bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of long non-coding RNA using single nucleotide epimutation analysis: a novel gene discovery approach
Authors: Kerachian Mohammad Amin , Azghandi Marjan 
Published: November 2022

AbstractBackgroundLong non-coding RNAs (lncRNAs) are involved in a variety of mechanisms related to tumorigenesis by functioning as oncogenes or tumor-suppressors or even harboring oncogenic and tumor-suppressing effects; representing a new class of cancer biomarkers and therapeutic targets. It is predicted that more than 35,000 ncRNA especially lncRNA are positioned at the intergenic regions of the human genome. Emerging research indicates that one of the key pathways controlling lncRNA expression and tissue specificity is epigenetic regulation.MethodsIn the current article, a novel approach for lncRNA discovery based on the intergenic position of most lncRNAs and a single CpG site methylation level representing epigenetic characteristics has been suggested.ResultsUsing this method, a novel antisense lncRNA named LINC02892 presenting three transcripts without the capacity of coding a protein was found exhibiting nuclear, cytoplasmic, and exosome distributions.ConclusionThe current discovery strategy could be applied to identify novel non-coding RNAs influenced by methylation aberrations.
Examining the variations in the implementation of interventions to address stillbirth from the national to subnational levels: experiences from Uganda
Authors: Ssegujja Eric , Andipatin Michelle 
Published: November 2022

Abstract
Background
The current global burden of stillbirth disproportionately affects regions such as sub-Saharan Africa, where Uganda is located. To respond to this burden, policies made at the national level were diffused from the centre and translated into service delivery at the district level, which is charged with implementation under the decentralization of health services arrangement. Variations emerge whenever policy recommendations are moved from national to subnational levels, with some aspects often lost along the way. Tools are available to facilitate knowledge of determinants of policy and innovation implementation within the healthcare system. However, the extent to which these have been applied to explain variations in implementation of interventions to address stillbirth reduction in Uganda remains scant. The aim of this article was to examine the variations in the implementation of interventions to address stillbirth from the national to the subnational levels in Uganda using the Consolidated Framework for Implementation Research (CFIR).

Methods
The study adopted a qualitative case study design. Data were collected from a purposively selected sample of key informants drawn from both the national and subnational levels. All interviews were conducted in English and transcribed verbatim. ATLAS.ti was used to guide the coding process, which used a codebook developed following the CFIR domains as codes and constructs as sub-codes. Analysis followed a content analysis technique.

Results
National-level factors that favoured implementation of interventions to address stillbirth included the desire to comply with global norms, incentives to improve performance for stillbirth reduction indicators for better comparison with global peers, and clear policy alternatives as process implementation advanced by champions. Variations at the subnational level revealed aspirations to address service delivery gaps which fell within maternal health routine standard of care and ongoing health systems strengthening initiatives. Coalescing existing networks around maternal and child health was a key mobilization factor for advocacy and programming, with a promise that the set targets would be operationalized at the subnational level. The key champions were defined by their official roles within the district health systems, which enhanced accountability. Feedback and reflection were distinguished from the national to subnational through joint assemblies and formal audit reviews, respectively.

Conclusions
A heavy influence of the global events directed national-level adaptation of interventions to address stillbirth. Implementation context at the subnational level led to local adaptation and translation of policy provisions from the national level to suit the context, which to a greater extent explains the variations in the final content of policy provisions delivered.
The prevalence and management of chronic pain in the Chinese population: findings from the China Pain Health Index (2020)
Authors: Jiang Yingying , Xu Tingling , Mao Fan , Miao Yu , Liu Botao , Xu Liyuan , Li Lingni , Sternbach Nikoletta , Zhou Maigeng , Fan Bifa 
Published: November 2022

Abstract
Background
Chronic pain is a common disease; about 20% of people worldwide suffer from it. While compared with the research on the prevalence and management of chronic pain in developed countries, there is a relative lack of research in this field in China. This research aims to construct the China Pain Health Index (CPHI) to evaluate the current status of the prevalence and management of chronic pain in the Chinese population.

Methods
The dimensions and indicators of CPHI were determined through literature review, Delphi method, and analytical hierarchy process model, and the original values ​​of relevant indicators were obtained by collecting multi-source data. National and sub-provincial scores of CPHI (2020) were calculated by co-directional transformation, standardization, percentage transformation of the aggregate, and weighted summation.

Results
The highest CPHI score in 2020 is Beijing, and the lowest is Tibet. The top five provinces are Beijing (67.64 points), Shanghai (67.04 points), Zhejiang (65.74 points), Shandong (61.16 points), and Tianjin (59.99 points). The last five provinces are Tibet (33.10 points), Ningxia (37.24 points), Guizhou (39.85 points), Xinjiang (39.92 points), and Hainan (40.38 points). The prevalence of chronic pain is severe in Heilongjiang, Chongqing, Guizhou, Sichuan, and Fujian. Guizhou, Hainan, Xinjiang, Beijing, and Guangdong display a high burden of chronic pain. The five provinces of Guangdong, Shanghai, Beijing, Jiangsu, and Zhejiang have better treatment for chronic pain, while Tibet, Qinghai, Jilin, Ningxia, and Xinjiang have a lower quality of treatment. Beijing, Shanghai, Qinghai, Guangxi, and Hunan have relatively good development of chronic pain disciplines, while Tibet, Sichuan, Inner Mongolia, Hebei, and Guizhou are relatively poor.

Conclusion
The economically developed provinces in China have higher CPHI scores, while economically underdeveloped areas have lower scores. The current pain diagnosis and treatment situation in economically developed regions is relatively good, while that in financially underdeveloped areas is rather poor. According to the variations in the prevalence and management of chronic pain among populations in different provinces in China, it is necessary to implement chronic pain intervention measures adapted to local conditions.
Single cell profiling of CD45+ spinal cord cells reveals microglial and B cell heterogeneity and crosstalk following spinal cord injury
Authors: Fisher Elizabeth S. , Amarante Matthew A. , Lowry Natasha , Lotz Steven , Farjood Farhad , Temple Sally , Hill Caitlin E. , Kiehl Thomas R. 
Published: November 2022

Abstract
Background
Immune cells play crucial roles after spinal cord injury (SCI). However, incomplete knowledge of immune contributions to injury and repair hinders development of SCI therapies. We leveraged single-cell observations to describe key populations of immune cells present in the spinal cord and changes in their transcriptional profiles from uninjured to subacute and chronic stages of SCI.

Methods
Deep-read single-cell sequencing was performed on CD45+ cells from spinal cords of uninjured and injured Swiss-webster mice. After T9 thoracic contusion, cells were collected 3-, 7-, and 60-day post-injury (dpi). Subpopulations of CD45+ immune cells were identified informatically, and their transcriptional responses characterized with time. We compared gene expression in spinal cord microglia and B cell subpopulations with those in published models of disease and injury. Microglia were compared with Disease Associated Microglia (DAM) and Injury Responsive Microglia (IRM). B cells were compared to developmental lineage states and to an Amyotrophic Lateral Sclerosis (ALS) model.

Results
In uninjured and 7 dpi spinal cord, most CD45+ cells isolated were microglia while chronically B cells predominated. B cells accumulating in the spinal cord following injury included immature B to mature stages and were predominantly found in the injury zone. We defined diverse subtypes of microglia and B cells with altered gene expression with time after SCI. Spinal cord microglia gene expression indicates differences from brain microglia at rest and in inflammatory states. Expression analysis of signaling ligand–receptor partners identified microglia–B cell interactions at acute and chronic stages that may be involved in B cell recruitment, retention, and formation of ectopic lymphoid follicles.

Conclusions
Immune cell responses to SCI have region-specific aspects and evolve with time. Developmentally diverse populations of B cells accumulate in the spinal cord following injury. Microglia at subacute stages express B cell recruitment factors, while chronically, they express factors predicted to reduce B cell inflammatory state. In the injured spinal cord, B cells create ectopic lymphoid structures, and express secreted factors potentially acting on microglia. Our study predicts previously unidentified crosstalk between microglia and B cells post-injury at acute and chronic stages, revealing new potential targets of inflammatory responses for SCI repair warranting future functional analyses.
Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination
Authors: Hwang Mihyun , Savarin Carine , Kim Jihye , Powers Jennifer , Towne Natasha , Oh Hyunsuk , Bergmann Cornelia C. 
Published: November 2022

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination.MethodsWild-type (WT) and Trem2 deficient (Trem2−/−) mice were infected with a sublethal glia tropic murine coronavirus (MHV–JHM) intracranially. Disease progression and survival were monitored daily. Leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone-marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform.ResultsBMDM recruited to SCs in response to infection highly upregulatedTrem2mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression inTrem2−/−mice could not be attributed to altered virus control or an elevated proinflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genesLplandCd36in microglia, but a more complex pattern in BMDM.ConclusionsTrem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments.
Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway
Authors: Zhao Pengzhan , Wei Yutian , Sun Guangchi , Xu Lei , Wang Tian , Tian Yufei , Chao Honglu , Tu Yiming , Ji Jing 
Published: November 2022

Abstract
Background
The microglia-mediated inflammatory response is a vital mechanism of secondary damage following traumatic brain injury (TBI), but the underlying mechanism of microglial activation is unclear.

Methods
Controlled cortical impact (CCI) was induced in adult male C57BL/6J mice, and glutamate was used to construct a classical in vitro injury model in the primary microglia. Microglial activation was determined by western blot and immunostaining. The inflammatory factors were measured by enzyme-linked immunosorbent assay. The oxidative stress marker and mitochondrial reactive oxygen species (ROS) were measured by immunoblotting and MitoSox Red staining. Transmission electron microscopy was used to observe the typical morphology of necroptotic cells.

Results
Our quantitative proteomics identified 2499 proteins; 157 were significantly differentially expressed in brain tissue between the 6 h after CCI (CCI6h) group and sham group, and 109 were significantly differentially expressed between the CCI24h and sham groups. Moreover, compared with the sham group, the terms “acute-phase response”, “inflammation”, and “protein binding” were significantly enriched in CCI groups. Fetuin-A, a liver-secreted acute-phase glycoprotein, was involved in these biological processes. Using an experimental TBI model, we found that the Fetuin-A level peaked at 6 h and then decreased gradually. Importantly, we showed that administration of Fetuin-A reduced the cortical lesion volume and edema area and inhibited the inflammatory response, which was associated with suppressing microglial necroptosis, thus decreasing microglial activation. Furthermore, administration of Fetuin-A attenuated mitochondrial oxidative stress in glutamate-treated microglial cells, which is a critical mechanism of necroptosis suppression. In addition, we demonstrated that Fetuin-A treatment promoted translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus in vivo; however, the Nrf-2 inhibitor ML385 and si-heme oxygenase-1 (si-HO-1) disrupted the regulation of oxidative stress by Fetuin-A and induced increased ROS levels and necroptosis in glutamate-treated microglial cells. Fetuin-A also protected neurons from adverse factors in vivo and in vitro.

Conclusions
Our results demonstrated that Fetuin-A activated Nrf-2/HO-1, suppressed oxidative stress and necroptosis levels, and thereby attenuates the abnormal inflammatory response following TBI. The findings suggest a potential therapeutic strategy for TBI treatment.
Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins
Authors: Szabova Ludmila , Gordon Melanie B. , Lu Lucy , Pate Nathan , Bassel Laura , Iacovelli Anthony J. , Karim Baktiar , Homan Philip J. , Householder Deborah B. , Guerin Theresa M. , Burkett Sandra , Day Amanda M. , Custer Wendi , Weaver Ohler Zoe 
Published: November 2022

Abstract
Background
Breast cancer is a heterogenous disease with several histological and molecular subtypes. Models that represent these subtypes are essential for translational research aimed at improving clinical strategy for targeted therapeutics.

Methods
Different combinations of genetic aberrations (Brca1 and Trp53 loss, and inhibition of proteins of the Rb family) were induced in the mammary gland by injection of adenovirus expressing Cre recombinase into the mammary ducts of adult genetically engineered mice. Mammary tumors with different genetic aberrations were classified into molecular subtypes based on expression of molecular markers and RNAseq analysis. In vitro potency assays and Western blots were used to examine their drug sensitivities.

Results
Induction of Brca1 and Trp53 loss in mammary ductal epithelium resulted in development of basal-like hormone receptor (HR)-negative mammary tumors. Inhibition of Rb and Trp53 loss or the combination of Rb, Trp53 and Brca1 aberrations resulted in development of luminal ductal carcinoma positive for ER, PR, and Her2 expression. HR positivity in tumors with Rb, Trp53 and Brca1 aberrations indicated that functionality of the Rb pathway rather than Brca1 status affected HR status in these models. Mammary tumor gene expression profiles recapitulated human basal-like or luminal B breast cancer signatures, but HR-positive luminal cancer models were endocrine resistant and exhibited upregulation of PI3K signaling and sensitivity to this pathway inhibition. Furthermore, both tumor subtypes were resistant to CDK4/6 inhibition.

Conclusions
Examination of molecular expression profiles and drug sensitivities of tumors indicate that these breast cancer models can be utilized as a translational platform for evaluation of targeted combinations to improve chemotherapeutic response in patients that no longer respond to hormone therapy or that are resistant to CDK4/6 inhibition.
Comparative analysis of the anthelmintic efficacy of European heather extracts on Teladorsagia circumcincta and Trichostrongylus colubriformis egg hatching and larval motility
Authors: Shepherd Francesca , Chylinski Caroline , Hutchings Michael R. , Lima Joana , Davidson Ross , Kelly Robert , Macrae Alastair , Salminen Juha-Pekka , Engström Marica T. , Maurer Veronika , Steinshamn Håvard , Fittje Susanne , Perez Angela Morell , García Rocío Rosa , Athanasiadou Spiridoula 
Published: November 2022

Abstract
Background
Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in anthelmintic resistance, alternatives are sought after. A promising alternative is the use of bioactive plant feeding due to the presence of plant secondary metabolites (PSMs) such as proanthocyanidins (PAs). This study focussed on the perennial shrub heather (Ericaceae family), a plant rich in PAs, highly abundant across Europe and with previously demonstrated anthelmintic potential.

Methods
In vitro assays were used to investigate heather’s anthelmintic efficacy against egg hatching and larval motility. Heather samples were collected from five European countries across two seasons, and extracts were tested against two GIN species: Teladorsagia circumcincta and Trichostrongylus colubriformis. Polyphenol group-specific ultraperformance liquid chromatography-tandem mass spectrometry analysis was performed to identify relevant polyphenol subgroups present, including the PA concentration and size and ratio of the subunits. Partial least squares analysis was performed to associate efficacy with variation in PSM composition.

Results
Heather extracts reduced egg hatching of both GIN species in a dose-dependent manner by up to 100%, while three extracts at the highest concentration (10 mg/ml) reduced larval motility to levels that were not significantly different from dead larvae controls. PAs, particularly the procyanidin type, and flavonol derivatives were associated with anthelmintic activity, and the particular subgroup of polyphenols associated with the efficacy was dependent on the GIN species and life stage.

Conclusions
Our results provide in vitro evidence that heather, a widely available plant often managed as a weed in grazing systems, has anthelmintic properties attributed to various groups of PSMs and could contribute to sustainable GIN control in ruminant production systems across Europe.

Graphical Abstract
Plasma adiponectin levels predict cognitive decline and cortical thinning in mild cognitive impairment with beta-amyloid pathology
Authors: Kim Keun You , Ha Junghee , Kim Minae , Cho So Yeon , Kim Hyunjeong , Kim Eosu ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2022

Abstract
Background
Blood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer’s disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aβ) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aβ on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aβ conditions (Aβ [+] and Aβ [−]) in individuals with mild cognitive impairment (MCI).

Methods
Of 156 participants with MCI from the longitudinal cohort study of Alzheimer’s Disease Neuroimaging Initiative (ADNI), 31 were Aβ (−) and 125 were Aβ (+) as determined by CSF analysis. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aβ conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined.

Results
Of the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aβ (+) and (−) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aβ (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aβ (+) condition (beta = − 0.004, p = 0.012 for the right side; beta = − 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aβ (−) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aβ status.

Conclusion
Plasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aβ (+) MCI.
Secret shopper studies: an unorthodox design that measures inequities in healthcare access
Authors: Rankin Kelsey A. , Mosier-Mills Alison , Hsiang Walter , Wiznia Daniel H. 
Published: November 2022

AbstractSecret shopper studies are particularly potent study designs that allow for the gathering of objective data for a variety of research hypotheses, including but not limited to, healthcare delivery, equity of healthcare, and potential barriers to care. Of particular interest during the COVID-19 pandemic, secret shopper study designs allow for the gathering of data over the phone. However, there is a dearth of literature available on appropriate methodological practices for these types of studies. To make these study designs more widely accessible, here we outline the case for using the secret shopper methodology and detail best practices for designing and implementing them.