR1,RCOR2, andRCOR3, respectively). Emerging evidence suggests that the CoREST family can target unique genes independently of REST, in various neural and glial cell types during different developmental stages. However, there is limited knowledge regarding the expression and function of the CoREST family in human neurodevelopment. To address this gap, we employed 2D and 3D human pluripotent stem cell (hPSC) models to investigateRESTandRCORgene expression levels. Our study revealed a significant increase inRCOR3expression in glutamatergic cortical and GABAergic ventral forebrain neurons, as well as mature functional NGN2-induced neurons. Additionally, a simplified astrocyte transdifferentiation protocol resulted in a significant decrease inRCOR2expression following differentiation.RESTexpression was notably reduced in mature neurons and cerebral organoids, along withRCOR2in the latter. In summary, our findings provide the first insights into the cell-type-specific expression patterns ofRCORgenes in human neuronal and glial differentiation. Specifically,RCOR3expression increases in neurons, whileRCOR2levels decrease in astrocytes. The dynamic expression patterns ofRESTandRCORgenes during hPSC neuronal and glial differentiation underscore the potential distinct roles played by REST and CoREST proteins in regulating the development of these cell types in humans.

Graphical abstract

Highlights

RESTandRCORgenes display cell-type specific expression patterns in neural cells

RCOR3(encodes CoREST3) is upregulated during neuronal and astrocyte differentiation

RCOR2(encodes CoREST2) is downregulated during differentiation of astrocytes

Evidence of potential cell-type specific functions of the CoREST family