bluuebunny/crossref_metadata_2025 huggingface dataset:
Balancing Formal and Informal Caregiving Resources for Older Adults: The Role of Spatial Proximity of Family
Authors: Oh Gyeongrim , Lee Samsik
Published: February 2025

Objectives

To explore how informal and formal home care was balanced for older adults under the weakening informal caregiving systems due to sociodemographic changes in South Korea, this study examined the relationship between the two types of care and the effects of proximity to family caregivers on them.

Methods

We analyzed adults aged 65 years and older from the 7th wave of the Korean Longitudinal Study of Aging (KLoSA) (n = 722) with limitations in activities of daily living (ADL) or instrumental activities of daily living (IADL), or dementia. Multinomial logistic regression (MLR) was adopted to analyze the impact of family structure on the choice of informal caregivers. Two-stage least squares (2SLS), Heckman, and IV-Heckman models were applied to address endogeneity and sample selection biases.

Results

The results demonstrated that spouses and children close to older parents appeared to be primary caregivers. According to the IV-Heckman model, informal care substitutes for formal home care (b = -0.416, p < .01), and both being married (b = 0.715, p < .01) and proximity to children within one hour (b = 0.888, p < .01) appeared to facilitate formal home care use.

Discussion

This study reveals that Informal and formal home care are inextricably linked. Spouses and adult children close to parents play a pivotal role in directly providing informal care and indirectly facilitating formal home care. Balancing informal/formal home care should be considered in medium- and long-term plans to improve older adults' well-being and reduce formal care's financial burden.
Evolution of the Brain and Behavior
Authors: Breedlove S. Marc , Watson Neil V.
Published: February 2025

This chapter outlines the evolutionary journey of brains and behavior, exploring the intriguing contrasts and similarities between humans and their closest relatives, chimpanzees and bonobos. While the genetic difference between these species is surprisingly small, humans differ from chimps and bonobos by only 1.3%, yet their behaviors, anatomy, and neurobiology vary dramatically. It notes humans' possession of advanced cognitive abilities, complex languages, and larger brains, which have evolved rapidly in recent history, enabling higher functions that distinguish us from other primates. The chapter emphasizes how scientists investigate these differences by studying the nervous systems of various species, seeking to uncover how specific brain features correlate with behavior. It also highlights the broader story of evolution, tracing its roots in observations of shared anatomical structures, fossil evidence, and the process of descent with modification, which continues to shape species across generations.
Homeostasis
Authors: Breedlove S. Marc , Watson Neil V.
Published: February 2025

This chapter examines the physiological and behavioral processes that regulate the body, with a focus on how these systems can sometimes work against efforts to maintain health. It highlights a study of contestants from The Biggest Loser, particularly Danny C., who lost a dramatic amount of weight but struggled to keep it off, eventually regaining most of it. This phenomenon illustrates the challenges of long-term weight management and the body's tendency to revert to its original state. The chapter introduces homeostasis, the body's regulation of internal conditions like temperature and energy, to maintain an optimal environment for cells. It also explores how deviations from homeostasis trigger drives to restore balance, including the role of mechanisms like negative feedback and redundancy in maintaining stability.
Sensation & Perception
Authors: Wolfe Jeremy M. , Levi Dennis M. , Holt Lori L. , Bartoshuk Linda M. , Herz Rachel S. , Klatzky Roberta L. , Merfeld Daniel M.
Published: February 2025

Sensation and Perception, which is now in its seventh edition, introduces readers to the world of human senses and helps answer such interesting questions as: “Why do some substances taste sweet?” or “Why does music sound musical?” The chapters consider fundamental questions about the human senses and the impact that answers to those questions have on medical and societal issues. Presenting a balanced blend of neuroscience and cognitive psychology, this book studies the interaction and multisensory nature of sensory experiences. The first chapters consider the origins of vision and spatial vision, perceiving and recognizing objects, and color. Next, chapters turn to space perception and binocular vision; attention and scene perception; and visual motion perception. Then the text moves from vision to hearing and looks at the physiology and psychoacoustics of hearing; hearing in the environment; music and speech perception; and vestibular sensation. Finally, the other senses are touched upon with chapters focusing on touch, olfaction, and taste.
Taste
Authors: Wolfe Jeremy M. , Levi Dennis M. , Holt Lori L. , Bartoshuk Linda M. , Herz Rachel S. , Klatzky Roberta L. , Merfeld Daniel M.
Published: February 2025

This chapter explores the science of taste, distinguishing it from flavor, which combines retronasal olfaction, taste, and somatosensory cues. It describes how taste buds in tongue papillae detect chemicals and transmit signals via cranial nerves to the brain. The chapter then identifies sweet, salty, sour, and bitter as the four basic tastes and examines ongoing debates about adding umami and fat as a result of their roles in nutrient detection. Genetic variations in taste perception, especially in bitter sensitivity, create unique “taste worlds” for individuals and influence food preferences and health outcomes, such as cancer and cardiovascular disease. Taste and flavor guide survival by helping humans avoid toxins with bitter and sour tastes and seek essential nutrients with sweet and salty tastes.
Suggested solutions for Chapter 23
Authors: Clayden Jonathan , Greeves Nick , Warren Stuart
Published: February 2025

This chapter provides solutions to the problems posed in Chapter 23 of Clayden, Greeves & Warren Organic Chemistry, second edition, on chemoselectivity and protecting groups.
External Attention
Authors: Chun Marvin M. , Most Steven B.
Published: February 2025

This chapter delves into the complex nature of attention, explaining it as a collection of cognitive mechanisms that enable individuals to focus on relevant stimuli while filtering out the irrelevant. A core function, selection allows the prioritisation of certain information, influenced by factors such as spatial attention, temporal attention, or feature-based attention. Debates on whether attention operates early (filtering by physical traits) or late (post-meaning processing) highlight the flexibility of selection depending on cognitive demands. Attention also modulates perception, enhancing sensory sensitivity and sustaining vigilance for tasks requiring prolonged focus. Lastly, while attention shapes awareness, control over it is limited by reflexive shifts, prior learning, and emotional biases, raising questions about the extent of autonomy in directing mental focus.
Memory Systems
Authors: Chun Marvin M. , Most Steven B.
Published: February 2025

This chapter explores memory systems, explaining how the brain encodes, stores, and retrieves information while focusing on explicit and implicit memories. It describes how sensory regions encode memories, how distributed cortical networks store them, and how these original areas reactivate during retrieval. The hippocampus processes explicit memories, such as episodic and semantic types, while implicit memories, including procedural skills and priming, rely on more resilient and widespread neural systems. Spatial memory enables navigation, with the hippocampus and related structures, like place and grid cells, constructing cognitive maps and tracking positions in the environment. These findings illuminate the dynamic mechanisms that support memory and their crucial role in understanding and navigating the world.
Judgment and Decision Making
Authors: Chun Marvin M. , Most Steven B.
Published: February 2025

This chapter delves into the dual processes of human thought, contrasting the rapid, instinctive ‘fast thinking’ (System 1) with the deliberate, analytical ‘slow thinking’ (System 2). It examines how heuristics—mental shortcuts—aid in making judgments under uncertainty, though they often lead to biases such as representativeness and availability. The chapter then explores decision-making strategies, highlighting how emotions, subjective value, and risk perceptions deviate from rational norms, as explained by Prospect Theory and concepts such as loss aversion and framing. It also introduces neuroeconomics as an interdisciplinary approach, revealing how brain mechanisms underpin decision-making, reward evaluation, and individual variability in preferences. Through studies on brain activity and the effects of damage, the chapter connects cognitive processes to economic behaviours and the potential of tools like neuromarketing, raising ethical considerations for their application.
Sophorolipids from Starmerella bombicola: an alternative for treating skin lesions caused by herpes simplex virus type 1
Authors: Bigotto Briani Gisele , Dahmer Débora , Dyna André Luiz , Barboza Mario Gabriel Lopes , de Matos Ricardo Luis Nascimento , Baldo Cristiani , Bracarense Ana Paula Frederico Rodrigues Loureiro , Galhardi Ligia Carla Faccin , Lonni Audrey Alesandra Stinghen Garcia , Celligoi Maria Antonia Pedrine Colabone
Published: February 2025

Aims

This study aims to evaluate the antiviral activity of sophorolipids against herpes simplex virus type 1 (HSV-1) and develop an anti-herpetic formulation for treatment of cutaneous lesions caused by HSV-1.

Methods and results

The antiherpetic activity of sophorolipids was evaluated in vitro against both sensitive (KOS) and acyclovir-resistant HSV-1 strains. used as a model to assess the antiviral activity of sophorolipids against non-enveloped viruses Poliovirus was used as a model to assess the antiviral activity of sophorolipids against non-enveloped viruses. The results showed that sophorolipids exhibit effective antiviral activity against both strains with low cytotoxicity to VERO cells. However, antiviral activity against poliovirus was not observed, suggesting that sophorolipids specifically target enveloped virus. In vivo, the sophorolipid-based cream formulation demonstrated good stability and efficacy in reducing herpetic lesions, including those caused by the drug-resistant strain. Promising antiviral activity was confirmed through histopathological analysis, indicating a reduced occurrence of tissue damage in the treated group compared to the viral control.

Conclusions

Sophorolipids, whether isolated or incorporated as an active ingredient in a cream formulation, represent a promising and innovative alternative for the treatment of cutaneous lesions caused by HSV-1, including strains resistant to the reference drug.
Modelling the density and mass of the Milky Way’s proto-galaxy components with APOGEE-Gaia
Authors: Horta Danny , Schiavon Ricardo P
Published: February 2025

Unravelling galaxy formation theory requires understanding galaxies both at high and low redshifts. A possible way to connect both realms is by studying the oldest stars in the Milky Way (i.e. the proto-Galaxy). We use the APOGEE-Gaia surveys to perform a purely chemical dissection of Milky Way (MW) stellar populations, and identify samples of stars likely belonging to proto-Galactic fragments. The metallicity dependence of the distribution of old MW stars in the [Mg/Mn]–[Al/Fe] enables the distinction of at least two populations in terms of their star formation histories: a rapidly evolved population likely associated with the main progenitor system of the proto-MW; and populations characterized by less efficient, slower, star formation. In the Solar neighbourhood less efficient star forming populations are dominated by the Gaia-Enceladus/Sausage accretion debris. In the inner Galaxy, they are largely associated with the Heracles structure. We model the density of chemically defined proto-Galaxy populations, finding that they are well represented by a Plummer model with a scale radius of $a\sim 3.5$ kpc, and an oblate ellipsoid with flattening parameters [$p\sim 0.8$; $q\sim 0.6$]; this finding indicates that the MW plausibly hosts a low-mass, metal-poor, bulge component. We integrate this density for chemically unevolved stars between $-2 \lt \mathrm{[Fe/H]} \lt -0.5$ to obtain a minimum stellar mass for the proto-Galaxy of $M_{*} (r\lt 10~\mathrm{kpc}) = 9.1\pm 0.2\times 10^{8}$ M$_{\odot }$. Our results suggest the proto-Milky Way is at least comprised of two significant fragments: the main in situ progenitor and the Heracles structure.
Targeting sickle cell pathobiology and pain with novel transdermal curcumin
Authors: Goel Yugal , Arellano Mya A , Fouda Raghda T , Garcia Natalie R , Lomeli Reina A , Kerr Daniel , Argueta Donovan A , Gupta Mihir , Velasco Graham J , Prince Richard , Banerjee Probal , Jana Sirsendu , Alayash Abdu I , Friedman Joel M , Gupta Kalpna
Published: February 2025

Several comorbidities of sickle cell disease (SCD) originate from red blood cell (RBC) instability, chronic inflammation, and oxidative stress. Development of scalable, cost-effective therapeutics suitable for chronic administration to prevent, attenuate, and perhaps reverse the consequences of RBC instability is needed. Curcumin has many of these attributes as a safe compound with antisickling, antiinflammatory, and antioxidant properties, but its translational potential has been constrained due to limited bioavailability from oral administration. The present study demonstrates the rapid and high bioavailability of a novel topical/transdermal (TD) curcumin gel formulation in the plasma and blood cells and its effectiveness in humanized sickle cell mice in: (i) ameliorating features of sickle cell pain hypersensitivity and axonal injury; (ii) reducing multiple manifestations of RBC instability including evidence of decreased hemolysis (reduced lactate dehydrogenase levels), enhanced RBC ATP levels along with decreased oxidative damage; (iii) decreasing multiple proinflammatory cytokines including interleukin-6, monocyte chemoattractant protein-1, granulocyte–macrophage colony-stimulating factor, and activation, normal T cell expressed and secreted protein in skin secretome; and (iv) reducing mast cell degranulation and activation. Our data suggest that an easy-to-use novel TD curcumin gel formulation has the potential to ameliorate chronic pain, improve RBC stability, and reduce inflammatory consequences of SCD.
Characterization of the Swi6/HP1 binding motif in its partner protein reveals the basis for the functional divergence of the HP1 family proteins in fission yeast
Authors: Oya Tomoyuki , Tanaka Mayo , Hayashi Aki , Yoshimura Yuriko , Nakamura Rinko , Arita Kyohei , Murakami Yota , Nakayama Jun‐ichi
Published: February 2025

The heterochromatin protein 1 (HP1) family recognizes lysine 9‐methylated histone H3 (H3K9me) and recruits other transacting factors to establish higher order chromatin structures. In the fission yeast Schizosaccharomyces pombe (S. pombe), two HP1 family proteins, Swi6 and Chp2, play distinct roles in recruiting transacting factors: Swi6 primarily recruits Epe1, a Jumonji C domain‐containing protein involved in histone H3K9 demethylation, whereas Chp2 recruits Mit1, a component of the Snf2/Hdac Repressive Complex. However, detailed mechanisms of how multiple HP1 family proteins and their respective interactors work cooperatively or exclusively to form higher order chromatin structures remain elusive. In this study, we investigated the interactions between Swi6 and Epe1. We found that Swi6 interacts with Epe1 through its chromoshadow domain, and identified a unique motif, named the FVI motif, in Epe1 involved in this interaction through detailed mapping of the region. Enhanced green fluorescent protein (EGFP) tethering assays showed that the FVI motif is sufficient to recruit ectopically expressed EGFP to heterochromatic regions, and mutational analyses revealed that conserved hydrophobic residues in this motif are essential for proper targeting. Structural simulations further supported the importance of these residues in Swi6 binding. Interestingly, Mit1 containing the Epe1 FVI motif was recruited to the heterochromatic regions by Swi6 but not by Chp2. Cells expressing mutant Mit1 maintained heterochromatic silencing even in chp2∆ cells, suggesting that Chp2 is not required for heterochromatin formation when Mit1 is recruited by Swi6. These findings highlight distinct HP1‐binding motifs in interactors, contributing to functional divergence among HP1 family proteins.
Current insights into anaesthesia and critical care management of patients with hepatocellular carcinoma
Authors: Monsel Antoine , Sitbon Alexandre , Roux Charles , Eyraud Daniel , Scatton Olivier , Vezinet Corinne , Oré Marie-Virginie , Gallet Jérémy , Wagner Mathilde , Thabut Dominique , Boughdad Sarah , Renaud Florence , Mazzola Alessandra , Goumard Claire , Allaire Manon ,   the Liver Institute of la Pitié-Salpêtrière (LIPS)—University Hospital in Paris
Published: February 2025

BACKGROUND

The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide, due to the increasing prevalence of liver diseases associated with metabolic dysfunction and better management of cirrhosis and its complications. The diversification of HCC treatments has recently increased, with the choice of strategy based on HCC characteristics, liver function and comorbidities. The combination of new therapies has transformed the prognosis, with up to 70% survival at 5 years.

OBJECTIVE

The aim of this review was to analyse the most recent data on preoperative evaluation, peri-operative anaesthetic management of liver resection, liver transplantation and other types of procedures, and to highlight the multidisciplinary aspect of such management.

MAIN FINDINGS AND DISCUSSION

The importance of preanaesthetic evaluation will depend largely on the procedure proposed, associated co-morbidities and the stage of liver disease. This assessment should verify stabilisation of all comorbidities, and evaluate the degree of portal hypertension, cirrhosis severity and sarcopenia. Liver resection and liver transplantation for HCC present specific surgical challenges, and minimally invasive techniques improve recovery. Nonsurgical procedures considered as therapeutic (ablation) or standby (regional embolisation) are diverse, and all expose patients to specific intra-anaesthetic complications, sometimes requiring intensive care management. Peri-operative anaesthetic strategies deployed in the management of liver resection or nonsurgical procedures involve specific management of fluids, coagulation, narcosis and analgesia, which can impact on patients’ overall, and cancer prognosis. Lastly, new down-staging strategies combining several types of procedure and possibly immunotherapy, also call for collegial reflection on posthepatic transplant immunosuppression, which must remain tailored to each individual patient.
Eighteen-year analysis of anaesthetic management in Brugada syndrome
Authors: Borrell-Vega Jaume , Fernández Font José Daniel , Linares Miguel , Martínez-Pallí Graciela , Isabel-Roquero Alba , Mont Lluis , Brugada Josep , Arbelo Elena , Giménez-Milà Marc
Published: February 2025

BACKGROUND

Brugada syndrome (BrS) is a genetic disorder that increases the risk of ventricular tachyarrhythmias and sudden cardiac death (SCD). Certain drugs (propofol, local anaesthetics), fever, bradycardia, increased vagal tone and electrolyte imbalances can trigger or worsen BrS arrhythmias.

OBJECTIVE

To evaluate the incidence of malignant ventricular arrhythmias during the perioperative period in patients with BrS, hypothesising that common anaesthetic drugs may be safe to use during daily clinical practice.

DESIGN

The BRUGANAES study was an observational, retrospective project including BrS patients who underwent various types of anaesthesia.

SETTING

BrS patients undergoing any type of anaesthesia intervention from 1 January 2006, to 31 December 2023, from a tertiary hospital in Barcelona.

MAIN OUTCOME MEASURES

The primary outcome was the occurrence of malignant ventricular arrhythmias and/or SCD during and up to 30 days postanaesthesia. Secondary outcomes included adverse events during hospitalisation, 30-day readmission rates and 30-day mortality rates.

RESULTS

Among 652 BrS patients registered in the hospital, 111 patients and 189 procedures were analysed. General anaesthesia was administered in 51.3% of cases, sedation in 36% and regional/neuraxial anaesthesia exclusively in 12.7%. Overall, nonrecommended drugs (propofol, ketamine and local anaesthetics) were used in 129 (68.3%) procedures, either bolus and/or continuous infusion. Epidural blocks were performed in 34% of regional anaesthesia cases, mostly in obstetrics, and subarachnoid blocks in 31.8%. The primary outcome occurred in two patients intraoperatively (1% of procedures): one with bradycardia-induced ventricular fibrillation after a nonrecommended drug and one with transient ventricular tachycardia after a drug not listed as potentially harmful.

CONCLUSION

To date, this is one of the largest cohorts describing the perioperative approach for BrS patients, including a wide range of anaesthesia procedures and drugs. Most of the patients undergoing anaesthesia for an interventional procedure received an anaesthetic drug classified as not recommended.
Pain experience of children with Christianson syndrome
Authors: Premachandran Shajenth , Ocay Don Daniel , Beaulieu Claudie , Balduzzi Jonathan , Ye Diana-Luk , Davidova Albena , Bokhari Rakan , Ouellet Jean A. , Orlowski John , Gendron Louis , Sharif-Naeini Reza , Ferland Catherine E.
Published: February 2025

Children with Christianson syndrome (CS), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the alkali cation/proton exchanger SLC9A6/NHE6, display severe cognitive impairments, mutism, and sensory abnormalities such as hyposensitivity to pain. However, it is unclear whether these children display other sensory abnormalities and whether their pain hyposensitivity is the result of an elevated pain threshold or a complete insensitivity to pain. To better characterize the sensory abnormalities in this disorder, we used a combination of a mouse model of CS and pain questionnaires directed at nonverbal patients with CS. We recruited 14 young male participants with CS and subjected them to a novel observational tool, the Pain Sensory and Painful Situations Questionnaire (PSQ), which takes multiple painful situations into account to broaden the description of pain expression. By analyzing social expressive behaviours of pain in these nonverbal patients, the PSQ documented that over 60% of the participants were unaffected by mechanical or inflammatory painful stimuli. This reduced pain sensitivity was also observed in the mouse CS model. Surprisingly, CS mice also displayed aversive reactions to innocuous stimuli, which prompted us to examine whether such reactions were also present in children with CS. Indeed, the results from the PSQ revealed that 30% to 50% of these patients showed an aversive response to normally innocuous stimuli like light touch and gusts of air. Our results demonstrate that children with CS have aversive reactions to innocuous stimuli and are hyposensitive to painful stimuli, the latter making them at risk for developing complications from unreported injuries.
Rectal cancer approach strategies after neoadjuvant treatment - a systematic review and network meta-analysis
Authors: Meng Cong , Shu Wenlong , Sun Liting , Wu Si , Wei Pengyu , Gao Jiale , Shi Jinyao , Li Yang , Yang Zhengyang , Yao Hongwei , Zhang Zhongtao
Published: February 2025

Background and Aims:

An increasing number of patients with rectal cancer who respond well to neoadjuvant chemoradiotherapy (nCRT) are being considered for organ preservation programs. However, due to the lack of high-level evidence, the survival outcomes of the organ preservation programs are still full of controversy and uncertainty.

Methods:

To assess the effects of total mesorectal excision surgery (TME), watch-and-wait (W&W) and local excision (LE) on long-term outcomes after nCRT, we searched PubMed, Embase, and Web of Science for articles published between 1 January 2010, and 1 December 2023.

Results:

We found 7029 pieces of literature, of which 26 studies met the inclusion criteria, and recruited 2778 participants in the network meta-analysis. Risk of bias assessment showed that most included studies had a low risk of bias. Low-certainty evidence suggests that the TME group was significantly superior to all other interventions for the 2-year local regrowth rate. (W&W group [OR, 0.20; 95% CI, 0.12–0.35], LE group compared with TME group [3.00; 1.60 to 5.80]). There was no significant difference in the 2-year local regrowth rate between W&W and LE group (OR, 0.60; 95% CI, 0.32 to 1.20). There was high to moderate certainty evidence that at three years, the W&W group had a significant advantage in overall survival compared with the TME group (OR, 0.37; 95% CI, 0.09 to 0.95). After five years, no significant difference in overall survival was found between the three treatment modalities.

Conclusions:

We concluded that TME achieved the most significant reduction in 2-year local regrowth rates. However, the W&W strategy and LE demonstrated non-inferiority to TME in long-term survival outcomes.
A novel alpha-synuclein K58N missense variant in a patient with Parkinson’s disease
Authors: Al-Azzani Mohammed , Weber Sandrina , Ramalingam Nagendran , Ramón Maria , Shvachiy Liana , Mestre Gonçalo , Zech Michael , Sicking Kevin , Ibáñez de Opakua Alain , Jayanthi Vidyashree , Amaral Leslie , Agarwal Aishwarya , Chandran Aswathy , Chaves Susana R. , Winkelmann Juliane , Trenkwalder Claudia , Schwager Maike , Pauli Silke , Dettmer Ulf , Fernández Claudio O. , Lautenschläger Janin , Zweckstetter Markus , Busnadiego Ruben Fernandez , Mollenhauer Brit , Outeiro Tiago Fleming
Published: February 2025

Mutations and multiplications in the SNCAgene, encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson’s disease (PD). We report the identification of a novelSNCAmissense mutation (NM_000345.4, cDNA 174G>C; protein K58N) in a PD patient using whole exome sequencing, and describe comprehensive molecular and cellular analysss of the effects of this novel mutation. The patient exhibited typical sporadic PD with early onset and a benign disease course. Biophysical studies revealed that the K58N substitution causes local structural effects, disrupts binding to membranes, and enhances aSyn in vitro aggregation. K58N aSyn produces fewer inclusions per cell, and fails to undergo condensate formation. The mutation increases the cytoplasmic distribution of the protein, and has minimal effect on the dynamic reversibility of serine-129 phosphorylation. In total, the identification of this novel mutation advances our understanding of aSyn biology and pathobiology.
Predicting antibody kinetics and duration of protection against SARS-CoV-2 following vaccination from sparse serological data
Authors: Deichmann Julia , Barda Noam , Canetti Michal , Peretz Yovel , Ottolenghi Yael , Lustig Yaniv , Regev-Yochay Gili , Lipsitch Marc
Published: February 2025

Vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generates an antibody response that shows large inter-individual variability. This variability complicates the use of antibody levels as a correlate of protection and the evaluation of population- and individual-level infection risk without access to broad serological testing. Here, we applied a mathematical model of antibody kinetics to capture individual anti-SARS-CoV-2 IgG antibody trajectories and to identify factors driving the humoral immune response. Subsequently, we evaluated model predictions and inferred the corresponding duration of protection for new individuals based on a single antibody measurement, assuming sparse access to serological testing. We observe a reduced antibody response in older and in male individuals, and in individuals with autoimmune diseases, diabetes and immunosuppression, using data from a longitudinal cohort study conducted in healthcare workers at Sheba Medical Center, Israel, following primary vaccination with the BNT162b2 COVID-19 vaccine. Our results further suggest that model predictions of an individual’s antibody response to vaccination can be used to predict the duration of protection when serological data is limited, and could serve as a tool to estimate infection risk over time on both the population and individual level.
The effects of human presence, restraint, and stressed neighbors on corticosterone levels in domesticated budgerigars (Melopsittacus undulatus)
Authors: Reichard Dustin G. , Summers Kelly V.
Published: February 2025

Limiting stress during interactions between captive animals and humans is important for effective husbandry. One physiological change during the vertebrate stress response is the release of glucocorticoid hormones. Here, we measured plasma corticosterone in female domesticated budgerigars (Melopsittacus undulatus) to test whether human presence, restraint, or removal and return of a newly stressed neighbor increases corticosterone. The presence of humans for 15 minutes at the beginning of the experiment did not significantly elevate corticosterone above baseline levels, suggesting that birds that acclimate to humans are minimally affected by their presence. However, at the end of the experiment after multiple blood sampling events, the same human presence test significantly elevated corticosterone above baseline and human presence levels measured at the beginning of the experiment. Thus, repeated blood sampling could cause progressively stronger stress responses to human presence. Restraint-induced corticosterone levels were significantly higher than all other treatments, indicating that human handling activates the stress response. After stressed birds were returned home, corticosterone levels of their neighbors were significantly higher than baseline at 25- and 45-minutes post-return. However, the 25- and 45-minute corticosterone levels were not significantly different from each other, or levels induced by human presence at the beginning or end of the experiment. This outcome suggests that social transmission of stress was limited across the sampled time frame. These data highlight the importance of evaluating the costs and benefits of different human-animal interactions in captivity, including in domesticated species that are more tolerant of forced proximity to humans.

Research Highlights

Human presence only elevated plasma corticosterone after multiple blood sampling events.

Restraint significantly increased corticosterone levels relative to all other treatments.

Minimal evidence for social transmission of stress.
Posttranscriptional activity of the eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis
Authors: Zhou Fang , Culjkovic-Kraljacic Biljana , Bach Christian , Feng Li , Mishima Yuta , Borden Katherine L. B. , Tenen Daniel G
Published: February 2025

HoxA9, a homeodomain-containing transcription factor, is mis-expressed in over half of acute myeloid leukemia (AML) cases, and is associated with poor prognosis. Previous studies indicated that HoxA9 binds to the eukaryotic translation initiation factor eIF4E in primary specimens and that HoxA9 stimulated the RNA export and translation efficiency of selected RNAs via eIF4E. However, the relevance of this to its leukemogenic transformation capacity was unknown. Here, we used a double point mutation (HoxA9AA) to disrupt the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature. Surprisingly, the mutation dramatically increased AML latency from a median of 90 to 280 days and resulted in incomplete penetrance. Re-transplantation of bone marrow cells from leukemic animals demonstrated even more pronounced differences in disease kinetics and penetrance with all animals succumbing to disease by day 60 in the wildtype group, while some HoxA9AA mice never developed leukemia. Collectively, these findings uncover a novel, transcription-independent mechanism of HoxA9-driven leukemogenesis through eIF4E and positions eIF4E as a potential therapeutic target AML patients expressing high levels of HoxA9.

Key Points

A double point mutation in HoxA9 disrupted the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature.

Eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis and is important for the maintenance of acute myeloid leukemia.
Oral Metformin May Exacerbate Diabetic Neuropathy: A Two-Sample Mendelian Randomization Study
Authors: Wang Xiaoyong , Wu Yujuan , Ma Ningning , Chen Jueying , Chen Yuanjin , Shi Jiaoling
Published: February 2025

Objective

Given the important role of metformin in diabetes treatment and the uncertainty regarding its relationship with diabetic neuropathy, this study aims to assess the causal relationship between metformin and diabetic neuropathy using Mendelian randomization.

Methods

Instrumental variables were derived from publicly available genome-wide association study datasets. Two study cohorts were assigned: a training cohort (exposure ID: ukb-a-159) and a testing cohort (ID: ukb-b-14609), with the outcome ID being finn-b-DM_NEUROPATHY for both.

The primary analysis used inverse variance weighting (IVW) for Mendelian randomization, supplemented by weighted median (WMed), weighted mode (WM), simple mode (SM), and MR Egger regression (MER). To test for heterogeneity, pleiotropy, and publication bias, we conducted leave-one-out sensitivity analyses, MR Egger regression, and further assessed with funnel plots.

Results

Mendelian randomization analysis showed a significant positive causal relationship between metformin and diabetic neuropathy in both the training set (IVW: logOR 14.73, 95% CI [9.60, 19.86], p=1.78E-08) and the testing set (IVW: logOR 15.83, 95% CI [11.10, 20.56], p=5.54E-11). The WMed, WM, SM, and MER models all consistently supported this conclusion, with no evidence of pleiotropy or heterogeneity, indicating robust results.

Conclusion

From an epidemiological perspective, this study reveals a significant positive correlation between metformin use and diabetic neuropathy through Mendelian randomization analysis. This finding not only provides new insights into the field of diabetes treatment but also suggests that the use of metformin may be associated with the potential side effect of increased risk of diabetic neuropathy.
Heterogeneous constraint and adaptation across the malaria parasite life cycle
Authors: Perkins Sarah A. , Neafsey Daniel E. , Early Angela M.
Published: February 2025

Evolutionary forces vary across genomes, creating disparities in how traits evolve. In organisms with complex life cycles, it is unclear how intrinsic differences among discrete life stages impact evolution. We looked for life history-driven changes in patterns of adaptation inPlasmodium falciparum, a malaria-causing parasite with a multi-stage life cycle. Categorizing genes based on their expression in different life stages, we compared patterns of between- and within- species polymorphism across stages by estimating nonsynonymous to synonymous substitution rate ratios (dN/dS) and mean pairwise nucleotide diversity (𝞹NS/𝞹S). Considering these alongside estimates of Tajima’sD, fixation probability, adaptive divergence proportion and rate, andFST, we looked for changes in the drift-selection balance in life stages subject to transmission bottlenecks and changes in ploidy. We observed signals of reduced selection efficacy in genes exclusively expressed in sporozoites, the parasite form transmitted from mosquitoes to humans and often targeted by vaccines and monoclonal antibodies. We discuss implications for how parasites evolve to resist therapeutics and consider functional, molecular, and population genetic factors that could contribute to these patterns.
The Protective Role of Intestinal Alkaline Phosphatase in Inflammatory Bowel Disease-Associated Non-Alcoholic Fatty Liver Disease
Authors: Liu Yang , Lv Hao , Zhang Haonan , Yu Shou , He Qiao , Cao Gang
Published: February 2025

Background

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition characterized by weight loss as a prominent feature. Non-alcoholic fatty liver disease (NAFLD), typically linked to obesity and metabolic dysregulation, is increasingly recognized as being influenced by the gut-liver axis. Notably, IBD patients exhibit a heightened susceptibility to NAFLD, although the underlying mechanisms remain poorly understood. Intestinal alkaline phosphatase (IAP), an endogenous enzyme, plays a critical role in preventing intestinal bacterial translocation. We hypothesized that IAP may serve as a potential therapeutic agent for mitigating IBD-associated NAFLD.

Methods

An IBD model was established using three cycles of 2% dextran sulfate sodium (DSS) administration. Mice were subsequently treated with L-phenylalanine or IAP. The activity of stool IAP, gut microbiota composition, hepatic lipid accumulation, inflammatory markers, and gut microbiome diversity were assessed.

Results

DSS treatment markedly reduced IAP levels. Suppression of IAP significantly increased gut permeability and exacerbated hepatic inflammation and lipid deposition. Conversely, IAP supplementation restored these parameters, improved gut microbial diversity, and normalized microbiota composition. However, IAP failed to ameliorate hepatic inflammation and lipid accumulation in Toll-like receptor 4 (TLR4) knockout mice.

Conclusion

Deficiency in endogenous IAP contributes to the onset of NAFLD in the context of IBD. Oral IAP supplementation enhances gut barrier integrity, stabilizes gut microbiota, and prevents NAFLD development in IBD through a TLR4-dependent mechanism.
Cost-effectiveness of human papillomavirus self-sampling in the Swedish cervical screening program
Authors: Östensson Ellinor , Borgfeldt Christer , Pedersen Kine , Hellman Kristina , Sy Stephen , Lei Jiayao , Burger Emily A. , Clements Mark S.
Published: February 2025

Background

In Sweden, the cervical cancer screening programme is based on primary human papillomavirus (HPV) testing with either clinician-collected cervical sampling or home-based vaginal self-sampling. We assessed the effectiveness and cost-effectiveness of primary HPV clinician-collected sampling and primary HPV self-collected sampling for unvaccinated cohorts of Swedish women.

Methods

A model-based analysis was performed to project long-term costs and quality-adjusted life-years (QALYs). Screening strategies included no screening, 18 clinician-collected strategies and 36 self-sampling strategies, with variations in the screening frequency, start age and follow-up management. We estimated incremental cost-effectiveness ratios benchmarked against willingness-to-pay (WTP) thresholds of €50,000 and €100,000 per QALY gained.

Results

Compared with the 2022 recommendations (with primary clinician-collected HPV testing from ages 23 with 5-yearly screening to age 50 and 7-yearly screening through to age 64), self-sampling at the same intensity would lead to similar effectiveness and a 36% reduction in costs. Among the clinician-collected sampling strategies, the optimal strategies involved primary HPV testing from age 25 with 10-yearly screening with extended genotyping (at €50,000 per QALY gained), or 7- and 10-yearly screening for €100,000. Across all strategies, the optimal strategies included primary self-sampling from age 25 with direct referral to colposcopy for HPV-16/18/45 with 7- and 10-yearly screening at €50,000 per QALY gained, and 5- and 7-yearly screening for €100,000 per QALY gained. These results were sensitive to the assumed accuracy of self-sampling compared with clinician-collected sampling.

Conclusions

Transitioning from clinician-collected cervical sampling to vaginal HPV self-sampling is likely to be cost-effective for unvaccinated women in Sweden.

Highlights

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For an analysis restricted to clinician-collected sampling, the 2022 Swedish population-based recommendations (primary HPV testing from age 23 with 5-yearly screening to age 50 and 7-yearly screening between ages 50 and 64 years) were on the cost-efficiency frontier, however longer screening intervals were optimal.

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For all of the considered strategies, the optimal strategies were primary vaginal self-sampling from age 25 years with direct referral to colposcopy for HPV 16, 18 and 45 with seven- and ten-yearly screening at €50,000 per QALY gained, and with five- and seven-yearly screening at €100,000 per QALY gained.
Nuclear CK1δ as a Critical Determinant of PER:CRY Complex Dynamics and Circadian Period
Authors: Serrano Fidel E. , Marzoll Daniela , Ruppert Bianca , Diernfellner Axel C. R. , Brunner Michael
Published: February 2025

The mammalian circadian clock is governed by a feedback loop in which the transcription activator CLOCK:BMAL1 induces expression of its inhibitors, PERs and CRYs, which form a complex with CK1δ, the main circadian kinase. The spatiotemporal dynamics of this feedback mechanism and the precise role of CK1δ remain incompletely understood. Using an inducible cell system, we demonstrate that nuclear CK1δ is a key determinant of circadian period. The availability of CK1δ is limited due to rapid degradation and export of unassembled active kinase. Our findings reveal that active CK1δ promotes cytoplasmic localization of the PER2:CRY1 complex and triggers the dissociation of CRY1, which subsequently accumulates in the nucleus. We propose that late in the circadian cycle, cytoplasmic PER:CRY:CK1δ complexes may serve as a reservoir, gradually releasing CRY1 into the nucleus. This mechanism ensures rebinding of CLOCK:BMAL1 to DNA and prolonged attenuation of transcriptional activity after the degradation of PER proteins.
Modeling Epithelial Morphogenesis and Cell Rearrangement during Zebrafish Epiboly: Tissue Deformation, Cell-Cell Coupling, and the Mechanical Response to Stress
Authors: Minsuk Sharon B. , Sego T. J. , Umulis David M. , Mullins Mary C. , Glazier James A.
Published: February 2025

Morphogenesis in early development involves complex and extreme deformations in response to intra- and intercellular forces. Zebrafish epiboly, the spreading of the blastoderm to cover and engulf the large yolk cell, is a key early event that sets the stage for gastrulation, but is poorly understood. The enveloping layer (EVL), the thin squamous outer epithelium of the blastoderm, bound at its edges to the yolk cell by tight junctions, plays a central role. The marginal EVL cells receive through their tight junctions, forces generated in the yolk cell, and propagate those forces through the rest of the EVL; and the resulting EVL expansion is required for epiboly of the deep cells within the blastoderm. However, we don’t know how these exogenous forces are generated and regulated; several alternative force generation mechanisms have been proposed. In order to model their relative contributions, we need a mechanical model of the EVL capable of responding to such forces and undergoing the drastic deformation of epiboly. The expanding EVL more than doubles its surface area and experiences significant shear as it deforms from a thin cap at the pole to become a complete sphere, necessarily requiring extensive internal rearrangement. We constructed an agent-based model of the EVL and its response to exogenous forces using the center-based simulation framework, Tissue Forge. Our model captures the large viscoelastic deformation of the EVL by cell rearrangement, and incorporates algorithmic strategies to accommodate these dynamic changes while maintaining tissue cohesion. Features observed in living embryos, such as the straightening of the initially ragged leading edge, also emerge in the model. We identified two key components required for realistic epiboly in the model: first, a mechanism to enable tissue remodeling by cell rearrangement without tearing the tissue, and second, a regulatory negative feedback on the forces driving EVL expansion, to synchronize the advancement of the EVL margin. We discuss the implications of these findings for the behavior of living EVL and the mechanisms that drive epiboly.
Nurturing sustainability: the interplay among digital marketing communication, online customer experience and sustainable purchase intention
Authors: Thakur Anand , Singla Kavita , Singla Kamini , Ansari Alisha , Mishra Ankita , Kaur Simran , Kaur Parwinder
Published: February 2025

Purpose

This study aims to delve into the underlying factors that play a pivotal role in shaping effective digital marketing communication (DMC) to promote sustainability. Further, it explores the mediating effect of online customer experience (OCE) on the dynamic relationship between DMC and sustainable purchase intention (SPI) and the moderating impact of social media marketing activities (SMMAs) on the relationship between DMC and OCE.

Design/methodology/approach

Based on single cross-sectional survey, 300 responses from green apparel users are analyzed by using partial least squares-structural equation modeling to corroborate the relationships among DMC, OCE, SMMAs and SPI.

Findings

Perceived usefulness, ease of use, web attractiveness, hedonic motivation and subjective norms significantly impact DMC, which in turn positively influences OCE and SPI. Further, OCE significantly mediates the relationship between DMC and SPI, highlighting the crucial role of OCE. The moderation analysis shows that interactivity negatively moderates the DMC-OCE relationship, suggesting that excessive interactivity may diminish the OCE, while personalization and trendiness do not have significant moderating effects.

Practical implications

The findings provide valuable insights for marketers to align their DMC strategies with sustainable business initiatives to create a seamless online experience, thereby fostering SPI in the contemporary digital era.

Originality/value

While previous studies have examined aspects of these relationships separately, this study integrates them into a cohesive framework to provide a more holistic understanding of how digital marketing strategies can promote sustainability.