bluuebunny/crossref_metadata_2025 huggingface dataset:
Buprenorphine/naloxone – one formulation that doesn’t fit all: a case report
Authors: Braun Hannan M. , Taylor Jessica L. , Axelrath Sarah
Published: July 2024

Background

Sublingual buprenorphine, approved for treatment of opioid use disorder since 2002, is most commonly available in co-formulation with naloxone. Naloxone is an opioid antagonist minimally absorbed when sublingual (SL) buprenorphine/naloxone is taken as prescribed; it is thought to reduce potential for misuse via intravenous administration. However, growing data and clinical experience demonstrate that previously accepted assumptions about the pharmacokinetics of these medications may not apply to all patients.

Case presentation

We present a patient whose adverse post-administration side effects on SL buprenorphine/naloxone resolved with transition to SL buprenorphine monoproduct.

Discussion

Naloxone can be detected in nearly all patients taking SL buprenorphine/naloxone, though with apparent variability in clinical effect. In a minority of patients, naloxone can contribute to adverse and potentially treatment-limiting side effects. Furthermore, the naloxone component is commonly misunderstood by patients and providers and can foster mistrust in the therapeutic relationship if providers are perceived to be withholding a more tolerable formulation. Prescribers should have a low threshold to offer buprenorphine alone when clinically appropriate.
N-linked glycosylation of PD-L1/PD-1: an emerging target for cancer diagnosis and treatment
Authors: Duan Zhiyun , Shi Runhan , Gao Bo , Cai Jiabin
Published: July 2024

During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field.
tRNA-derived fragment 3′tRF-AlaAGC modulates cell chemoresistance and M2 macrophage polarization via binding to TRADD in breast cancer
Authors: Mo Dongping , Tang Xun , Ma Yuyan , Chen Dayu , Xu Weiguo , Jiang Ning , Zheng Junyu , Yan Feng
Published: July 2024

Background

Drug resistance, including Adriamycin-based therapeutic resistance, remains a challenge in breast cancer (BC) treatment. Studies have revealed that macrophages could play a pivotal role in mediating the chemoresistance of cancer cells. Accumulating evidence suggests that tRNA-Derived small RNAs (tDRs) are associated the physiological and pathological processes in multiple cancers. However, the underlying mechanisms of tDRs on chemoresistance of BC in tumor-associated macrophages remain largely unknown.

Methods

The high-throughput sequencing technique was used to screen tDRs expression profile in BC cells. Gain- and loss-of-function experiments and xenograft models were performed to verify the biological function of 3′tRF-Ala-AGC in BC cells. The CIBERSORT algorithm was used to investigate immune cell infiltration in BC tissues. To explore the role of 3′tRF-Ala-AGC in macrophages, M2 macrophages transfected with 3′tRF-Ala-AGC mimic or inhibitor were co-cultured with BC cells. Effects on Nuclear factor-κb (NF-κb) pathway were investigated by NF-κb nuclear translocation assay and western blot analysis. RNA pull-down assay was performed to identify 3′tRF-Ala-AGC interacting proteins.

Results

A 3′tRF fragment of 3′tRF-AlaAGC was screened, which is significantly overexpressed in BC specimens and Adriamycin-resistant cells. 3′tRF-AlaAGC could promote cell malignant activity and facilitate M2 polarization of macrophages in vitro and in vivo. Higher expression of M2 macrophages were more likely to have lymph node metastasis and deeper invasion in BC patients. Mechanistically, 3′tRF-AlaAGC binds Type 1-associated death domain protein (TRADD) in BC cells, and suppression of TRADD partially abolished the enhanced effect of 3′tRF-AlaAGC mimic on phenotype of M2. The NF-κb signaling pathway was activated in BC cells co-cultured with M2 macrophages transfected with 3′tRF-AlaAGC mimic.

Conclusions

3′tRF-AlaAGC might modulate macrophage polarization via binding to TRADD and increase the effect of M2 on promoting the chemoresistance in BC cells through NF-κb signaling pathway.
Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology
Authors: Do Carmo Sonia , Kautzmann Marie-Audrey I. , Bhattacharjee Surjyadipta , Jun Bokkyoo , Steinberg Carolyn , Emmerson Joshua T. , Malcolm Janice C. , Bonomo Quentin , Bazan Nicolas G. , Cuello A. Claudio
Published: July 2024

Background

Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved.

Methods

In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer’s-like amyloid and tau pathologies at early and advanced pathological stages.

Results

Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.

Conclusions

Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.
Overcoming the age-dependent SARS-CoV-2 vaccine response through hybrid immunity: analysis of humoral and cellular immunity with mass cytometry profiling
Authors: Gerelkhuu Zayakhuu , Park Sehee , Lee Kyoung Hwa , Kim Yong Chan , Kwon Sook Jin , Song Kyoung-Ho , Kim Eu Suk , Song Young Goo , Park Yoon Soo , Ahn Jin Young , Choi Jun Yong , Choi Won Suk , Bae Seongman , Kim Sung-Han , Kim Shin-Woo , Kwon Ki Tae , Jeong Hye Won , Peck Kyong Ran , Kang Eun-Suk , Koh June-Young , Ko Jae-Hoon , Yoon Tae Hyun
Published: July 2024

Background

Age-dependent immune responses to coronavirus disease 2019 (COVID-19) vaccinations and breakthrough infections (BIs) in young and middle-aged individuals are unclear.

Methods

This nationwide multicenter prospective cohort study analyzed immune responses in participants of the ChAdOx1 (ChAd)-ChAd-mRNA vaccine group using cytometry by time-of-flight, anti-spike protein antibody (Sab) and anti-nucleocapsid antibody (Nab) titers, plaque reduction neutralization tests (PRNTs), and interferon-gamma (IFN-γ) release assays at various time points.

Results

We evaluated 347 participants with an average age of 38.9 ± 9.4 years (range: 21–63). There was a significant inverse correlation between age and Sab levels after the second dose (slope − 14.96, P = 0.032), and this was more pronounced after the third dose (slope − 208.9, P < 0.001). After BIs, older participants showed significantly higher Sab titers (slope 398.8, P = 0.001), reversing the age-related decline observed post-vaccination. This reversal was also observed in PRNTs against wild-type SARS-CoV-2 and the BA.1 and BA.5 variants. IFN-γ responses increased markedly after the third dose and Bis, but showed a weak positive correlation with age, without statistical significance. Immune cell profiling revealed an age-dependent decrease in the proportions of B-cell lineage cells. The proportions of naive CD4+ and CD8+ T cells were inversely correlated with age, whereas the proportions of mature T cell subsets with memory function, including memory CD4+ T, CD8+ TEM, CD8+ TEMRA, and TFH cells, increased with age.

Conclusions

Age-dependent waning of the serologic response to COVID-19 vaccines occurred even in middle-aged individuals, but was reversed after BIs. IFN-γ responses were preserved, compensating for the decrease in naive T cell populations, with an increase in memory T cell populations.
Safety & efficacy of a robotic hip exoskeleton on outpatient stroke rehabilitation
Authors: Macaluso Rebecca , Giffhorn Matt , Prokup Sara , Cleland Brice , Lee Jusuk , Lim Bokman , Lee Minhyung , Lee Hwang-Jae , Madhavan Sangeetha , Jayaraman Arun
Published: July 2024

Objective

The objective of this study was to analyze the safety and efficacy of using a robotic hip exoskeleton designed by Samsung Electronics Co., Ltd., Korea, called the Gait Enhancing and Motivating System-Hip (GEMS-H), in assistance mode only with the poststroke population in an outpatient-rehabilitation setting.

Methods

Forty-one participants with an average age of 60 and average stroke latency of 6.5 years completed this prospective, single arm, interventional, longitudinal study during the COVID-19 pandemic. Significant modifications to the traditional outpatient clinical environment were made to adhere to organizational physical distancing policies as well as guidelines from the Centers for Disease Control. All participants received gait training with the GEMS-H in assistance mode for 18 training sessions over the course of 6–8 weeks. Performance-based and self-reported clinical outcomes were assessed at four time points: baseline, midpoint (after 9 training sessions), post (after 18 training sessions), and 1-month follow up. Daily step count was also collected throughout the duration of the study using an ankle-worn actigraphy device. Additionally, corticomotor excitability was measured at baseline and post for 4 bilateral lower limb muscles using transcranial magnetic stimulation.

Results

By the end of the training program, the primary outcome, walking speed, improved by 0.13 m/s (p < 0.001). Secondary outcomes of walking endurance, balance, and functional gait also improved as measured by the 6-Minute Walk Test (47 m, p < 0.001), Berg Balance Scale (2.93 points, p < 0.001), and Functional Gait Assessment (1.80 points, p < 0.001). Daily step count significantly improved with and average increase of 1,750 steps per day (p < 0.001). There was a 35% increase in detectable lower limb motor evoked potentials and a significant decrease in the active motor threshold in the medial gastrocnemius (-5.7, p < 0.05) after training with the device.

Conclusions

Gait training with the GEMS-H exoskeleton showed significant improvements in walking speed, walking endurance, and balance in persons with chronic stroke. Day-to-day activity also improved as evidenced by increased daily step count. Additionally, corticomotor excitability changes suggest that training with this device may help correct interhemispheric imbalance typically seen after stroke.

Trial Registration

This study is registered with ClinicalTrials.gov (NCT04285060).
Adverse cardiac events of hypercholesterolemia are enhanced by sitagliptin in sprague dawley rats
Authors: Palfrey Henry A. , Kumar Avinash , Pathak Rashmi , Stone Kirsten P. , Gettys Thomas W. , Murthy Subramanyam N.
Published: July 2024

Background

Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. Therefore, studies on the combined effects of Cho and Met were carried out using male Sprague Dawley rats. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. We hypothesized that feeding a dietary combination of Cho and Met would result in adverse cardiac effects and would be attenuated upon administration of sitagliptin.

Methods

Adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with an aqueous preparation of sitagliptin (100 mg/kg/d) or vehicle (water) from day 10 through 35. On day 36, rats were euthanized, and tissues were collected for analysis.

Results

Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin.

Conclusions

Adverse cardiac outcomes in HChol were enhanced by the administration of sitagliptin, and such effects were alleviated by Met. Our findings could be significant for understanding or revisiting the risk-benefit evaluation of sitagliptin in type 2 diabetics, and especially those who are known to consume atherogenic diets.
Quantitative PSMA-PET parameters in localized prostate cancer: prognostic and potential predictive value
Authors: Bela Andela Stephanie , Amthauer Holger , Furth Christian , Rogasch Julian M. , Beck Marcus , Mehrhof Felix , Ghadjar Pirus , van den Hoff Jörg , Klatte Tobias , Tahbaz Rana , Zips Daniel , Hofheinz Frank , Zschaeck Sebastian
Published: July 2024

Background

PSMA-PET is increasingly used for staging prostate cancer (PCA) patients. However, it is not clear if quantitative imaging parameters of positron emission tomography (PET) have an impact on disease progression and are thus important for the prognosis of localized PCA.

Methods

This is a monocenter retrospective analysis of 86 consecutive patients with localized intermediate or high-risk PCA and PSMA-PET before treatment The quantitative PET parameters maximum standardized uptake value (SUVmax), tumor asphericity (ASP), PSMA tumor volume (PSMA-TV), and PSMA total lesion uptake (PSMA-TLU = PSMA-TV × SUVmean) were assessed for their prognostic significance in patients with radiotherapy or surgery. Cox regression analyses were performed for biochemical recurrence-free survival, overall survival (OS), local control, and loco-regional control (LRC).

Results

67% of patients had high-risk disease, 51 patients were treated with radiotherapy, and 35 with surgery. Analysis of metric PET parameters in the whole cohort revealed a significant association of PSMA-TV (p = 0.003), PSMA-TLU (p = 0.004), and ASP (p < 0.001) with OS. Upon binarization of PET parameters, several other parameters showed a significant association with clinical outcome. When analyzing high-risk patients according to the primary treatment approach, a previously published cut-off for SUVmax (8.6) showed a significant association with LRC in surgically treated (p = 0.048), but not in primary irradiated (p = 0.34) patients. In addition, PSMA-TLU (p = 0.016) seemed to be a very promising biomarker to stratify surgical patients.

Conclusion

Our data confirm one previous publication on the prognostic impact of SUVmax in surgically treated patients with high-risk PCA. Our exploratory analysis indicates that PSMA-TLU might be even better suited. The missing association with primary irradiated patients needs prospective validation with a larger sample size to conclude a predictive potential.

Trial registration Due to the retrospective nature of this research, no registration was carried out.
Identification of truncated variants in GLI family zinc finger 3 (GLI3) associated with polydactyly
Authors: Wang Run-Yan , Xiong Qin , Chang Si-Hua , Jin Jie-Yuan , Xiang Rong , Zeng Lei , Yu Fang
Published: July 2024

Background

Polydactyly is a prevalent congenital anomaly with an incidence of 2.14 per 1000 live births in China. GLI family zinc finger 3 (GLI3) is a classical causative gene of polydactyly, and serves as a pivotal transcription factor in the hedgehog signaling pathway, regulating the development of the anterior-posterior axis in limbs.

Methods

Three pedigrees of polydactyly patients were enrolled from Hunan Province, China. Pathogenic variants were identified by whole-exome sequencing (WES) and Sanger sequencing.

Results

Three variants in GLI3 were identified in three unrelated families, including a novel deletion variant (c.1372del, p.Thr458GlnfsTer44), a novel insertion-deletion (indel) variant (c.1967_1968delinsAA, p.Ser656Ter), and a nonsense variant (c.2374 C > T, p.Arg792Ter). These variants were present exclusively in patients but not in healthy individuals.

Conclusions

We identified three pathogenic GLI3 variants in polydactyly patients, broadening the genetic spectrum of GLI3 and contributing significantly to genetic counseling and diagnosis for polydactyly.
SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing
Authors: Redin Esther , Sridhar Harsha , Zhan Yingqian A. , Pereira Mello Barbara , Zhong Hong , Durani Vidushi , Sabet Amin , Manoj Parvathy , Linkov Irina , Qiu Juan , Koche Richard P. , de Stanchina Elisa , Astorkia Maider , Betel Doron , Quintanal-Villalonga Álvaro , Rudin Charles M.
Published: July 2024

Introduction

Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC.

Methods

ATACseq and RNAseq experiments were performed in SCLC cells after pharmacological inhibition of SMARCA4. DNA binding of SMARCA4 was characterized by ChIPseq in high-NE SCLC patient derived xenografts (PDXs). Enrichment analyses were applied to transcriptomic data. Combination of FHD-286 and afatinib was tested in vitro and in a set of chemo-resistant SCLC PDXs in vivo.

Results

SMARCA4 expression positively correlates with that of NE genes in both SCLC cell lines and patient tumors. Pharmacological inhibition of SMARCA4 with FHD-286 induces the loss of NE features and downregulates neuroendocrine and neuronal signaling pathways while activating non-NE factors. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, enhancing NE programs. Enrichment analysis applied to high-confidence SMARCA4 targets confirmed neuron related pathways as the top GO Biological processes regulated by SMARCA4 in SCLC. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST transcript splicing. Furthermore, SMARCA4 inhibition drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib.

Conclusions

This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.
Parapneumonic empyema in children: a scoping review of the literature
Authors: Buonsenso Danilo , Cusenza Francesca , Passadore Lucrezia , Bonanno Francesca , Calanca Carolina , Mariani Francesco , Di Martino Carlotta , Rasmi Sonia , Esposito Susanna
Published: July 2024

Community-acquired pneumonia can lead to a serious complication called empyema, which refers to pus within the pleural space. While it poses a significant threat to morbidity, particularly in children, it is fortunately not associated with high mortality rates. However, determining the best course of management for children, including decisions regarding antibiotic selection, administration methods, and treatment duration, remains a topic of ongoing debate. This scoping review aims to map the existing literature on empyema in children, including types of studies, microbiology, therapies (both antimicrobial and surgical) and patient outcomes. We systematically searched PubMed and SCOPUS using the terms “pediatric” (encompassing children aged 0 to 18 years) and “pleural empyema” to identify all relevant studies published since 2000. This search adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA ScR) checklist.

A total of 127 studies was included. Overall, 15 attempted to compare medical treatments (alone or in combination with pleural drainage or fibrinolysis) with more invasive surgical approaches, and six studies compared diverse surgical interventions. However, the diversity of study designs makes it difficult to derive firm conclusions on the optimal approach to pediatric empyema. The heterogeneity in inclusion criteria, pharmacological/surgical approaches and settings limit the ability to draw definitive conclusions. Overall, 78 out of 10,896 children (0.7%) included in the review died, with mortality being higher in Asia and Africa. Our scoping review highlights important gaps regarding several aspects of empyema in children, including specific serotypes of the most common bacteria involved in the etiology, the optimal pharmacological and surgical approach, and the potential benefits of newer antibiotics with optimal lung penetration. New trials, designed on a multi-country level a higher number of patients and more rigorous inclusion criteria and designs, should be urgently funded.
Modelling the demographic history of human North African genomes points to a recent soft split divergence between populations
Authors: Serradell Jose M. , Lorenzo-Salazar Jose M. , Flores Carlos , Lao Oscar , Comas David
Published: July 2024

Background

North African human populations present a complex demographic scenario due to the presence of an autochthonous genetic component and population substructure, plus extensive gene flow from the Middle East, Europe, and sub-Saharan Africa.

Results

We conducted a comprehensive analysis of 364 genomes to construct detailed demographic models for the North African region, encompassing its two primary ethnic groups, the Arab and Amazigh populations. This was achieved through an Approximate Bayesian Computation with Deep Learning (ABC-DL) framework and a novel algorithm called Genetic Programming for Population Genetics (GP4PG). This innovative approach enabled us to effectively model intricate demographic scenarios, utilizing a subset of 16 whole genomes at > 30X coverage. The demographic model suggested by GP4PG exhibited a closer alignment with the observed data compared to the ABC-DL model. Both point to a back-to-Africa origin of North African individuals and a close relationship with Eurasian populations. Results support different origins for Amazigh and Arab populations, with Amazigh populations originating back in Epipaleolithic times, while GP4PG supports Arabization as the main source of Middle Eastern ancestry. The GP4PG model includes population substructure in surrounding populations (sub-Saharan Africa and Middle East) with continuous decaying gene flow after population split. Contrary to ABC-DL, the best GP4PG model does not require pulses of admixture from surrounding populations into North Africa pointing to soft splits as drivers of divergence in North Africa.

Conclusions

We have built a demographic model on North Africa that points to a back-to-Africa expansion and a differential origin between Arab and Amazigh populations.
Epigenomic identification of vernalization cis-regulatory elements in winter wheat
Authors: Liu Yanhong , Liu Pan , Gao Lifeng , Li Yushan , Ren Xueni , Jia Jizeng , Wang Lei , Zheng Xu , Tong Yiping , Pei Hongcui , Lu Zefu
Published: July 2024

Background

Winter wheat undergoes vernalization, a process activated by prolonged exposure to low temperatures. During this phase, flowering signals are generated and transported to the apical meristems, stimulating the transition to the inflorescence meristem while inhibiting tiller bud elongation. Although some vernalization genes have been identified, the keycis-regulatory elements and precise mechanisms governing this process in wheat remain largely unknown.

Results

In this study, we construct extensive epigenomic and transcriptomic profiling across multiple tissues—leaf, axillary bud, and shoot apex—during the vernalization of winter wheat. Epigenetic modifications play a crucial role in eliciting tissue-specific responses and sub-genome-divergent expressions during vernalization. Notably, we observe that H3K27me3 primarily regulates vernalization-induced genes and has limited influence on vernalization-repressed genes. The integration of these datasets enables the identification of 10,600 putative vernalization-related regulatory elements including distal accessible chromatin regions (ACRs) situated 30Kb upstream ofVRN3, contributing to the construction of a comprehensive regulatory network. Furthermore, we discover that TaSPL7/15, integral components of the aging-related flowering pathway, interact with theVRN1promoter andVRN3distal regulatory elements. These interactions finely regulate their expressions, consequently impacting the vernalization process and flowering.

Conclusions

Our study offers critical insights into wheat vernalization’s epigenomic dynamics and identifies the putative regulatory elements crucial for developing wheat germplasm with varied vernalization characteristics. It also establishes a vernalization-related transcriptional network, and uncovers that TaSPL7/15 from the aging pathway participates in vernalization by directly binding to theVRN1promoter andVRN3distal regulatory elements.
Toxoplasma gondii bradyzoite-specific BAG1 is nonessential for cyst formation due to compensation by other heat-shock proteins
Authors: Wu Weiling , Chen Qiqi , Zou Weihao , Chen Jiating , Zhu Di , Yang Huijing , Ouyang Lishan , Liu Xiaojun , Peng Hongjuan
Published: July 2024

Background

Toxoplasma gondii is an opportunistic pathogenic protozoan that infects all warm-blooded animals, including humans, and causes zoonotic toxoplasmosis. The bradyzoite antigen 1 (BAG1), known as heat-shock protein (HSP)30, is a specific antigen expressed during the early stage of T. gondii tachyzoite–bradyzoite conversion.

Methods

A bag1 gene knockout strain based on the T. gondii type II ME49 was constructed and designated as ME49Δbag1. The invasion, proliferation, and cyst formation efficiency in the cell model and survival in the mouse model were compared between the ME49 and ME49Δbag1 strains after infection. Quantitative polymerase chain reaction (qPCR) was used to detect the transcriptional level of important genes, and western-blot was used to detect protein levels.

Results

ME49Δbag1 displayed significantly inhibited cyst formation, although it was not completely blocked. During early differentiation induced by alkaline and starvation conditions in vitro, the proliferation of ME49Δbag1 was significantly accelerated relative to the ME49 strain. Meanwhile, the transcription of the HSP family and bradyzoite formation deficient 1 (bfd1) were significantly enhanced. The observed upregulation suggests a compensatory mechanism to counterbalance the impaired stress responses of T. gondii following bag1 knockout. On the other hand, the elevated transcription levels of several HSP family members, including HSP20, HSP21, HSP40, HSP60, HSP70, and HSP90, along with BFD1, implied the involvement of alternative regulatory factors in bradyzoite differentiation aside from BAG1.

Conclusions

The data suggested that when bag1 was absent, the stress response of T. gondii was partially compensated by increased levels of other HSPs, resulting in the formation of fewer cysts. This highlighted a complex regulatory network beyond BAG1 influencing the parasite’s transformation into bradyzoites, emphasizing the vital compensatory function of HSPs in the T. gondii life cycle adaptation.

Graphical Abstract
The erythrocyte sedimentation rate and other markers of inflammation in cats tested for Leishmania infantum and feline immunodeficiency virus antibodies
Authors: Donato Giulia , Caspanello Tiziana , Caprì Alessandra , De Majo Massimo , Iannelli Nicola Maria , Rosace Flavia , Bruno Federica , Castelli Germano , Pennisi Maria Grazia , Masucci Marisa
Published: July 2024

Background

In endemic areas,Leishmania infantumand feline immunodeficiency virus (FIV) co-infection occurs in cats, and may favour a progressive course of feline leishmaniosis. Abnormalities in serum protein fractions have been reported, but inflammation markers have scarcely been studied. Erythrocyte sediment rate (ESR) is a marker of inflammation that is poorly used in veterinary medicine, but it has been evaluated in EDTA blood using a recently introduced automatic device. We studied ESR and a pool of feline markers of inflammation (MoI) in catsL. infantum(Li+) and/or FIV antibody-positive (Li+FIV+/FIV+) with the aims (a) to evaluate ESR as MoI in cats with the infectious and clinical conditions considered and (b) to provide data about a pool of MoI never investigated in the feline infections studied and in other cat diseases before.

Methods

This prospective controlled study included 35 study group cats (Li+,n = 20; FIV +,n = 8;Li+FIV+,n = 7) and ten healthy antibody-negative control cats. Clinical findings at physical examination and selected clinical pathological abnormalities related to inflammation were statistically analysed in relation to the infectious status and ESR values.

Results

ESR values were higher inLi+, FIV+, andLi+FIV+cats compared with control cats, and 40% of the study group cats had ESR values above the reference interval (RI). ESR positively correlated with some positive MoI and negatively with some negative MoI studied. Additionally, a higher prevalence of ESR values above the RI has been detected in cats with hypoalbuminemia or hypergammaglobulinemia and higher ESR values were measured in cats with serum protein electrophoresis (SPE) fraction abnormalities. Correlations were also found with erythrocytes, hemoglobin, hematocrit and some erythrocyte indices. FIV+andLi+FIV+cats had a higher prevalence of increased ESR values, and almost all had SPE abnormalities and more severe clinical presentations compared withLi+cats.

Conclusions

Abnormal levels of MoI were found in almost all parameters studied, particularly in FIV+andLi+FIV+cats. Also, ESR can be used as a marker of inflammation in cats withL. infantumand/or FIV infection.

Graphical Abstract
Infrapatellar fat pad size and subcutaneous fat in knee osteoarthritis radiographic progression: data from the osteoarthritis initiative
Authors: Lee Kwanghoon , Banuls-Mirete Marina , Lombardi Alecio F. , Posis Alexander I.B. , Chang Eric Y. , Lane Nancy E. , Guma Monica
Published: July 2024

Objectives

Adipose tissue has been associated with knee osteoarthritis (KOA) pathogenesis, but the longitudinal changes in adipose tissue with KOA progression have not been carefully evaluated. This study aimed to determine if longitudinal changes of systemic and local adipose tissue is associated with radiographic progression of KOA.

Methods

This case-control study used data from the Osteoarthritis Initiative (OAI) and included 315 cases (all the right knees with a minimum of Kellgren-Lawrence score (KL) of 0 and an increase of ≥ 1 KL from baseline to 48 months) and 315 controls matched by age, sex, race, and baseline KL. Cross sectional area of IPFP (IPFP CSA) and subcutaneous adipose tissue around the distal thigh (SCATthigh) were measured using MRI images at baseline and 24 months. Conditional logistic regression models were fitted to estimate associations of obesity markers, IPFP CSA, and SCATthigh with radiographic KOA progression. Mediation analysis was used to assess whether IPFP CSA or SCATthigh mediates the relationships between baseline BMI and radiographic KOA progression.

Results

24-month changes of IPFP CSA (ΔIPFP CSA) and SCATthigh (ΔSCATthigh) were significantly greater in cases compared to controls, whereas Δ BMI and Δ abdominal circumference were similar in both groups during follow-up. Adjusted ORs for radiographic KOA progression were 9.299, 95% CI (5.357–16.141) per 1 SD increase of Δ IPFP CSA and 1.646, 95% CI (1.288–2.103) per 1 SD increase of Δ SCATthigh. ΔIPFP CSA mediated the association between baseline BMI and radiographic KOA progression (87%).

Conclusions

Subjects with radiographic progression of KOA, had significant increases in IPFP CSA and subcutaneous adipose tissue while BMI and abdominal circumference remained stable. Additional studies are needed to confirm these associations.
Sex differences in the association between metabolic score for insulin resistance and the reversion to normoglycemia in adults with prediabetes: a cohort study
Authors: Liang Xiaomin , Xing Zemao , Lai Kai , Li Xiaohong , Gui Shuiqing , Li Ying
Published: July 2024

Background

The metabolic score for insulin resistance (MetS-IR) has become a valid indicator to evaluate insulin resistance. Our investigation sought gender differences in the correlation between MetS-IR and the reversion from prediabetes to normoglycemic status.

Methods

This retrospective research, carried out in 32 areas across 11 cities with several centers in China, encompassed 15,423 participants with prediabetes. We employed a Cox proportional hazards regression model to examine the link between MetS-IR and the reversion to normoglycemic status. We also applied cubic spline functions and smooth curve fitting to detect non-linear relationships. Additionally, we embarked on a range of sensitivity analyses.

Results

The study included 15,423 participants, with 10,009 males (64.90%) and 5,414 females (35.10%). The average follow-up time was 2.96 ± 0.93 years, and 6,623 individuals (42.94%) reversed normoglycemia. A non-linear correlation was discovered among MetS-IR and reversion to normoglycemic status in men, with a turning point at 55.48. For a one-unit rise in MetS-IR below this point, the chance of reversal to normoglycemic levels declined by 3% (HR = 0.97, 95% CI:0.96–0.97, P < 0.0001). In women, the association was linear, with every unit rise in MetS-IR leading to a 3% reduction in transitioning to normal glycemic levels. (HR = 0.97, 95% CI: 0.97–0.98, p < 0.0001).

Conclusion

A negative correlation was discovered between MetS-IR and reversion to normoglycemic status in adults with prediabetes. Specifically, a non-linear association was observed for males, while females exhibited a linear correlation.
Investigation of the effect of relative humidity on micro lime consolidation of degraded earthen structures
Authors: Zeng Renjian , Schwantes Gesa
Published: July 2024

Micro lime, hydrated lime (Ca (OH)2) with particle sizes of 1-3μ dispersed in isopropanol, can be used to reinforce deteriorated earthen structures. The consolidation effect depends on the amount of moisture present in the structure or in the ambient air. This study investigates the influence of different levels of relative humidity (RH) on the consolidation effect of micro lime on earthen structures, the chemical processes responsible for the consolidation and the physical changes to the structure. The aim is to gain a deeper understanding of the underlying chemical reactions and to identify a potential limit to the applicability of this consolidation method in low RH environments. The fact that many of these sites are located in arid climates greatly influences the practical application of micro lime in the conservation of historical earthen structures. To characterize the consolidation effect of micro lime, unconfined compressive strength and exposure to wet and dry cycles were used. The properties of the reaction products and the bonding between soil particles and micro lime were investigated using thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), mercury intrusion porosimetry (MIP) and scanning electron microscopy (SEM). At RH levels of 25%, 45%, 65% and 90%, the unconfined compressive strength (UCS) and the modulus of deformation at 50% strength (E50) of the micro lime-reinforced specimens demonstrated an increase with humidity. This led to a significant improvement in their ability to resist the effects of dry–wet cycles. Results from thermal gravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) indicate that micro lime interacts with the soil matrix via carbonation, with the reaction rate increasing with humidity. At 25% RH, vaterite was produced and residual free lime was observed, whereas at humidity levels of 45% and above, the reaction yielded vaterite and aragonite. The lime treatment did not significantly alter the pore structure of the soil specimens. The total porosity of the specimens was only slightly reduced, with the main effect of the lime treatment being a reduction in the number of large pores.
An interactive 3D atlas of sentinel lymph nodes in breast cancer developed using SPECT/CT
Authors: Situ Josephine , Buissink Poppy , Mu Annie , Chung David K V , Finnegan Rob , Gamage Thiranja P Babarenda , Jayathungage Don Tharanga D , Walker Cameron , Reynolds Hayley M
Published: July 2024

Background

The identification and assessment of sentinel lymph nodes (SLNs) in breast cancer is important for optimised patient management. The aim of this study was to develop an interactive 3D breast SLN atlas and to perform statistical analyses of lymphatic drainage patterns and tumour prevalence.

Methods

A total of 861 early-stage breast cancer patients who underwent preoperative lymphoscintigraphy and SPECT/CT were included. Lymphatic drainage and tumour prevalence statistics were computed using Bayesian inference, non-parametric bootstrapping, and regression techniques. Image registration of SPECT/CT to a reference patient CT was carried out on 350 patients, and SLN positions transformed relative to the reference CT. The reference CT was segmented to visualise bones and muscles, and SLN distributions compared with the European Society for Therapeutic Radiology and Oncology (ESTRO) clinical target volumes (CTVs). The SLN atlas and statistical analyses were integrated into a graphical user interface (GUI).

Results

Direct lymphatic drainage to the axilla level I (anterior) node field was most common (77.2%), followed by the internal mammary node field (30.4%). Tumour prevalence was highest in the upper outer breast quadrant (22.9%) followed by the retroareolar region (12.8%). The 3D atlas had 765 SLNs from 335 patients, with 33.3–66.7% of axillary SLNs and 25.4% of internal mammary SLNs covered by ESTRO CTVs.

Conclusion

The interactive 3D atlas effectively displays breast SLN distribution and statistics for a large patient cohort. The atlas is freely available to download and is a valuable educational resource that could be used in future to guide treatment.
Antibiotic therapy for bacterial pneumonia
Authors: Kato Hideo
Published: July 2024

Pneumonia is a common infection in patients of all ages. Determining its etiology and selecting antibiotic therapy are challenging for physicians in both private practice and hospitals. Moreover, the coronavirus disease pandemic revealed the importance of prevention and treatment of secondary bacterial pneumonia in patients hospitalized with viral respiratory infections. This review focuses on the types of bacteria that cause pneumonia and provides new insights into antibiotic therapy for bacterial pneumonia. Moreover, it also reviews the current state of knowledge regarding secondary bacterial pneumonia.
Early contraceptive implant removal and associated factors among women attending public family planning clinics, Mbarara City, Southwestern Uganda: a cross-sectional study
Authors: Rwebazibwa Joseph , Migisha Richard , Munaru Gideon , Byamukama Onesmus , Abesiga Lenard , Mugyenyi Godfrey R. , Kalyebara Paul Kato , Tibaijuka Leevan , Ngonzi Joseph , Kajabwangu Rogers , Turanzomwe Stuart , Mohammed Fadumo , Muhumuza Joy , Collins Agaba David , Fajardo Yarine Tornes , Ssalongo Wasswa G. M. , Kayondo Musa , Kanyesigye Hamson
Published: July 2024

Background

Early implant removal not only results in method wastage and strains healthcare resources but also exposes women to the risk of unplanned pregnancies and associated complications if an alternative contraceptive is not promptly adopted. Studies have demonstrated that prevalence and factors associated with contraceptive use vary across different cultures and regions even within Uganda. We determined the prevalence and associated factors of early implant removal, among women attending public family planning clinics in Mbarara City, southwestern Uganda.

Methods

We conducted a cross-sectional study from April to July 2023 at four public family planning clinics in Mbarara City. We consecutively enrolled women and administered a questionnaire to obtain data on demographic, and medical characteristics. We defined early removal as implant discontinuation within a period < 2 years. We excluded women who did not have a written record of the date of insertion of the contraceptive implants. We used modified Poisson regression analysis to determine factors associated with early implant removal.

Results

We enrolled 406 women, with a mean age of 29 ± 6 years. The prevalence of early contraceptive implant removal was 53% (n = 210; 95%, CI: 48-58%). Factors associated with early implant removal were experiencing side effects (adjusted prevalence ratio [aPR] = 1.63, 95% CI: 1.20–2.21), inserting an implant to achieve career goals (aPR = 1.88, 95% CI: 1.26–2.81) and intending to use the implant for < 24 months (aPR = 1.36, 95% CI: 1.11–1.66).

Conclusion

Approximately half of the surveyed women removed their contraceptive implant early. Women who experienced side effects, chose an implant due to career obligations and those whose intended implant use was < 2 years were more likely to have an early contraceptive implant removal compared to their counterparts. We recommend strengthening of pre- and post- insertion counselling to address concerns among those who may experience side-effects. Women who intend to use implants for < 2 years and those who have career obligations should be encouraged to use short-acting methods as an option.
The punitive gap: NRC, due process and denationalisation politics in India’s Assam
Authors: Siddique Nazimuddin , Ramachandran Sujata
Published: July 2024

The creation of the National Register of Citizens (NRC) in Assam is indicative of the sharpening tensions surrounding citizenship, belonging and integration in India. Officially aimed at demarcating the “legitimate citizens”, its implementation is believed to have resulted in the partial exclusion of the so-called “Doubtful Voters” and denationalisation of the “illegitimate residents”. These frictions associated with citizenship identity and rights are nowhere as acute as in the northeastern Indian state of Assam, where measures of retroactive revocation, administrative erasure and withdrawal of citizenship rights have been systematically deployed against religious and linguistic minorities. Using new research with some NRC rejected applicants in western Assam and other materials, this article identifies the central aspects of the implementation gap in the crucial, albeit problematic task of locating the rightful “Assamese-Indian” citizens. Linking our work to the idea of the ‘process is the punishment’, we conceptualise these conspicuous inconsistencies in the NRC citizenship determination processes and their results as the “punitive gap”. We have identified the distinctive contours of this gap in terms of the massive economic costs, intensification of social (including gender and religion-based) inequalities, increased control through social suspicion and unpredictable outcomes for the marginal Miya Muslim community. The article highlights how this punitive gap has constantly eroded key components of due process, of procedural and substantive protections of the rights of individuals, during the NRC determination exercise and after the release of the final draft list.
SOLAMEN syndrome with cardiovascular damage
Authors: Zhao Xiong , Yue Xiaojie , Yuan Shifan , Dai Yefeng , Gu Hao
Published: July 2024

SOLAMEN syndrome is a rare, recently recognized congenital syndrome that is characterized by progressive and hypertrophic diseases involving multiple systems, including segmental overgrowth, lipomatosis, arteriovenous malformation (AVM) and epidermal nevus. According to literatures, SOLAMEN syndrome is caused by heterozygous PTEN mutation. Phenotypic overlap complicates the clinical identification of diseases associated with PTEN heterozygous mutations, making the diagnosis of SOLAMEN more challenging. In addition, SOLAMEN often presents with segmental tissue overgrowth and vascular malformations, increasing the possibility of misdiagnosis as klipple-trenaunay syndrome or Parks-Weber syndrome. Here, we present a case of a child presenting with macrocephaly, patchy lymphatic malformation on the right chest, marked subcutaneous varicosities and capillaries involving the whole body, overgrowth of the left lower limb, a liner epidermal nevus on the middle of the right lower limb, and a large AVM on the right cranial thoracic entrance. Based on the typical phenotypes, the child was diagnosed as SOLAMEN syndrome. detailed clinical, imaging and genetic diagnoses of SOLAMEN syndrome was rendered. Next-generation sequencing (NGS) data revealed that except for a germline PTEN mutation, a PDGFRB variant was also identified. A subsequent echocardiographic examination detected potential cardiac defects. We suggested that given the progressive nature of AVM and the potential severity of cardiac damage, regular echocardiographic evaluation, imaging follow-up and appropriate interventional therapy for AVM are recommended.