bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting splicing for hematological malignancies therapy
Authors: Szelest Monika , Giannopoulos Krzysztof 
Published: November 2024

AbstractAlterations in splicing patterns of leukemic cells have a functional impact and influence most cellular processes since aberrantly spliced isoforms can provide a proliferative advantage, enable to evade apoptosis, induce metabolic reprogramming, change cell signaling and antitumor immune response, or develop drug resistance. In this Review, we first characterize the general mechanism of mRNA processing regulation with a focus on the role of splicing factors, which are commonly mutated in blood neoplasms. Next, we provide a comprehensive summary on the current understanding of alternative splicing events, which confer resistance to targeted treatment strategies and immunotherapy. We introduce the functional consequences of mis-spliced variants (CD19-∆ex2, CD22-∆ex2, CD22-∆ex5-6, CD33-∆ex2, PIK3CD-S, BCR-ABL35INS, BIM-γ, FPGS-8PR, dCK-∆ex2-3, and SLC29A1-∆ex13) production in leukemic cells. Of therapeutic relevance, we summarize novel strategies focused on pharmacological correction of aberrant splicing, including small-molecule splicing modulators and splice-switching oligonucleotides. We also include the findings of recent preclinical investigation of the antisense strategies based on modified oligonucleotides. Finally, we discuss the potential of emerging combination therapies for the treatment of hematological disorders with disrupted splicing.
Multi-omics approaches define novel aphid effector candidates associated with virulence and avirulence phenotypes
Authors: Thorpe Peter , Altmann Simone , Lopez-Cobollo Rosa , Douglas Nadine , Iqbal Javaid , Kanvil Sadia , Simon Jean-Christophe , Carolan James C. , Bos Jorunn , Turnbull Colin 
Published: November 2024

Abstract
Background
Compatibility between plant parasites and their hosts is genetically determined {Citation}both interacting organisms. For example, plants may carry resistance (R) genes or deploy chemical defences. Aphid saliva contains many proteins that are secreted into host tissues. Subsets of these proteins are predicted to act as effectors, either subverting or triggering host immunity. However, associating particular effectors with virulence or avirulence outcomes presents challenges due to the combinatorial complexity. Here we use defined aphid and host genetics to test for co-segregation of expressed aphid transcripts and proteins with virulent or avirulent phenotypes.

Results
We compared virulent and avirulent pea aphid parental genotypes, and their bulk segregant F1 progeny on Medicago truncatula genotypes carrying or lacking the RAP1 (Resistance to Acyrthosiphon pisum 1) resistance quantitative trait locus. Differential gene expression analysis of whole body and head samples, in combination with proteomics of saliva and salivary glands, enabled us to pinpoint proteins associated with virulence or avirulence phenotypes. There was relatively little impact of host genotype, whereas large numbers of transcripts and proteins were differentially expressed between parental aphids, likely a reflection of their classification as divergent biotypes within the pea aphid species complex. Many fewer transcripts intersected with the equivalent differential expression patterns in the bulked F1 progeny, providing an effective filter for removing genomic background effects. Overall, there were more upregulated genes detected in the F1 avirulent dataset compared with the virulent one. Some genes were differentially expressed both in the transcriptome and in the proteome datasets, with aminopeptidase N proteins being the most frequent differentially expressed family. In addition, a substantial proportion (27%) of salivary proteins lack annotations, suggesting that many novel functions remain to be discovered.

Conclusions
Especially when combined with tightly controlled genetics of both insect and host plant, multi-omics approaches are powerful tools for revealing and filtering candidate lists down to plausible genes for further functional analysis as putative aphid effectors.
COVID-19 inflammatory signature in a Mozambican cohort: unchanged red blood series and reduced levels of IL-6 and other proinflammatory cytokines
Authors: Maphossa Vânia , Guiliche Onélia , Babetine Teresa , Castiano Celso , Inlamea Osvaldo , Marengue Marino , Capitine Igor , Chambal Lúcia , Tivane Almiro , Sacarlal Jahit , Terra-Granado Eugênia , Chissumba Raquel Matavele 
Published: November 2024

Summary
Background
Alterations in haematological, biochemical parameters and cytokine levels, were reported in patients with COVID-19, however, there is an underrepresentation of the African population, which could provide evidence for understanding SARS-CoV-2 pathogenesis and useful tools for clinical management of cases. In this study, we aimed to determine the haematological, biochemical and cytokine profile in Mozambican individuals with SARS-CoV-2.

Methods
A cohort of 85 Mozambican individuals with RT-PCR SARS-CoV-2 results, was stratified into negative, asymptomatic, mild, moderate, and severe categories. Haematological, biochemical and cytokines measurement were performed on samples from the study participants. Principal component analysis (PCA) was performed to identify similar patterns among the study cases. Comparisons between groups were performed using the Kruskal-Wallis test. Receiver operating characteristic (ROC) and area under the curve (AUC) analysis were conducted to evaluate the ability of these parameters to distinguish severe from non-severe cases of SARS-CoV-2 infection.

Results
SARS-CoV-2 infection was associated with a significant (p < 0.05) decrease in peripheral blood absolute counts of total lymphocytes and eosinophils, below the reference values along with no abnormal change (p > 0.05) in red blood cell count, haemoglobin, platelets and other red series parameters. At the serum level, SARS-CoV-2 infection was associated with an increase in serum levels of C-reactive protein (C-RP) and glucose above the reference values and to a significant reduction a significant (p < 0.05) reduction in levels of interferon-gamma (INF-γ), Tumour Necrosis Factor alfa (TNF-α) and the interleukin 1 beta (IL-1β) and IL-6 in severe cases, when compared to negative cases. Haematological, biochemical and cytokine profiles segregate severe from non-severe cases of COVID-19 with an excellent performance of C-RP (AUC = 0.95; p < 0.001) and good performance of lymphocytes (AUC = 0.88; p < 0.001) and IL-15 (AUC = 0.86; p < 0.001).

Conclusion
The lack of variation in red and platelet series, coupled with a decrease in the levels of classical pro-inflammatory in severe cases, deviates from what has been reported in other contexts suggesting, that there may be peculiarities in COVID-19 manifestation within the context of this study population. Furthermore, these results identify parameters with potential for clinical management of COVID-19 and therefore good resource allocation, particularly for severe cases.
Second primary cancers in patients with a pharyngeal index tumour: a register-based cohort study
Authors: Nikkilä Rayan , Hirvonen Elli , Haapaniemi Aaro , Pitkäniemi Janne , Malila Nea , Mäkitie Antti 
Published: November 2024

Abstract
Background
While prior research on the SPC (second primary cancer) risk among pharyngeal carcinoma (PC) patients has been conducted in other regions, the European perspective is underrepresented. Our register-based cohort study aims to assess the subsite-specific risk of SPC among individuals initially diagnosed with a pharyngeal index tumour.

Methods
Standardized incidence ratios (SIR) of SPC were calculated relative to the general population for all patients diagnosed with a primary oropharyngeal, nasopharyngeal, and hypopharyngeal carcinoma (OPC, NPC, and HPC) in Finland during 1953–2021.

Results
A total of 4701 PC patients – 3320 men (71%) and 1381 women (29%) – were identified. The average and median follow-up times were 5.7 and 2.8 years, respectively. A SPC was diagnosed in 561 patients (11.9%): in 12.3% of men (n = 410) and 10.9% of women (n = 151). For male PC patients, the overall SIR for an SPC at any primary site was 1.83 (95% CI: 1.65–2.01). For female patients, the corresponding SIR was 1.89 (95% CI: 1.60–2.22). OPC and HPC showed increased risks for SPCs of the mouth/pharynx (SIR 4.41 and 6.91, respectively) and respiratory organs (SIR 3.51 and 4.80). OPC patients also had an increased risk in digestive organs (SIR 1.83). Male NPC patients exhibited increased risks for oral/pharyngeal, brain, and haematolymphoid SPCs (SIRs 5.14, 6.60, and 3.05, respectively).

Conclusion
PC patients face an 80% higher SPC risk, which persists decades after treatment. Healthcare professionals must be aware of this, providing counselling and encouraging a healthy lifestyle, including smoking cessation, while monitoring symptoms.
Motor outcomes in individuals born small for gestational age at term: a systematic review
Authors: Taiar Hoda , Benum Silje Dahl , Aakvik Kristina Anna Djupvik , Evensen Kari Anne I. 
Published: November 2024

Abstract
Background
Being born small for gestational age (SGA) is a risk factor for motor difficulties. Previous reviews exploring this topic are mostly focused on children born preterm. We aimed to review the literature to determine the association between being born SGA at term and motor outcomes.

Methods
PubMed and Embase were searched for relevant articles without any restrictions on publication year or participants’ age. Inclusion criteria were SGA exposure at term (≥ 37 weeks of gestation), cohort studies or randomized controlled trials with motor outcome assessed by standardized motor tests with results reported as continuous scores (mean/median) compared with a control group. Exclusion criteria were abstracts, editorials and commentaries, articles in non-English language or no full text available. Reviews were screened for relevant articles. Quality of included studies was assessed by the Newcastle-Ottawa Scale.

Results
In total, 674 records were identified by the literature search and screened by two independent authors. Thirteen original articles were eligible and included in a qualitative synthesis, and five (38%) of these were included in a meta-analysis. Nine (69%) studies were from high-income countries. Most studies were carried out in early childhood, and only one study in adulthood. Seven (54%) articles reported that individuals born SGA at term had poorer scores on standardized motor tests compared with controls, while no differences were reported in five (38%) articles. One article did not report p-values, although the differences were comparable to the other studies. Group differences were of small to moderate effect size (0.19 to 0.65 standard deviation units). The pooled effect size was -0.43 (95% confidence interval: -0.60 to -0.25). Adjustment for covariates were reported in seven (54%) articles and did not change the results. Proportions of motor difficulties, reported in five (38%) articles, ranged from 8.9 to 50% in individuals born SGA from infancy to adolescence.

Conclusions
This systematic review shows that being born SGA, also at term, may be a risk factor for poorer motor outcomes throughout childhood, confirmed by a meta-analysis in early childhood. Further research is needed to establish the risk of adult motor difficulties in individuals born SGA at term.
Engagement in a virtual group-based walking intervention for persons with schizophrenia: a qualitative study
Authors: Browne Julia , Battaglini Claudio , Imamoglu Aslihan , Stiles Bryan , Jarskog L. Fredrik , Sheeran Paschal , Abrantes Ana M. , Elliott Tonya , Gonzalez Oscar , Penn David L. 
Published: November 2024

Abstract
Background
Exercise is beneficial for persons with schizophrenia; however, high dropout rates limit the impact of interventions. Virtual exercise programs have the potential to improve engagement; however, few intervention studies of virtual programs have been conducted in this population.

Methods
This study examined qualitative data from 15 adults with schizophrenia who participated in a pilot randomized controlled trial of Virtual PACE-Life, a live, video-delivered group walking intervention guided by self-determination theory. Interviews elicited feedback on the intervention, barriers and facilitators to engagement, recommendations for intervention refinement, and preferences for exercise programming modality. Rapid qualitative analysis was used to explore similarities and differences between completers (i.e., those that attended ≥ 50% of virtual walking sessions; n = 9) and non-completers (i.e., those that attended < 50% of virtual walking sessions; n = 6).

Results
Both groups viewed Virtual PACE-Life positively but found the virtual exercise sessions challenging and inadequate for facilitating social interaction. Work obligations impacted completers’ attendance whereas technological issues and forgetting impacted non-completers’ attendance at virtual walking sessions. Completers preferred virtual exercise programs and non-completers preferred in-person exercise programs.

Conclusions
These findings suggest that future virtual group-based walking programs should prioritize enhancing the social aspect, offering scheduling choices, and regularly assessing the perceived difficulty of exercise sessions. These modifications not only have the potential to improve intervention engagement but they also may increase participant autonomy and relatedness, core components of self-determination theory.
Strategies to optimise the health equity impact of digital pain self-reporting tools: a series of multi-stakeholder focus groups
Authors: Ali Syed Mustafa , Gambin Amanda , Chadwick Helen , Dixon William G. , Crawford Allison , Van der Veer Sabine N. 
Published: November 2024

Abstract
Background
There are avoidable differences (i.e., inequities) in the prevalence and distribution of chronic pain across diverse populations, as well as in access to and outcomes of pain management services. Digital pain self-reporting tools have the potential to reduce or exacerbate these inequities. This study aimed to better understand how to optimise the health equity impact of digital pain self-reporting tools on people who are experiencing (or are at risk of) digital pain inequities.

Methods
This was a qualitative study, guided by the Health Equity Impact Assessment tool—digital health supplement (HEIA-DH). We conducted three scoping focus groups with multiple stakeholders to identify the potential impacts of digital pain self-reporting tools and strategies to manage these impacts. Each group focused on one priority group experiencing digital pain inequities, including older adults, ethnic minorities, and people living in socio-economically deprived areas. A fourth consensus focus group was organised to discuss and select impact management strategies. Focus groups were audio-recorded, transcribed verbatim, and analysed using a framework approach. We derived codes, grouped them under four pre-defined categories from the HEIA-DH, and illustrated them with participants’ quotes.

Results
A total of fifteen people living with musculoskeletal pain conditions and thirteen professionals took part. Participants described how digital pain self-reports can have a positive health equity impact by better capturing pain fluctuations and enriching patient-provider communication, which in turn can enhance clinical decisions and self-management practices. Conversely, participants identified that incorrect interpretation of pain reports, lack of knowledge of pain terminologies, and digital (e.g., no access to technology) and social (e.g., gender stereotyping) exclusions may negatively impact on people’s health equity. The participants identified 32 strategies, of which 20 were selected as being likely to mitigate these negative health equity impacts. Example strategies included, e.g., option to customise self-reporting tools in line with users’ personal preferences, or resources to better explain how self-reported pain data will be used to build trust.

Conclusion
Linked to people’s personal and social characteristics, there are equity-based considerations for developing accessible digital pain self-reporting tools, as well as resources and skills to enable the adoption and use of these tools among priority groups. Future research should focus on implementing these equity-based considerations or strategies identified by our study and monitoring their impact on the health equity of people living with chronic pain.
From gene to therapy: a review of deciphering the role of ABCD1 in combating X-Linked adrenoleukodystrophy
Authors: Zuo Xinxin , Chen Zeyu 
Published: November 2024

AbstractX-linked adrenoleukodystrophy (X-ALD) is a severe genetic disorder caused by ABCD1 mutations, resulting in the buildup of very-long-chain fatty acids, leading to significant neurological decline and adrenal insufficiency. Despite advancements in understanding the mechanisms of X-ALD, its pathophysiology remains incompletely understood, complicating the development of effective treatments. This review provides a comprehensive overview of X-ALD, with a focus on the genetic and biochemical roles of ABCD1 and the impacts of its mutations. Current therapeutic approaches are evaluated, discussing their limitations, and emphasizing the need to fully elucidate the pathogenesis of X-ALD. Additionally, this review highlights the importance of international collaboration to enhance systematic data collection and advance biomarker discovery, ultimately improving patient outcomes with X-ALD.
Variability and repeatability of spinal manipulation force–time characteristics in thoracic spinal manipulation on a manikin
Authors: Nyirö Luana , Gorrell Lindsay M. , Cecchini Valentina , Menon Carlo , Elgendi Mohamed , Schweinhardt Petra 
Published: November 2024

Abstract
Background
As part of multimodal therapy, spinal manipulation (SM) is a recommended and effective treatment for musculoskeletal pain. However, the underlying physiological mechanisms for pain relief are largely unknown. SM thrusts can be described and quantified using force–time characteristics (e.g. preload force, peak force, thrust speed, thrust duration, and thrust impulse). If these biomechanical parameters of SM are important for clinical outcomes, a large variability in the delivery of SM could lead to inconsistent responses and could thereby potentially mask a significant clinical effect. Our goal was to determine variability, and repeatability of thoracic spinal manipulation (SM) force–time profiles in a sample of Swiss chiropractors.

Methods
All interventions were performed on a human analogue manikin. Participating chiropractors received three case scenarios with the following scenarios: 50-year-old male patient, 30-year-old male athlete, and a 70-year-old female patient, each presenting with uncomplicated musculoskeletal thoracic pain. Clinicians were asked to perform three consecutive thoracic SM thrusts for each of the scenarios and repeated the same interventions after 24–48 h.

Results
Eighty-one chiropractors participated in the study, including 32 females (39.5%) with a mean age of 45.22 ± 12.96 years. The variability in SM force–time characteristics between clinicians was substantial, with preload forces ranging from 4.50 to 450.25 N and peak forces ranging from 146.08 to 1285.17 N. Significant differences between case scenarios were observed for peak force (p < 0.0001), maximum thrust speed (p = 0.0002), and thrust impulse (p = 0.0004). Except for thrust duration, repeatability within and between sessions was fair to excellent (ICCs between 0.578 and 0.957).

Conclusion
Substantial variability in application of SM was evident across clinicians and between case scenarios. Despite substantial clinician-dependent variability, the high repeatability of thoracic SM thrusts suggests a level of standardization in SM delivery, indicating that chiropractors might have ‘their’ individual force–time profile that they are capable to reproduce. Further research based on these findings should explore how to enhance the consistency, effectiveness, and safety of thoracic SM delivered clinically to humans.
Electroacupuncture alleviates neuropathic pain in a rat model of CCD via suppressing P2X3 expression in dorsal root ganglia
Authors: Zheng Yu , Jiang Minjian , Wei Zhouyuan , Chi Hengyu , Kang Yurong , Li Siyi , Zheng Yinmu , He Xiaofen , Shao Xiaomei , Fang Jianqiao , Jiang Yongliang 
Published: November 2024

Abstract
Background
Sciatica and low back pain are prevalent clinical types of neuropathic pain that significantly impair patients' quality of life. Conventional therapies often lack effectiveness, making these conditions challenging to treat. Electroacupuncture (EA) is an effective physiotherapy for pain relief. Prior research has demonstrated a relationship between the frequency of neuropathic pain and the analgesic impact of EA stimulation. This work aimed to assess the analgesic effects of EA in a rat model of chronic compression of the dorsal root ganglion (CCD) and to understand the underlying processes.

Methods
We established a rat CCD model to simulate sciatica and low back pain. EA was applied to rats with CCD at various frequencies (2 Hz, 100 Hz, and 2/100 Hz). The paw withdrawal threshold (PWT) was measured to assess analgesic effects. Additionally, protein levels of the purinergic receptor P2X3 (P2X3) and the expression of nociceptive neuronal markers were analyzed using immunohistochemistry and western blot (WB) techniques. The study also measured levels of proinflammatory cytokines TNF-α and IL-1β in the dorsal root ganglion (DRG). The involvement of P2X3 receptors was further investigated using the P2X3 agonist, α,β-methylene ATP (α,β-meATP).

Results
CCD rats developed pronounced mechanical allodynia. EA stimulation at all tested frequencies produced analgesic effects, with 2/100 Hz showing superior efficacy compared to 2 Hz and 100 Hz. The expression of P2X3 was increased in ipsilateral DRG of CCD model rats. P2X3 were co-labeled with isolectin B4 (IB4) and transient receptor potential vanilloid (TRPV1), indicating their role in nociception. 2/100 Hz EA treatment significantly reduced mechanical allodynia and inhibited the overexpression of P2X3, TRPV1, substance P (SP), and calcitonin gene-related peptide (CGRP) in the ipsilateral DRG of CCD model rats. Additionally, EA reduced the levels of proinflammatory cytokines TNF-α and IL-1β in the ipsilateral DRG, indicating an anti-inflammatory effect. The P2X3 agonist α,β-me ATP attenuated the analgesic effect of 2/100 Hz EA in CCD rats. The WB and immunofluorescence results consistently demonstrated P2X3 inhibition contributed to the analgesic effects of 2/100 Hz EA on CCD-induced neuropathic pain.

Conclusions
Our findings suggest that 2/100 Hz EA alleviates neuropathic pain in rats by inhibiting the upregulation of P2X3 receptors in the ipsilateral DRG. This study backs up EA as a viable treatment option for sciatica and low back pain in clinical settings.