bluuebunny/crossref_metadata_2025 huggingface dataset:
A dual thermo/pH-sensitive hydrogel as 5-Fluorouracil carrier for breast cancer treatment
Authors: Luo Kairan , Hu Wenbin
Published: January 2025

Intelligent hydrogels are promising in constructing scaffolds for the controlled delivery of drugs. Here, a dual thermo- and pH-responsive hydrogel called PCG [poly (N-isopropyl acrylamide-co-itaconic acid)/chitosan/glycerophosphate (PNI/CS/GP)] was established as the carrier of 5-fluorouracil (5-FU) for triple-negative breast cancer (TNBC) treatment. The PCG hydrogel was fabricated by blending synthesized [poly (N-isopropyl acrylamide-co-itaconic acid), pNIAAm-co-IA, PNI] with CS in the presence of GP as a crosslinking agent. The interaction between PCG hydrogel compositions was characterized by Fourier transforms infrared, NMR spectroscopy, and scanning electron microscopy. The PCG hydrogel presented an interconnected and porous structure with similar pore size, rapid swelling/deswelling rate in response to both temperature and pH change, and biocompatibility, upon which it was proposed as a great drug carrier. 5-FU had a dual thermo- and pH-responsive controlled release behavior from the PCG hydrogel and displayed an accelerated release rate in an acidic pH environment than in a neutral pH condition. The application of 5-FU-loaded PCG hydrogel exhibited a more promoted anticancer activity than 5-FU against the growth of TNBC cells both in vitro and in vivo. The outcomes suggested that the PCG hydrogel could be an excellent platform for local drug-delivery systems in the clinical therapy of TNBC.
Dual inhibition of TYK2 and PD-L1 boosts immune response in triple negative breast cancer
Authors: Xiang Huali , Tu Binfeng , Feng Xin , Chen Linjing , Huang Yajuan
Published: January 2025

Recent studies have shown that Janus Kinase inhibitors can enhance the tumor therapeutic effect of immune checkpoint inhibitors. However, it remains to be studied whether TYK2 selective inhibitors can enhance the therapeutic effect of small molecule PD-L1 inhibitors in triple-negative breast cancer (TNBC). We verified the efficacy of the combination of the selective TYK2 inhibitor Deucravacitinib and the small molecule inhibitor of PD-L1, INCB086550, in two TNBC animal models: a syngeneic mouse model (4T1 with humanized PD-L1) and a peripheral blood mononuclear cell (PBMC)-humanized model (MDA-MB-231). Following that, we explored the regulation of immune cell activity in tumors by the combined treatment using flow cytometry. Finally, we validated the expression of genes related to the regulated immune cells through reverse transcription-PCR. Both animal models demonstrated that the addition of a TYK2 inhibitor to a PD-L1 inhibitor significantly enhanced the antitumor capabilities of mice with good safety profiles. The combined therapy significantly elevated the counts of T, B, and natural killer cells while concurrently diminishing myeloid-derived suppressor cells in the syngeneic model. Similarly, in the PBMC-humanized model, this therapy markedly augmented progenitor-like and proliferative precursor-like CD8 T cells, while effectively diminishing exhausted and terminally differentiated CD8 T cell populations. This enhanced antitumor effect is associated with the modulation of antitumor immune-related gene expression by the combined therapy. The combination of TYK2 inhibitors and immune checkpoint inhibitors is a potentially effective strategy for treating TNBC.
Understanding the rising abuse of veterinary medicine xylazine: a review
Authors: Ikram Areeba , Ikram Sameen , Zainab Asra , Inam Mubah , Azhar Ayesha , Elsayed Saeed Ahmed Saleh
Published: January 2025

Xylazine, the new “zombie drug” is a veterinary medicine utilized for anesthesia, sedation, muscle relaxation and pain relief, to facilitate the approach of medical examinations, X rays, minor superficial surgeries, and any other painful manipulative procedure across a variety of species. Xylazine use as an adulterant among other drugs of abuse like heroin and fentanyl was first reported in Puerto Rico in 2006. Over time it has made its way to illicit drug trades, implicated in xylazine-positive overdose deaths. It acts as an ‘Alpha 2 Adrenergic Agonist’ and accelerates the activation of ‘inhibitory neurons’ in CNS. Owing to its inhibitory effects, prolonged duration of action and easy accessibility, xylazine serves widely as a recreational drug. Its long-drawn abuse aggravates toxic effects including hypotension, necrotic skin lesion, respiratory and CNS depression and cardiac arrest.

Xylazine, a veterinary tranquilizer, not approved for human use by the FDA has emerged as a new drug of abuse on the streets. Multiple studies suggest a high rise in xylazine associated overdose deaths especially in the United States due to its endemic region of Puerto Rico, where it is widely and easily available. FDA has issued a high alert highlighting rise in “zombie drug” abuse. Awareness of xylazine and its fatal outcomes among public is of immense importance in preventing its abuse.
Technological innovation and revolution with single-use digital flexible ureteroscopes: a review from section of EAU Endourology
Authors: Talyshinskii Ali , Tzelves Lazaros , Ventimiglia Eugenio , Yuen Steffi Kar Kai , Gauhar Vineet , Traxer Oliver , Somani Bhaskar
Published: January 2025

Purpose of review

Numerous scope-related innovations have taken place in the field of endourology. The presented analytical review is aimed at studying the technical innovations of the single-use digital flexible ureteroscopes. In November 2024, a comprehensive search was done for information on latest disposable flexible digital ureteroscopes, as well as their various unique characteristics. A thorough examination was conducted for image qualities; sizes and channels; and deflection capabilities. Furthermore, supplementary features about the latest advances were assigned to a separate group including ‘Unique’ solutions. Using the last search query, various innovations in flexible ureteroscopy in general were also searched and sorted into appropriate groups.

Recent findings

Modern single-use flexible digital ureteroscopes are characterized by advanced technologies for transmitting light and images, miniaturization, as well as by a number of unique solutions that were previously characteristic only of semi-rigid or fiberoptic endoscopes. These include features such as integrated buttons for data recording, self-locking mechanism, separate ports, rotating shaft, direct-in-scope suction, pressure monitoring, enhanced tip control and customizable settings.

Since their introduction in urology, endoscopes have undergone many changes, as illustrated by the example of single-use flexible digital ureteroscopes. The imaging quality has improved, the dimensions of both the distal tip and shaft have decreased, with over 15 manufactures producing and distributing these scopes. A lot of new additional new features are likely to enhance the efficacy and safety of ureteroscopic procedures.
Massive fecaloma causing bilateral hydronephrosis and acute kidney injury: a case report and review of the literature
Authors: AlJardali Baraa , Nasrallah Oussama G. , Deeba Samer , El Hajj Albert
Published: January 2025

Introduction and importance:

Postrenal acute kidney injury is caused by urinary outflow obstruction either by urethral obstruction or bilateral ureteral obstruction. Fecal impaction was rarely reported to cause hydronephrosis or acute kidney injury.

Case presentation:

A 76-year-old woman presented with abdominal pain, severe constipation, and lethargy. CT scan showed a massive rectosigmoid fecaloma with changes consistent with stercoral colitis with bilateral hydroureteronephrosis due to the mass effect from the large fecaloma on the distal ureters. Creatinine had climbed to 1.7 mg/dL with electrolyte disturbances. On the sixth day of hospitalization the patient had perforation of the left colon requiring Hartmann’s procedure. The hydronephrosis resolved after surgery with complete recovery from acute kidney injury as creatinine went back to baseline of 0.46 mg/dL.

Clinical discussion:

The literature described a few cases of fecalomas causing hydronephrosis due to compression of the urinary tract. The presence of a urinary tract infection in the presence of ureteral obstruction poses a risk of developing obstructive pyelonephritis thereby requiring urgent treatment of the cause.

Conclusion:

Most fecalomas can be cleared using conservative measures. However, recognition of the need of surgical intervention in timely manner is paramount to avoid complications including acute kidney injury and bowel perforation
The Relationship of PRAME Expression with Clinicopathologic Parameters and Immunologic Markers in Melanomas: In Silico Analysis
Authors: Cakir Yasemin , Lebe Banu
Published: January 2025

PRAME is a cancer testis antigen whose expression is limited in normal tissues but is increased in cancers. Although there are studies revealing its oncogenic and immunogenic role, the relationship between PRAME expression and immunity in melanomas is not very clear. We aimed to reveal the relationship between PRAME expression and clinicopathologic parameters, immunologic markers, survival in melanomas. PRAME alteration data in TCGA SKCM data set was obtained from cBioPortal. Analyzes regarding clinicopathologic parameters were performed through cBioPortal and UALCAN, survival-related analyzes were performed through cBioPortal, GEPIA2. The correlation analyzes between PRAME expression and immune cell infiltration, immunity-related genes were performed in TIMER2.0, TISIDB, GEPIA2. PRAME protein-protein interaction network was constructed in STRING. The correlated genes with PRAME were listed in LinkedOmics, gene set enrichment and pathway analyses were performed through LinkInterpreter. In cases with low PRAME expression, there was a higher frequency of metastasis and p53 mutation, a more advanced tumor stage and a lower nodal stage. Strong relationship between PRAME expression and immune cell infiltration. A negative correlation was detected between expression of PRAME and many immunomodulatory genes (P<0.05). Positively correlated genes with PRAME expression were involved in metabolic pathways; negatively correlated genes were involved in pathways related to cell differentiation, immunologic processes. No significant relationship was found between PRAME expression and survival (P>0.05). Our findings reveal a strong interaction between PRAME expression and tumorigenicity, the immune system and shed light on further clinical studies including PRAME-targeted studies.
Fall Risk Assessment in Acute Rehabilitation: Comparison of Two Assessment Tools
Authors: Menard Heidi E. , Castro-Pearson Sandra , Dahle Nate , Edmonds Stephanie W. , Kozitza Brandy J. , Webb Johanna J. , Bryant Ruth A.
Published: January 2025

Purpose

Many fall risk assessment tools exist. However, few of these fall risk assessment tools have been tested in the acute rehabilitation setting. The purpose of our study was to compare the accuracy of the Hendrich II Fall Risk Model (HIIFRM) and Sunnyview Test Scale in predicting falls. We also identified factors associated with falls in the rehabilitation patient.

Design and Methods

In this retrospective cohort study, we extracted electronic health record data from two acute inpatient rehabilitation units and compared the predictive validity of the HIIFRM and the Sunnyview Test Scale.

Results

Our sample included 134 fallers and 1,667 nonfallers. The HIIFRM and the Sunnyview Test Scale had similar predictive performance with area under the receiver operating characteristic curve (AUC) of .62 and .60, respectively.

Conclusion

The HIIFRM and the Sunnyview Test Scale had poor performance (AUC < .70) predicting falls in this acute rehabilitation setting. Using a fall risk assessment tool alone does not consider unique risk factors and makes implementation of individualized prevention interventions challenging. Nurses need a framework to use individualized factors to determine high fall risk. Further research is needed to clarify variables specific to the inpatient rehabilitation population.

Clinical Relevance

Current fall risk assessment tools are inadequate in the inpatient rehabilitation setting; an individualized fall prevention plan is recommended to ensure patient safety.
CBCT-Based Analysis of Factors Influencing the Quality of New Bone Formation Following Mandibular Distraction Osteogenesis in Children With Pierre Robin Sequence
Authors: Zhou Jiawei , Mao Zhe , Chen Kairui , Xu Shuzheng , Cui Yingqiu
Published: January 2025

The aim of this study was to explore the factors influencing the quality of new bone formation after distraction osteogenesis in children with Pierre Robin sequence (PRS). Using cone-beam computed tomography (CBCT), bone density relative grayscale values of the region of new bone formation before and 3 to 4 months after mandibular distraction osteogenesis (MDO) were measured in 80 children with PRS, and correlation analysis was conducted with the potential clinical influencing factors of the children. CBCT reconstruction of the panoramic film showed that the new bone formation was good at 3 to 4 months after MDO. There was a statistically significant difference in the gray value of cancellous bone before and after the operation (P<0.01). The gray values of bilateral mandibular new bone after MDO were related to cleft palate, preoperative weight, preoperative body mass index (BMI), and distraction length. Finally, the variables included in the multiple linear regression model were cleft palate and preoperative BMI. At 3 to 4 months after MDO, the mineralization degree of cancellous bone in the central region of the bilateral mandibular new bone formation area was lower. The presence of cleft palate and preoperative BMI were identified as the main factors influencing the new bone formation in bilateral mandibles after MDO. This may be attributed to the catch-up nutritional acquisition and growth promotion in children, which facilitates new bone formation, along with greater chewing muscle strength to prevent mineral loss from bones.
Fish reproductive phenology shifts with increasing temperature and year
Authors: Koenigbauer S. T. , Cubbage M. L. , Warren L. D. , Tellier J. M. , Selz O. M. , Sass G. G. , Höök T. O.
Published: January 2025

Temperate fishes often spawn in response to environmental cues, such as temperature, thereby facilitating larval emergence concurrent with suitable biotic and abiotic conditions, such as plankton blooms. Climatic changes may alter the reproductive phenology of spring- and autumn-spawning freshwater fish populations. Such effects may depend on the sensitivity of reproductive phenology to ambient temperatures. We applied a meta-analysis approach to test whether annual temperature and year affected fish reproductive phenology. Based on preliminary tests in walleye (
Sander vitreus
) and Lake Constance whitefish (
Coregonus arenicolus
), we hypothesized that increasing temperature would promote earlier spring-spawning and later autumn-spawning. We found spawning was significantly earlier in the spring and later in the autumn. We found that migration of autumn-spawning species occurred earlier with warmer temperatures, implying that with increasing temperatures, migrating autumn-spawning species will increase residence time in tributaries. We also found that spring-spawning fishes reproduced earlier in more recent years, while we observed no significant effect in autumn-spawners. Spring- and autumn-spawning fishes displayed interannual variation in spawning dates (mean range of 34.4 and 27.0 days over 33.9 years, respectively), with spring-spawning fishes displaying a significantly broader range in spawning dates.
Hidden population turnover of small odontocetes in the northwestern North Pacific during the Holocene
Authors: Kishida Takushi , Sawada Kyohei , Namigata Sakiko , Takabatake Takamune , Suzuki Miwa , Takezoe Nanami , Yamamoto Takumi , Nakanishi Toshimichi , Kitagawa Hiroyuki
Published: January 2025

Despite numerous studies on the rise and fall of terrestrial megafauna in the late Quaternary, knowledge about marine megafauna from this period remains limited. In this study, we performed radiocarbon dating and partial mitochondrial DNA sequencing from the skeletal remains of three species of small odontocetes (Pacific white-sided dolphins, Dall’s porpoises and harbour porpoises) excavated from prehistoric archaeological sites around the Japanese shore dating back to 8500–1000 years ago (ya). Pacific white-sided dolphins that habituated the eastern coast of Hokkaido around 2000 ya belonged to different maternal groups than those from over 5000 ya and today. Furthermore, the species composition excavated from eastern Hokkaido sites varies between 5000 and 2000 ya. These findings suggest two significant population turnovers of small odontocetes on the east coast of Hokkaido, a transitional zone between the coastal area of East Asia and the offshore North Pacific. Notably, the first turnover, occurring between 5000 and 2000 ya, represents the oldest evidence of local population turnovers of marine megafauna during the late Quaternary.
Skin adaptation in lower limb amputees assessed through Raman spectroscopy and mechanical characterization
Authors: Hayes Jack , Andrews Jennifer , Abdelwahab Omar , Andriuskevicius Tomas , Briggs Tom , Gordon Ralph , Worsley Peter , Higgins Claire A. , Masen Marc
Published: January 2025

Following lower limb amputation residuum skin from the lower leg is used to reconstruct the residual limb. Unlike skin on the sole of the foot (plantar skin), leg skin is not inherently load bearing. Despite this, leg skin is required to be load bearing in the prosthetic socket. Current hypotheses propose that lower limb amputee skin can adapt to become load bearing with repeated prosthesis use. Here, we show using confocal Raman spectroscopy, mechanical characterization and cytokine analysis that adaptations occur which actually result in impaired barrier function, higher baseline inflammation, increased coefficient of friction and reduced stiffness. Our results demonstrate that repeated frictional trauma does not confer beneficial adaptations in amputee skin. We hypothesize that non-plantar skin lacks the biological capabilities to respond positively to repeated mechanical trauma in the same manner observed in plantar skin. This finding highlights the need for improved therapies as opposed to current mechanical conditioning or product solutions that directly relate to improving load-bearing capacity on the skin of lower limb amputees. This study also highlights the importance of measuring multiple parameters of application-specific skin at different scales for skin tribology applications.
Characterization of 1,8-diazabicyclo(5.4.0)undec-7-ene-hydroxyl-based ionic liquid for CO
2
capture
Authors: Amat Syarafana O. , Yunus Normawati M. , Wilfred Cecilia D.
Published: January 2025

Six 1,8-diazabicyclo(5.4.0)undec-7-ene-based ionic liquids (ILs) linked with ethyl or propyl hydroxyl cations, coupled with thiocyanate, dicyanamide and bistriflimide anions, were synthesized through a two-step reaction: quaternization and ion exchange. The characterization of the ILs was carried out using
1
H and
13
C nuclear magnetic resonance spectroscopy (NMR) and Fourier-transform infrared spectroscopy (FTIR). The NMR results confirmed the structures of all the ILs, and these were supported by the FTIR results. In addition, the physicochemical properties, namely thermal stability, density and refractive index, were determined. The effects of the chain length in the cation and the identity of the anion on CO
2
absorption were studied in a pressure drop equipment at different pressures. It was found that CO
2
sorption increased with increasing pressure and the number of nitrile groups present. The highest CO
2
sorption is reported to be 0.96 mol CO
2
mol
−1
IL at 20 bar.
Multiple drivers of spring migration timing for red deer over the past 16 years in northern Europe
Authors: Hjermann Tilde Katrina Slotte , Rivrud Inger Maren , Meisingset Erling L. , Mysterud Atle
Published: January 2025

The timing of migration is fundamental for species exploiting seasonally variable environments. For ungulates, earlier spring migration is expected with earlier vegetation green-up. However, other drivers, such as access to agricultural farmland and variation in local conditions, are also known to affect migration. We investigated the timing of spring migration for 96 male and 201 female red deer (
Cervus elaphus
) using a long-term dataset (2005–2020). Overall, the timing of migration was mainly characterized by large individual variability between and within years (95% range 6 April to 18 June). The spring migration timing was, as expected, later with colder winter and spring conditions (North Atlantic Oscillation (NAO) winter and April indices) and later peak vegetation green-up (NDVI), with a five-day delay in green-up causing a migration delay of 1.2 days. Timing was also influenced by local conditions in summer and winter home ranges. Red deer with greater access to farmland and a more variable topography (hence variable plant phenology) in winter delayed migration. Similarly, individuals with higher-elevation summer ranges (with delayed onset of plant growth) also delayed migration. Our analyses highlight that the timing of red deer migration is determined by multiple drivers affecting foraging conditions in the landscape, indicative of considerable phenotypic plasticity.
Antibiotic use and antimicrobial resistance: Knowledge, Attitude and Practices survey of medical students to evaluate undergraduate training curriculum
Authors: Saksena Rushika , Parida Annapurna , Jain Madhura , Gaind Rajni
Published: January 2025

Introduction. A better understanding of knowledge, attitude and practices of undergraduate medical students towards antimicrobial resistance (AMR) is necessary to identify gaps in the current training curriculum.

Methods. A 20-point Likert scale-based questionnaire divided into three parts, knowledge, attitude and practices, relating to antibiotic use and resistance was devised. Students attending each year of the undergraduate medical programme were approached to participate in the study over a 1-week period. Knowledge, Attitude and Practices scores of each year were compared through logistic ordinal regression and the Kruskal–Wallis (KW) test.

Results. Two hundred and eight students participated in the study. Overall, knowledge of about intended use of antibiotics, fixed drug combinations and awareness about AMR was good (average score of 73.75%). Steady improvement in knowledge scores was observed from the first year (−0.441) to the final year (0.00). The medical students had favourable attitude towards rational antimicrobial use (Likert score ≥4), including the need to spread awareness about AMR amongst students and the public and following doctor’s prescriptions. Self-medication was reported by 28.4% of students and hoarding of leftover doses by 49.1%. Attitude score had a direct correlation with the knowledge score on the KW test (χ
2=29.6, P≤0.5) but had no significant correlation with antimicrobial practices (χ
2=3.9, P≥0.5). The gaps identified in students’ practices included self-medication, skipping of dosing and hoarding of leftover medication.

Conclusion. As improvement in knowledge did not correlate with better personal behaviours regarding antibiotics, the current curriculum needs to include AMR as a focus area to ensure good antibiotic prescribing practices in future practitioners.
Molecular characterization of enteroviruses circulating among pigs and goats in two Central African countries, Cameroon and the Central African Republic
Authors: Modiyinji Abdou Fatawou , Joffret Marie-Line , Nombot-Yazenguet Marina Prisca de Marguerite , Endengue Zanga Marie-Claire , Sadeuh-Mba Serge , Njouom Richard , Bessaud Maël
Published: January 2025

To date, data on animal enteroviruses (EVs) are scarce, especially in Central Africa. The aim of this study was to characterize EVs among pigs and goats in Cameroon and the Central African Republic (CAR). A total of 226 pig and goat faecal samples collected in two previous studies carried out in Cameroon and CAR were pooled and screened with molecular assays targeting EV-Es, EV-Fs and EV-Gs. EV genomes were amplified by RT-PCR and their sequences were obtained by Illumina sequencing and de novo assembly. Based on the capsid sequences, 27 EV-G sequences were identified and assigned to 11 virus types, while no EV-E or EV-F was observed. Phylogenetic analysis revealed that the EV-Gs detected in Central Africa do not form specific clusters compared to EV-Gs previously reported in other continents. This suggests a worldwide circulation of EV-Gs, which is likely due to the massive international trade of live animals. One human EV, EV-C99, which belongs to the species Enterovirus C, was detected in pigs. This is the third detection of such an event in a similar context, reinforcing the hypothesis that some EV-Cs could be infecting pigs. Our work provides new data on the genetic diversity of EVs circulating among domestic animals in Central Africa.
Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome
Authors: Zgadzay Yury , Mirabello Claudio , Wanes George , Pánek Tomáš , Chauhan Prashant , Nystedt Björn , Zíková Alena , Whitford Paul C. , Gahura Ondřej , Amunts Alexey
Published: January 2025

The assembly of the mitoribosomal small subunit involves folding and modification of rRNA, and its association with mitoribosomal proteins. This process is assisted by a dynamic network of assembly factors. Conserved methyltransferases Mettl15 and Mettl17 act on the solvent-exposed surface of rRNA. Binding of Mettl17 is associated with the early assembly stage, whereas Mettl15 is involved in the late stage, but the mechanism of transition between the two was unclear. Here, we integrate structural data fromTrypanosoma bruceiwith mammalian homologs and molecular dynamics simulations. We reveal how the interplay of Mettl15 and Mettl17 in intermediate steps links the distinct stages of small subunit assembly. The analysis suggests a model wherein Mettl17 acts as a platform for Mettl15 recruitment. Subsequent release of Mettl17 allows a conformational change of Mettl15 for substrate recognition. Upon methylation, Mettl15 adopts a loosely bound state which ultimately leads to its replacement by initiation factors, concluding the assembly. Together, our results indicate that assembly factors Mettl15 and Mettl17 cooperate to regulate the biogenesis process, and present a structural data resource for understanding molecular adaptations of assembly factors in mitoribosome.
Rewilded Highland Cattle in conservation grazing may not groom more when horseflies are present and temperature is higher
Authors: Kim Jinhwi , Korner Pius , Amrhein Valentin , Lovasz Lilla
Published: January 2025

Grooming behavior in domestic cattle serves various functions, including hygiene maintenance, social bonding, and stress alleviation. We examined the grooming patterns of rewilded Highland cattle, to describe their behavioral adaptations and responses to environmental factors in a conservation grazing system. We observed 21 Highland cattle in a French nature reserve from November 2020 to September 2021 using mixed focal and scan sampling methods, recording a total of 1225 grooming bouts. Grooming primarily consisted of self-grooming (83%), followed by tree-grooming (16%), and social-grooming (1%). The average grooming duration per bout was 48.2 seconds per 15-minute interval, indicating a stable and consistent grooming pattern across all observed cattle. We used linear and generalized mixed effect models to assess the effects of environmental factors such as the presence of horseflies, the Temperature-Humidity Index (THI), and habitat type. Our results showed that grooming behavior was influenced by habitat and group, while environmental stressors had only minor effects on grooming duration and frequency. This limited response may be attributed to the relatively low density of horseflies in our study area and the opportunity of adaptive behaviors, such as wallowing, to manage heat and ectoparasites. By examining grooming behavior under near-natural conditions, this study provides a baseline for understanding behavioral patterns and adaptations in rewilded cattle, while also serving as a potential reference for identifying behavioral changes in domestic cattle and informing future management practices.
Variations in iron profile among dialysis adherent chronic kidney disease patients and compare with the non-adherence chronic kidney disease patients
Authors: Ogolla Collince Odiwuor , Karani Lucy W. , Musyoki Stanslaus
Published: January 2025

Background

Chronic kidney disease (CKD) constitutes one of the most important global health challenges and iron deficiency (ID) anemia are both frequent complications, especially in patients on dialysis. Dialysis treatment is an important aspect of addressing these complications, yet the treatment adherence rate is low in CKD patients and the association between dialysis adherence and differences in iron profiles among CKD patients is unclear.

Objectives

This study aimed to assess differences in iron profile in dialysis-adherent and non-adherent chronic kidney disease subjects and analyze the profiles between both groups.

Methods

One hundred twenty patients undergoing hemodialysis were included in this cross-sectional study, divided into two groups based on two subcategories of dialysis adherence-adherent (n=60) and nonadherent (n=60). The parameters of iron profile-also defined as serum ferritin, transferrin saturation (TSAT), hemoglobin, and serum iron-were studied. Further, multivariate regression analysis was carried out, adjusting possible confounders such as age, sex, diabetes, and duration of dialysis. Results: Serum ferritin was significantly higher among patients in the adherent group when compared with those in the non-adherent group (235.6 120.2 ng/mL vs. 185.2 105.3 ng/mL; p=0.03), TSAT (33.4 9.3% vs. 28.8 10.2%; p=0.02), and hemoglobin level (11.5 1.8 g/dL vs. 10.2 2.1 g/dL; p=0.04). That is, non-adherence to the therapy was associated with a significantly higher number of patients having iron deficiency anemia (63% in non-adherent vs. 40% in adherent patients; p=0.01). Multivariate analysis confirmed that dialysis adherence was independently associated with better iron status (p<0.05 for all parameters).

Conclusion

In hemodialysis patients, adherence to dialysis presents as a strong predictor of better iron profile. More “iron parameters” were better and showed a decreased reliance on iron deficiency anemia for adherents. Such improvement, however, may significantly reduce anemia-associated complications through strategies that improve adherence to dialysis treatment by optimizing iron metabolism among chronic kidney disease patients.

What this study adds

This study demonstrates a significant relationship between adherence to dialysis and improved iron profiles, showing that a chronic kidney disease patient who is adherent has a better iron status and a reduced rate of having iron deficiency anemia compared with an individual who is nonadherent.
Chromatin Changes Associated with Neutrophil Extracellular Trap (NET) Formation in Whole Blood Reflect Complex Immune Signaling
Authors: Cayford Justin , Atteberry Brandi , Singh-Taylor Akanksha , Retter Andrew , Berman Benjamin P. , Kelly Theresa K
Published: January 2025

Background

Neutrophils are key players in innate immunity, forming neutrophil extracellular traps (NETs) to defend against infections. However, excess NET formation is implicated in inflammatory conditions such as sepsis and immunothrombosis. Studying NET formation in isolated neutrophils provides important mechanistic insights but does not reflect the complexity of immune interactions in whole blood, limiting our understanding of neutrophil responses.

Methods

This study investigates chromatin accessibility changes using Assay for Transposase-Accessible Chromatin with sequencing (ATAC-Seq) during phorbol 12-myristate 13-acetate (PMA) induced NET formation in whole blood. We compared chromatin accessibility patterns in neutrophils following PMA treatment in isolation and whole blood to assess the impact of other immune cells and signaling environment.

Results

Whole blood PMA stimulation elicited consistent chromatin accessibility changes across donors, demonstrating organized chromatin decondensation during NET formation. The chromatin response was characterized by increased accessibility in genomic regions enriched for immune-specific pathways, highlighting the role of immune cell interactions in NET formation. Differentially accessible regions (DARs) present following PMA induction in whole blood and isolated neutrophils showed greater association with NET-related and inflammatory transcription factors, while DARs specific to isolated neutrophils showed fewer relevant motifs. Pathway analysis indicated that whole blood responses involved more robust activation of immune-specific pathways, such as interleukin and cytokine signaling, compared to isolated neutrophils.

Conclusions

Our findings underscore the importance of studying NET formation within a whole blood environment to capture the complexity of neutrophil responses and immune cell interactions. This understanding is crucial for identifying effective therapeutic targets in NET-associated inflammatory diseases.
Humidity-driven ABA depletion determines plant-pathogen competition for leaf water
Authors: Yasuda Shigetaka , Shinozawa Akihisa , Hirase Taishi , Weng Yuanjie , Ishizaki Haruka , Suzuki Ryuji , Ueda Shioriko , Sk Rahul , Yotsui Izumi , Toyota Masatsugu , Okamoto Masanori , Saijo Yusuke
Published: January 2025

Bacterial phytopathogens, such asPseudomonas syringaepv. tomato (Pst) DC3000, induce water-soaked lesions in the leaf apoplast under high humidity, facilitating infection. However, it remains largely unclear how plants regulate their resistance to restrict bacterial infection in response to humidity. Here, we demonstrate that abscisic acid (ABA)-catabolizing ABA 8’-hydroxylase, encoded byCYP707A3, plays a critical role in this resistance inArabidopsis thaliana. Elevated humidity inducesCYP707A3expression, which is essential for reducing ABA levels and promoting stomatal opening, thereby limiting bacterial water-soaking and infection following leaf invasion. High humidity also increases cytosolic Ca2+levels via the Ca2+channels CNGC2 and CNGC4, with partial involvement from CNGC9, activating the calmodulin-binding transcription activator CAMTA3 to driveCYP707A3induction. However,PstDC3000 counteracts this defense response using type III secretion effectors, particularly AvrPtoB, facilitating water-soaking. These findings provide insights into the mechanisms underlying the competition between plants and bacteria for leaf water under elevated humidity.
Repeated intraperitoneal administration of the GABABreceptor agonist baclofen reduces body weight in the mouse
Authors: Ebenezer Ivor S
Published: January 2025

Chronic intraperitoneal (ip) administration of the GABABreceptor agonist baclofen has been shown to reduce body weight in rats without significantly affecting daily food intake. The present study was undertaken to extend these observations to another rodent species. Male C57B/10 mice (n=27) that had free access to food and water were injected once daily for 15 days with either saline or baclofen (4 or 8 mg / kg; i.p). Body weight and food intake were measured 24h after each injection. Statistical analysis of the results revealed that the 4 mg / kg dose of baclofen significantly reduced body weight gain in the mice during the first 5 days while the 8 mg / kg dose reduced body weight gain throughout the 15 days of the study when compared with saline control animals (F(2,21)=4.88, P<0.02). Baclofen (4 or 8 mg / kg) generally had no significant effects on daily 24h food intake except on days 1 and 2 when the 8 mg / kg dose produced small but significant decreases in food intake (P<0.05) that were probably due to the initial depressant effects of the drug on behaviour. The results of this study extend previous findings in rat to another rodent species and show that systemic administration of the GABABreceptor agonist baclofen reduces body weight gain in the mouse without affecting daily food intake. These results lend further support to the hypothesis that GABABreceptor agonists decreases body weight by increasing metabolic rate.
Hypoxia-Mediated Molecular Interactions of Tissue-Specific Mesenchymal Stem Cells Drive Metabolic Reprogramming and Immunomodulation in Acute Graft-versus-Host Disease
Authors: Mendiratta Mohini , Mendiratta Meenakshi , Malhotra Lakshay , Rai Sandeep , Sarangathem Vijaya , Dahiya Prince , Gupta Ritu , Bakhshi Sameer , Dadhwal Vatsla , Pushpam Deepam , Aggarwal Mukul , Gupta Aditya Kumar , Malik Prabhat Singh , Pramanik Raja , Mahapatra Manoranjan , Seth Tulika , Dhawan Rishi , Bandyopadhyay Sabyasachi , Hariprasad GuruRao , Nayak Baibaswata , Singh Thoudam Debraj , Kumar Sachin , Mir Riyaz Ahmed , Sharawat Surender Kumar , Prakash Hridayesh , Mohanty Sujata , Sahoo Ranjit Kumar
Published: January 2025

Background

Mesenchymal stem cells (MSCs) mediate immunomodulation through various mechanisms, including apoptosis, efferocytosis, and mitochondrial transfer. Our study investigates the impact of hypoxia preconditioning on the immune metabolic reprogramming and immunomodulatory potential of MSCs in acute graft-versus-host disease (aGVHD). Additionally, we explored the differential immunomodulatory effects of tissue-specific MSCs, specifically bone marrow (BM) and Wharton’s Jelly (WJ), and elucidated the mechanisms underlying variability in their therapeutic efficacy.

Methods

MSCs were isolated from BM and WJ and subjected to hypoxia preconditioning. Their immunometabolic programming potential was assessed by evaluating T-cell proliferation, regulatory T-cell (Treg) induction, effector T-cell differentiation toward Th2, Th9 phenotypes, and macrophage polarization, T-cell bioenergetics in the direct co-culture systems.

Results

WJ-MSCsHYPexhibited superior immunomodulatory properties compared to BM-MSCsHYP, by inhibiting T-cell proliferation, enhancing Treg induction, and promoting anti-inflammatory macrophage polarization. WJ-MSCsHYPdemonstrated enhanced mitochondrial transfer to T-cell, improving mitochondrial health, reducing ROS, and promoting oxidative phosphorylation, leading to immune homeostasis. Unlike BM-MSCs, WJ-MSCs exhibited higher rates of apoptosis, which facilitated immune modulation through mechanisms independent of efferocytosis.

Conclusion

Our findings highlight that WJ-MSCsHYPis a superior candidate for aGVHD by utilizing apoptosis, mitochondrial transfer, and metabolic reprogramming to achieve immune regulation.
Tracking changes in stability of North Sea Atlantic cod in 40 years
Authors: Tao Hsiao-Hang , Hsieh Chih-hao , Hidalgo Manuel , Dakos Vasilis
Published: January 2025

Tracking changes in the stability of low-abundance populations is vital for conservation. While the stability of natural populations is often assessed based on linear dynamics, many exhibit state-dependent dynamics, such as the iconic Atlantic cod in the North Sea (Gadus morhua). This fish population experienced an abrupt decline in the year 2000 and has not shown a clear sign of recovery despite relaxed fishing pressure. To understand the mechanisms behind the recovery dynamics, we used a dynamical systems approach to reconstruct the state space of the population from yearly abundance data of age groups between 1982-2021. Specifically, we estimated yearly interaction matrices of age groups and derived yearly population stability, defined as the rate of recovery to or departure from the current state after a small perturbation to the matrix. We found that since the abrupt decline in abundance of North Sea cod in the year 2000, the population continued to fluctuate closer to the transition threshold; some age groups experienced weaker self-regulation; and age-1 group became more sensitive to perturbations than older groups. These results provide important information on North Sea cod’s resilience and capacity to buffer natural and anthropogenic impacts.
Serial intravital microscopy reveals temporal dynamics of autoreactive germinal centers in the spleen
Authors: Pohl Layla , Wittenborn Thomas R. , Shahrokhtash Ali , Kastberg Kristian S. , Fahlquist-Hagert Cecilia , Jensen Lisbeth , Sardella Donato , Pulfer Alain , Sutherland Duncan , Gonzalez Santiago F. , Schiessl Ina Maria , Degn Søren E.
Published: January 2025

The spleen plays a key role in clearing blood-borne infections and is involved in autoimmune and hematological disorders. It undergoes extensive remodeling during inflammation and immune reactions, but its localization in the peritoneal cavity has hampered studies of these dynamic changes. Here, we establish and validate a protocol for serial 2-photon microscopy of the murine spleen to capture dynamic processes in the living animal. As a proof-of-principle, we elucidate the expansion and contraction of autoreactive germinal centers (GCs) induced by epicutaneous application of the small-molecule TLR7 agonist resiquimod (R848). Leveraging a biocompatible abdominal imaging window, intravital labeling techniques, and fluorescent reporters, we follow GCs up to 180 µm below the capsule for more than 2 weeks by tracking follicular dendritic cell (FDC) networks. This was accomplished without appreciable perturbation of normal physiology, paving the way for a deeper understanding of the biology of the spleen and its associated disease states.

Highlight

An abdominal imaging window allowing the study of dynamic processes in the spleen of live mice over the course of several weeks.
DTPPI: predicting drug interactions using a weighted drug-protein network
Authors: Szydlik Szymon , Taheri Golnaz
Published: January 2025

Polypharmacy, the practice of using multiple drugs to treat complex diseases, poses a significant risk of drug-drug interactions (DDIs), which can lead to unanticipated adverse drug reactions (ADRs) and toxicity. Identifying and understanding these DDIs is crucial to ensuring the safety of polypharmacy. Traditional laboratory-based methods for detecting DDI are costly and time consuming, prompting the development of computational approaches. However, many of these methods face limitations, mainly the lack of utilization of biological networks to model drug mechanics. Such an approach could lead to a new technique with better and more accurate DDI predictions. In response to these challenges, we propose the DTPPI network, a novel machine learning approach that leverages a drug-target-protein-protein interaction network to improve DDI prediction. By extracting topological features and combining them with biological drug features, the DTPPI method enhances the performance of a multilayer perceptron model. The evaluation results showed an AUC of 0.64 for topological characteristics alone, 0.89 for biological characteristics, and 0.91 for combined features, demonstrating that integrating topological and biological data significantly improves the prediction accuracy of DDI. Materials and implementations are available at:https://github.com/Golnazthr/DTPPI

Highlights

Constructs a weighted graph network to model interactions among drugs, proteins, and targets, applicable to all drug types.

Extracts six universal topological features from the graph, independent of chemical structure.

Enhances DDI prediction by using topological features alone or alongside traditional drug features.

Incorporates an MLP model for superior predictive accuracy using combined features.
Multi-Center “Replica Study” Challenges the Impact of Electronic Cigarette Aerosols on Cisplatin Resistance in Head and Neck Cancer Cells
Authors: Emma R. , Carota G. , Partsinevelos K. , Rust S. , Sun A. , Giordano A. , Volarevic V. , Lesmana R. , Goenawan H. , Barliana M. I. , Arsenijevic A. , Kastratovic N. , Spasic B. , Giardina Chiara , Cantali Miriana , Polosa R. , Caruso M. , Li Volti G.
Published: January 2025

Background

Cisplatin chemoresistance is a critical challenge in the treatment of head and neck squamous cell carcinoma (HNSCC). Since previous research has suggested that nicotine and e-cigarette (e-cig) aerosol might increase cisplatin resistance in oral cancer cells, this multicenter replication study aimed to replicate the work by Manyanga et al. (2021) and evaluate the oncologic implications of e-cigarette exposure during chemotherapy.

Methods

This in vitro study involved standardized and harmonized protocols in international laboratories to examine the effects of cigarette smoke (1R6F) and e-cig aerosols with different concentrations of nicotine (0, 12, and 20 mg/ml nicotine) on cisplatin sensitivity in HNSCC cell lines (SCC-25, FaDu, and UM-SCC-1). Aerosols from 1R6F smoke and e-cig vapor were collected using a smoking and vaping machine, following ISO20778:2018 and ISO20768:2018 puffing regimes. The smoke and vapor were collected in PBS and diluted to 10 puffs/5L for HNSCC cell treatment. Chemosensitivity, clonogenicity, expression of gene for repair of cisplatin-induced DNA damage and gene and protein expression of cisplatin transporters were assessed by MTS, NRU, trypan blue, PCR, and Western blot assays, respectively.

Results

Contrary to previous findings, exposure to e-cig aerosols did not significantly modulate cisplatin sensitivity in all cell lines. IC50 values, cytotoxicity assays, and clonogenic survival rates remained similar between e-cig treatments and cisplatin alone. Analysis of gene and protein expression revealed sporadic changes in the levels of transporters and repairs of cisplatin-induced DNA damage.

Conclusions

This study did not fully substantiate previous claims of increased cisplatin resistance due to e-cigarette aerosols and nicotine. The variability in gene and protein expression among different cell lines underscores the need for cautious interpretation and further investigation of the role of e-cigarette components in cancer treatment. These findings provide a critical perspective for shaping public health policies and clinical practices related to e-cigarette use during chemotherapy.
Phase II trial of chemotherapy, cetuximab and erlotinib in patients with metastatic or recurrent squamous cell carcinoma of the head and neck
Authors: Bhatia Aarti , Mehra Ranee , Bauman Jessica , Khan Saad A. , Wei Wei , Neumeister Veronique , Sandoval-Schaefer Teresa , Alpaugh R. Katherine , Lango Miriam , Rimm David L. , Ridge John A. , Burtness Barbara
Published: January 2025

Prognosis for patients with recurrent/metastatic (R/M) head and neck squamous cell cancer (HNSCC) remains poor. We hypothesized that the addition of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to standard therapy would improve responses by inhibiting nuclear translocation of EGFR and designed a phase 2 trial of chemotherapy, cetuximab and erlotinib in patients with R/M HNSCC.

24 patients were enrolled and treated with carboplatin, paclitaxel and cetuximab administered in 21-day cycles. Erlotinib was added with cycle 2. Primary end point was objective response rate (ORR). Secondary end points were toxicity, overall survival (OS) and laboratory correlates.

Median age was 65.5 years. Median duration on treatment was 4.6 months. ORR with cycle 1 of treatment was 33.3%, and for cycle 2 and beyond was 62.5%. Median progression-free survival (PFS) was 6.2 months, and median OS was 10.6 months. Most common treatment-related adverse events included anemia, neutropenia, skin rash, diarrhea, and hypomagnesemia.

Dual EGFR blockade was tolerable and efficacious in this small patient sample. With an ORR of 62.5%, the study met its primary endpoint. PFS and OS were comparable to historical controls. Dual EGFR targeting without the chemotherapy backbone is worthy of further study.

Clinical trial information:NCT01316757. Study registered March 8th, 2011