bluuebunny/crossref_metadata_2025 huggingface dataset:
Using a Decision Tree Approach to Analyze Key Factors Influencing Intraoperative-Acquired Pressure Injury
Authors: Shi Guirong , Jiang Liping , Liu Ping , Xu Xin , Wu Qunfang , Zhang Peipei
Published: August 2023

OBJECTIVE

To determine the key factors influencing intraoperative-acquired pressure injury (IAPI).

METHODS

Researchers assessed 413 surgical patients in a Shanghai tertiary hospital using an information collection form and an IAPI occurrence record form. Analysis took place using the classification and regression tree algorithm and multiple logistic regression.

RESULTS

A total of 43 surgical patients (10.4%) had IAPI, including 32 stage 1 cases (74.4%), and 11 stage 2 cases (25.6%). The multiple logistic regression analysis indicated that operation duration, surgical position, preoperative hypertension, and preoperative Braden Scale risk score were independently associated with IAPI development. The decision tree showed that preoperative Braden Scale score, surgical position, operation grade, operation duration, age, prealbumin level, and body mass index were important factors and that preoperative Braden Scale score was the most critical decision variable. The cross-validation method was used to indicate a model accuracy of 91.8%.

CONCLUSIONS

The decision tree effectively identified key factors for IAPI, complementing the logistic regression analysis and providing a scientific basis for the further development of structural risk assessment, prevention, and treatment strategies for IAPI.
“Soap Scrap” Technique: A Tissue-Preserving Approach to Treating Wounds with Undermining or Pockets
Authors: Melnychuk Igor , Juriga Julia
Published: August 2023

This retrospective case series introduces a tissue-preserving approach to treat complicated wounds with undermined edges or wounds with pockets. Wounds with undermining or pockets are commonly encountered in clinical practice and can be difficult to manage when trying to achieve wound closure. Traditionally, epibolic edges need to be resected or cauterized with silver nitrate, whereas wound undermining or pockets need to be resected or unroofed. The method described herein consists of three components: sharp debridement of all undermined areas or inside walls of wound pockets, compression, and immobilization. Compression can be performed using multilayered compression alone, modified negative-pressure therapy, or both. Immobilization of all wound layers can be achieved using a brace, removable Cam Walker, or a cast.

This article reports on 11 patients who had unfavorable upper and lower extremity wounds with undermined areas or wound pockets who were treated using this methodology. The average patient age was 73 years, and the average wound depth was 1.12 cm. The average undermined area was 1.7 (range, 0.2–5.0) cm. Wounds healed in an average of 9.1 weeks; all wounds healed between 3 and 15 weeks. This series demonstrates a novel tissue-preserving approach to treating wounds with undermining or wounds with pockets using debridement, immobilization, and compression.
Review of the Etiology, Diagnosis, and Therapy of Left Atrial Thrombus
Authors: Feldman Jared M. , Wang Andy , Frishman William H. , Aronow Wilbert S.
Published: August 2023

Thrombi in the left atrial appendage (LAA) are an important cause of systemic thromboembolism in patients with atrial fibrillation. The gold standard for the diagnosis of LAA thrombi is a transesophageal echocardiogram, although cardiac multidetector computed tomography, intracardiac echocardiogram, and cardiac magnetic resonance imaging are alternative diagnostic imaging modalities. When an LAA thrombus is diagnosed, effective anticoagulation is recommended for at least 3 weeks or until thrombus resolution is confirmed on repeat transesophageal echocardiogram. Recent prospective research shows the efficacy of nonvitamin K oral anticoagulants in the treatment of LAA thrombus, which offers a promising alternative to vitamin K antagonists. As an alternative approach, left atrial aspiration thrombectomy has been described in case reports, though there is limited evidence comparing its efficacy to anticoagulation alone.
Reflections on a Career in Plastic Surgery: A National Survey of Retired Surgeons
Authors: Veeramani Anamika , Comer Carly D. , Elmer Nicholas , Shiah Eric , Celestin Arthur , Simmons Christopher , Sommers Katie , McClure Gina T. , Lin Samuel J. , Lee Bernard T.
Published: August 2023

Introduction:

Retired plastic surgeons can provide valuable insights for the greater plastic surgery community. The purpose of this study was to gather demographics, personal reflections, and advice for a career in plastic surgery from retired American plastic surgeons.

Methods:

An email survey was distributed to 825 members of the American Society of Plastic Surgeons during September 2021. The survey distribution was designed to engage members of the plastic surgery community, who were retired from surgical practice in the United States. The form consisted of 29 questions, five of which were free response. Descriptive statistical analyses were performed.

Results:

A total of 214 completed surveys were received, with a response rate of 25.9%. The average age at retirement was 67.6 years. The majority of respondents were men (87.6%) and White (93.3%); 46.9% of surgeons practiced at individual private practice. Ninety percent of surgeons indicated that they would choose to practice as a plastic surgeon again. Free responses provided positive career reflections and advice for young plastic surgeons regarding navigating the changing landscape of healthcare.

Conclusions:

Retired plastic surgeons are interested in engaging with the plastic surgery community and demonstrate continued interest in the future of the field. Efforts can be made to avail the field of their expertise and experience.
POFUT1 promotes gastric cancer progression through Notch/Wnt dual signaling pathways dependent on the parafibromin-NICD1-β-catenin complex
Authors: Dong Shuang , Wang Zhirong , Xiong Wujun
Published: August 2023

Background:

Aberrant glycosylation performed by glycosyltransferases is a leading cause of gastric cancer (GC). Protein O-fucosyltransferase 1 (POFUT1) expression is increased in GC specimens and cells. In this study, the biological effects and mechanisms of POFUT1 underlying the development of GC were investigated.

Methods:

POFUT1 downregulated and upregulated GC cells were established. The effects of POFUT1 on cell proliferation, metastasis and apoptosis were examined using cell counting kit-8 (CCK8) assay, transwell assay, and flow cytometry. Subcutaneous xenograft tumor models were established followed by immunohistochemistry staining of resected tumors. Facilitating modulators and transcription factors were detected by western blot, immunofluorescence, luciferase reporter assay, and co-immunoprecipitation.

Results:

POFUT1 played a pro-oncogenic role both in vivo and in vitro, which promoted proliferation and metastasis, as well as inhibited apoptosis in GC cells. POFUT1 promoted Cyclin D3 expression and inhibited the expression of apoptotic proteins, such as Bcl-2-associated X protein (Bax) and cleaved caspase 3, facilitating tumor growth. Moreover, POFUT1 accelerated matrix metalloproteases expression and attenuated E-cadherin expression, contributing to GC metastasis. In addition, POFUT1 expression promoted the expression and nuclear translocation of Notch1 intracellular domain (NICD1) and β-catenin and inhibited β-catenin phosphorylation degradation, accompanied by the activation of recombination signal binding protein-Jκ (RBP-J) and T-cell factor (TCF) transcription factors, respectively. It is notable that parafibromin integrated NICD1 and β-catenin, enabling the concerted activation of Wnt and Notch signaling targeted proteins.

Conclusion:

These observations indicated that POFUT1 promoted GC development through activation of Notch and Wnt signaling pathways, which depended on the parafibromin-NICD1-β-catenin complex. This work provides new evidence for the further diagnosis and treatment of GC.
Renal denervation: recent developments in clinical and preclinical research
Authors: Drawz Paul , Baumann Daniel , Dayton Alex
Published: August 2023

Purpose of review

Renal denervation represents a new dimension to hypertension treatment, with multiple device manufacturers seeking premarket FDA approval currently. Interest in the efficacy and safety of the treatment has spurred compelling mechanistic studies into the function of renal nerves and downstream impacts of denervation.

Recent findings

A trial of the ultrasound Paradise Catheter system (RADIANCE II) found a 6.3 mmHg reduction in SBP relative to sham controls. A trial of the Symplicity Spyral system (SPYRAL HTN-ON MED) found an insignificant reduction in SBP relative to sham controls. Individuals were taking antihypertensive medications during the study, and investigators note the sham group experienced a larger medication burden than the denervated group. Recent preclinical studies have evaluated potential risks of renal denervation, how sympathetic activity broadly is affected, as well as identifying possible biomarkers to identify individuals where denervation would be more successful.

Studies of renal denervation continue to find a robust antihypertensive effect, especially in studies wherein medications are withdrawn. Further investigation into mechanisms and indicators for usage of the technique will be important in identifying the patient population most likely to benefit from usage of renal denervation.
The role of SLC16A11 variations in diabetes mellitus
Authors: Aguilar-Salinas Carlos A. , Tusie Luna María Teresa
Published: August 2023

Purpose of review

The aim of this study was to summarize the existing evidence that proves the association between an ethnic-specific SLC16A11 risk haplotype and type 2 diabetes found in the Latin American population.

Recent findings

The association has been replicated in consortia studies, especially in early-onset type 2 diabetes. No association has been found with gestational diabetes. Mild obesity-related diabetes is the most common T2D subphenotype found in patients with the risk haplotype. The SLC16A11 risk haplotype is associated with decreased insulin action, higher acute insulin secretory response to an intravenous glucose bolus and higher serum alanine aminotransferase levels.

The study of underrepresented populations in large genomic databases is a valuable resource to gain new knowledge about the pathophysiology of complex traits, especially if these groups have suffered repeated selection process caused by famine, migrations and war. This is the case of diabetes, obesity and lipid disorders in Latin American countries. Here, we summarize the existing evidence of a proof-of concept finding: the association between the SLC16A11 ethnic-specific risk haplotype and T2D.
Camouflage using three-dimensional surface disruption
Authors: King Jemma , Hemmi Jan M. , Kelley Jennifer L.
Published: August 2023

Disruptive markings are common in animal patterns and can provide camouflage benefits by concealing the body's true edges and/or by breaking the surface of the body into multiple depth planes. Disruptive patterns that are accentuated by high contrast borders are most likely to provide false depth cues to enhance camouflage, but studies to date have used visual detection models or humans as predators. We presented three-dimensional-printed moth-like targets to wild bird predators to determine whether: (1) three-dimensional prey with disrupted body surfaces have higher survival than three-dimensional prey with continuous surfaces, (2) two-dimensional prey with disruptive patterns or enhanced edge markings have higher survival than non-patterned two-dimensional prey. We found a survival benefit for three-dimensional prey with disrupted surfaces, and a significant effect of mean wing luminance. There was no evidence that false depth cues provided the same protective benefits as physical surface disruption in three-dimensional prey, perhaps because our treatments did not mimic the complexity of patterns found in natural animal markings. Our findings indicate that disruption of surface continuity is an important strategy for concealing a three-dimensional body shape.
Regulation strategies for two-output biomolecular networks
Authors: Alexis Emmanouil , Schulte Carolin C. M. , Cardelli Luca , Papachristodoulou Antonis
Published: August 2023

Feedback control theory facilitates the development of self-regulating systems with desired performance which are predictable and insensitive to disturbances. Feedback regulatory topologies are found in many natural systems and have been of key importance in the design of reliable synthetic bio-devices operating in complex biological environments. Here, we study control schemes for biomolecular processes with two outputs of interest, expanding previously described concepts based on single-output systems. Regulation of such processes may unlock new design possibilities but can be challenging due to coupling interactions; also potential disturbances applied on one of the outputs may affect both. We therefore propose architectures for robustly manipulating the ratio/product and linear combinations of the outputs as well as each of the outputs independently. To demonstrate their characteristics, we apply these architectures to a simple process of two mutually activated biomolecular species. We also highlight the potential for experimental implementation by exploring synthetic realizations both
in vivo
and
in vitro
. This work presents an important step forward in building bio-devices capable of sophisticated functions.
Continuation of the Stieltjes series to the large regime by finite-part integration
Authors: Tica Christian D. , Galapon Eric A.
Published: August 2023

We devise a prescription to use a novel convergent expansion in the strong-asymptotic regime for the Stieltjes integral and its generalizations (Galapon EA. 2017
Proc. R. Soc A
473
, 20160567) to sum the associated divergent series of Stieltjes across all asymptotic regimes. The novel expansion makes use of the divergent negative-power moments, which we treated as Hadamard’s finite part integrals. The result allowed us to compute the ground state energy of the quartic, sextic anharmonic oscillators as well as the

P
T

symmetric cubic oscillator, and the funnel potential across all perturbation regimes from a single expansion that is built from the divergent weak-coupling perturbation series and incorporates the known leading-order strong-coupling behaviour of the spectra.
Effective governing equations for dual porosity Darcy–Brinkman systems subjected to inhomogeneous body forces and their application to the lymph node
Authors: Girelli A. , Giantesio G. , Musesti A. , Penta R.
Published: August 2023

We derive the homogenized governing equations for a double porosity system where the fluid flow within the individual compartments is governed by the coupling between the Darcy and the Darcy–Brinkman equations at the
microscale
, and are subjected to inhomogeneous body forces. The homogenized
macroscale
results are obtained by means of the asymptotic homogenization technique and read as a double Darcy differential model with mass exchange between phases. The role of the microstructure is encoded in the effective hydraulic conductivities which are obtained by solving periodic cell problems whose properties are illustrated and compared. We conclude by solving the new model by means of a semi-analytical approach under the assumption of azimuthal axisymmetry to model the movement of fluid within a lymph node.
Cryptic species in time and space: an assessment of cryptic diversity within eight nominal species of Hydrozoa (Cnidaria)
Authors: Miglietta Maria Pia , Pruski Sarah
Published: August 2023

Sampling in multiple localities, coupled with molecular barcoding, has shown that nominal species with wide geographical distribution often harbour local cryptic species in allopatry. Cryptic species in sympatry, however, can be easily missed if they have different seasonality, because they can be identified only through long-term frequent sampling (i.e. sampling through time of the same species in the same location). This is especially true in planktonic invertebrates that exhibit strong seasonality. By integrating mitochondrial 16S sequences of eight species of Hydrozoa (Cnidaria) collected weekly for a year in one Gulf of Mexico region, with sequences gathered globally, we investigate the presence of cryptic species within a temporal gradient (regionally) and on a spatial (worldwide) scale. We find that eight species of Hydrozoa are composed of 28 cryptic species, with 16 of them appearing in sympatry but with non-overlapping seasonality. The high number of sympatric cryptic species could only be discovered through extensive and prolonged regional sampling efforts. The bi-dimensional cryptic diversity (in time and space) highlighted in this study is essential for understanding processes of evolution, biogeography dispersal in the sea, and for more realistic biodiversity assessments.
Epidemiology of Haemophilus influenzae in children on Lombok Island, Indonesia
Authors: Putri Nina Dwi , Salsabila Korrie , Prayitno Ari , Aprianti Shindy Claudya , Paramaiswari Wisiva Tofriska , Krisna Made Ananda , Safari Dodi
Published: August 2023

The

Haemophilus influenzae

serotype b (Hib) conjugate vaccine routine immunization programme has been implemented for almost a decade; however, there is limited surveillance of

H. influenzae

carriage rates in the Indonesian population.

H. influenzae

was isolated from nasopharyngeal (NP) swab specimens of healthy children on Lombok Island, West Nusa Tenggara Province, Indonesia from 2018 to 2019. Serotyping was performed using quantitative polymerase chain reaction. We identified

H. influenzae

in 40 of the 96 (41.6 %) NP swab specimens. We identified 39 non-typeable

H. influenzae

(NTHi) isolates and 1 Hib isolate.
A big and hairy business: Investigating the interplay of species traits and trade dynamics in the tarantula pet market
Authors: Fukushima Caroline S. , Toomes Adam , Veríssimo Diogo , Cardoso Pedro
Published: August 2023

Species traits significantly influence pet trade dynamics, affecting demand, exploitation, and extinction risk. We examined the effect of species- and advertisement-level attributes on tarantula abundance and price in online markets, exploring rarely-considered fine-scale traits. Data from 977 ads showing 217 species and 81 ‘trade names’’ were collected from eight e-commerce websites located in six countries and analyzed using Structural Equation Models. Hairy, aggressive, and popular tarantulas were more abundant in commerce. Big, recently described species with ontogenetic changes in color and urticating hairs, with no evidence of captive breeding, had higher average price. Variability of prices in the ads were mainly explained by differences in website, lifestage and sex of the individual advertised. After accounting for these drivers of market abundance and price, we found only weak evidence of direct price-rarity relationships, implying they are largely independently determined. This can have important implications for the future management and regulation of the international tarantula trade. Understanding consumer behavior in the pet trade is crucial for effective conservation efforts and we recommend using online ad data to track and understand supply and demand in tarantula trade. Leveraging marketing insights can enhance conservationists’ influence on consumers, promoting sustainable practices and benefit sharing for wildlife-dependent communities. Hobbyist communities may be the most strategic messenger for conservation messaging trying to reach consumers in the tarantula pet trade.

Article impact statement

Tarantula price and abundance in pet trade are shaped by species traits and advertisement attributes.
The experience of family carers for people with moderate to advanced dementia within a domestic home setting: a systematically constructed narrative synthesis
Authors: James Charles , Walshe Catherine , Swarbrick Caroline
Published: August 2023

Background

Caring for someone with moderate to advanced dementia within a domestic home setting can be burdensome and time-consuming. To ensure the effectiveness of care planning and delivery, especially towards the end of life, understanding the nature and impact of such caregiving on the family carer is important. Synthesising existing research will allow greater insight into this experience.

Review question

‘How do family carers describe their experience of providing home-based care for people with moderate to advanced dementia?’

Design

A narrative synthesis of qualitative research exploring the experiences of people with moderate to advanced dementia and their family carers was conducted. Databases (MEDLINE, CINAHL, EMBASE, PsychINFO, Web of Science and Academic Search Complete) were searched from 1984 to 2020. Similarities and differences between papers were grouped using textual narrative synthesis.

Findings

This paper reports findings from a PhD thesis (James, 2021). Included papers (n=17) incorporated those focused on caring for people with advanced dementia (n=8), and those with moderate dementia (n=9). Family carers reported an experience of loss, burden, and grief. Experiences of internal conflict also led to psychological distress. These experiences had a negative impact on the general health of the family carer. Improvement in the family carer’s inter-relationships and the feeling of being useful or having a sense of meaning were reported as positive aspects of caregiving.

Conclusion

A complete description of family carers’ experiences may be inadequate in conveying an acknowledgement of dementia as an illness within the domestic home. Their justifications and determinants for balancing family carers’ challenges and distress to morals also remain unclear. Further research is required to ascertain how family carers may proportionally balance their personified loss with their personified value earlier in the disease trajectory.
In vivo time-lapse imaging and analysis of mitochondria in neural progenitor cells in the developing brain
Authors: Feng Martin S. , Kettelberger Maggie R. , Bestman Jennifer E.
Published: August 2023

Neural progenitor cells (NPCs) are the highly polarized dividing stem cells of the developing brain that give rise to all neurons and glia. Early on, NPCs divide symmetrically and expand the pool of progenitor cells, but as development continues the NPCs begin to asymmetrically divide to produce neurons. The mechanisms that govern this irreversible commitment to neurogenesis are not fully understood, but in other stem cell populations the regulation of mitochondria and cell metabolism is key to controlling stem cell fate. Here we use timelapse 3D confocal microscopy to observe NPCs, their cellular progeny, and their mitochondria in the developingXenopustectum. Our results track individual NPCs over days and show that they contain abundant mitochondria that form complicated networks distributed throughout the cells. We find that NPCs preparing to divide shift mitochondria toward the cell body where they become asymmetrically distributed, suggesting that the cells control which progeny inherit mitochondria. This uneven distribution of mitochondria in cell preparing to divide led us to test the role that mitochondria play in cell division. We overexpressed the mitochondrial biogenesis master regulator, PGC-1a, which induced the NPCs to asymmetrically divide and produce neurons, while PGC-1a knockdown limited neurogenesis. Together these data suggest that the regulation of mitochondria by NPCs prior to cell division and their unequal inheritance during cell division, contributes to the fate of the newborn cells in the developing brain.
EZH2 inhibition sensitizes IDH1R132H mutant gliomas to histone deacetylase inhibitor
Authors: Sprinzen Houghton Lisa , Garcia Franklin Godinez , Mela Angeliki , Lei Liang , Upadhyayula Pavan , Mahajan Aayushi , Humala Nelson , Manier Lisa , Caprioli Richard , Quiñones-Hinojosa Alfredo , Casaccia Patrizia , Canoll Peter
Published: August 2023

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis, however its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H mutated glioma that shows elevated production of 2-Hydroxyglutarate (2-HG) and increased tri-methylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wildtype cells, combination treatment with Tazemetostat is synergistic in both mutant and wildtype models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

Main Points

Murine gliomas initiated by the IDH1R132H mutation (in the presence of additional genetic alterations, such as p53 loss and PDGF overexpression) recapitulate the metabolic and transcriptional features of the proneural subtype, as they are characterized by increased 2HG levels, and are enriched for OPC lineage-restricted genes compared to IDH-wildtype murine gliomas. In murine IDH1-R132H glioma cells, EZH2 inhibition is not cytotoxic as a monotherapy but reduces levels of H3K27me3 and increases levels of H3K27ac. IDH1R132H cells are relatively resistant to Panobinostat cytotoxicity compared to IDH-wildtype cells, but combining treatment with EZH2 inhibition synergistically kills glioma cells and increases H3K27ac.
SR2: Sparse Representation Learning for Scalable Single-cell RNA Sequencing Data Analysis
Authors: Zhao Kai , So Hon-Cheong , Lin Zhixiang
Published: August 2023

Single-cell RNA-sequencing (scRNA-seq) technology has been widely used to measure the transcriptome of cells in complex and heterogeneous systems. Integrative analysis of multiple scRNA-seq data can transform our understanding of various aspects of biology at the single-cell level. Many computational methods are proposed for data integration. However, few methods for scRNA-seq data integration explicitly model variation from heterogeneous biological conditions for interpretation. Modeling the variation helps understand the effect of biological conditions on complex biological systems.

Our study proposes SR2 to capture gene expression patterns from heterogeneous biological conditions and discover cell identity simultaneously. Therefore, it can uncover the effect of biological conditions on the gene expression of cells and simultaneously achieve state-of-the-performance in cell identity discovery in our comprehensive comparison. Notably, SR2 is extended to model the effects of biological conditions on gene expression for cell populations, thus uncovering the effect of biological conditions on gene expression for cell populations and identifying putative condition-associated cell populations. To improve its scalability, we incorporate a batch-fitting strategy to ensure it is scalable to scRNA-seq data with arbitrary sample sizes. Moreover, the broad applicability of SR2 in biomedical studies has been demonstrated via applications. The complete package of SR2 is available athttps://github.com/kai0511/SR2.
Quantitative description of the phase separation behavior of the multivalent SLP65-CIN85 complex
Authors: Maier Joachim , Sieme Daniel , Wong Leo E. , Dar Furqan , Wienands Jürgen , Becker Stefan , Griesinger Christian
Published: August 2023

Biomolecular condensates play a major role in cell compartmentalization, besides membrane-enclosed organelles. The multivalent SLP65 and CIN85 proteins are downstream B cell receptor (BCR)-signaling effectors, required for a proper immune response. Both proteins phase separate together with vesicles to form pre-signaling clusters. Within this tripartite system, six PRMs of SLP65 interact promiscuously with three SH3 domains of the CIN85 monomer, establishing 18 individual SH3-PRM interactions whose individual dissociation constants we determined. Based on these 18 dissociation constants, we measured the phase separation properties of the natural SLP65/CIN85 system as well as designer constructs that emphasize the strongest SH3/PRM interactions. By modelling these various SLP65/CIN85 constructs with the program LASSI (LAttice simulation engine for Sticker and Spacer Interactions) we reproduced the observed phase separation properties. In addition, LASSI revealed a deviation in the experimental measurement, which was independently identified as a previously unknown intramolecular interaction. Thus, thermodynamic properties of the individual PRM/SH3 interactions allow to model the phase separation behavior of the SLP65/CIN85 system faithfully.
ddRAD-seq-derived SNPs reveal novel association signatures for fruit-related traits in peach
Authors: Ksouri Najla , Sánchez Gerardo , Forcada Carolina Font i , Contreras-Moreira Bruno , Gogorcena Yolanda
Published: August 2023

Breeding for new peach cultivars with enhanced traits is a prime target in breeding programs. In this study, we used a discovery panel of 90 peach accessions in order to dissect the genetic architecture of 16 fruit-related traits. ddRAD-seq genotyping and the intersection between three variant callers yielded 13,045 high-confidence SNPs. These markers were subjected to an exhaustive association analysis by testing up to seven GWAS models. Blink was selected as the most adjusted, simultaneously balancing false positive and negative associations. Totally, we identified 16 association signals for six traits showing high broad-sense heritability: harvest date, fruit weight, flesh firmness, contents of flavonoids, anthocyanins and sorbitol. By assessing the allelic effect of significant markers on phenotypic attributes, nine SNP alleles were denoted favorable. A promising marker (SNC_034014.1_7012470) was found to be simultaneously associated with harvest date and fruit firmness conferring a positive allelic effect on both traits. We anticipate that this marker could be used to improve firmness in late harvested cultivars. Candidate causal genes were shortlisted when fulfilling the following criteria: i) position within the linkage disequilibrium block, ii) functional annotation and iii) expression pattern. A bibliographic review of previously reported QTLs mapping nearby the associated markers allowed us to benchmark the accuracy of our approach. Despite the moderate germplasm size, ddRAD-seq allowed us to produce an accurate representation of peach’s genome resulting in SNP markers suitable for empirical association studies. Together with candidate genes, they lay the foundation for further genetic dissection of peach key traits.
Uridine as a potentiator of aminoglycosides through activation of carbohydrate transporters
Authors: Lang Manon , Renard Stéphane , El-Meouche Imane , Amoura Ariane , Denamur Erick , Brosschot Tara , Ingersoll Molly , Bacqué Eric , Mazel Didier , Baharoglu Zeynep
Published: August 2023

Aminoglycosides (AGs) are broad-spectrum antibiotics effective against Gram-negative bacteria. AG uptake depends on membrane potential, but the precise mechanisms are incompletely understood. We report here a new mechanism of active AG uptake in Gram-negative bacteria. InE. coli, overexpression of various carbohydrate transporters increases susceptibility to AGs. Conversely, deletion of a single transporter has little impact. We propose a new uptake model where AGs act as substrates for redundant carbohydrate transporters. This mechanism appears to be shared among Gram-negative ESKAPE pathogens. We screened for molecules that induce transporters’ expression and identified uridine. When uridine is co-administered with AGs under conditions mimicking urinary tract infections, the efficacy of AG therapies is significantly improved againstE. coli, including resistant strains, due to enhanced bacterial uptake. Based on previous knowledge on the use of uridine in humans, we propose that uridine can be a potentiating adjuvant to AG treatment of infectious diseases in the hospital.
Disordered C-terminal domain drives spatiotemporal confinement of RNAPII to enhance search for chromatin targets
Authors: Ling Yick Hin , Ye Ziyang , Liang Chloe , Yu Chuofan , Park Giho , Corden Jeffry L. , Wu Carl
Published: August 2023

Efficient gene expression requires RNA Polymerase II (RNAPII) to find chromatin targets precisely in space and time. How RNAPII manages this complex diffusive search in 3D nuclear space remains largely unknown. The disordered carboxy-terminal domain (CTD) of RNAPII, which is essential for recruiting transcription-associated proteins, forms phase-separated dropletsin vitro, hinting at a potential role in modulating RNAPII dynamics. Here, we use single-molecule tracking and spatiotemporal mapping in living yeast to show that the CTD is required for confining RNAPII diffusion within a subnuclear region enriched for active genes, but without apparent phase separation into condensates. Both Mediator and global chromatin organization are required for sustaining RNAPII confinement. Remarkably, truncating the CTD disrupts RNAPII spatial confinement, prolongs target search, diminishes chromatin binding, impairs pre-initiation complex formation, and reduces transcription bursting. This study illuminates the pivotal role of the CTD in driving spatiotemporal confinement of RNAPII for efficient gene expression.
SUPERVISED WHITE MATTER BUNDLE SEGMENTATION IN GLIOMA PATIENTS WITH TRANSFER LEARNING
Authors: Riccardi Chiara , Ghezzi Sofia , Amorosino Gabriele , Zigiotto Luca , Sarubbo Silvio , Jovicich Jorge , Avesani Paolo
Published: August 2023

In clinical neuroscience, the segmentation of the main white matter bundles is propaedeutic for many tasks such as pre-operative neurosurgical planning and monitoring of neuro-related diseases. Automating bundle segmentation with data-driven approaches and deep learning models has shown promising accuracy in the context of healthy individuals. The lack of large clinical datasets is preventing the translation of these results to patients. Inference on patients’ data with models trained on healthy population is not effective because of domain shift. This study aims to carry out an empirical analysis to investigate how transfer learning might be beneficial to overcome these limitations. For our analysis, we consider a public dataset with hundreds of individuals and a clinical dataset with several tens of glioma patients. We focus our preliminary investigation on the corticospinal tract. The results show that transfer learning might be effective in partially overcoming the domain shift.
CCT and Cullin1 regulate the TORC1 pathway to promote dendritic arborization in health and disease
Authors: Lottes Erin N. , Ciger Feyza H. , Bhattacharjee Shatabdi , Timmins-Wilde Emily A. , Tete Benoit , Tran Tommy , Matta Jais , Patel Atit A. , Cox Daniel N.
Published: August 2023

The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in homeostatic dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy inDrosophilaClass IV (CIV) multidendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1),in vitro.Through targeted genetic manipulations, we have confirmed that LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases dendritic complexity in CIV neurons. Both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus we examined CIV dendritic development in disease conditions as well. Expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by TORC1 disinhibition via Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through regulation of TORC1 in both health and disease.

SIGNIFICANCE

The insulin pathway has become an increasingly attractive target for researchers interested in understanding the intersection of metabolism and brain health. We have found connections between the insulin pathway and cytosolic protein maintenance in the development of neuronal dendrites. These pathways converge on the dendritic cytoskeleton, particularly microtubules. Neurons expressing mutant Huntingtin also show defects in dendritic development and the underlying cytoskeleton, and we find that disinhibition of the insulin pathway can rescue dendritic hypotrophy in these neurons. This work advances our understanding of the molecular interactions between the insulin pathway and neuronal development in both health and Huntington’s Disease conditions.
The G2phase controls binary division ofToxoplasma gondii
Authors: Hawkins Lauren M. , Wang Chengqi , Chaput Dale , Batra Mrinalini , Marsilia Clem , Awshah Danya , Suvorova Elena S.
Published: August 2023

Division of apicomplexan parasites differs drastically from the division of their host cells. A fraction of apicomplexans divides in the traditional binary mode, such asToxoplasma gondiiin asexual stages, whereas the vast majority instead divide in a multinuclear fashion. Such variety of replication modes and a dearth of conserved conventional regulators have hindered the progress of apicomplexan cell cycle studies. We previously identified five Cdk-related kinases (Crk) involved in endodyogenic division ofT. gondiitachyzoites. The current study investigates the roles of a novel essential cell cycle kinase TgCrk4. We identified this kinase cyclin partner and demonstrated that TgCrk4 regulates processes carried out during conventional G2phase, such as repression of chromosome rereplication and centrosome re-duplication. Accumulation of TgCyc4 in the nucleus and on the centrosomes supported the role of TgCrk4-TgCyc4 complex as a coordinator of chromosome and centrosome cycles inT. gondii. Examination of the TgCrk4-deficient tachyzoites confirmed a cell cycle stop prior to the TgCrk6-regulated spindle assembly checkpoint. Furthermore, we identified an ortholog of the DNA replication licensing factor Cdt1 that was a dominant interactor of the TgCrk4-TgCyc4 complex.T. gondiiCdt1 is highly divergent but preserved critical signature domains and appeared to play a minimal or no role in licensing DNA replication in G1phase. Functional analyses indicated the primary role of TgCdt1 is in controlling chromosome rereplication and centrosome reduplication. Global phosphoproteome analyses identified immediate TgCrk4 substrates, such as DNA replication licensing factor TgORC4, component of the anaphase-promoting complex TgCdc20, γ-tubulin nucleation factor TgGCP2, and the catalytic subunit of cell cycle phosphatase TgPP2ACA. Importantly, our phylogenetic and structural analyses revealed that the functional TgCrk4-TgCyc4 complex was encoded in the limited group of apicomplexans dividing in a binary fashion. Together with the minimal representation of binary division in Apicomplexa phylum, our findings support the novel view of apicomplexans acquiring binary division to repress ancestral multinuclear mechanisms.
Myogenetic Oligodeoxynucleotide Induces Myocardial Differentiation of Murine Pluripotent Stem Cells
Authors: Ishioka Mina , Nihashi Yuma , Sunagawa Yoichi , Umezawa Koji , Shimosato Takeshi , Kagami Hiroshi , Morimoto Tatsuya , Takaya Tomohide
Published: August 2023

An 18-base myogenetic oligodeoxynucleotide (myoDN), iSN04, acts an anti-nucleolin aptamer and induces myogenic differentiation of skeletal muscle myoblasts. This study investigated the effect of iSN04 on murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In the undifferentiated state, iSN04 inhibited the proliferation of ESCs and iPSCs but did not affect the expression of pluripotent markers. In the differentiating condition, iSN04 treatment of ESCs/iPSCs from day 5 onward dramatically induced the differentiation intoNkx2-5+beating cardiomyocytes with upregulation ofGata4, Isl1, andNkx2-5, whereas iSN04 treatment from earlier stages completely inhibited cardiomyogenesis. RNA sequencing revealed that iSN04 treatment from day 5 onward contributes to the generation of cardiac progenitors by modulating the Wnt signaling pathway. Immunostaining showed that iSN04 suppressed the cytoplasmic translocation of nucleolin and restricted it to the nucleoli. These results demonstrate that nucleolin inhibition by iSN04 facilitates the terminal differentiation of cardiac mesoderm into cardiomyocytes, but interferes with the differentiation of early mesoderm into the cardiac lineage. This is the first report on the generation of cardiomyocytes from pluripotent stem cells using a DNA aptamer. Since iSN04 did not induce hypertrophic responses in primary-cultured cardiomyocytes, iSN04 would be useful and safe for the regenerative therapy of heart failure using stem cell-derived cardiomyocytes.
Analytical code sharing practices in biomedical research
Authors: Sharma Nitesh Kumar , Ayyala Ram , Deshpande Dhrithi , Patel Yesha M , Munteanu Viorel , Ciorba Dumitru , Fiscutean Andrada , Vahed Mohammad , Sarkar Aditya , Guo Ruiwei , Moore Andrew , Darci-Maher Nicholas , Nogoy Nicole A , Abedalthagafi Malak S. , Mangul Serghei
Published: August 2023

Data-driven computational analysis is becoming increasingly important in biomedical research, as the amount of data being generated continues to grow. However, the lack of practices of sharing research outputs, such as data, source code and methods, affects transparency and reproducibility of studies, which are critical to the advancement of science. Many published studies are not reproducible due to insufficient documentation, code, and data being shared. We conducted a comprehensive analysis of 453 manuscripts published between 2016-2021 and found that 50.1% of them fail to share the analytical code. Even among those that did disclose their code, a vast majority failed to offer additional research outputs, such as data. Furthermore, only one in ten papers organized their code in a structured and reproducible manner. We discovered a significant association between the presence of code availability statements and increased code availability (p=2.71×10−9). Additionally, a greater proportion of studies conducting secondary analyses were inclined to share their code compared to those conducting primary analyses (p=1.15*10−07). In light of our findings, we propose raising awareness of code sharing practices and taking immediate steps to enhance code availability to improve reproducibility in biomedical research. By increasing transparency and reproducibility, we can promote scientific rigor, encourage collaboration, and accelerate scientific discoveries. We must prioritize open science practices, including sharing code, data, and other research products, to ensure that biomedical research can be replicated and built upon by others in the scientific community.
Niclosamide potentiates TMEM16A and induces vasoconstriction
Authors: Liang Pengfei , Wan Yui Chun S. , Yu Kuai , Hartzell H. Criss , Yang Huanghe
Published: August 2023

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering niclosamide as a TMEM16A inhibitor to treat diseases such as asthma, COPD, and hypertension. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation, shining light on developing specific TMEM16A modulators to treat human diseases.
A demand-based framework explains prioritization strategies upon transient limitations of different amino acids
Authors: Gupta Ritu , Adhikary Swagata , Dalpatraj Nidhi , Laxman Sunil
Published: August 2023

Cells require disparate amounts of distinct amino acids, which themselves have discrete biosynthetic costs. However, it remains unclear if and how cells respond differently to their scarcity. To explore this, we re-organized amino acids into distinct groups based on their metabolic origins. Subsequently, using yeast we assessed responses to transient disruptions in amino acid supply, and uncover diverse restoration responses for distinct amino acids. Cells hierarchically prioritize restoring glutamate-, sulfur-, pentose-phosphate- and pyruvate-derived amino acids. Particularly, the strongest response is to the glutamate-derived amino acid arginine. We find that the extent and priority of the restoration response is determined by the composite demand for an amino acid, coupled with low individual biosynthetic costs of that amino acid. We propose that cells employ a conserved strategy guided by the law of demand, to prioritize amino acids restoration upon transient limitation.
Chondroitin and dermatan sulfate exposure induces a wound healing state in fibroblasts through Cux1-mediated SerpinB2 transcriptional repression
Authors: Diaz-Pizarro Alba , Del Valle-Del Pino Nuria , Galán Enrique , Carvajal-González Jose María , Román Ángel-Carlos , Mulero-Navarro Sonia
Published: August 2023

Mucopolysaccharidoses (MPS) are a group of syndromes characterized by the accumulation of sulfated glycosaminoglycans (sGAGs), leading to profound connective tissue alterations, including impaired endochondral ossification. The function of sGAGs involves determining the mechanical properties of the extracellular matrix and regulating growth factor signaling pathways, such as Fgf2. In this study, we investigated the deposition of chondroitin sulfate and dermatan sulfate, two major sGAGs, and their resemblance to wound healing states in human fibroblasts. Our findings indicate that this condition alters cell adhesion, providing a potential explanation for fibrosis-like changes observed in MPS patients. Furthermore, we elucidate the molecular pathway responsible for this effect, wherein increased Cathepsin L activation leads to the processing of the transcription factor Cux1 into a stable form capable of regulating the expression of target genes, including SERPINB2. The presence of similar changes in cell adhesion in human-induced pluripotent stem cell-derived mesenchymal cells further reinforces the significance of sGAGs in cell adhesion and sheds light on possible mechanisms underlying altered endochondral ossification in MPS patients.