bluuebunny/crossref_metadata_2025 huggingface dataset:
Facility-Based Indicators to Manage and Scale Up Cervical Cancer Prevention and Care Services for Women Living With HIV in Sub-Saharan Africa: a Three-Round Online Delphi Consensus Method
Authors: Davidović Maša , Asangbeh Serra Lem , Taghavi Katayoun , Dhokotera Tafadzwa , Jaquet Antoine , Musick Beverly , Van Schalkwyk Cari , Schwappach David , Rohner Eliane , Murenzi Gad , Wools-Kaloustian Kara , Anastos Kathryn , Omenge Orang'o Elkanah , Boni Simon Pierre , Duda Stephany N. , von Groote Per , Bohlius Julia ,   on behalf of the International Epidemiology Databases to Evaluate AIDS
Published: January 2024

Background:

Of women with cervical cancer (CC) and HIV, 85% live in sub-Saharan Africa, where 21% of all CC cases are attributable to HIV infection. We aimed to generate internationally acceptable facility-based indicators to monitor and guide scale up of CC prevention and care services offered on-site or off-site by HIV clinics.

Methods:

We reviewed the literature and extracted relevant indicators, grouping them into domains along the CC control continuum. From February 2021 to March 2022, we conducted a three-round, online Delphi process to reach consensus on indicators. We invited 106 experts to participate. Through an anonymous, iterative process, participants adapted the indicators to their context (round 1), then rated them for 5 criteria on a 5-point Likert-type scale (rounds 2 and 3) and then ranked their importance (round 3).

Results:

We reviewed 39 policies from 21 African countries and 7 from international organizations; 72 experts from 15 sub-Saharan Africa countries or international organizations participated in our Delphi process. Response rates were 34% in round 1, 40% in round 2, and 44% in round 3. Experts reached consensus for 17 indicators in the following domains: primary prevention (human papillomavirus prevention, n = 2), secondary prevention (screening, triage, treatment of precancerous lesions, n = 11), tertiary prevention (CC diagnosis and care, n = 2), and long-term impact of the program and linkage to HIV service (n = 2).

Conclusion:

We recommend that HIV clinics that offer CC control services in sub-Saharan Africa implement the 17 indicators stepwise and adapt them to context to improve monitoring along the CC control cascade.
The PAncreatic Surgery Composite Endpoint (PACE)
Authors: Nickel Felix , Kuemmerli Christoph , Müller Philip C. , Schmidt Mona W. , Schmidt Leon P. , Wise Philipp , Klotz Rosa , Tjaden Christine , Diener Markus , Probst Pascal , Hackert Thilo , Büchler Markus W.
Published: January 2024

Objective:

To provide a composite endpoint in pancreatic surgery.

Background:

Single endpoints in prospective and randomized studies have become impractical due to their low frequency and the marginal benefit of new interventions.

Methods:

Data from prospective studies were used to develop (n=1273) and validate (n=544) a composite endpoint based on postoperative pancreatic fistula, postpancreatectomy hemorrhage, as well as reoperation and reinterventions. All patients had pancreatectomies of different extents. The association of the developed PAncreatic surgery Composite Endpoint (PACE) with prolonged length of hospital stay >75th percentile and mortality was assessed. A single-institution database was used for external validation (n=2666). Sample size calculations were made for single outcomes and the composite endpoint.

Results:

In the internal validation cohort, the PACE demonstrated an area under the curve of 78.0%, a sensitivity of 90.4%, and a specificity of 67.6% in predicting a prolonged length of hospital stay. In the external cohort, the area under the curve was 76.9%, a sensitivity of 73.8%, and a specificity of 80.1%. The 90-day mortality rate was significantly different for patients with a positive versus a negative PACE both in the development and internal validation cohort (5.1% vs 0.9%; P< 0.001), as well as in the external validation cohort (8.5% vs 1.2%, P< 0.001). The PACE enabled sample size reductions of up to 80.5% compared to single outcomes.

Conclusions:

The PACE performed well in predicting prolonged hospital stays and can be used as a standardized and clinically relevant endpoint for future prospective trials enabling lower sample sizes and therefore improved feasibility compared to single outcome parameters.
Netosis in Surgery
Authors: James Philippa , Kaushal Devesh , Beaumont Wilson Robert
Published: January 2024

Objective:

To provide surgeons with an understanding of the latest research on NETosis, including the pathophysiology and treatment of conditions involving NETs in the care of surgical patients.

Background:

A novel function of neutrophils, the formation of neutrophil extracellular traps (NETs), was described in 2004. Neutrophils form mesh-like structures of extruded decondensed chromatin, comprising DNA and histones decorated with bactericidal proteins. These NETs exert antimicrobial action by trapping microorganisms and preventing their wider dissemination through the body.

Results:

A narrative review of the existing literature describing NETosis was conducted, including NET pathophysiology, conditions related to NET formation, and treatments relevant to surgeons.

Conclusions:

In addition to its canonical antimicrobial function, NETosis can exacerbate inflammation, resulting in tissue damage and contributing to numerous diseases. NETs promote gallstone formation and acute pancreatitis; impair wound healing in the early postoperative period and in chronic wounds; and facilitate intravascular coagulation, cancer growth, and metastasis. Agents that target NET formation or removal have shown promising efficacy in treating these conditions, although large clinical trials are required to confirm these benefits.
A Multisite Study on the Effect of a Urinary Incontinence Self-Management Program on Community-Dwelling Older Women in Korea
Authors: Park Sunah , So Aeyoung
Published: January 2024

PURPOSE:

The purpose of this study was to evaluate the effects of a urinary incontinence (UI) self-management program on UI symptoms, knowledge, and self-efficacy in community-dwelling older women.

DESIGN:

A 1-group pretest-posttest design.

SUBJECTS AND SETTING:

Participants were recruited from 14 primary healthcare posts (PHCPs) in South Chungcheong Province, rural South Korea. A total of 163 women participated in a 5-session UI self-management program.

METHODS:

The UI self-management program was sequentially conducted across 14 PHCPs between May and November 2016. In each PHCP, 6 to 22 women participated in the program. The program consisted of weekly 90-minute sessions that were conducted across 5 weeks. Each session included a lecture on UI, reflective discussion, pelvic floor muscle training, and the assignment of homework (exercises and a daily bladder diary). Main outcome variables were measured using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), Urinary Incontinence Knowledge Scale (UIKS), and Geriatric Self-Efficacy Index for Urinary Incontinence (GSE-UI), which were administered before and after the intervention. Descriptive statistics were computed, and Wilcoxon signed-rank tests analyzed the data.

RESULTS:

The intervention resulted in a significant decrease in the ICIQ-SF scores, which was indicative of improvement in UI severity (pretest: 6.64 [SD 6.15], posttest: 4.76 [SD 5.08], P = .001), significant increases in the UIKS (pretest: 15.69 [SD 6.36], posttest: 23.14 [SD 5.54], P = .001] and GSE-UI (pretest: 75.34 [SD 31.80], [posttest: 86.20 [SD 27.06], P = .001) scores.

CONCLUSIONS:

The UI self-management program improved UI symptoms, knowledge, and self-efficacy among community-dwelling older women.
Microbial Transfer by Intermittent Catheters
Authors: Dean Nicole L. , Gras James , Lantz Ellen E. , Patterson Jillian P. , Inglese Gary , Goldstine Jimena V. , Medina-Rivera Mariely , Bionda Nina , Strickland Aaron D. , Sileika Tadas S.
Published: January 2024

PURPOSE:

The purpose of this study was to evaluate the effects of various protective features (eg, catheter cap, introducer tip, and catheter sleeve) of hydrophilic intermittent catheters against contamination with urinary tract infection–associated microorganisms using an in vitro model.

DESIGN:

An in vitro study of microbial transfer.

MATERIALS AND METHODS:

Gloves were contaminated with uropathogenic microorganisms and used to simulate intermittent catheterization of male anatomical models with and without the protective features present in 5 commercially available hydrophilic catheters. Using this contaminated touch transfer method, both the meatus of the sterile male anatomical models and sterile surgical gloves of an operator were inoculated with a high level of microorganisms (107 and 109 colony-forming units [CFU], respectively). The operator then performed catheterization of the anatomical model. The most relevant segments of the catheter were sampled, and the level of microbial transfer and catheter contamination was quantified. Results from experimental and sample replicates from the 3 microbial species and 5 catheters (sleeved and unsleeved) were analyzed by pair-wise t tests and analysis of variance.

RESULTS:

Of the 5 commercially available sleeved intermittent catheters evaluated in this study, use of catheters with multiple protective components (ring cap, introducer tip, and catheter sleeve) resulted in significant improvement in protection against contamination with a 25- to 2500-fold lower level of microbial contamination (C1 segment) across all species as compared to catheters protected with only sleeves or un-sleeved catheters.

CONCLUSIONS:

The combination of a ring cap, protective introducer tip, and protective sleeve provides additional protection when compared to sleeve alone from transferring microbial contamination from the meatus to the advancing catheter. Additional research is needed to determine whether these design features result in fewer urinary tract infections among intermittent catheter users.
Management of a Peristomal Abscess in a Patient With an Ileostomy
Authors: Wei Huiyan , Qiu Jin , Li Aini , Hu Hongyang
Published: January 2024

BACKGROUND:

Peristomal abscess (PA) is an uncommon but challenging peristomal skin complication. The initial treatment of the PA usually includes incision and drainage of the abscess, resulting in a peristomal wound. The presence of the wound makes it difficult to maintain a seal between the ostomy skin barrier and the peristomal skin resulting in frequent removal and application of the skin barrier to prevent leakage and allow for daily wound care.

CASE:

Ms T was a 52-year-old woman with an ileostomy resulting from a prior left hemicolectomy for colon cancer who developed a PA. Treatment of the PA was implemented, along with a modified 2-piece skin barrier that allowed access to the peristomal wound for daily dressing changes while maintaining a seal around the ostomy.

CONCLUSION:

The modified 2-piece skin barrier technique proved a successful treatment for the management of the PA without frequent changes of the ostomy pouching system.
Promoting surgical smoke management in a pediatric operating room: a best practice implementation project
Authors: Moore Hailey , Palokas Michelle
Published: January 2024

Introduction:

The routine use of heat-producing tools in the perioperative setting generates surgical smoke. Surgical smoke poses a known health hazard for perioperative staff working in the operating room.

Objective:

The objective of this best practice project was to promote evidence-based practices regarding surgical plume management in a pediatric operating room.

Methods:

This project was guided by the JBI Model of Evidence-Based Healthcare and used the JBI Practical Application of Clinical Evidence System and the Getting Research into Practice audit and feedback strategy to promote evidence-based practices regarding surgical smoke management in a pediatric operating room. Seven audit criteria representing best-practice recommendations were used. A baseline audit was conducted, followed by the implementation of multiple strategies developed by the key stakeholders. The project was finalized with a follow-up audit to determine any changes in compliance with best-practice recommendations.

Results:

Baseline audit data indicated an average of 41% compliance with best practices across all audit criteria, revealing the need for significant improvement in five of the seven criteria. Three barriers were identified and strategies were implemented, including the development and implementation of an educational module and a surgical smoke exposure risk assessment tool. Follow-up audits showed an overall improvement of 30% among five of the seven audit criteria.

Conclusions:

This project yielded improvements with best practices for surgical smoke management in the perioperative setting. However, additional work is required to ensure the sustainability of best practices in this setting.
Invasive Streptococcus pyogenes Infection: A case report

Authors: BAZHAR SAMIA , ElBenaissi Yassine , Benaissa Elmostafa , Ben Lahlou Yassine , Chadli Mariama
Published: January 2024

The Group A Streptococcus, also known as Streptococcus pyogenes, is a human pathogen causing various infections, ranging from mild, such as tonsillitis and impetigo, to severe and invasive conditions like septicemia and necrotizing fasciitis. Despite a decline in incidence and severity during the 20th century due to antibiotics, there has been a reported increase in severe cases since the 1980s in industrialized countries. 
This summary highlights a case of invasive Group A Streptococcus infection in a 28-year-old diagnosed at the microbiology laboratory of the Mohammed V Military Training Hospital in Rabat, Morocco.
A 28-year-old patient, with a history of chickenpox, presented with acute febrile oligoarthritis. Following a recent flu-like syndrome and febrile tonsillitis, the patient experienced asymmetric inflammatory oligoarthralgia affecting the left knee, left ankle, and right shoulder, accompanied by functional impairment of the left lower limb. Upon admission, clinical examination revealed swelling, positive patellar tap, and sternal involvement. Laboratory and imaging findings indicated an abscessed collection in the left knee and anterior mediastinitis. Emergency aspirations revealed Group A Streptococcus, specifically Streptococcus pyogenes, leading to a diagnosis of septic arthritis. Dual antibiotic therapy and knee joint drainage resulted in symptom resolution after 45 days.
The rise in severe Group A Streptococcus infection underscores the need for early detection and treatment. Widely sharing the French High Council for Public Health’s antibiotic prophylaxis recommendations is crucial for awareness. Collaborating between clinicians and microbiologists is essential for effective management.
Diverse GABA signaling in the inner retina enables spatiotemporal coding
Authors: Matsumoto Akihiro , Morris Jacqueline , Looger Loren L. , Yonehara Keisuke
Published: January 2024

Summary paragraph

GABA (ψ-aminobutyric acid) is the primary inhibitory neurotransmitter in the mammalian central nervous system (CNS)1,2. There is a wide range of GABAergic neuronal types, each of which plays an important role in neural processing and the etiology of neurological disorders3–5. However, there is no comprehensive understanding of this functional diversity, due to the lack of genetic tools to target and study the multitude of cell types. Here we perform two-photon imaging of GABA release in the inner plexiform layer (IPL) of the mouse retina using the newly developed GABA sensor iGABASnFR2. By applying varied light stimuli to isolated retinae, we reveal over 40 different GABA-releasing neurons, including some not previously described. Individual types show unique distributions of synaptic release sites in the sublayers comprising the IPL, allowing layer-specific visual encoding. Synaptic input and output sites are aligned along specific retinal orientations for multiple neuronal types. Furthermore, computational modeling reveals that the combination of cell type-specific spatial structure and unique release kinetics enables inhibitory neurons to suppress and sculpt excitatory signals in response to a wide range of behaviorally relevant motion structures. Our high-throughput approach provides the first comprehensive physiological characterization of inhibitory signaling in the vertebrate CNS. Future applications of this method will enable interrogation of the function and dysfunction of diverse inhibitory circuits in health and disease.
Association of red cell distribution width to albumin ratio with risk of all-cause and cause-specific mortality: two prospective cohort studies
Authors: Hao Meng , Jiang Shuai , Li Xiangnan , Wang Shuming , Li Yi , Tang Jingdong , Hu Zixin , Zhang Hui
Published: January 2024

Background

The red cell distribution width to albumin ratio (RAR) has emerged as a reliable prognostic marker for mortality in various diseases. However, whether RAR is associated with mortality remains unknown in the general population.

Objective

Explore whether RAR is associated with all-cause and cause-specific mortality, and to elucidate the dose-response relationship between them.

Methods

This study included 50622 participants aged 18+ years from US National Health and Nutrition Examination Survey (NHANES), and 418950 participants aged 37+ years from UK Biobank. The potential association between RAR and the risk of all-cause and cause-specific mortality was evaluated by Cox proportional hazard models. Restricted cubic spline regressions were applied to estimate the possible nonlinear relationships.

Results

NHANES documented 7590 deaths over a median follow-up of 9.4 years, and UK Biobank documented 36793 deaths over a median follow-up of 14.5 years. In multivariable analysis, elevated RAR were significantly associated with a higher risk of all-cause mortality (NHANES: hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.81-1.93; UK Biobank: HR: 2.01, 95% CI: 1.96-2.06), as well as mortality due to malignant neoplasms, heart disease, cerebrovascular diseases, respiratory diseases, diabetes mellitus, and others in both the two cohorts (all P-value < 0.05).

Conclusions

Higher baseline RAR was strongly and independently associated with increased risk of all-cause and cause-specific mortality in the general population. RAR was a promising indicator that simply, reliably, and inexpensively accessible for identifying high-risk of mortality in clinical practice.
Seasonal behavioral patterns of the Caquetá titi monkey (Plecturocebus caquetensis)
Authors: Carolina Acero-Murcia Adriana , Leidy Almario-Vaquiro , Zaida Ortega , Javier García-Villalba , René López-Camacho , Thomas Defler
Published: January 2024

The Caquetá titi monkey (Plecturocebus caquetensis) is Critically Endangered (CR) due to habitat destruction associated with extensive livestock ranching and farming. But unfortunately, information on the ecology and behavior of the species is scarce. Here we describe seasonal behavioral patterns and home range size ofP. caquetensisin a 23-ha forest fragment in Colombia. In 2013, we collected focal animal behavioral data of a group of seven individuals ofP. caquetensis. Overall, titi monkeys spent 33% of their time feeding, 4% locomotion, 42% resting, and 21% engaging in social interactions, such as grooming and vocalizations. However, the activity budgets differed substantially between seasons. In the dry season titi monkeys invested significantly more time feeding than in the rainy season, when they spent more time moving. They invested a similar amount of time in social interactions in both seasons. Home range size was larger during the rainy season; but the core areas of the home ranges had a similar size and they overlapped across seasons, suggesting the overall importance of this area for titi monkeys. These findings constitute the first study on the seasonal ecology and home range of this Critically Endangered species, and it identifies a priority local conservation area.
Poincaré and SimBio: a versatile and extensible Python ecosystem for modeling systems
Authors: Silberberg Mauro , Hermjakob Henning , Malik-Sheriff Rahuman S. , Grecco Hernán E.
Published: January 2024

Chemical Reaction Networks (CRNs) play a pivotal role in diverse fields such as systems biology, biochemistry, chemical engineering, and epidemiology. High-level modelling of CRNs enables various simulation approaches, including deterministic and stochastic methods. However, existing Python tools for CRN modelling typically wrap external C/C++ libraries for modelling and simulation, limiting their extensibility and integration with the broader Python ecosystem. In response, we developed Poincaré and SimBio, two novel Python packages for the definition and simulation of dynamical systems and CRNs. Poincaré serves as a foundation for dynamical system modelling, while SimBio extends this functionality to CRNs, including support for the Systems Biology Markup Language (SBML). Poincaré and SimBio are developed as pure Python packages enabling users to easily extend their simulation capabilities by writing new or leveraging other Python packages. Moreover, this does not compromise the performance, as code can be Just-In-Time compiled with Numba. Our benchmark tests using curated models from the BioModels repository, demonstrate that these tools may provide a potentially superior performance advantage, compared to other existing tools. Additionally, to ensure a user-friendly experience, our packages use standard typed modern Python syntax that provides a seamless integration with Integrated Development Environments (IDEs). Python-centric approach significantly enhances code analysis, error detection, and refactoring capabilities, positioning Poincaré and SimBio as valuable tools for the modelling community.
A Germinal Center Checkpoint of AIRE in B Cells Limits Antibody Diversification
Authors: Zhou Jordan Z. , Huang Bihui , Pei Bo , Sun Guang Wen , Pawlitz Michael D. , Zhang Wei , Li Xinyang , Hokynar Kati C. , Yao Fayi , Perera Madusha L. W. , Wei Shanqiao , Zheng Simin , Polin Lisa A. , Poulik Janet M. , Ranki Annamari , Krohn Kai , Cunningham-Rundles Charlotte , Yang Naibo , Bhagwat Ashok S. , Yu Kefei , Peterson Pärt , Kisand Kai , Vuong Bao Q. , Cerutti Andrea , Chen Kang
Published: January 2024

In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in GC B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.
Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms
Authors: Mealka Matthew , Sierra Nicole A. , Matteo Diego Avellaneda , Albekioni Elene , Khoury Rachel , Mai Timothy , Conley Brittany M. , Coleman Nalani J. , Sabo Kaitlyn A. , Komives Elizabeth A. , Bobkov Andrey A. , Cooksy Andrew L. , Silletti Steve , Schiffer Jamie M. , Huxford Tom , Sohl Christal D.
Published: January 2024

Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
Sensory representations in primary visual cortex are not sufficient for subjective imagery
Authors: Cabbai Giulia , Racey Chris , Simner Julia , Dance Carla , Ward Jamie , Forster Sophie
Published: January 2024

The contemporary definition of mental imagery is characterized by two aspects: a sensory representation resembling, but not resulting from, perception, and an associated subjective experience. Neuroimaging demonstrated imagery-related sensory representations in primary visual cortex (V1) that show striking parallels to perception. However, it remains unclear whether these representations always reflect subjective experience, or they can be dissociated from it. We addressed this question by comparing sensory representations and subjective imagery among visualizers and aphantasics, the latter with an impaired ability to experience imagery. Importantly, to test for the presence of sensory representations independently of the ability to generate imageryon demandwe examined both spontaneous and voluntary imagery forms.

Using multivariate fMRI, we tested for decodable sensory representations in V1 and subjective visual imagery reports that occurred either spontaneously (during passive listening of evocative sounds) or in response to the instruction tovoluntarilygenerate imagery of the sound content (always while blindfolded inside the scanner). Among aphantasics, V1 decoding of sound content was at chance during voluntary imagery, and lower than in visualizers, but it succeeded during passive listening, despite them reporting no imagery. In contrast, in visualizers, decoding accuracy in V1 was greater in voluntary than spontaneous imagery (while being positively associated with the reported vividness of both imagery types). Finally, for both conditions, decoding in precuneus was successful in visualizers but at chance for aphantasics. Together, our findings show that V1 representations can be dissociated from subjective imagery, while implicating a key role of precuneus in the latter.
Feedforward and disinhibitory circuits differentially control activity of cortical somatostatin-positive interneurons during behavioral state transitions
Authors: Van Velze Marcel de Brito , Dhanasobhon Dhanasak , Martinez Marie , Morabito Annunziato , Berthaux Emmanuelle , Pinho Cibele Martins , Zerlaut Yann , Rebola Nelson
Published: January 2024

Local inhibitory neurons (INs), specifically those involved in disinhibitory circuits like somatostatin (SST) and vasoactive intestinal peptide (VIP)-positive INs, are essential for regulating cortical function during behavior. However, it is unclear the mechanisms by which these INs are recruited during active states and whether their activity is consistent across different sensory cortices. We now reveal that in mice, locomotor activity strongly recruits SST-INs in primary somatosensory (S1) but not visual (V1) cortex. This diverse engagement of SST-INs could not be explained by differences in VIP-IN function but was absent in the presence of visual sensory drive suggesting involvement of feedforward sensory pathways. In agreement, inactivating the somatosensory thalamus, but not decreasing VIP-INs activity, significantly reduces the recruitment of SST-INs in S1 by locomotion. Finally, model simulations suggest differences in SST-INs activity can be explained by varying ratios of VIP-driven inhibition and thalamus-driven cortical excitation. Our work suggests that by integrating feedforward activity with neuromodulation, SST-INs play a central role in adapting sensory processing to behavioral states.
Long mounting with repeated copulations inZygogramma bicolorata: A test of adaptive significance of a curious mating behaviour
Authors: Pal Rabi Sankar , Nandy Bodhisatta
Published: January 2024

Long matings are abundant in insects despite the range of the costs involved. The causes and consequences of the evolution of long matings remain an interesting problem for behavioural ecologists. We studied the Parthenium beetle (Zygogramma bicolorata), which is known to show extraordinarily long copulations. Our detailed investigation showed, for the first time, that the long mounting in this species entails repeated copulation. Each of these copulations is preceded and succeeded by a leg-rubbing behaviour. We found the same characteristic pattern in laboratory and semi-natural conditions. We conducted a series of interrupted mounting assays to examine the fitness consequences of the duration of mounting. We tested multiple hypotheses regarding the transfer of sperm and non-sperm components, and the function of leg rubbing in modulating the female copulatory behaviour. Sperm transfer and fertility did not exhibit a linear increase with the number of copulations. There was also no evidence of nutrient transfer by the males. In contrast, our experiments reveal significant cost of long mounting in these beetles. We showed female remating behaviour can be modulated by the long previous mounting. Our data also suggest that leg rubbing may reduce female resistance to mating. While the long mating possibly serves as copulatory mate guarding, the males may increase their competitive ability through modulating female remating. We also propose leg rubbing to be a copulatory courtship behaviour. Our study provides preliminary insights into the evolution of long mating in such systems and necessitates further research on sexual selection.
Insulin Amyloid Morphology is Encoded in H-bonds and Electrostatics Interactions Ruling Protein Phase Separation
Authors: Lenton Samuel , Chaaban Hussein , Khaled Mohammed , van de Weert Marco , Strodel Birgit , Foderà Vito
Published: January 2024

Ion-protein interactions regulate biological processes and are the basis of key strategies of modulating protein phase diagrams and stability in drug development. Here, we report the mechanisms by which H-bonds and electrostatic interactions in ion-protein systems determine phase separation and amyloid formation. Using microscopy, small-angle X-ray scattering, circular dichroism and atomistic molecular dynamics (MD) simulations, we found that anions specifically interacting with insulin induced phase separation by neutralising the protein charge and forming H-bond bridges between insulin molecules. The same interaction was responsible for an enhanced insulin conformational stability and resistance to oligomerisation. Under aggregation conditions, the anion-protein interaction translated into the activation of a coalescence process, leading to amyloid-like microparticles. This reaction is alternative to conformationally-driven pathways, giving rise to elongated amyloid-like fibrils and occurs in the absence of preferential ion-protein binding. Our findings depict a unifying scenario in which common interactions dictated both phase separation at low temperatures and the occurrence of pronounced heterogeneity in the amyloid morphology at high temperatures, similar to what has previously been reported for protein crystal growth.
Efficient analysis of toxicity and mechanism of food contaminants using network toxicology and molecular docking strategy: A Case Study of Aflatoxin B1
Authors: Chu Zi-Yong , Zi Xue-Jiao
Published: January 2024

The present study aims to promote network toxicology and molecular docking strategies for the efficient evaluation of the toxicity of food contaminants. With the example of liver injury induced by the food contaminant Aflatoxin B1, this study effectively investigated the putative toxicity of food contaminants and the potentially molecular mechanisms. Initially, we obtained a preliminary overview of the toxicity of Aflatoxin B1 by using the ProTox-II and ADMETlab 2.0 databases. Subsequently, it was possible to identify 156 potential targets associated with Aflatoxin B1 and liver injury by using the ChEMBL, SwissTargetPrediction, GeneCards and DisGeNET databases. These were further refined by the STRING 5.0 database and Cytoscape 3.9.0 software for 23 core targets, including AKT1, SRC and EGFR. Then, GO and KEGG pathway analyses performed by Metascape database indicated that the core targets of Aflatoxin B1-induced hepatotoxicity were mainly enriched in cancer-related signalling pathways. Speedy molecular docking using Quick Vina confirmed the strong binding energy between Aflatoxin B1 and the core targets. In summary, Aflatoxin B1 may induce liver injury by regulating cell proliferation, cell survival, cell growth, cellular immune responses, and cellular signalling cascade responses in hepatocytes. We have provided a theoretical basis for understanding the molecular mechanism of Aflatoxin B1 hepatotoxicity and for the prevention and treatment of Aflatoxin B1-induced cancers in food contaminants. Furthermore, our network toxicology and molecular docking methods also provide an effective method for the rapid evaluation of the toxicity of food contaminants, which effectively solves the cost and ethical problems associated with the use of experimental animals.

Graphical Abstract
Timing matters: A meta-analysis on the dynamic effect of stress on salivary immunoglobulin
Authors: Seizer Lennart , Stasielowicz Lukasz , Löchner Johanna
Published: January 2024

The impact of psychological stress on physiological systems has been a focus of extensive research, particularly in understanding its diverse effects on immune system activity and disease risk. This meta-analysis explores the dynamic effect of acute stress on salivary immunoglobulin-A (S-IgA) levels, a key biomarker for secretory immunity within the oral environment. Analyzing data from 34 samples comprising 87 effect sizes and a total of 1,025 subjects, a multi-level approach is employed to account for the temporal variability in measuring the stress response. The results reveal a significant increase in S-IgA levels peaking around 10 minutes after stress exposure, followed by a return to baseline levels approximately 30 minutes later. In addition, the meta-analysis identified several research gaps of the extant literature, such as limitations in the considered time lag after stress. In conclusion, the findings emphasize the temporal nuances of the stress-induced S-IgA response, which can help to infer potential biological pathways and guide sampling designs in future studies. Further, we highlight the use of a multi-level metaanalysis approach to investigate the temporal dependencies of the interplay between stress and immune functioning.
Widespread 3’ UTR splicing regulates expression of oncogene transcripts in sequence-dependent and independent manners
Authors: Riley Jack J. , Alexandru-Crivac Cristina N. , Bryce-Smith Sam , Wilson Stuart A. , Sudbery Ian M.
Published: January 2024

Background

Splicing in 3’ untranslated regions (3’ UTRs) is generally considered a signal to elicit transcript degradation via nonsense-mediated decay (NMD) due to the presence of an exon junction complex (EJC) downstream of the stop codon. However, 3’ UTR intron (3UI)-containing transcripts are widespread and highly expressed in both normal tissues and cancers.

Results

Here we present and characterise a novel transcriptome assembly built from 7897 solid tumour and normal samples from The Cancer Genome Atlas. We identify thousands of 3UI-containing transcript isoforms, many of which are expressed across multiple cancer types. We find that the expression of core NMD component UPF1 negatively correlates with global 3UI splicing between normal samples, however this correlation is lost in colon cancer. We find that 3UIs found exclusively within 3’ UTRs (bona-fide3UIs) are not predominantly NMD-sensitising, unlike introns present in 3’ UTRs due to premature termination. We identify HRAS as an example where 3UI splicing rescues the transcript from NMD.Bona-fide, but not premature termination codon (PTC) carrying 3UI-transcripts are spliced more in cancer samples compared to matched normals in the majority of cancer types analysed. In colon cancer, differentially spliced 3UI-containing transcripts are enriched in the canonical Wnt signalling pathway, with CTNNB1 being the most over-spliced in colon cancer compared to normal. We show that manipulating Wnt signalling can further regulate splicing of Wnt component transcript 3’ UTRs.

Conclusions

Our results indicate that 3’ UTR splicing is not a rare occurrence, especially in colon cancer, where 3’ UTR splicing regulates transcript expression in EJC-dependent and independent manners.
Aberrant activation of wound healing programs within the metastatic niche facilitates lung colonization by osteosarcoma cells
Authors: Reinecke James B , Jimenez Garcia Leyre , Gross Amy C , Cam Maren , Cannon Matthew V , Gust Matthew J , Sheridan Jeffrey P , Gryder Berkley E , Dries Ruben , Roberts Ryan D
Published: January 2024

Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation. Experimental design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics was used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and non-tumor cells within the metastatic microenvironment. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. Conclusions: Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a pro-metastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.
On-chip large-scale-integration and 2D collective modes of genetically programmed artificial cells
Authors: Ricouvier Joshua , Mostov Pavel , Shabtai Omer , Tayar Alexandra , Karzbrun Eyal , Khakimzhan Aset , Noireaux Vincent , Daube Shirley Shulman , Bar-Ziv Roy
Published: January 2024

The on-chip large-scale-integration of genetically programmed artificial cells capable of exhibiting collective modes is an important goal for fundamental research and technology. Here, we report assembly of a 2D layout of 1024 monolithic DNA compartments as artificial cells on a 5-millimeter square silicon chip. Homeostatic cell-free protein synthesis reactions driven by genetic circuits occur inside the compartments. We created a reaction-diffusion system with a 30x30 square lattice of artificial cells interconnected by thin capillaries for diffusion of products. Driving the system by a genetic oscillator revealed emergent collective modes of synchrony and propagating phase waves in 2D, with dynamics controlled by geometry. This demonstrates a class of nonequilibrium autonomous systems, where chemical energy consumed to make proteins induces 2D collective patterns of gene expression on multicellular scales, with applications in biological computing, sensing, and materials synthesis.
The inevitability and superfluousness of cell types in spatial cognition
Authors: Luo Xiaoliang , Mok Robert M. , Love Bradley C.
Published: January 2024

Discoveries of functional cell types, exemplified by the cataloging of spatial cells in the hippocampal formation, are heralded as scientific breakthroughs. We question whether the identification of cell types based on human intuitions has scientific merit and suggest that “spatial cells” may arise in non-spatial computations of sufficient complexity. We show that deep neural networks (DNNs) for object recognition, which lack spatial grounding, contain numerous units resembling place, border, and head-direction cells. Strikingly, even untrained DNNs with randomized weights contained such units and support decoding of spatial information. Moreover, when these “spatial” units are excluded, spatial information can be decoded from the remaining DNN units, which highlights the superfluousness of cell types to spatial cognition. Now that large-scale simulations are feasible, the complexity of the brain should be respected and intuitive notions of cell type, which can be misleading and arise in any complex network, should be relegated to history.
Exploring unique sequence repeat patterns and secondary structures in rDNA internal transcribed spacers ITS1 and ITS2 for characterization of catfish species
Authors: IMRAN MOHD , NAFEES SANA
Published: January 2024

The genetic variabilities in internal transcribed spacers ITS1 and ITS2 of rDNA are explored to a limited extent in vertebrates including fish species. This study explores unique molecular signature in these spacers from multiple fish species from the order siluriformes. Supporting the concerted evolution, both ITS1 and ITS2 were found prevalent with microsatellite and random repeats, with diverse distribution in each species in term of nucleotide composition, position and length, giving a species-specific impression in repeats. Their secondary structures too have shown distinct structural homology with variations in helix length, loops, and non-canonical bps, where ITS2 4-helix carries additional nine conserved motifs while that of ITS1 was found highly branched with multiple sub-branching unique to each species and a long tail helix common in all. This combination of secondary structures and repeats have formed unique molecular signatures distinguishing each species. Since the evolutionary and maturation biology of rDNA is similar in vertebrates, these molecular signatures in internal spacers could effectively contribute in the molecular characterization of other species too.
Sleep selectively and durably enhances real-world sequence memory
Authors: Diamond N.B , Simpson S. , Baena Pérez D. , Murray B. , Fogel S. , Levine B.
Published: January 2024

Sleep is thought to play a critical role in the retention of episodic memories. Yet it remains unclear whether and how sleep actively transforms memory for specific experiences. More generally, little is known about sleep’s effects on memory for multidimensional real-world experiences, both overnight and in the days to months that follow. In an exception to the law of forgetting, we showed that sleep actively and selectively improves retrieval of a one-time real-world experience (a controlled but immersive art tour) – specifically boosting memory for the order of tour items (sequential associations), but not perceptual details from the tour (featural associations). This above-baseline increase in sequence memory was not evident after a matched period of wakefulness. Moreover, the sleep-induced advantage of sequence over featural memory grew over time up to one-year post-encoding. Finally, overnight polysomnography showed that sleep-related memory enhancement was associated with the duration and neurophysiological hallmarks of slow-wave sleep previously linked to neural replay, particularly spindle-slow wave coupling. These results suggest that sleep serves a crucial and selective role in enhancing sequential organization in episodic memory at the expense of specific details, linking sleep-related neural mechanisms to the transformation and enhancement of memory for complex real-life experiences.

Significance Statement

Sleep affects the retention of episodic memories. Yet, it remains unclear whether sleep active transforms how we remember past experiences, overnight and beyond. We investigated memory for different dimensions underlying a dynamic real-world event – sequential associations versus atemporal featural associations – before and after sleep or wakefulness, and serially up to a year later. Sleep actively and selectively enhanced sequence memory, with this preferential sequence retention growing with time. Overnight memory enhancement is associated with the duration and neurophysiological hallmarks of slow-wave sleep previously linked to sequential neural replay, particularly spindle-slow wave coupling. Our findings support an active role for sleep in transforming different aspects of real-world memory, with sequence structure coming to dominate long-term memory for dynamic real-world experiences.
Red blood cell dynamics during malaria infection challenge the assumptions of mathematical models of infection dynamics
Authors: Peters Madeline Amanda Erzen , King Aaron A. , Wale Nina
Published: January 2024

For decades, mathematical models have been used to understand the course and outcome of malaria infections (i.e., infection dynamics) and the evolutionary dynamics of the parasites that cause them. A key conclusion of these models is that red blood cell (RBC) availability is a fundamental driver of infection dynamics and parasite trait evolution. The extent to which this conclusion holds will in part depend on model assumptions about the host-mediated processes that regulate RBC availability i.e., removal of uninfected RBCs and supply of RBCs. Diverse mathematical functions have been used to describe host-mediated RBC supply and clearance, but it remains unclear whether they adequately capture the dynamics of RBC supply and clearance during infection. Here, we use a unique dataset, comprising time-series measurements of erythrocyte (i.e., mature RBC) and reticulocyte (i.e., newly supplied RBC) densities duringPlasmodium chabaudimalaria infection, and a quantitative data-transformation scheme to elucidate whether RBC dynamics conform to common model assumptions. We found that RBC clearance and supply are not well described by mathematical functions commonly used to model these processes. Furthermore, the temporal dynamics of both processes vary with parasite growth rate in a manner again not captured by existing models. Together, these finding suggest that new model formulations are required if we are to explain and ultimately predict the within-host population dynamics and evolution of malaria parasites.