bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequence diversity of apidaecin-like peptides arresting the terminating ribosome
Authors: Huang Weiping , Baliga Chetana , Vázquez-Laslop Nora , Mankin Alexander S
Published: July 2024

The Proline-rich Antimicrobial Peptide (PrAMP) apidaecin (Api) inhibits translation by binding in the ribosomal nascent peptide exit tunnel, trapping release factors RF1 or RF2, and arresting ribosomes at stop codons. To explore the extent of sequence variations of the native 18-amino acid Api that allows it to preserve its activity, we screened a library of synthetic mutant Api genes expressed in bacterial cells, resulting in nearly 350000 peptide variants with multiple substitutions. By applying orthogonal negative and positive selection strategies, we identified a number of multi-substituted Api variants capable of arresting ribosomes at stop codons. Our findings underscore the critical contribution of specific amino acid residues of the peptide for its on-target function while significantly expanding the variety of PrAMPs acting on the terminating ribosome. Additionally, some of the tested synthesized multi-substituted Api variants exhibit improved antibacterial activity compared to that of the wild type PrAMP and may constitute the starting point to develop clinically useful antimicrobials.
End resection and telomere healing of DNA double-strand breaks during nematode programmed DNA elimination
Authors: Estrem Brandon , Davis Richard E , Wang Jianbin
Published: July 2024

Most DNA double-strand breaks (DSBs) are harmful to genome integrity. However, some forms of DSBs are essential to biological processes, such as meiotic recombination and V(D)J recombination. DSBs are also required for programmed DNA elimination (PDE) in ciliates and nematodes. In nematodes, the DSBs are healed with telomere addition. While telomere addition sites have been well characterized, little is known regarding the DSBs that fragment nematode chromosomes. Here, we used embryos from the human and pig parasitic nematode Ascaris to characterize the DSBs. Using END-seq, we demonstrate that DSBs are introduced before mitosis, followed by extensive end resection. The resection profile is unique for each break site, and the resection generates 3′-overhangs before the addition of neotelomeres. Interestingly, telomere healing occurs much more frequently on retained DSB ends than on eliminated ends. This biased repair of the DSB ends may be due to the sequestration of the eliminated DNA into micronuclei, preventing neotelomere formation at their ends. Additional DNA breaks occur within the eliminated DNA in both Ascaris and Parascaris, ensuring chromosomal breakage and providing a fail-safe mechanism for PDE. Overall, our data indicate that telomere healing of DSBs is specific to the break sites responsible for nematode PDE.
Neoadjuvant combination treatment with checkpoint inhibitors, chemotherapy, and BRAF/MEK inhibitors for BRAFV600E glioblastoma results in sustained response: A case report
Authors: Wagle Naveed , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Juarez Tiffany M , Kesari Santosh
Published: July 2024

Radiation’s confounding and adverse effects on tumor microenvironment and normal brain could potentially be delayed by upfront combination treatment. We present a patient with newly diagnosed BRAFV600E-mutant, PD-L1-positive glioblastoma treated with off-label RAF/MEK inhibitors encorafenib/binimetinib after progressing on postoperative immune checkpoint blockade and temozolomide (no radiation administered: NCT03425292). Complete response occurred 6 months after adding encorafenib/binimetinib, and clinical benefit was sustained for over 20 months. Treatment was well tolerated with manageable toxicities, with quality of life and cognitive function maintained throughout treatment. Adding encorafenib/binimetinib to immunotherapy and temozolomide conferred favorable and lasting efficacy for our BRAFV600E-mutant glioblastoma patient, justifying future studies.
Two pyridoxal phosphate homeostasis proteins are essential for management of the coenzyme pyridoxal 5′-phosphate in Arabidopsis
Authors: Farkas Peter , Fitzpatrick Teresa B
Published: July 2024

Coenzyme management is important for homeostasis of the pool of active metabolic enzymes. The coenzyme pyridoxal 5′-phosphate (PLP) is involved in diverse enzyme reactions including amino acid and hormone metabolism. Regulatory proteins that contribute to PLP homeostasis remain to be explored in plants. Here, we demonstrate the importance of proteins annotated as PLP homeostasis proteins (PLPHPs) for controlling PLP in Arabidopsis (Arabidopsis thaliana). A systematic analysis indicates that while most organisms across kingdoms have a single PLPHP homolog, Angiosperms have two. PLPHPs from Arabidopsis bind PLP and exist as monomers, in contrast to reported PLP-dependent enzymes, which exist as multimers. Disrupting the function of both PLPHP homologs perturbs vitamin B6 (pyridoxine) content, inducing a PLP deficit accompanied by light hypersensitive root growth, unlike PLP biosynthesis mutants. Micrografting studies show that the PLP deficit can be relieved distally between shoots and roots. Chemical treatments probing PLP-dependent reactions, notably those for auxin and ethylene, provide evidence that PLPHPs function in the dynamic management of PLP. Assays in vitro show that Arabidopsis PLPHP can coordinate PLP transfer and withdrawal from other enzymes. This study thus expands our knowledge of vitamin B6 biology and highlights the importance of PLP coenzyme homeostasis in plants.
Development of Movement and Postural Patterns in Full-Term Infants Who Are at Low Risk in Belgium, India, Norway, and the United States
Authors: Boswell Lynn , Adde Lars , Fjørtoft Toril , Pascal Aurelie , Russow Annemarie , Støen Ragnhild , Thomas Niranjan , Van den Broeck Christine , de Regnier Raye-Ann
Published: July 2024

Objective

The objective of this study was to investigate the influences on motor development in infants who are at low risk from Belgium, India, Norway, and the United States using the General Movement Assessment at 10–16 weeks postterm age.

Methods

This was a cross-sectional study of prospectively enrolled full-term infants at low risk (n = 186). Certified General Movement Assessment observers rated the fidgety movements, quality of the movement patterns, age-adequacy of the movement repertoire, postural patterns, movement character, and overall Motor Optimality Score–Revised (MOS-R). Scores were evaluated for associations with sex, birth weight category, gestational age, postterm age at video, and country.

Results

The majority of infants had normal fidgety movements (179/186, 96.2%). This did not vary by sex, birth weight, gestational age, postterm age at video, or country. All infants showed normal>atypical movement patterns. Variability was seen for age adequacy (optimal: 137/183, 74.9%), postural patterns (normal>atypical: 164/183, 89.6%), and smooth/ fluent movement character (138/183, 75.4%). Gestational age and postterm age at video were associated with atypical postural patterns, but in multivariable regression, only younger postterm age retained significance (OR = 2.94, 95% CI = 1.05–8.24). Lack of age adequacy was associated with postterm age (OR = 13.15, 95% CI = 4.36–39.72) and country (compared with Norway; Belgium OR = 3.38 95% CI = 12.4–9.22; India OR = 3.16, 95% CI = 1.01–9.87; United States not significant). Infants from India also showed lower rates of an optimal MOS-R (25–28) than infants from Norway.

Conclusion

The normality and temporal organization of fidgety movements did not differ by sex, birth weight, postterm age, or country, suggesting that the fidgety movements are free of cultural and environmental influences. The majority of full-term infants who were healthy in this cohort showed normal scores for all aspects of motor development tested using the MOS-R. Differences in age adequacy and MOS-R by country warrant investigation with larger cohorts and longitudinal follow-up.

Impact

Understanding variations in typical motor development is essential to interpreting patterns of movement and posture in infants at risk for atypical development. Using the framework of Prechtl’s General Movement Assessment, this study showed that the development of movement and posture in healthy infants was affected by age and country of birth, but the development of the fidgety movements appeared to be free of these influences. Local norms may be needed to interpret the Motor Optimality Score-Revised in all populations, but further research on this topic is needed.
Homotopy Theoretic Properties Of Open Books
Authors: Huang Ruizhi , Theriault Stephen
Published: July 2024

We study the homotopy groups of open books in terms of those of their pages and bindings. Under homotopy theoretic conditions on the monodromy we prove an integral decomposition result for the based loop space on an open book, and under more relaxed conditions we prove a rational loop space decomposition. The latter case allows for a rational dichotomy theorem for open books, as an extension of the classical dichotomy in rational homotopy theory. As a direct application, we show that for Milnor’s open book decomposition of an odd sphere with monodromy of finite order the induced action of the monodromy on the homology groups of its page cannot be nilpotent.
Behavioral Engagement and Activation Model Study (BEAMS): A latent class analysis of adopters and non-adopters of digital health technologies among people with Type 2 diabetes
Authors: Piette John D , Lee Keni C S , Bosworth Hayden B , Isaacs Diana , Cerrada Christian J , Kainkaryam Raghu , Liska Jan , Lee Felix , Kennedy Adee , Kerr David
Published: July 2024

Many people with Type 2 diabetes (T2D) who could benefit from digital health technologies (DHTs) are either not using DHTs or do use them, but not for long enough to reach their behavioral or metabolic goals. We aimed to identify subgroups within DHT adopters and non-adopters and describe their unique profiles to better understand the type of tailored support needed to promote effective and sustained DHT use across a diverse T2D population. We conducted latent class analysis of a sample of adults with T2D who responded to an internet survey between December 2021 and March 2022. We describe the clinical and psychological characteristics of DHT adopters and non-adopters, and their attitudes toward DHTs. A total of 633 individuals were characterized as either DHT “Adopters” (n = 376 reporting any use of DHT) or “Non-Adopters” (n = 257 reporting never using any DHT). Within Adopters, three subgroups were identified: 21% (79/376) were “Self-managing Adopters,” who reported high health activation and self-efficacy for diabetes management, 42% (158/376) were “Activated Adopters with dropout risk,” and 37% (139/376) were “Non-Activated Adopters with dropout risk.” The latter two subgroups reported barriers to using DHTs and lower rates of intended future use. Within Non-Adopters, two subgroups were identified: 31% (79/257) were “Activated Non-Adopters,” and 69% (178/257) were “Non-Adopters with barriers,” and were similarly distinguished by health activation and barriers to using DHTs. Beyond demographic characteristics, psychological, and clinical factors may help identify different subgroups of Adopters and Non-Adopters.
Benefits of using both the Hunger Vital Sign and brief nutrition security screener in health-related social needs screening
Authors: Calloway Eric E , Coakley Kathryn E , Carpenter Leah R , Gargano Tony , Yaroch Amy L
Published: July 2024

Food security is a commonly screened for health-related social need at hospitals and community settings, and until recently, there were no tools to additionally screen for nutrition security. The purpose of this study was to assess the potential advantage of including a one-item brief nutrition security screener (BNSS) alongside the commonly used two-item Hunger Vital Sign (HVS) food security screener for identifying individuals with diet-related health risks. Cross-sectional survey data were collected from April to June 2021. Generalized linear mixed models were used to assess associations between screening status and dietary and health variables. Recruitment was done across five states (California, Florida, Maryland, North Carolina, and Washington) from community-based organizations. Participants (n = 435) were, on average, 44.7 years old (SD = 14.5), predominantly women (77%), and racially/ethnically diverse. In adjusted analyses, being in the food insecure and nutrition insecure group (but not the food insecure and nutrition secure or food secure and nutrition insecure groups) was associated with significantly increased odds for self-reported “fair” or “poor” general health [OR = 2.914 (95% CI = 1.521–5.581)], reporting at least one chronic condition [2.028 (1.024–4.018)], and “low” fruit and vegetable intake [2.421 (1.258–4.660)], compared with the food secure and nutrition secure group. These findings support using both the HVS and BNSS simultaneously in health-related social needs screening to identify participants at the highest risk for poor dietary and health outcomes and warrant further investigation into applying these screeners to clinical and community settings.
Turbulence in Indian aviation financing sector: time to understand and implement the Cape Town regime in the true spirit
Authors: Bhat B. Sandeepa
Published: July 2024

India, being a vast country with middle-income population, requires speedy and economic means of transportation for connecting its different parts. With rail and road transportation not having immense success in providing speedy means of transportation, aviation connectivity is of prime importance to India. Unfortunately, the Indian aviation sector is having a disastrous run over the years with several big players ending up in bankruptcy. Added to this, several Indian laws stand as impediments to enforcing the rights of financiers in the aviation sector. Accordingly, the financiers are not willing to take the risk of investing in the Indian aviation sector. This issue has been continuing even after India has become a party to the Cape Town regime relating to aviation financing in 2008. The failure to implement the Cape Town regime is the chief reason for continued turbulence in Indian aviation financing. Hence, a probe into the Cape Town regime relating to aviation financing with a view to implement it in the true spirit attains great significance in India.
Balanced Business Decision-making for Clinical Practices: Fulfilling “Mission” and “Margin”
Authors: Chandawarkar Rajiv , Nadkarni Prakash
Published: July 2024

Clinical practices, both private and academic, need to be profitable to sustain themselves and grow. To manage them and drive profits, one needs leadership that has a well-rounded understanding of multiple facets. When business decisions are based on financial data alone, they meet the goal of profit margin but alienate clinicians; when made using clinical data alone, they fulfill the clinical mission but ignore the bottom line. Here, we explain the benefits of a sound business-minded leadership that integrates the nuances of financial data, the cadence of clinical practices, and the value of resources, and makes meaningful business decisions. These decisions create a strong bond between physicians and their administrative leaders, aligning their “mission” (provide better care), and their “margin” (profitability and growth). We explain critical aspects of each source of information and how to use them together to make business decisions. Recognizing that clinicians may not have access to methods of financial analysis, we also supply a prepopulated Excel spreadsheet that has all equations baked in, so that it can be readily used, filling in their own data to generate financial ratios. This work explains how sound decisions can be made using financial metrics, clinical data (here, plastic surgery), and resource utilization, to identify areas that can be improved and take steps to achieve results.
Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors
Authors: Kent Deniz , Ng Soon Seng , Syanda Adam M. , Khoshkenar Payam , Ronzoni Riccardo , Li Chao Zheng , Zieger Marina , Greer Cindy , Hatch Stephanie , Segal Joe , Blackford Samuel J.I. , Im Yu Ri , Chowdary Vivek , Ismaili Taylor , Danovi Davide , Lewis Patrick A. , Irving James A. , Sahdeo Sunil , Lomas David A. , Ebner Daniel , Mueller Christian , Rashid S. Tamir
Published: July 2024

Background:

Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 “Z” genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease.

Methods:

We conducted a high-throughput image-based small molecule screen using patient-derived induced pluripotent stem cell-hepatocytes (iPSC-hepatocytes). Identified targets were validated in vitro using 3 independent patient iPSC lines. The effects of the identified target, leucine-rich repeat kinase 2 (LRRK2), were further evaluated in an animal model of A1ATD through histology and immunohistochemistry and in an autophagy-reporter line. Autophagy induction was assessed through immunoblot and immunofluorescence analyses.

Results:

Small-molecule screen performed in iPSC-hepatocytes identified LRRK2 as a potentially new therapeutic target. Of the commercially available LRRK2 inhibitors tested, we identified CZC-25146, a candidate with favorable pharmacokinetic properties, as capable of reducing polymer load, increasing normal AAT secretion, and reducing inflammatory cytokines in both cells and PiZ mice. Mechanistically, this effect was achieved through the induction of autophagy.

Conclusions:

Our findings support the use of CZC-25146 and leucine-rich repeat kinase-2 inhibitors in hepatic proteinopathy research and their further investigation as novel therapeutic candidates for A1ATD.
Amplifying Chinese physicians’ emphasis on patients’ psychological states beyond urologic diagnoses with ChatGPT – a multicenter cross-sectional study
Authors: Peng Lei , Liang Rui , Zhao Anguo , Sun Ruonan , Yi Fulin , Zhong Jianye , Li Rongkang , Zhu Shimao , Zhang Shaohua , Wu Song
Published: July 2024

Background:

Artificial intelligence (AI) technologies, particularly large language models (LLMs), have been widely employed by the medical community. In addressing the intricacies of urology, ChatGPT offers a novel possibility to aid in clinical decision-making. This study aimed to investigate the decision-making ability of LLMs in solving complex urology-related problems and assess their effectiveness in providing psychological support to patients with urological disorders.

Materials and methods:

This study evaluated the clinical and psychological support capabilities of ChatGPT 3.5 and 4.0 in the field of urology. A total of 69 clinical and 30 psychological questions were posed to the AI models, and both urologists and psychologists evaluated their response. As a control, clinicians from Chinese medical institutions responded to closed-book conditions. Statistical analyses were conducted separately for each subgroup.

Results:

In multiple-choice tests covering diverse urological topics, ChatGPT 4.0 was performed comparably to the physician group, with no significant overall score difference. Subgroup analyses revealed variable performance based on disease type and physician experience, with ChatGPT 4.0 generally outperforming ChatGPT 3.5 and exhibiting competitive results against physicians. When assessing the psychological support capabilities of AI, it is evident that ChatGPT 4.0 outperforms ChatGPT 3.5 across all urology-related psychological problems.

Conclusions:

The performance of LLMs in dealing with standardized clinical problems and providing psychological support has certain advantages over clinicians. AI stands out as a promising tool for potential clinical aid.
Experiences of Black Women With Pelvic Floor Disorders—A Qualitative Analysis Study
Authors: Chyu Jennifer , Alimi Oriyomi , Popat Shreeya , Smith-Mathus Gjanje , Lee Una J.
Published: July 2024

Importance

Disparities research in Black women with pelvic floor disorders (PFDs) has primarily focused on epidemiology or surgical outcomes, but little is known about the patient perspective on seeking PFD care.

Objective

To provide quality and equitable care to Black women with PFDs, we conducted a qualitative study to hear their perspectives and lived health care experiences.

Study Design

Black women seeking care for PFDs at a tertiary care institution were invited to participate in qualitative interviews. Open-ended questions explored participants’ knowledge, attitudes, and health care experiences. Interviews were transcribed verbatim and coded line-by-line. Inductive content analysis was performed to identify key themes, and consensus was achieved among the research team.

Results

Eight Black women aged 21–83 years consented to participate. Patients noted a stigma surrounding PFDs, both among health care professionals and their community. They noted several barriers to care: financial, logistical, and racial bias. They cited difficulties in patient–health care professional communication, including not feeling heard or treated as an individual. They preferred gender and racial concordance with their physicians. These women expressed both a desire for more knowledge and to share this knowledge and advocate for other women.

Conclusions

Black women expressed distinct obstacles in their PFD health care. They reported not feeling heard or treated as a unique individual. The themes derived from this study identify complex patient-centered needs that can serve as the basis for future quality improvement work and/or hypothesis-driven research. By grounding health disparities research in patient perspectives, we can improve the health care experiences of Black women.
Measurement of Physical Activity Using Fitness Trackers Before and After Midurethral Sling
Authors: Cope Zebulun S. , Stewart J Ryan , Gupta Ankita , Hobson Deslyn T.G. , Warehime Jenna , Feroz Rehan , Scheidel Sarah , Meriwether Kate V. , Lenger Stacy M. , Gaskins Jeremy T. , Sumy Sharmin , Francis Sean
Published: July 2024

Importance

Urinary incontinence can be a barrier to performing physical activities for many women. A midurethral sling (MUS) has shown symptom improvement for women experiencing stress urinary incontinence (SUI), suggesting the hypothesis that physical activity rates should increase after treatment.

Objective

The aim of this study was to determine the change in objectively measured physical activity levels in women following placement of MUS for SUI.

Study Design

In this prospective cohort study, patients undergoing MUS placement, with or without concomitant pelvic reconstructive surgery, were provided a commercial activity tracker. Physical activity was tracked for at least 1 week preoperatively and up to 6 months postoperatively. Participants were required to wear the tracker for at least 2 weeks in the postoperative period. The primary outcome, mean caloric daily expenditure (MCDE), was compared preoperatively and postoperatively.

Results

Seventy-two patients met criteria for data inclusion. The device was worn for a mean of 18.4 ± 12.1 days preoperatively and 91.7 ± 53.3 days postoperatively. Mean participant age was 51.9 ± 9.4 years. The MCDE was significantly higher postoperatively (preoperatively: 1,673 kcal/d vs postoperatively: 2,018 kcal/d; P < 0.01). There were no significant differences in postoperative MCDE in participants who had only MUS as the primary procedure versus participants who also had a concomitant procedure (2,020 ± 216 kcal/d vs 2,015 ± 431 kcal/d; P = 0.95). Of participants with class II/III obesity, 45% had at least a 500 kcal/d increase postoperatively.

Conclusions

Treatment of SUI with MUS is associated with a significantly greater caloric expenditure in the postoperative period.
A model of marmoset monkey vocal turn-taking
Authors: Grijseels Dori M. , Fairbank Daniella A. , Miller Cory T.
Published: July 2024

Vocal turn-taking has been described in a diversity of species. Yet, a model that is able to capture the various processes underlying this social behaviour across species has not been developed. To this end, here we recorded a large and diverse dataset of marmoset monkey vocal behaviour in social contexts comprising one, two and three callers and developed a model to determine the keystone factors that affect the dynamics of these natural communicative interactions. Notably, marmoset turn-taking did not abide by coupled-oscillator dynamics, but rather call timing was overwhelmingly stochastic in these exchanges. Our features-based model revealed four key factors that encapsulate the majority of patterns evident in the behaviour, ranging from internal processes, such as particular states of the individual driving increased calling, to social context-driven suppression of calling. These findings indicate that marmoset vocal turn-taking is affected by a broader suite of mechanisms than previously considered and that our model provides a predictive framework with which to further explicate this natural behaviour at both the behavioural and neurobiological levels, and for direct comparisons with the analogous behaviour in other species.
Sexually antagonistic coevolution of the male nuptial gift and female feeding behaviour in decorated crickets
Authors: Burns-Dunn Samuel , Mortys Tassie , House Clarissa M. , Mitchell Christopher , Duffield Kristin R. , Foquet Bert , Sadd Ben M. , Sakaluk Scott K. , Hunt John
Published: July 2024

The evolution of nuptial gifts has traditionally been considered a harmonious affair, providing benefits to both mating partners. There is growing evidence, however, that receiving a nuptial gift can be actively detrimental to the female. In decorated crickets (
Gryllodes sigillatus
), males produce a gelatinous spermatophylax that enhances sperm transfer but provides little nutritional benefit and hinders female post-copulatory mate choice. Here, we examine the sexually antagonistic coevolution of the spermatophylax and the female feeding response to this gift in
G. sigillatus
maintained in experimental populations with either a male-biased or female-biased adult sex ratio. After 25 generations, males evolving in male-biased populations produced heavier spermatophylaxes with a more manipulative combination of free amino acids than those evolving in female-biased populations. Moreover, when the spermatophylax originated from the same selection regime, females evolving in male-biased populations always had shorter feeding durations than those evolving in female-biased populations, indicating the evolution of greater resistance. Across populations, female feeding duration increased with the mass and manipulative combination of free amino acids in the spermatophylax, suggesting sexually antagonistic coevolution. Collectively, our work demonstrates a key role for interlocus sexual conflict and sexually antagonistic coevolution in the mating system of
G. sigillatus
.
Giants’ cooperation: a draft genome of the giant ciliate Muniziella cunhai suggests its ecological role in the capybara’s digestive metabolism
Authors: Cedrola Franciane , Senra Marcus Vinicius Xavier , Morales Millke Jasmine Arminini , Fregulia Priscila , Canesin Lucas , Dias Roberto Júnio Pedroso , Solferini Vera Nisaka
Published: July 2024

Several hundred ciliate species live in animals’ guts as a part of their microbiome. Among them, Muniziella cunhai (Trichostomatia, Pycnotrichidae), the largest described ciliate, is found exclusively associated with Hydrochoerus hydrochaeris (capybara), the largest known rodent reaching up to 90 kg. Here, we present the sequence, structural and functional annotation of this giant microeukaryote macronuclear genome and discuss its phylogenetic placement. The 85 Mb genome is highly AT rich (GC content 25.71 %) and encodes a total of 11 397 protein-coding genes, of which 2793 could have their functions predicted with automated functional assignments. Functional annotation showed that M. cunhai can digest recalcitrant structural carbohydrates, non-structural carbohydrates, and microbial cell walls, suggesting a role in diet metabolization and in microbial population control in the capybara’s intestine. Moreover, the phylogenetic placement of M. cunhai provides insights on the origins of gigantism in the subclass Trichostomatia.
Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer’s disease
Authors: Sonsalla Michelle M. , Babygirija Reji , Johnson Madeline , Cai Samuel , Cole Mari , Yeh Chung-Yang , Grunow Isaac , Liu Yang , Vertein Diana , Calubag Mariah F. , Trautman Michaela E. , Green Cara L. , Rigby Michael J. , Puglielli Luigi , Lamming Dudley W.
Published: July 2024

Age is the greatest risk factor for Alzheimer’s disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.
Large-Scale Comparative Transcriptomic Analysis of CHO Cell Functional Adaptation to Recombinant Monoclonal Antibody Production
Authors: Alexandru-Crivac Cristina N. , Cartwright Joseph F. , Taylor Ryan , Sweeney Bernadette M. , Feary Marc , Chathoth Keerthi T. , Fabian Daniel K. , Allsopp Harry , Brown Adam J. , James David C.
Published: July 2024

To comparatively evaluate cellular constraints on recombinant monoclonal antibody (mAb) production by Chinese Hamster Ovary (CHO) cells, we analysed the transcriptomes of 24 clonally derived CHO cell lines engineered with PiggyBac transposon technology to stably produce four recombinant monoclonal antibodies (mAbs) at varying specific production rates. Fed-batch cultures were sampled at exponential (day 5) and stationary (day 10) phases of culture for analysis by RNA-Seq. Recombinant mRNAs accounted for a large proportion of total mRNA across all clones, and efficient use of heavy chain (HC) mRNA to synthesise recombinant mAb (qP per HC mRNA) varied significantly with respect to both mAb product and cell line. Comparative bioinformatic analyses of CHO transcriptomes focussed on mAb specific production rate and utilised both data-driven and hypothesis-led approaches, specifically (i) production or non-production of recombinant mAb, (ii) changes in the abundance of functional groups of mRNAs abundance with mAb specific production rate and (iii) comparative analysis of informatically-mined gene subsets associated with cellular functions hypothesised to impact recombinant mAb synthesis and secretion. These analyses revealed widespread constitutive and adaptive changes in mRNA abundance associated with mAb production across a variety of cellular functions. Typically, most mechanistically consistent changes in mRNA abundance co-varying with mAb production were evident at the stationary phase sample point. These data revealed both recombinant mAb-specific limitations on cellular synthetic capacity and a generic adaptive strategy used by CHO cells to support high-level mAb production. The latter was achieved by directed and permissive regulation of endoplasmic reticulum and other processes to accommodate increased synthetic flux.
Optimizing Genetic Testing Strategy for Suspected Attenuated Adenomatous Polyposis: Effective Solutions in Public Health Systems
Authors: García-Simón Natalia , Valentín Fátima , Royuela Ana , Hidalgo-Calero Beatriz , Blázquez-Martín Ricardo , de-Miguel-Reyes Montserrat , Sánchez-Zapardiel José M , Adán-Merino Luisa , Rodríguez-Festa Alejandro , Gallego-Gil Patricia , Mediavilla-Medel Pilar , Quiñonero-Moreno Laura , Gutiérrez Lourdes , Herreros-de-Tejada Alberto , Sánchez Antonio , Provencio Mariano , Romero Atocha
Published: July 2024

BACKGROUND

Attenuated familial adenomatous polyposis (AFAP) and MUTYH-associated polyposis (MAP) represent key hereditary attenuated adenomatous polyposis syndromes, withAPCandMUTYHbeing the associated genes. While guidelines recommend genetic testing based on polyp count for diagnosing these syndromes, age is often overlooked despite its influence on polyp prevalence.

AIM

To enhance genetic testing strategies for suspected attenuated adenomatous polyposis by combining polyp count and age in a probability calculator.

METHODS

Retrospective study of adult patients referred to NGS genetic testing for suspected attenuated adenomatous polyposis (accumulated history of <100 adenomas) (discovery cohort, N=138). Data collected included age, adenoma count at the time of genetic testing, and test results. Multivariable logistic regression model was developed to link a positive genetic test result with age and adenoma count. The model was externally validated with populations from two tertiary hospitals in our region (validation cohort, N=259).

RESULTS

In the discovery cohort, 13 (9.4%) patients tested positive for pathogenic mutations. Positive cases were younger (odds ratio (OR): 0.91, 95% confidence interval (95%IC): 0.86-0.96) and developed more adenomas (OR: 1.08, 95%IC: 1.04-1.13) compared to negative cases. The logistic regression model combining age and polyp count demonstrated an AUC of 0.92. Using a cutoff probability of 3.5%, the model achieved 100% sensitivity and 58% specificity in identifying positive cases. In the external validation, the model accurately predicted 14 out of 16 positive cases (88%). The remaining two positive cases were a patient with anAXIN2mutation in heterozygosis, and a patient with aNTHL1mutation in homozygosis. Performance evaluation of both hospitals yielded AUC values of 0.77 and 0.90.

CONCLUSIONS

Older individuals, particularly those with few polyps, may have diminished chances of detecting hereditary syndromes. Incorporating age as a criterion for genetic testing referral has the potential to refine patient selection and improve cost-effectiveness.

Core tip

This retrospective muli-center observational study aims to investigate the weight of age and polyp count on patients diagnosed with hereditary attenuated adenomatous polyposis syndrome compared to those with sporadic polyposis. Base on this, a probability calculator has been developed to enhance the efficiency and cost-effectiveness of genetic testing protocols for attenuated adenomatous polyposis syndromes within public health systems.
CARDIOGENIC SHOCK MORTALITY ACCORDING TO AETIOLOGY IN A MEDITERRANEAN COHORT: RESULTS FROM THE SHOCK-CAT STUDY
Authors: García-García Cosme , López-Sobrino Teresa , Sanz-Girgas Esther , Cueto Maria Ruiz , Aboal Jaime , Pastor Pablo , Buera Irene , Sionis Alessandro , Andrea Rut- , Rodríguez-López Judit , Sánchez-Salado JC , Querol Carlos Tomas , Bañeras Jordi , Sole Albert Ariza , Lupón Josep , Bayés-Genís Antoni , Rueda Ferran
Published: July 2024

Background and objectives

Mortality in cardiogenic shock (CS) remains elevated, with the potential for CS causes to impact prognosis and risk stratification. The aim was to investigate in-hospital prognosis and mortality in CS patients according to aetiology. We also assessed the prognostic accuracy of CardShock and IABP-SHOCK II scores.

Methods

Shock-CAT study was a multicentre, prospective, observational study conducted from December 2018-November 2019 in eight University hospitals in Catalonia, including non-selected consecutive CS patients. Data on clinical presentation, management, including mechanical circulatory support (MCS) were analysed comparing acute myocardial infarction (AMI) related CS and non-AMI-CS. The accuracy of CardShock and IABP-SHOCK II scores to assess 90-days mortality risk were also compared.

Results

A total of 382 CS patients were included, age 65.3 (SD 13.9) years, 75.1% men. Patients were classified as AMI-CS (n=232, 60.7%) and non-AMI-CS (n=150, 39.3%). In the AMI-CS group, 77.6% were STEMI. Main aetiologies for non-AMI-CS were heart failure (36.2%), arrhythmias (22.1%) and valve disease (8.0%). AMI-CS patients required more MCS than non-AMI-CS (43.1% vs 16.7%, p<0.001). In-hospital mortality was higher in AMI-CS (37.1 vs 26.7%, p=0.035), with a two-fold increased risk after multivariate adjustment (OR 2.24, p=0.019). The IABP-SHOCK II had superior discrimination for predicting 90-days mortality when compared with CardShock in AMI-CS patients (AUC 0.74 vs 0.66, p=0.047) although both scores performed similarly in non-AMI-CS (AUC 0.64 vs 0.62, p=0.693).

Conclusions

In our cohort, AMI-CS mortality was increased by two-fold when compared to non- AMI-CS. IABP-SHOCK II score provides better 90-days mortality risk prediction than CardShock score in AMI-CS, but both scores performed similar in non-AMI-CS patients.
High feasibility of salivary therapeutic drug monitoring in linezolid, but less in tedizolid: A single-dose study in healthy subjects
Authors: Kawasuji Hitoshi , Tsuji Yasuhiro , Miyaki Keiko , Aoyama Takahiko , Kurosaki Fumihiro , Ezaki Masayoshi , Koshiyama Yuki , Takegoshi Yusuke , Kaneda Makito , Murai Yushi , Kimoto Kou , Nagaoka Kentaro , Yamamoto Yoshihiro
Published: July 2024

Background

Salivary therapeutic drug monitoring (TDM) offers the potential to reduce the risks, burden, time, and costs of blood-based TDM, but its feasibility in oxazolidinone antibiotics and the influence of food intake remain unknown.

Methods

A total of 12 healthy volunteers participated in this study. Linezolid and tedizolid were intravenously administered to 6 participants each. Saliva samples were taken at 15 time points and peripheral venous blood samples were also taken at 12 time points simultaneously with saliva. Total and unbound serum and saliva concentrations of linezolid and tedizolid were measured using high-performance liquid chromatography.

Results

Individual concentration–time curves in saliva versus serum (total and unbound) were similar in linezolid, but different in tedizolid. Saliva concentrations were significantly correlated with total and unbound serum concentrations in both agents. However, concentrations in each case and area under the concentration–time curve from 0 to 10 h (AUC0–10) in saliva were correlated with those in total or unbound serum for linezolid, but not for tedizolid. The mean saliva-to-serum (total and unbound) concentration and AUC0–10ratios were 0.90 and 0.90 in total and 1.09 and 0.99 in unbound. Food intake did not influence these correlations in linezolid.

Conclusions

The analysis of linezolid in saliva is applicable for TDM as a promising alternative to conventional serum sampling without correlation factors, but application of tedizolid is less feasible. Easy sampling using a noninvasive technique may facilitate TDM even in underdeveloped countries with limited resources and specific patient categories.
MeCP2 Interacts with the Super Elongation Complex to Regulate Transcription
Authors: Sonn Jun Young , Kim Wonho , Iwanaszko Marta , Aoi Yuki , Li Yan , Parkitny Luke , Brissette Janice L. , Weiner Lorin , Al-Ramahi Ismael , Botas Juan , Shilatifard Ali , Zoghbi Huda Y.
Published: July 2024

Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome, a postnatal neurodevelopmental disorder that occurs in ∼1/10,000 live female births. MeCP2 binds to methylated cytosines across genomic DNA and recruits various partners to regulate gene expression. MeCP2 has been shown to repress transcriptionin vitroand interacts with co-repressors such as the Sin3A and NCoR complexes. Based on these observations, MeCP2 has been largely considered as a repressor of transcription. However, a mouse model of RTT displays many down-regulated genes, and those same genes are up-regulated in aMECP2duplication mouse model. Furthermore, TCF20, which has been associated with transcriptional activation, have recently been identified as a protein interactor of MeCP2. These data broaden the potential functions of MeCP2 as a regulator of gene expression. Yet, the molecular mechanisms underlying MeCP2-dependent gene regulation remain largely unknown. Here, using a humanMECP2gain-of-functionDrosophilamodel, we screened for genetic modifiers ofMECP2-induced phenotypes. Our approach identified several subunits of theDrosophilasuper elongation complex, a P-TEFb containing RNA polymerase II (RNA pol II) elongation factor required for the release of promoter-proximally paused RNA pol II, as genetic interactors ofMECP2. We discovered that MeCP2 physically interacts with the SEC in human cells and in the mouse brain. Furthermore, we found that MeCP2 directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Finally, loss of MeCP2 in the mouse cortex caused reduced binding of AFF4 specifically on a subset of genes involved in the regulation of synaptic function, which also displayed the strongest decrease in RNA pol II binding in the genebody. Taken together, our study reveals a previously unrecognized mechanism through which MeCP2 regulates transcription, providing a new dimension to its regulatory role in gene expression.
Evaluating Swiss growth reference curves: A comparative analysis in Zurich schoolchildren
Authors: Leuenberger Lorenz M. , Belle Fabiën N. , Mozun Rebeca , Spycher Ben D. , Mallet Maria C. , Jenni Oskar G. , Saner Christoph , Latzin Philipp , Moeller Alexander , Kuehni Claudia E.
Published: July 2024

INTRODUCTION

Switzerland has an ongoing debate about the appropriateness of national growth reference curves. The Swiss Society of Pediatrics currently recommends the growth references of the World Health Organization (WHO), while the Center for Pediatric Endocrinology Zurich has proposed alternative growth references based on local data. Specialists and researchers also use International Obesity Task Force (IOTF) references to define overweight and obesity. We investigated the fit of these three growth references to anthropometric measurements from schoolchildren in the canton of Zurich and assessed the prevalence of overweight, obesity, and short stature across the three references.

METHODS

We analyzed data from 3755 children aged 6-17 years of the cross sectional LuftiBus in the school (LUIS) study, collected between 2013-2016 in the canton of Zurich. We calculated z-scores of height, weight, and body mass index (BMI) based on WHO, local, and IOTF references. We compared the mean and distribution of z-scores to the expected standard normal distribution using the Anderson-Darling test. We classified BMI based on cutoff values given by the three references: overweight (WHO: >90.0thpercentile; local: >82.9[girls], >78.9[boys]; IOTF: >89.3[girls], >90.5[boys]), and obesity (WHO: >97.0; local: >96.8[girls], >95.5[boys]; IOTF: >98.6[girls], >98.9[boys]). We defined short stature as <3rdpercentile of height-for-age.

RESULTS

The mean z-scores in LUIS were 0.56 for height, 0.28 for weight, and 0.06 for BMI based on WHO references; 0.15 for height, 0.06 for weight, and -0.01 for BMI based on local references; and 0.19 for BMI based on IOTF references. WHO references provided a worse fit to the LUIS children than local references. Anderson-Darling goodness of fit A2was 578.1 (WHO) vs. 48.1 (local) for height and 124.0 vs. 10.0 for weight, with lower values indicating better fit. WHO (A2: 24.3) and local references (A2: 0.8) fit the BMI of LUIS children better than IOTF (A2: 64.1). The WHO classified fewer children as overweight than the local and IOTF references (WHO: 9% vs. local: 15% vs. IOTF: 13%) but more children as obese (6% vs. 4% vs. 3%). The WHO defined fewer children as being of short stature than the local references (1% vs. 3%).

CONCLUSIONS

Our findings suggest that anthropometric data of schoolchildren in Zurich differ notably from WHO and IOTF references potentially leading to misclassification of overweight, obesity, and short stature. Nationally representative and longitudinally collected data are needed to develop new Swiss growth references.
Dynamics of positional information in the vertebrate neural tube
Authors: Marković Anđela , Briscoe James , Page Karen M
Published: July 2024

In developing embryos, cells acquire distinct identities depending on their position in a tissue. Secreted signaling molecules, known as morphogens, act as long-range cues to provide the spatial information that controls these cell fate decisions. In several tissues, both the level and the duration of morphogen signaling appear to be important for determining cell fates. This is the case in the forming vertebrate nervous system where antiparallel morphogen gradients pattern the dorsal-ventral axis by partitioning the tissue into sharply delineated domains of molecularly distinct neural progenitors. How information in the gradients is decoded to generate precisely positioned boundaries of gene expression remains an open question. Here, we adopt tools from information theory to quantify the positional information in the neural tube and investigate how temporal changes in signaling could influence positional precision. The results reveal that the use of signaling dynamics, as well as the signaling level, substantially increases the precision possible for the estimation of position from morphogen gradients. This analysis links the dynamics of opposing morphogen gradients with precise pattern formation and provides an explanation for why time is used to impart positional information.
Genome-wide relaxation of selection and the evolution of the island syndrome in Orkney voles
Authors: Wang Xuejing , Heckel Gerald
Published: July 2024

Island populations often experience different ecological and demographic conditions than their counterparts on the continent, resulting in divergent evolutionary forces affecting their genomes. Random genetic drift and selection both may leave their imprints on island populations, although the relative impact depends strongly on the specific conditions. Here we address their contributions to the island syndrome in a rodent with an unusually clear history of isolation. Common voles (Microtus arvalis) were introduced by humans on the Orkney archipelago north of Scotland >5000 years ago and rapidly evolved to exceptionally large size. Our analyses show that the genomes of Orkney voles were dominated by genetic drift, with extremely low diversity, variable Tajima'sD, and very high divergence from continental conspecifics. IncreaseddN/dSratios over a wide range of genes in Orkney voles indicated genome-wide relaxation of purifying selection. We found evidence of hard sweeps on key genes of the lipid metabolism pathway only in continental voles. The marked increase of body size in Orkney—a typical phenomenon of the island syndrome—may thus be associated to the relaxation of positive selection on genes related to this pathway. On the other hand, a hard sweep on immune genes of Orkney voles likely reflects the divergent ecological conditions and possibly the history of human introduction. The long-term isolated Orkney voles show that adaptive changes may still impact the evolutionary trajectories of such populations despite the pervasive consequences of genetic drift at the genome level.