bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymeric nanocarriers delivery systems in ischemic stroke for targeted therapeutic strategies
Authors: Zhu Lin , Zhong Weijie , Meng Xuchen , Yang Xiaosheng , Zhang Wenchuan , Tian Yayuan , Li Yi 
Published: July 2024

AbstractIschemic stroke is a complex, high-mortality disease with multifactorial etiology and pathogenesis. Currently, drug therapy is mainly used treat ischemic stroke in clinic, but there are still some limitations, such as limited blood-brain barrier (BBB) penetration efficiency, a narrow treatment time window and drug side effects. Recent studies have pointed out that drug delivery systems based on polymeric nanocarriers can effectively improve the insufficient treatment for ischemic stroke. They can provide neuronal protection by extending the plasma half-life of drugs, enhancing the drug’s permeability to penetrate the BBB, and targeting specific structures and cells. In this review, we classified polymeric nanocarriers used for delivering ischemic stroke drugs and introduced their preparation methods. We also evaluated the feasibility and effectiveness and discussed the existing limitations and prospects of polymeric nanocarriers for ischemic stroke treatment. We hoped that this review could provide a theoretical basis for the future development of nanomedicine delivery systems for the treatment of ischemic stroke.
Graphical Abstract
Chlorpromazine overcomes temozolomide resistance in glioblastoma by inhibiting Cx43 and essential DNA repair pathways
Authors: Matarrese Paola , Signore Michele , Ascione Barbara , Fanelli Giulia , Paggi Marco G. , Abbruzzese Claudia 
Published: July 2024

Abstract
Background
In the fight against GBM, drug repurposing emerges as a viable and time-saving approach to explore new treatment options. Chlorpromazine, an old antipsychotic medication, has recently arisen as a promising candidate for repositioning in GBM therapy in addition to temozolomide, the first-line standard of care. We previously demonstrated the antitumor efficacy of chlorpromazine and its synergistic effects with temozolomide in suppressing GBM cell malignant features in vitro. This prompted us to accomplish a Phase II clinical trial to evaluate the efficacy and safety of adding chlorpromazine to temozolomide in GBM patients with unmethylated MGMT gene promoter. In this in vitro study, we investigate the potential role of chlorpromazine in overcoming temozolomide resistance.

Methods
In our experimental set, we analyzed Connexin-43 expression at both the transcriptional and protein levels in control- and chlorpromazine-treated GBM cells. DNA damage and subsequent repair were assessed by immunofluorescence of γ-H2AX and Reverse-Phase Protein microArrays in chlorpromazine treated GBM cell lines. To elucidate the relationship between DNA repair systems and chemoresistance, we analyzed a signature of DNA repair genes in GBM cells after treatment with chlorpromazine, temozolomide and Connexin-43 downregulation.

Results
Chlorpromazine treatment significantly downregulated connexin-43 expression in GBM cells, consequently compromising connexin-dependent cellular resilience, and ultimately contributing to cell death. In line with this, we observed concordant post-translational modifications of molecular determinants involved in DNA damage and repair pathways. Our evaluation of DNA repair genes revealed that temozolomide elicited an increase, while chlorpromazine, as well as connexin-43 silencing, a decrease in DNA repair gene expression in GBM cells.

Conclusions
Chlorpromazine potentiates the cytotoxic effects of the alkylating agent temozolomide through a mechanism involving downregulation of Cx43 expression and disruption of the cell cycle arrest essential for DNA repair processes. This finding suggests that chlorpromazine may be a potential therapeutic strategy to overcome TMZ resistance in GBM cells by inhibiting their DNA repair mechanisms.
Association between number of confidants and adolescent anxiety/depression: a school-based study
Authors: Nishida Asuka , Foo Jerome Clifford , Yamaguchi Satoshi , Togo Fumiharu , Shimodera Shinji , Nishida Atsushi , Okazaki Yuji , Sasaki Tsukasa 
Published: July 2024

Abstract
Background
Having no or few confidants is found to be associated with more severe mental health problems and a higher prevalence of depression in adults, but research examining this association in adolescents is scarce. Social relationships may be particularly critical during adolescence, as it is an important developmental period during which vulnerability to mental health problems increases. The present study examined the relationship between having no or few confidants and anxiety/depressive symptoms in adolescents.

Methods
Cross-sectional self-report survey targeting 7–12th grade students (age range: 12–18) was conducted in public junior and senior high schools in Mie and Kochi, Japan. Data from 17,829 students (49.7% boys) were analyzed. Associations between anxiety/depressive symptoms (12-item General Health Questionnaire; score range: 0–12) and the number of confidants (None, 1–3, or ≥ 4) were examined using multilevel regression analyses. The analyses were stratified by gender and school level (junior/senior high), and adjusted for experiences of being physically abused and bullied and the interactions of these experiences with the number of confidants.

Results
Having no or 1–3 confidants was associated with more anxiety/depressive symptoms, compared to having ≥ 4 confidants (p < 0.001) in all stratified groups. Having no confidants was associated with more anxiety/depressive symptoms than having 1–3 confidants (p < 0.001); in senior high boys, no difference was observed between having no confidants and having 1–3 confidants. In addition, in senior high boys, victims of bullying who have confidants reported significantly less anxiety/depressive symptoms than the victims who have no confidants (p < 0.01).

Conclusions
Adolescents who had no or few confidants had more anxiety/depressive symptoms. Attention needs to be paid to better identify these adolescents, and avenues to support them need to be established.
Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers
Authors: Kabeer Farhia , Tran Hoa , Andronescu Mirela , Singh Gurdeep , Lee Hakwoo , Salehi Sohrab , Wang Beixi , Biele Justina , Brimhall Jazmine , Gee David , Cerda Viviana , O’Flanagan Ciara , Algara Teresa , Kono Takako , Beatty Sean , Zaikova Elena , Lai Daniel , Lee Eric , Moore Richard , Mungall Andrew J. ,   IMAXT Consortium, Williams Marc J. , Roth Andrew , Campbell Kieran R. , Shah Sohrab P. , Aparicio Samuel 
Published: July 2024

Abstract
Background
The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states.

Results
We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure.

Conclusions
Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.
Leveraging neighborhood representations of single-cell data to achieve sensitive DE testing with miloDE
Authors: Missarova Alsu , Dann Emma , Rosen Leah , Satija Rahul , Marioni John 
Published: July 2024

AbstractSingle-cell RNA-sequencing enables testing for differential expression (DE) between conditions at a cell type level. While powerful, one of the limitations of such approaches is that the sensitivity of DE testing is dictated by the sensitivity of clustering, which is often suboptimal. To overcome this, we present miloDE—a cluster-free framework for DE testing (available as an open-source R package). We illustrate the performance of miloDE on both simulated and real data. Using miloDE, we identify a transient hemogenic endothelia-like state in mouse embryos lacking Tal1 and detect distinct programs during macrophage activation in idiopathic pulmonary fibrosis.
Joint effect of atrial fibrillation and obesity on mortality in critically ill patients
Authors: Zhang Hong-Da , Ding Lei , Mi Li-Jie , Zhang Ai-Kai , Liu Yuan-Dong , Peng Fu-Hua , Yan Xin-Xin , Shen Yu-Jing , Tang Min 
Published: July 2024

Abstract
Background
The interplay between atrial fibrillation (AF) and obesity on mortality in critically ill patients warrants detailed exploration, given their individual impacts on patient prognosis. This study aimed to assess the associations between AF, obesity, and 1-year mortality in a critically ill population.

Methods
Utilizing data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, we conducted a retrospective analysis of adult patients admitted to the intensive care unit. The primary endpoint was 1-year mortality, analyzed through Cox regression with hazard ratio (HR) and Kaplan-Meier survival methods.

Results
The study included 25,654 patients (median age 67.0 years, 40.6% female), with 39.0% having AF and 36.1% being obese. Multivariate COX regression analysis revealed that AF was associated with a 14.7% increase in the risk of 1-year mortality (p < 0.001), while obesity was linked to a 13.9% reduction in mortality risk (p < 0.001). The protective effect of obesity on mortality was similar in patients with (HR = 0.85) and without AF (HR = 0.86). AF led to a slightly higher risk of mortality in patients without obesity (HR = 1.16) compared to those with obesity (HR = 1.13). Kaplan-Meier survival curves highlighted that non-obese patients with AF had the lowest survival rate, whereas the highest survival was observed in obese patients without AF.

Conclusions
AF significantly increased 1-year mortality risk in critically ill patients, whereas obesity was associated with a decreased mortality risk. The most adverse survival outcomes were identified in non-obese patients with AF.
Exosomes repairment for sciatic nerve injury: a cell-free therapy
Authors: Xin Guang-Da , Liu Xue-Yan , Fan Xiao-Di , Zhao Guan-Jie 
Published: July 2024

AbstractSciatic nerve injury (SNI) is a common type of peripheral nerve injury typically resulting from trauma, such as contusion, sharp force injuries, drug injections, pelvic fractures, or hip dislocations. It leads to both sensory and motor dysfunctions, characterized by pain, numbness, loss of sensation, muscle atrophy, reduced muscle tone, and limb paralysis. These symptoms can significantly diminish a patient’s quality of life. Following SNI, Wallerian degeneration occurs, which activates various signaling pathways, inflammatory factors, and epigenetic regulators. Despite the availability of several surgical and nonsurgical treatments, their effectiveness remains suboptimal. Exosomes are extracellular vesicles with diameters ranging from 30 to 150 nm, originating from the endoplasmic reticulum. They play a crucial role in facilitating intercellular communication and have emerged as highly promising vehicles for drug delivery. Increasing evidence supports the significant potential of exosomes in repairing SNI. This review delves into the pathological progression of SNI, techniques for generating exosomes, the molecular mechanisms behind SNI recovery with exosomes, the effectiveness of combining exosomes with other approaches for SNI repair, and the changes and future outlook for utilizing exosomes in SNI recovery.
Exploring the role of plant hydraulics in canopy fuel moisture content: insights from an experimental drought study on Pinus halepensis Mill. and Quercus ilex L.
Authors: Cakpo Coffi Belmys , Ruffault Julien , Dupuy Jean-Luc , Pimont François , Doussan Claude , Moreno Myriam , Jean Nathan , Jean Frederic , Burlett Regis , Delzon Sylvain , Trueba Santiago , Torres-Ruiz José M. , Cochard Hervé , Martin-StPaul Nicolas 
Published: July 2024

Abstract
Key Message
Understanding the impact of extreme drought on the canopy fuel moisture content (CFMC) is crucial to anticipate the effects of climate change on wildfires. Our study demonstrates that foliage mortality, caused by leaf embolism, can substantially diminish CFMC during drought on Pinus halepensis Mill. and Quercus ilex L. It emphasizes the importance of considering plant hydraulics to improve wildfire predictions.

Context
Canopy fuel moisture content (CFMC), which represents the water-to-dry mass ratio in leaves and fine twigs within the canopy, is a major factor of fire danger across ecosystems worldwide. CFMC results from the fuel moisture content of living foliage (live fuel moisture content, LFMC) and dead foliage (dead fuel moisture content, DFMC) weighted by the proportion of foliage mortality in the canopy (αDead). Understanding how LFMC, αDead, and ultimately CFMC are affected during extreme drought is essential for effective wildfire planning.

Aims
We aimed to understand how plant hydraulics affect CFMC for different levels of soil water deficit, examining its influence on both LFMC and αDead.

Methods
We conducted a drought experiment on seedlings of two Mediterranean species: Aleppo pine (Pinus halepensis Mill.) and Holm oak (Quercus ilex L.). Throughout the drought experiment and after rewatering, we monitored CFMC, LFMC, and αDead along with other ecophysiological variables.

Results
LFMC exhibited a significant decrease during drought, and as leaf water potentials reached low levels, αDead increased in both species, thereby reducing CFMC. Distinct water use strategies resulted in species-specific variations in dehydration dynamics.

Conclusion
Our findings demonstrate that as drought conditions intensify, foliage mortality might become a critical physiological factor driving the decline in CFMC.
Steady-state pharmacokinetics of lamivudine in end-stage kidney failure persons with detectable and undetectable HIV-1 RNA in peritoneal dialysis effluent
Authors: Mooko Teboho , Bisiwe Feziwe Busiswa , Mondleki Enkosi , Morobadi Molefi Daniel , Chikobvu Perpetual , Nyaga Martin Munene , Bala Asis , Goedhals Dominique , Mofokeng Thabiso Rafaki Petrus , Kemp Gabre , Ndlovu Kwazi Celani Zwakele 
Published: July 2024

Abstract
Background
Renally adjusted lamivudine dosages are effective. However, some of the kidney failure patients managed with lamivudine-containing regimens are failing to suppress HIV in peritoneal dialysis (CAPD) effluent. The steady-state lamivudine pharmacokinetics among these patients was evaluated.

Methods
This overnight open-label pharmacokinetic study enrolled participants living with HIV and managed with CAPD. Lamivudine levels in blood serum and CAPD effluent samples were quantified using liquid chromatography coupled with a mass spectrometer. Pharmacokinetic measures were obtained through non-compartmental analysis.

Results
Twenty-eight participants were recruited with a median antiretroviral (ARV) drug duration of 8 (IQR,4.5–10.5) years and a CAPD duration of 13.3 (IQR,3.3–31.9) months. 14.3% (4/28) had detectable unsuppressed HIV-1 viral load in CAPD effluents. The majority (78,6%,22/28) of participants received a 50 mg dose, while 10.7% (3/28), and another 10.7% (3/28) received 75 mg and 300 mg dosages, respectively. Among those treated with 75 and 300 mg, 66.7% (2/3) and 33.3% (1/3) had detectable HIV-VL in CAPD, respectively. The peritoneal membrane characteristics and CAPD system strengths were variable across the entire study population. Lamivudine exposure was increased in blood serum (50 mg-AUC0-24 h, 651.3 ng/mL; 75 mg-AUC0-24 h, 677.84 ng/mL; 300 mg-AUC0-24 h, 3135.89 ng/mL) compared to CAPD effluents (50 mg-AUC0-24 h, 384.91 ng/mL; 75 mg-AUC0-24 h, 383.24 ng/mL; 300 mg-AUC0-24 h, 2001.60 ng/mL) among the entire study population. The Cmax (50 mg, 41.5 ng/mL; 75 mg, 53.2 ng/mL; 300 mg, 199.1 ng/mL) and Cmin (50 mg, 17.8 ng/mL; 75 mg, 16.4 ng/mL; 300 mg, 76.4 ng/mL) measured in serum were within the therapeutic levels.

Conclusions
Steady-state lamivudine pharmacokinetic measures were variable among the entire study population. However, the total lamivudine exposure was within the therapeutic levels.
Carbapenem-resistant Acinetobacter baumannii infections among diabetic and non-diabetic patients and possible effective combination treatments
Authors: Ghareeb Aya M. , Raafat Marwa M. , Bazan Naglaa S. , Samir Reham 
Published: July 2024

Abstract
Background
Carbapenems are one of the most noteworthy choices for treating multidrug-resistant Acinetobacter baumannii (A. baumannii). Currently, carbapenem-resistant A. baumannii (CRAB) represents a healthcare problem worldwide, particularly among diabetic patients who are more susceptible to microbial infections. The aim of this study was to investigate the differences in antibiotic susceptibility profiles, the abundance of carbapenem resistance genes across A. baumannii-infected diabetic and non-diabetic patients, and the antimicrobial activity of different antibiotic combinations on highly resistant isolates.

Methods
Data of 99 A. baumannii-infected patients were collected during the period from 2018 to 2022 and categorized according to patients’ diabetes status into either diabetic or non-diabetic group. A total of 45 A. baumannii isolates were collected during 2021 and 2022 from the main hospital laboratory to be reidentified and genetically confirmed. Antibiotic susceptibility, including carbapenems, was determined using disc agar diffusion and broth microdilution methods. The isolates were screened for OXA-23, GES, VIM, and NDM carbapenem-resistant genes. Five antibiotic combinations were assessed using the double-disk synergy and checkerboard methods.

Results
The findings of the current study revealed that multidrug resistance increased gradually, from 56% in 2018 to 95.6% in 2022. Moreover, CRAB increased among diabetics and non-diabetics. Resistance rates of imipenem, meropenem, and doripenem reached 68.8%, 61.8%, and 47.4% in diabetics and 97.9%, 83.3%, and 50% in non-diabetics, respectively. The VIM gene was the most prevalent gene with prevalence rates of 100% and 96.15% in diabetics and non-diabetics, respectively. Moreover, all A. baumannii isolates carried at least two of the selected carbapenem-resistant genes. Across the different used combinations, only the tigecycline-meropenem combination showed synergistic activity in 50% of diabetic and 66.7% of non-diabetic isolates.

Conclusions
An increased carbapenem resistance was observed among A. baumannii-infected individuals, both diabetic and non-diabetic. The MEM/TCG combination was the only one that showed synergistic or additive effects against highly resistant isolates making it a viable alternative treatment option.
An automated optimized design of practical post-tensioned slabs
Authors: Farid Ahmed Fady , Kamal Abdulrahman , Rashed Youssef F. 
Published: July 2024

AbstractIn this paper, an efficient methodology that could be implemented within any analysis software is developed to automate the design process of post-tensioned slabs. Optimization techniques are used to compute the necessary number of strands. The present methodology is based on computing an innovative influence matrix that contains the effect of each strand on stresses at a set of control points (points of peak stresses). This matrix will be used in the optimization avoiding reanalysis in each optimization iteration. The sum of the squares of the difference between the allowable stress and the computed stresses at all control points is considered an objective function. The optimization is then carried out under the constraints that the stresses at each control point should not exceed the allowable limit and to ensure that the number of strands is an integer value. Alternatively, the proposed methodology could be used as a value-engineering tool. Practical examples are presented to demonstrate the efficiency of the developed methodology.
Schrödinger evolution of a scalar field in Riemannian and pseudo-Riemannian expanding metrics
Authors: Haba Z. 
Published: July 2024

Abstract
We study the quantum field theory (QFT) of a scalar field in the Schrödinger picture in the functional formulation. We derive a formula for the evolution kernel in a flat expanding metric. We discuss a transition between Riemannian and pseudo-Riemannian metrics

(signature inversion). We express the real time Schrödinger evolution by the Brownian motion. We discuss the Feynman integral for a scalar field in a radiation background. We show that the unitary Schrödinger evolution for positive time can go over for negative time into a dissipative evolution as a consequence of the imaginary value of

. The time evolution remains unitary if

in the Hamiltonian is replaced by

.
NFATc1 Is Required for Vitamin D- and Phosphate-Mediated Regulation of Osteocyte Lacuno-Canalicular Remodeling
Authors: Jagga Supriya , Hughes Ashleigh , Manoochehri Arash Niusha , Sorsby Melissa , Brooks Daniel J , Divieti Pajevic Paola , Liu Eva S 
Published: July 2024

Abstract
Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN remodeling. In osteoclasts, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) is critical for stimulating bone resorption. Since osteocytes also resorb matrix, we hypothesize that NFATc1 plays a role in 1,25D and phosphate-mediated LCN remodeling. Consistent with this, 1,25D and phosphate suppress Nfatc1 mRNA expression in IDG-SW3 osteocytes, and knockdown of Nfatc1 expression in IDG-SW3 cells blocks 1,25D- and phosphate-mediated suppression of matrix resorption gene expression and 1,25D- and phosphate-mediated suppression of RANKL-induced acidification of the osteocyte microenvironment. To determine the role of NFATc1 in 1,25D- and phosphate-mediated LCN remodeling in vivo, histomorphometric analyses of tibiae from mice lacking osteocyte-specific Nfatc1 in Vdrf/f;Dmp1Cre+ and Npt2aKO mice were performed, demonstrating that bones from these mice have decreased lacunar size and expression of matrix resorption genes, and improved canalicular structure compared to Vdrf/f;Dmp1Cre+ and Npt2aKO control. This study demonstrates that NFATc1 is necessary for 1,25D- and phosphate-mediated regulation of LCN remodeling.