bluuebunny/crossref_metadata_2025 huggingface dataset:
Method of accessing alcohol and binge drinking status in youth and young adults
Authors: Noel Jonathan K , Jacob Steve , Borden Samantha K , Gately Kelsey A , Rosenthal Samantha R
Published: December 2024

Aims

The study investigated relationships between how youth and young adults access alcohol and their binge drinking behaviors.

Methods

Data from the Rhode Island Student Survey (11- to 18-year-olds) and the Mobile Screen Time project (18- to 24-year-old) were included. Participants were asked whether they access alcohol through several different methods (e.g. gifts, purchase, theft), and a latent class analysis was conducted to identify patterns of behavior. Logistic regression models were used to determine if class assignment was associated with binge drinking, after adjusting for age, sexual/gender status, and identification as a Black, Indigenous, and other Person of Color.

Results

Among youth, participants who primarily accessed alcohol through friends had 6 times the odds of binge drinking (OR[95%CI] = 6.22 [4.08,9.49]), and those who accessed alcohol through all available sources had 23 times the odds (OR[95%CI] = 23.1 [9.08,58.6]). In young adults, participants who actively purchased alcohol had 3.7 times the odds of binge drinking (OR [95%CI] = 3.69 [1.62,8.37]).

Conclusions

Distinct means of accessing alcohol in youth and young adult populations can be identified, and different methods of access may be associated with increased binge drinking. Strong availability and ID checking policies are needed for on- and off-premise locations, and the implementation of parent-centered programs should be considered.
Just the Tip of the Iceberg: a Brief Report of the Tip-of-the-Tongue Score as an Embedded Validity Indicator for the Children’s Auditory and Visual Naming Tests
Authors: Hammond Jared B , Lichtenstein Jonathan D
Published: December 2024

Objective

Explore the tip-of-the-tongue (TOT) scores from the Children’s Auditory and Visual Naming Tests (cANT, cVNT) as embedded validity indicators (EVIs).

Method

A retrospective design of 98 consecutively referred youth aged 6–15 years (M = 11.28, SD = 2.80) that completed neuropsychological evaluation at a tertiary-care academic medical center.

Results

Invalid performance (i.e., ≥2 failed PVTs) occurred in 12.2% of the sample, with base rates of failure on individual PVTs ranging from 1.0% to 30.6%. Area under the curve (AUC) showed statistical significance for the auditory (AUC = 0.811, p = .004) but not the visual TOT. Logistic regression indicated the combination of both TOT scores with other PVTs increased correct identification of invalid performance to 85.7% versus 75% without TOT scores.

Conclusion

The utility of the TOT as a language-based EVI is one of many potential advantages of the cANT and cVNT compared to other confrontation naming tests. To confirm this, future studies with more diverse populations are warranted.
Daily activity is repeatable but varies across the breeding season in female great tits
Authors: Elderbrock Emily K , Brown Geoffrey M , Dochtermann Ned A , Galante Holland , Hau Michaela , Greives Timothy J
Published: December 2024

Wild animals typically organize activity around a 24-h day and daily timing across the year is optimized for both survival and reproductive success. Among-individual variation in chronotype, where individuals differ in when they begin or end their active day relative to a cue such as photoperiod, often exists within a population. Both intrinsic and extrinsic factors contribute to this variation and activity patterns may change across and within different life-history stages as energetic investment changes. Here we describe population level changes in free-living female great tit (Parus major) activity patterns of onset and offset of activity as well as assess variation and repeatability in daily activity both within- and across-breeding stages. We fitted individual females with accelerometers to track activity prior to nest building through chick rearing. Prior to clutch initiation females began their active day before sunrise, however, in the days prior to laying their first egg, activity was delayed until after sunrise. Females ended activity prior to sunset across the monitoring period and earliest during egg laying and incubation. In addition, females exhibited greater among- and within-individual variance in activity during parental care. Female daily activity was moderately repeatable within breeding stages and strongly covaried across several breeding stages. These findings expand our understanding of individual variation in activity patterns during reproduction and the potential fitness implications of chronotype in wild animals.
SGLT2 inhibitors and new frontiers in heart failure treatment regardless of ejection fraction and setting
Authors: Merlo Anna , D’Elia Emilia , Di Odoardo Luca , Sciatti Edoardo , Senni Michele
Published: December 2024

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular (CV) mortality and heart failure (HF) hospitalizations, independently from left ventricular ejection fraction (EF). Their efficacy has been assessed both in patients with reduced and preserved EF, with notable benefits in renal outcomes as well. The initiation of SGLT2i in the early phase of hospitalization for acute HF has proven to be safe and beneficial. The EMPULSE and DICTATE-AHF trials support early empagliflozin and dapagliflozin use, respectively, reducing worsening HF events, improving quality of life, and enhancing diuretic efficiency. Notably, these benefits emerge shortly after the initiation of therapy, underscoring the importance of early integration into guideline-directed medical therapy (GDMT). Despite concerns regarding deterioration of renal function, SGLT2i appear to be safe even in patients with low estimated glomerular filtration rates (eGFR). Data suggest that SGLT2i benefits persist without increased safety risks, reassuring clinicians of their efficacy in patients experiencing renal decline. Concerns about volume depletion induced by SGLT2i have also been addressed, with documented enhanced diuresis without adverse renal impacts. Moreover, SGLT2i have been associated with a lower risk of hyperkalaemia events, thus allowing for better optimization of GDMT, including the use of mineralocorticoid receptor antagonists. Overall, these findings highlight the broad CV, renal, and metabolic benefits of SGLT2i, advocating for their early and widespread use in HF management, regardless of EF or eGFR.
Can we slow down the decline in renal function?
Authors: Cice Gennaro , Calò Leonardo
Published: December 2024

The ‘chronic kidney disease’ (CKD) definition that best outlines the complex syndrome commonly called ‘kidney failure’ has become a problem of World Public Health due to its incidence and prevalence and due to exponentially increasing costs in every part of the world. The progressive reduction in the glomerular filtration rate, as known, goes hand in hand with an increase in cardiovascular risk understood as fatal and non-fatal heart attack, stroke, heart failure, and mortality. Therefore, every effort must aim at preventing or slowing down the decline in renal function in order to reduce not only critical renal events (the need for dialysis or transplantation among the most dreadful) but also the incidence of cardiovascular events. Since the disease is asymptomatic for a long time (often its detection is occasional and done with guilty delay), it is clearly important to make a correct and early evaluation of renal function with appropriate methods. Furthermore, it is crucial to make an aetiological diagnosis, when it is possible, of CKD because this will allow for the most targeted therapy possible. For a long time, an effective approach for the majority of people with CKD could only count on strict control of the diabetic disease and its complications, optimization of high blood pressure values, and the mandatory use of drugs blocking the renin–angiotensin–aldosterone system, particularly in the presence of albuminuria. Over time, this strategy proved to be only partially effective and the majority of patients nonetheless showed a progressive worsening of renal function. Only recently have we had access to two classes of innovative drugs such as glyphozines and incretins which have established themselves on the therapeutic scene because they have shown to be able to slow down the progression of CKD, first in patients with type 2 diabetes and subsequently in patients with CKD whether or not they have diabetes. Unexpectedly and convincingly, they have also been shown to significantly impact cardiovascular prognosis. From initially antidiabetic drugs, their effectiveness has forced the medical iconography to enrich itself with a new therapeutic niche by rightly speaking of ‘cardio-nephro-metabolic’ drugs.
Thoracic endovascular aortic repair (TEVAR) in a combined penetrating thoracic aortic and spinal cord injury
Authors: Amm Jacqueline , Laney Estelle , Robbertze Rubinette , Moeng Maeyane
Published: December 2024

Endovascular repair of aortic injuries secondary to blunt trauma has been widely described. However, literature on endovascular management in penetrating aortic injuries is scarce. The patient in this case report, a victim of penetrating thoracic aortic trauma, presented 5 days after injury with Brown–Sequard syndrome and a contained aortic injury (pseudoaneurysm) and was haemodynamically stable. Therefore, thoracic endovascular aortic repair was an option in this case. Endovascular repair carries a lower peri-operative morbidity and mortality rate than open repair. However, because most cases of penetrating thoracic vascular injury have haemodynamic instability, open surgery is considered the standard of care. This case demonstrates successful management of an aortic injury with a minimally invasive procedure.
Complex perianal abscess: a case report of shooting from the hip
Authors: Tilleard Peter , Swift Kate , Tani Daniel , Cheong Ju Yong
Published: December 2024

The perianal abscess is a common emergency surgical presentation. While in most cases simple drainage suffices, occasionally the abscess can track deeply presenting a management challenge. We describe the case of a complex circumferential horseshoe ischioanal abscess with extension below the levator ani through the greater sciatic notch and into the left gluteal region, with the collection involving the intergluteal space and gluteus maximus. The complex nature of the abscess warranted a novel joint approach by Colorectal surgery and Orthopaedic surgery teams. This case highlights the importance of maintaining a high degree of suspicion for, early recognition and imaging of deeper anorectal abscess extension.
Above knee amputation following periprosthetic joint infection after total knee arthroplasty: a fatal outcome
Authors: Purcell Catherine , Gangadharan Rajkumar , Ampat George
Published: December 2024

Primary total knee arthroplasty (TKA) is a successful and cost-effective procedure for which demand is increasing annually. Outcomes are generally good with satisfaction rates of 70%, so the procedure is commonly used in osteoarthritis management to improve mobility and alleviate pain. Above knee amputation (AKA) is a devastating complication of TKA. AKA is associated with high mortality, phantom pain, and non-ambulatory disability. In the US, the incidence of AKAs due to periprosthetic joint infection (PJI) is rising drastically, with the proportion of AKAs performed due to PJI having almost quadrupled from 1998 to 2013. We present the case of a patient who developed severe uncontrolled infection following routine TKA, resulting in an above-knee amputation and ultimately death. Due to the extremity of the outcome and the rising incidence of the complication involved, this is an important case to discuss.
Diffuse large B-cell lymphoma mimicking the cervical epidural hematoma in a patient who underwent spinal manipulation therapy: a case report and literature review
Authors: Kokot Klaudia , Chasles Oskar , Krakowiak Michał , Yuser Rami , Dzierżanowski Jarosław , Szmuda Tomasz , Maj Aleksandra , Nacewicz Jacek , Zieliński Piotr
Published: December 2024

The diffuse large B-cell lymphoma (DLBCL) mimicking an epidural hematoma in the cervical spine is an extremely unique case. We present a case of a 42-year-old man, who presented to the emergency department with symptoms of tetraparesis after a session of spinal manipulation therapy. magnetic resonance imaging visualized a lesion located at C3–C7 causing spinal cord compression with surrounding soft tissue edema suggesting epidural hematoma. The patient was admitted to the Neurosurgery Department and emergent laminectomy was performed. Intraoperatively, an infiltrating tumor was found, which was partially resected and sent for post-op histopathological examination, determining it to be a DLBCL. Our work aims to increase awareness of such cases, which may make it easier to make the proper diagnosis.
Holy Tongue or Conventional Language: The Concept and Status of the Hebrew Language among Medieval Karaite Jews
Authors: Zawanowska Marzena
Published: December 2024

The article examines the concept and status of the Hebrew language among medieval Karaites exploring whether they embraced linguistic relativism (the idea of ‘the holy tongue’), which was characteristic of rabbinic Judaism. It goes on to delve into the complex issue of why medieval Karaites, after initially (in the 9th century) advocating for a return to Hebrew, eventually (in the 11th century) abandoned this idea in favour of Arabic. Through terminological, genealogical, and functional analyses of source texts (dating primarily from the 10th century, when the ‘language breakthrough’ occurred), it demonstrates that the Karaites did not desacralize Hebrew but rather perceived it as a special language of divine origin and sacred significance while at the same time considered it a conventional language, adapted to human needs and cognitive capacities. The paper argues that these central beliefs—regarding Hebrew as both holy and conventional—motivated the Karaites’ efforts to revive it, and contemplates why they eventually discarded this attempt. It postulates that this change occurred due to intellectual/cultural, pragmatic/linguistic and eschatological considerations.
The Predicate Restriction in Najdi Arabic: A Theoretical Perspective
Authors: Alharbi Bader Yousef
Published: December 2024

One of the grammatical properties of the existential sentence is the predicate restriction, which states that only stage-level predicates are allowed in the coda position of the existential sentence; individual-level predicates are disallowed. This restriction has shown to be available in some languages but absent in others. The purpose of this theoretical study is twofold: firstly, to explore the availability of the effect of the predicate restriction in the existential sentence of Najdi Arabic; and secondly, to provide an account for its interesting behaviour. Assuming that the phrasal coda is a secondary predicative adjunct, it has been concluded that the predicate restriction is available in Najdi Arabic existential sentence. Only stage-level predicates are permitted in the coda position, whereas individual-level predicates are disallowed. The paper goes on to show that the ostensibly possible occurrence of individuallevel predicates in the existential sentence of Najdi Arabic may be ascribed to the fact that these adjective phrases are postnominal modifiers, rather than secondary predicates.
The morphology of some under-described verbal classes in the eastern Jibbali/Shehret variety of Sadḥ (Setḥ)
Authors: Castagna Giuliano , Al-Amri Suhail
Published: December 2024

This paper presents and describes the morphology of some underdescribed verbal classes in a variety of the Jibbali/Shehret language, which is part of the Modern South Arabian Languages (MSAL), a subgroup of the Semitic language family. The variety involved in this study is spoken in the coastal town of Sadḥ (natively called Setḥ) in the Dhofar governorate of the Sultanate of Oman, in the eastern part of the Jibbali/Shehret-speaking area, about 135 km to the east of Salalah, the governorate capital. The data presented, obtained through elicitation, sheds some light on the characteristics of a number of verbal classes in Jibbali/Shehret, which are only cursorily mentioned (or, in a few cases, completely disregarded) in the literature. Full paradigms are provided for most of the items described, along with a succinct summary of the relevant morpho-phonological phenomena involved.
The Role of Dietary Protein in Mitigating the Risk of Nonalcoholic Fatty Liver Disease
Authors: Shariq Abia , Khan Sarosh , Usmani Shajie Ur Rehman
Published: December 2024

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disease, mainly associated with excessive accumulation of fat in the liver. It has become a global health concern. The diagnosis of NAFLD is often done through liver biopsy; however, noninvasive methods have their own advantages. Dietary intervention, especially increased dietary protein alongside managing overall body weight, have been shown to be a promising strategy to lessen the impact of NAFLD. Dietary protein has been shown to reduce fat accumulation in the liver by increasing liver metabolism, eliciting satiety, improving insulin sensitivity, and enhancing muscle mass retention, collectively aiding in weight management. Both animal and plant proteins have benefits; however, plant proteins have demonstrated more metabolic advantages, while animal proteins have more downsides. Bridging the protein gap is critical, particularly in areas with limited availability to high-quality protein or in populations where dietary protein intake is inadequate. This commentary highlights the importance of obtaining sufficient protein from readily available and sustainable food sources. Furthermore, diets high in protein, like the Mediterranean diet, have proven to delay the advancement and likelihood of NAFLD. In conclusion, adequate dietary protein plays a crucial part in diminishing the risk of NAFLD, and efforts in public health should concentrate on addressing protein deficiency to decrease the growing burden of liver disease.
Pregnancy among thyroid cancer survivors: do thyroidectomy and radioactive iodine matter?
Authors: Teng Chung-Jen , Yeh Chiu-Mei , Liu Chia-Jen , Chen Tzeng-Ji , Huang Nicole , Chou Yiing-Jenq
Published: December 2024

Background

Thyroid cancer primarily affects young women and raises concerns about future fertility due to treatments of thyroidectomy and radioactive iodine (RAI) therapy. This study investigated the effects of these treatments on pregnancy probability in young female patients post-diagnosis.

Methods

A nationwide, population-based study using data from Taiwan’s National Health Insurance Research Database (2000–2017) examined pregnancy likelihood in women ≤45 years with thyroid cancer. The effects of thyroidectomy and RAI therapy on pregnancy were analyzed using logistic regression and Cox proportional-hazards models.

Results

In a cohort of 10 937 patients with thyroid cancer, 7022 (64.2%) underwent total thyroidectomy, with 718 receiving RAI treatment. The type of thyroidectomy and RAI treatment, even at doses exceeding 120 millicuries, did not reduce the likelihood of pregnancy. Age was identified as the most critical factor influencing pregnancy; women aged >30 years had a significantly lower likelihood of becoming pregnant than younger women did. Other factors associated with a reduced likelihood of pregnancy included comorbidity with diabetes (HR = 0.65, P = .002) and higher socioeconomic status (HR = 0.69, P = .085).

Conclusions

Thyroidectomy and RAI therapy do not diminish pregnancy probability in young women with thyroid cancer. Age remains a crucial factor, with younger women more likely to conceive. These findings are critical for fertility counseling and treatment planning.

Key message What is already known on this subjec?  Thyroid cancer primarily affects young women, and its standard treatments, including thyroidectomy and radioactive iodine (RAI) therapy, have raised concerns about their potential impact on fertility. Previous studies have shown that RAI treatment may temporarily affect ovarian function but typically does not have a significant long-term effect on fertility. What this study adds?  This nationwide population-based study found that neither total nor partial thyroidectomy, nor RAI treatment, adversely affects the likelihood of pregnancy in young women with thyroid cancer. Age was identified as the most significant factor influencing pregnancy, with younger women having a higher probability of becoming pregnant after treatment. How this study might affect research, practice, or policy?  Clinicians should recognize that age, rather than the type of thyroidectomy or RAI treatment, is the most critical factor influencing fertility in young women with thyroid cancer. This insight can guide personalized fertility counseling and treatment planning to optimize outcomes.
Effects of miRNAs in inborn error of metabolism and treatment strategies
Authors: Bayrak Harun , Sharafi Parisa , Özketen Ahmet Ç , Kılıç Mustafa
Published: December 2024

Metabolism is the name given to all of the chemical reactions in the cell involving thousands of proteins, including enzymes, receptors, and transporters. Inborn errors of metabolism (IEM) are caused by defects in the production and breakdown of proteins, fats, and carbohydrates. Micro ribonucleic acids (miRNAs) are short non-coding RNA molecules, ⁓19–25 nucleotides long, hairpin-shaped, produced from DNA. They play key roles in regulating gene expression of target mRNAs at both transcriptional and post-transcriptional levels. Altered expression of miRNAs has emerged as an additional molecular mechanism implicated in the pathogenesis of many diseases, this altered miRNA expression is also present in inherited metabolic diseases. A single miRNA can regulate targets associated with similar cellular processes and pathways, making miRNAs powerful therapeutics to restore the impaired cellular functions seen in disease phenotypes by enhancing the cellular response. Although the miRNA research field has advanced significantly in recent years, studies in IEM are still limited. Further research on miRNA expression specifically related to IEM may allow the identification of new biomarkers for the diagnosis, progression, and prognosis of diseases. In this review, the literature studies between miRNAs and IEMs, diagnosis, prognosis, follow-up, and treatment possibilities of miRNAs were analyzed. We present recent advances on miRNAs in IEM and an overview of current miRNA therapeutics for the clinic.
A narrative literature review of white matter microstructure in individuals at clinical high risk for psychosis
Authors: Su Wenjun , Wang Jijun , Tang Yingying
Published: December 2024

Schizophrenia is a severe psychiatric disorder characterized by widespread white matter (WM) alterations, manifesting as neurodevelopmental deficits and dysconnectivity abnormalities. Over the past two decades, studies have focused on the clinical high-risk (CHR) stage of psychosis and have yielded fruitful information on WM abnormalities that exist prior to the full onset of psychosis, shedding light on biological mechanisms underlying psychosis development. This review presents a summary of current findings on cross-sectional and longitudinal WM alterations in individuals with CHR and their links to clinical symptoms and neurocognitive dysfunction. Next, we review the utilization of WM characterization in predicting clinical outcomes. Taken together, the literature suggests the clinical significance of WM characteristics and their great potential in predicting the conversion to psychosis, despite some methodological and conceptual challenges that remain to be addressed in future studies. Future CHR research would greatly benefit from utilizing WM to guide pharmacological and non-pharmacological targeted treatments, optimize clinical prediction models, and enable more accurate clinical care.
Charged peptides enriched in aromatic residues decelerate condensate ageing driven by cross-β-sheet formation
Authors: Sanchez-Burgos Ignacio , Tejedor Andres R. , Feito Alejandro , Collepardo-Guevara Rosana , Espinosa Jorge R.
Published: December 2024

Biomolecular condensates, formed through liquid-liquid phase separation, play wide-ranging roles in cellular compartmentalization and biological processes. However, their transition from a functional liquid-like phase into a solid-like state—usually termed as condensate ageing—represents a hallmark associated with the onset of multiple neurodegenerative diseases. In this study, we design a computational pipeline to explore potential candidates, in the form of small peptides, to regulate ageing kinetics in biomolecular condensates. By combining equilibrium and non-equilibrium simulations of a sequence-dependent residue-resolution force field, we investigate the impact of peptide insertion—with different composition, patterning, and net charge—in the condensate phase diagram and ageing kinetics of archetypal proteins driving condensate ageing: TDP-43 and FUS. We reveal that small peptides composed by a specific balance of aromatic and charged residues can substantially decelerate ageing up to two orders of magnitude. The mechanism is controlled through condensate density reduction induced by peptide self-repulsive electrostatic interactions that specifically target protein regions prone to form cross-β-sheet fibrils. Our work proposes an efficient computational framework to rapidly scan the impact of small molecule insertion in condensate ageing and develop novel pathways for controlling phase transitions relevant to disease prevention.
LINK WORKER LED SOCIAL PRESCRIBING AS EARLY INTERVENTION FOR CHILDREN WITH SOCIAL-EMOTIONAL MENTAL HEALTH DIFFICULTIES
Authors: Charlton J. J. V , Battersby A , Drinkwater C , McKean M , Quibell T
Published: December 2024

Objective

To evaluate the impact of a novel approach to Social Prescribing (SP) embedded within education for primary-school aged children with early social-emotional mental health (SEMH) difficulties in socioeconomically deprived areas

Design

Repeated measures

Setting

10 primary schools

Patients

117 children aged 7-11 years with SEMH

Intervention

Children received weekly support with a Link Worker and support to attend community assets over 9 months.

Main outcome measures

Teacher (T) and parent (P) report Strengths and Difficulties Questionnaire measured SEMH, parent and child report Paediatric Quality of Life Inventory measured quality of life, and a child report vocabulary list measured expressive and receptive vocabulary.

Results

There was a significant effect of provision on SEMH reported by teachers (n-71) and parents (n=92), including total difficulties (95% CI .000-.001; 95% CI .015-.020), conduct difficulties (95% CI .012-.017; 95% CI .000-.001) and hyperactivity (95% CI .000-.001; 95% CI .000-.000, respectively) with moderate effect sizes. Parents (n=74) reported a significant improvement in children’s emotional (95% CI .066-.075) and school functioning (95% CI .005-008) with small effect sizes, however child reported quality of life (n=83) remained stable. There was a significant improvement in children’s receptive vocabulary (95% CI .019-.025) with moderate effect size, but not expressive vocabulary.

Conclusions

Outcomes indicate a potential role for SP embedded within education as a preventative strategy in children’s early social-emotional mental health and wellbeing. Further work is required to explore direct impacts on mental health services and long-term impacts on SEMH.

What is already known on this topic

Child-centred SP is emerging as an alternative approach to support within health and voluntary sectors, however there is a gap in SP embedded within education, and limited evidence for the impact of SP on child SEMH and wellbeing.

What this study adds

Early evidence for education-embedded SP as a potential preventative strategy in children’s mental health and wellbeing.

How this study might affect research, practice or policy

Outcomes have potential implications for supporting capacity of primary and secondary care services, a framework for collaborative delivery of support between education, health and voluntary sector services, and a defined SP model for further research.
Trastuzumab Deruxtecan Combination Strongly Enhances Responses and Overcomes Sotorasib Resistance inKRASG12C-Mutant NSCLC
Authors: Ozakinci Hilal , Desai Bina , Kalos Denise , Chen Dung-Tsa , Henry Menkara , Solanki Hitendra , Boyle Theresa A. , Trejo Bittar Humberto E. , Nazario Gina S. , Haura Eric B. , Marusyk Andriy , Pellini Bruna
Published: December 2024

Introduction

Recent advances in the treatment ofKRAS-mutant non-small cell lung cancer (NSCLC) have led to the development of KRASG12Cinhibitors, such as sotorasib and adagrasib. However, resistance and disease progression remain significant challenges. In this study, we investigated the therapeutic potential of combining trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate, with sotorasib inKRASG12C-mutant NSCLC, while also evaluating HER2 expression in NSCLC samples.

Methods

The HER2 expression dependence of xenograft responses to sotorasib, T-DXd, and their combination was evaluated in therapy-naïve and sotorasib-treated tumors by immunohistochemistry (IHC). Also, we analyzed 191 clinical (pre- or on-treatment) and rapid autopsy (post-treatment) samples from 31 patients with driver-positive and driver-negative advanced stage NSCLC, assessing HER2 expression using interpretation guidelines developed for breast cancer (BC) and gastroesophageal adenocarcinoma (GEA).

Results

In the majority of preclinical models, including sotorasib-resistant tumors, the sotorasib-T-DXd combination induced stronger and more durable responses compared to monotherapies. The strong effect of the combination therapy was likely attributable to sotorasib-induced adaptive HER2 upregulation; stronger HER2 expression in sotorasib-treated tumors was linked with stronger responses. Although HER2 expression was higher in samples from patients withKRASG12C-mutant NSCLC compared to NSCLC with other driver mutations or no drivers, the difference was not statistically significant. HER2 IHC score discrepancy was also observed between BC and GEA interpretation guidelines.

Conclusions

Our results support the potential clinical utility of the sotorasib-T-DXd combination, including tumors with intrinsic and acquired resistance to sotorasib monotherapy. Since the strengths of the responses depend on HER2 expression levels, successful clinical implementation necessitates optimizing patient selection. Our results highlight the complexities of accurate HER2 interpretation in NSCLC and highlight the need for standardized testing methods.
Isobaric Tagging and Data Independent Acquisition as Complementary Strategies for Proteome Profiling on an Orbitrap Astral Mass Spectrometer
Authors: Liu Xinyue , Dawson Shane L. , Gygi Steven P. , Paulo Joao A.
Published: December 2024

Comprehensive global proteome profiling that is amenable to high throughput processing will broaden our understanding of complex biological systems. Here, we evaluated two leading mass spectrometry techniques, Data Independent Acquisition (DIA) and Tandem Mass Tagging (TMT), for extensive protein abundance profiling. DIA provides label-free quantification with a broad dynamic range, while TMT enables multiplexed analysis using isobaric tags for efficient cross-sample comparisons. We analyzed 18 samples, including four cell lines (IHCF, HCT116, HeLa, MCF7) under standard growth conditions, in addition to IHCF treated with two H₂O₂ concentrations, all in triplicate. Experiments were conducted on an Orbitrap Astral mass spectrometer, employing Field Asymmetric Ion Mobility Spectrometry (FAIMS). Despite utilizing different acquisition strategies, both the DIA and TMT approaches achieved comparable proteome depth and quantitative consistency, with each method quantifying over 10,000 proteins across all samples, with slightly more protein-level precision for the TMT strategy. Relative abundance correlation analysis showed strong agreement at both peptide and protein levels. Our findings highlight the complementary strengths of DIA and TMT for high-coverage proteomic studies, providing flexibility in method selection based on specific experimental needs.
A tale of two shrimps – Speciation and demography of two sympatric shrimp species from hydrothermal vents
Authors: Methou Pierre , Johnson Shannon B. , Sherrin John , Shank Timothy M. , Chen Chong , Tunnicliffe Verena
Published: December 2024

Hydrothermal vents can serve as natural laboratories to study speciation processes due to their fragmented distribution often with geographic barriers between habitats. Two sympatric species ofRimicarisshrimps occur at vents on the Izu-Bonin-Mariana volcanic arcs:Rimicaris loihialso found near Hawai’i andR. cambonaealso present on the Tonga Arc. These two species biogeographically co-occur and are genetically highly similar, raising the question of the mechanisms of how they maintain distinct species, including the possibility of interbreeding. Here, we use barcoding and shotgun sequencing to test if hybridization is occurring. We also evaluate population demography over 10 years to assess population densities and sex ratios at vents. Our results supportR. cambonaeandR. loihias two distinct species despite sympatry throughout part of their range and presence of hybrids. Different sex ratios between species populations suggest that life-history traits such as different mating systems might reinforce reproductive barriers. We observed fluctuations in shrimp densities alongside their genetic diversity, linked to variations in hydrothermal activity over years. We suggest that geographic isolation after a rare, historical long-distance dispersal across volcanic arcs, followed by environmentally-driven genetic fluctuations may have fostered rapid divergence by allopatry, although sympatric speciation is not excluded.
Integrated analysis of COVID-19 multi-omics data for eQTLs reveals genetic mechanisms underlying disease severity
Authors: Lee Jeongha , Jeon Eun Young , Yu Liyang , Jo Hye-Yeong , Kim Sang Cheol , Park Woong-Yang , Park Hyun-Young , Zhao Siming , Choi Murim
Published: December 2024

The global pandemic caused by the SARS-CoV-2 virus provided an unprecedented opportunity to investigate genetic factors influencing the disease severity of the viral infection. Despite a plethora of recent research on both SARS-CoV-2 and COVID-19, few have taken a systems biology approach to address individual-level variation, especially based on non-European populations. Accordingly, we analyzed multi-omics data generated at three timepoints from 193 Korean COVID-19 patients with mild or severe symptoms, composed of whole genome sequencing, blood-based single-cell RNA-sequencing (2.15M cells), 195 cytokine profiles, and human leukocyte antigen (HLA) allele data. We identified expression quantitative trait loci (eQTLs), disease severity interacting eQTLs (n= 388), and disease progression interacting eQTLs (n= 945) for various cell types. We elucidated a complex regulatory mechanism involvingHLAgenes and their targets, and identified genetic determinants of cytokine levels. Finally, we show how regulation of ieQTLs is established by upstream transcription factors (TFs), illustrating complex regulation of theIGFBP7ieQTL by a combined action of two TFs, which is potentially important in conferring differential severity. This study illuminates an efficient molecular interrogation framework that can be applied toward understanding infectious disease progression in individuals of different genotypes.
Mental Health and Service Utilization Among Asian-Indians in the United States: A Scoping Review
Authors: Xavier Rose Mary , Kaur Harjas , Kalidindi Ram N.
Published: December 2024

Background:

Asian-Indians living in the US are severely underrepresented in mental health research. Though there are more studies on Asian-Indian mental health now than there was a decade ago, much remains unknown including the experience and prevalence of mental health disorders, service utilization, impact of cultural influences, and barriers and facilitators in seeking mental health support and treatment. The purpose of this scoping review was to examine mental health and mental health service utilization among Asian-Indians in the US.

Methods:

We conducted a scoping review of published literature. Two reviewers independently screened 2687 articles for potential inclusion—1976 were excluded based on title and abstract review alone and 675 on full-text review. An additional 8 articles identified during full text review resulted in a total of 44 articles included in the scoping review.

Results:

Of the 44 studies, 33 used a quantitative design, 3 studies used a multiple or mixed methods design and 8 used a qualitative design. Given the broad theme of our research question and since the final list of studies included varied widely in their focus and methods, we present our results using a descriptive, narrative synthesis.

Conclusions:

Cultural values, familial roles and support, and stigma significantly impact both mental health and help seeking behaviors of Asian Indians. There are major gaps in the literature surrounding child and youth mental health, mental health disorders and pathways to mental health care. These findings are discussed in the context of relevance for practice, policy and the need for high quality research.
ITGB4 promotes the progression of colorectal cancer by activating Wnt/β-catenin signaling pathway via targeting EZR
Authors: Wang Jing , Si Yi , Xuan Mingda , Han Shuangshuang , Liu Kunyi , Jiao Jiao , Men XiaoYan , Li HongFei , Yu Weifang , Liu Ting , Wang Jia
Published: December 2024

Background

Integrin Beta 4 (ITGB4), a member of the integrin family, was found to be abnormally highly expressed in colorectal cancer tissues and serum in our previous research, and it was associated with clinicopathological types and overall survival. This study further explores the potential mechanisms of ITGB4 in the occurrence and development of colorectal cancer, seeks downstream target genes and signaling pathways, and provides new insights for precision treatment of colorectal cancer.

Methods

Through bioinformatics analysis, it was verified that ITGB4 and EZR are highly expressed in tumor tissues of CRC patients and are associated with poor patient prognosis. The effects of ITGB4 on the proliferation, migration, invasion, and apoptosis of CRC cells were validated using CCK-8, wound healing assay, Transwell migration, and invasion assays. A nude mouse tumor formation experiment was conducted to validate the tumor-promoting effect of ITGB4 in vivo. Transcriptome sequencing was performed in SW480 cells with ITGB4 knockdown, and potential downstream targets and signaling pathways of ITGB4 were screened using KEGG enrichment analysis and bioinformatics analysis. The interaction between ITGB4 and downstream target genes was further demonstrated by immunofluorescence co-staining and co-immunoprecipitation. Key proteins in the downstream signaling pathway (β-catenin, c-Myc, and cyclinD1) were detected by Western blot to clarify the potential signaling pathway through which ITGB4 functions in CRC. Rescue experiments were conducted to validate the role of ITGB4 and its downstream target genes in the proliferation, migration, and invasion of colorectal cancer.

Results

ITGB4 is highly expressed in CRC tissues and cells. In vitro, downregulation of ITGB4 can inhibit the proliferation, migration, and invasion of CRC cells and promote apoptosis. In vivo, ITGB4 contributes to the growth of CRC tumor tissues and regulates the tumorigenic properties such as proliferation and invasion of CRC cells. Additionally, EZR has been preliminarily identified as a key downstream target of ITGB4, as the effects of ITGB4 knockdown on the proliferation, migration, and invasion of CRC cells can be rescued by overexpressing EZR. We also demonstrated that the ITGB4/EZR axis promotes the occurrence and development of CRC by activating the Wnt/β-catenin signaling pathway and regulating various biological functions of CRC cells.

Conclusions

ITGB4 targets and regulates EZR, and by activating the Wnt/β-catenin signaling pathway, it affects the proliferation, migration, and invasion of CRC, suggesting that ITGB4 may become a potential biomarker and therapeutic target.
Investigating Amino acid Enrichments and Patterns in Phase-Separating Proteins: Understanding Biases in Liquid-Liquid Phase Separation
Authors: Calvário Joana , Antunes Diogo , Cipriano Rita , Kalafatovic Daniela , Mauša Goran , Pina Ana S.
Published: December 2024

Liquid-Liquid Phase Separation (LLPS) forms membraneless organelles, enhancing biochemical processes. The stickers-and-spacers model explains LLPS but is mainly validated in Prion-like RNA Binding Proteins. We explore peptide motifs in LLPS in broader protein contexts. We developed a computational approach for motif discovery, implemented in 178 Phase-Separating Proteins (PhSePs), complemented by the FuzDrop and CIDER servers, which identified droplet-promoting regions (DPRs) and examined disorder-related characteristics. Our database of PhSePs was analyzed against proteins with low propensity for LLPS. This comparative analysis revealed 129 enriched peptide motifs with folds higher than 0.2, consisting of 3 to 6 residues, with tetrapeptides being the most prevalent. Key features of the enriched motifs included Gly-rich sequences punctuated with aromatic, charged, and polar residues, as well as homopeptide repeats (e.g., GGDR, SRGG, YGGG, QQQQ, PPPP). Analysis of motif presence, frequency, and co-occurrence revealed widely distributed motifs across different DPRs, identified motifs with significant repetitive patterns, and highlighted motif trios that are more likely to co-occur within a sequence. By harvesting this analysis, we developed a data-driven approach for minimalistic peptide design with LLPS propensity, further using the CIDER server for peptide characterization and peptide design refinement. We designed 8 peptides with various motif combinations and amino acid distributions, which were experimentally validated to undergo LLPS, exhibiting liquid-like behavior with diverse molecular mobility patterns and droplet dynamics. Our approach bridges a non-biased computational approach with experimental validation, offering insights into sequence determinants of phase separation, with the potential for designing minimalistic synthetic condensates with tailored properties.
Personalization of Closed-Chain Shoulder Models Yields High Kinematic Accuracy for Multiple Motions
Authors: Hammond Claire V. , Henninger Heath B. , Fregly Benjamin J. , Gustafson Jonathan A.
Published: December 2024

The shoulder joint complex is prone to musculoskeletal issues, such as rotator cuff-related pain, which affect two-thirds of adults and often result in suboptimal treatment outcomes. Current musculoskeletal models used to understand shoulder biomechanics are limited by challenges in personalization, inaccuracies in predicting joint and muscle loads, and an inability to simulate anatomically accurate motions. To address these deficiencies, we developed a novel, personalized modeling framework capable of calibrating subject-specific joint centers and functional axes for the shoulder complex. Leveraging in vivo biplane fluoroscopy data and the recent Joint Model Personalization Tool from the Neuromusculoskeletal Modeling Pipeline, we optimized joint parameters and body scale factors for shoulder models with varying degrees of freedom (DOFs). We initially created and tested open-chain scapula-only models (3DOF, 4DOF, and 5DOF) and found that increasing DOFs improved accuracy, with the 5 DOF model yielding the lowest marker distance errors (average = 0.8 mm, maximum = 5.2 mm) as compared to biplane fluorscopy data of the scapula across eight movement trials. We subsequently created closed-chain shoulder models incorporating scapula, clavicle, and humerus bodies. We found closed-chain shoulder models with 5 DOFs for the scapula achieved the highest accuracy (average = 0.9 mm, maximum = 5.7 mm) and showed consistent performance across subjects (n=3) in leave-one-out cross-validation tests (average marker distance errors = 1.0–1.4 mm). This framework minimizes errors in joint kinematics and provides a foundation for future models incorporating personalized musculature and advanced simulations, enhancing its potential clinical utility for rehabilitation and surgical planning.
Segregated localization of target-SNARE proteins within presynaptic terminals of Munc18-1 deficient photoreceptors
Authors: Huang Mengjia , Chow Chun Hin , Charish Jason , Indrawinata Karen , Harada Hidekiyo , Wallace Valerie A. , Monnier Philippe P. , Sugita Shuzo
Published: December 2024

Sec1/Munc18 family proteins are essential for SNARE-mediated vesicular exocytosis. However, where SNARE proteins are localized in Munc18-1 deficient presynaptic terminals remains unclear due to the rapid degeneration of neurons lacking Munc18-1. Here, we found that removing Munc18-1 from photoreceptor cells did not result in major cellular loss until postnatal day 14, which allowed us to investigate the role of Munc18-1 in endogenous presynaptic terminals. In the absence of Munc18-1, even before major photoreceptor cell degeneration, functional impairments were present. While Munc18-1 was not required for the pre-synaptic enrichment of the t-SNARE proteins syntaxin-3 and SNAP-25, it played a critical role in their proper localization. In wild-type conditions, t-SNAREs are highly colocalized. However, in the absence of Munc18-1, their distribution becomes strikingly segregated. Immuno-electron microscopy revealed that without Munc18-1, syntaxin-3 is retained within various organelle membranes rather than being targeted to synaptic plasma membranes. These findings provide the first evidence that Munc18-1 is important to prevent segregation of syntaxin-3 and SNAP-25 within presynaptic terminals.
Global Biogeography of Prokaryotes in Mangrove Sediments: Spatial Patterns and Ecological Insights from 16S rDNA Metabarcoding
Authors: Jamon-Haon Emma , Cuny Philippe , Rossi Alix , Sylvi Léa , Fiard Maud , Militon Cécile
Published: December 2024

The global asymmetry in the floristic diversity distribution within mangrove ecosystems is well-documented. However, sediment microbial communities, which play crucial ecological roles, are often overlooked in mangrove biogeography studies. This study aimed to investigate the diversity, composition, and distribution of prokaryotic communities across distinct mangrove bioregions (12 countries and territories from the Caribbean bioregion, Southeast America, East Africa, Indo-Malaysia and Australasia). We conducted a meta-analysis by compiling 16S rDNA datasets from 17 previous studies (540 samples) over a six year period (2014-2020) and applied community ecology analyses combined with random forest models. Although no significant correlation was observed between tree richness and microbial diversity, a microbial hotspot was identified in the Indo-West Pacific region. Microbiota associated with different mangroves displayed opposite latitudinal diversity gradients and beta-dispersions. Distance-decay relationships were weak but statistically significant. Random forest models identified key microbial taxa, and the OTUs shared across all bioregions suggested the presence of a potential core mangrove microbiota. Taxonomic and statistical analyses underscored the great heterogeneity of microbiota composition, heavily influenced by the study (e.g., molecular and bioinformatic methodologies). Future research on mangrove microbiome would benefit from standardized sampling and sequencing methods. Despite current limitations, distance-decay relationship confirmed the influence of dispersal barriers for mangrove sediment microbiota. This study also suggests that environmental factors, rather than plant diversity alone, may play a prominent role in shaping the diversity, composition and distribution of prokaryotic communities in mangrove sediments.