bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia
Authors: Saglia Claudia , Arruga Francesca , Scolari Caterina , Kalantari Silvia , Albanese Serena , Bracciamà Valeria , Corso Faini Angelo , Brach del Prever Giulia , Luca Maria , Romeo Carmelo , Mioli Fiorenza , Migliorero Martina , Tessaris Daniele , Carli Diana , Amoroso Antonio , Vaisitti Tiziana , De Sanctis Luisa , Deaglio Silvia 
Published: April 2024

Abstract

Objective
The calcium-sensing receptor (CASR) gene encodes a G protein–coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants.

Design and methods
To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs.

Results
Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT.

Conclusions
This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient’s phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.
Does environmental regulation promote green technological innovation of companies? Evidence from green patents of Chinese listed companies
Authors: Pan Aimin , Jiang Ping , Wang Chao , Wang Feifei 
Published: April 2024

Abstract
Environmental regulations stimulate Chinese listed companies to engage in green technology innovation. Moreover, the internal attributes of listed companies such as ownership form, the nature of the industry and locations affect the role of environmental regulations on green technology innovation. This paper selects data on Chinese-listed A-share enterprises from 2010-2019 and constructs a S-GMM model to analyze the impact of environmental regulations on green technology innovation through internal attributes of firms. The empirical results show that, first of all, in the sample period, tight environmental regulations hinder green technology innovation carried out by listed enterprises in state-owned heavy polluting industries in eastern China, and there is no innovation compensation effect. Secondly, green technology innovation in the previous period does not significantly promote green technology innovation in the current period. Finally, overvaluation of listed companies by investors encourage Chinese listed enterprises to engage in green technology innovation, especially among non-state-owned listed companies in non-heavy polluting industries. The findings of this paper provide empirical support for environmental regulation policy recommendations, that foster economic growth and promote green and low-carbon industrial transformation in the direction of high-quality development of the economy.
MiRNA-21-5p induces chicken hepatic lipogenesis by targeting NFIB and KLF3 to suppress the PI3K/AKT signaling pathway
Authors: Wu Yamei , Zhao Jing , Cui Can , Zhang Yao , Zhu Qing , Han Shunshun , Yang Chaowu , Yin Huadong 
Published: April 2024

Abstract
The liver plays a critical role in metabolic activity and is the body’s first immune barrier, and maintaining liver health is particularly important for poultry production. MicroRNAs (miRNAs) are involved in a wide range of biological activities due to their capacity as posttranscriptional regulatory elements. A growing body of research indicates that miR-21-5p plays a vital role as a modulator of liver metabolism in various species. However, the effect of miR-21-5p on the chicken liver is unclear. In the current study, we discovered that the fatty liver had high levels of miR-21-5p. Then the qPCR, Western blot, flow cytometry, enzyme-linked immunosorbent assay, dual-luciferase, and immunofluorescence assays were, respectively, used to determine the impact of miR-21-5p in the chicken liver, and it turned out that miR-21-5p enhanced lipogenesis, oxidative stress, and inflammatory responses, which ultimately induced hepatocyte apoptosis. Mechanically, we verified that miR-21-5p can directly target nuclear factor I B (NFIB) and kruppel-like factor 3 (KLF3). Furthermore, our experiments revealed that the suppression of NFIB promoted apoptosis and inflammation, and the KLF3 inhibitor accelerated lipogenesis and enhanced oxidative stress. Furthermore, the cotransfection results suggest that the PI3K/AKT pathway is also involved in the process of miRNA-21-5p-mediate liver metabolism regulation. In summary, our study demonstrated that miRNA-21-5p plays a role in hepatocyte lipogenesis, oxidative stress, inflammation, and apoptosis, via targeting NFIB and KLF3 to suppress the PI3K/AKT signal pathway in chicken.
Short communication: a novel multispecies bacteria-based direct-fed microbial supports in vitro gut barrier integrity challenged with a pathogen or pro-inflammatory cytokines*
Authors: Boll Erik J , Copani Giuseppe , Cappellozza Bruno I 
Published: April 2024

Abstract
We conducted two experiments to evaluate the effects of a novel bacterial-based direct-fed microbial (DFM) on intestinal barrier integrity using the in vitro transepithelial electrical resistance (TEER) assay. In experiment 1, human-derived Caco-2 cells received or not (CON) a DFM containing Ligilactobacillus (formerly Lactobacillus) animalis 506, Propionibacterium freudenreichii 507, Bacillus paralicheniformis 809, and B. subtilis 597 (BDP; BOVAMINE DEFEND® Plus) at a rate of 1 × 108 CFU/transwell. Concurrently with treatment application (CON or BDP), a pathogenic challenge of Clostridium perfringens type A was added alone (PAT) or with BDP (PAT + BDP) at a rate of 2.8 × 107 CFU/transwell in a 2 × 2 factorial arrangement. In experiment 2, Caco-2 cells were also assigned in a 2 × 2 factorial design to CON or BDP and then, 2 h post-treatment administration (CON and BDP), a mixture of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) was added alone (CYT) or with BDP (CYT + BDP) at a 10:1 ratio, respectively. In both experiments, TEER was measured for 18 h. In experiment 1, a DFM × pathogen × hour interaction was observed for TEER (P &lt; 0.0001). Adding the PAT alone initially tended to increase TEER vs. CON from 1.1 to 2.2 h (P ≤ 0.09), increased TEER at 3.2 h (P &lt; 0.01), but reduced TEER from 5.4 to the end of the experimental period at 18.4 h (P ≤ 0.01). On the other hand, adding DFM, with or without the pathogenic challenge, yielded greater TEER vs. CON-CON and CON-PAT for most of the experimental period (P ≤ 0.04). A similar interaction was detected and reported in experiment 2 (P &lt; 0.0001). The CYT challenge reduced mean TEER compared with all other treatments from 3.2 h to the remainder of the study (P ≤ 0.03). On the other hand, BDP-CYT was able to maintain the integrity of the epithelial cells when compared with CON-CON throughout the experimental period (P ≤ 0.03), the exception being at 3.2 h (P = 0.20). Moreover, BDP-CON increased (P ≤ 0.04) TEER when compared with CON-CON from 3.2 to 18.4 h, but also in comparison with BDP-CYT from 4.3 to 18.4 h post-DFM and challenge administration into the cells. In summary, C. perfringens type A and a pro-inflammatory cytokine cocktail compromised the integrity of intestinal epithelial cell monolayers in vitro, whereas adding a multispecies bacteria-based DFM counteracted these damaging effects.
Sphenoid plasmacytoma as initial presentation of multiple myeloma—case report
Authors: Chadli Sarra , Oudrhiri Mohammed Y , Maamar Mouna , Boutarbouch Mahjouba , Khibri Hajar , Haidouri Soukaina , Messaoud Ola , El-Aoufir Omar , Melhaoui Adyl , Ammouri Wafaa , Ouahabi Abdessamad , Harmouche Hicham , Adnaoui Mohammed , Tazi Mezalek Zoubida 
Published: April 2024

Abstract
Plasmacytoma is a rare plasma cell neoplasm. Whether solitary or associated with multiple myeloma (MM), it rarely involves the skull base, particularly the sphenoid bone. We present a unique case of sphenoid bone plasmacytoma secondary to MM, highlighting diagnostic and therapeutic challenges. A 56-year-old female presented with headaches, vomiting, epistaxis, and cranial nerve deficits. Cerebral imaging revealed a 65-mm tumor infiltrating the sphenoid bone and adjacent structures. Subtotal resection was performed using an endoscopic nasal approach. Histopathology revealed plasmacytoma, and diagnostic workup confirmed MM. By the end of biological exploration, relapse of the sphenoid plasmacytoma was observed, and the patient was successfully treated with radiotherapy, immunochemotherapy, and autologous stem cell transplantation. After 18-month follow-up, sustained complete remission was confirmed. Although rare, the diagnosis of plasmacytoma should be considered in cases of skull base tumors. This localization is highly predictive of MM, warranting comprehensive investigations to initiate prompt and adequate management.
Arabidopsis Fhit-like tumor suppressor resumes early terminated constitutive triple response1-10 mRNA translation
Authors: Zhang Ranran , Zhang Wei , Wang Chenrunshu , Wen Chi-Kuang 
Published: April 2024

Abstract
The Arabidopsis (Arabidopsis thaliana) constitutive triple response1-10 (ctr1-10) mutant produces a reduced level of CTR1 protein and exhibits a weak ctr1 mutant phenotype. Sequence analysis revealed highly active translation of the upstream open reading frame (uORF) at the extended 5′-UTR of the ctr1-10 mRNA, resulting from T-DNA insertion. Enhancer screening for ctr1-10 isolated the fragile histidine triad-1 (fhit-1) mutation. The fhit-1 ctr1-10 mutant phenotypically resembled strong ctr1 mutants and barely produced CTR1, and the fhit-1 mutation reduced the translation efficiency of ctr1-10 but not that of CTR1 mRNA. The human (Homo sapiens) Fhit that involves tumorigenesis and genome instability has the in vitro dinucleotide 5′,5′″-P1, P3-triphosphate hydrolase activity, and expression of the human HsFHIT or the hydrolase-defective HsFHITH96N transgene reversed the fhit-1 ctr1-10 mutant phenotype and restored CTR1 levels. Genetic editing that in situ disrupts individual upstream ATG codons proximal to the ctr1-10 mORF elevated CTR1 levels in ctr1-10 plants independent of FHIT. EUKARYOTIC INITIATION FACTOR3G (eIF3G), which is involved in translation and reinitiation, interacted with FHIT, and both were associated with the polysome. We propose that FHIT resumes early terminated ctr1-10 mORF translation in the face of active and complex uORF translation. Our study unveils a niche that may lead to investigations on the molecular mechanism of Fhit-like proteins in translation reinitiation. The biological significance of FHIT-regulated translation is discussed.
Pharmacodynamic effects following co-administration of cannabinoids and opioids: a scoping review of human experimental studies
Authors: Guy David , Wootten Jared C , Wong Michael , Turski Daniel , Lukewich Mark , Alboog Abdulrahman , Kandasamy Abirami R , Gregory Jonathan , Poolacherla Raju 
Published: April 2024

Abstract

Background
Cannabinoids are increasingly used in the management of chronic pain. Although analgesic potential has been demonstrated, cannabinoids interact with a range of bodily functions that are also influenced by chronic pain medications, including opioids.

Objective
We performed a scoping review of literature on the pharmacodynamic effects following the co-administration of cannabinoids and opioids.

Methods
We systematically searched EMBASE, PubMed, and PsycINFO for studies that experimentally investigated the co-effects of cannabinoids and opioids in human subjects. Available evidence was summarized by clinical population and organ system. A risk of bias assessment was performed.

Results
A total of 16 studies met the inclusion criteria. Study populations included patients with chronic non-cancer and cancer pain on long-term opioid regimens and healthy young adults without prior exposure to opioids who were subject to experimental nociceptive stimuli. Commonly administered cannabinoid agents included Δ9-tetrahydrocannabinol and/or cannabidiol. Co-administration of cannabinoids and opioids did not consistently improve pain outcomes; however, sleep and mood benefits were observed in chronic pain patients. Increased somnolence, memory and attention impairment, dizziness, gait disturbance, and nauseousness and vomiting were noted with co-administration of cannabinoids and opioids. Cardiorespiratory effects following co-administration appeared to vary according to duration of exposure, population type, and prior exposure to cannabinoids and opioids.

Conclusions
The available evidence directly investigating the pharmacodynamic effects following co-administration of cannabinoids and opioids for non-analgesic outcomes is scarce and suffers from a lack of methodological reporting. As such, further research in this area with comprehensive methodologic reporting is warranted.
Prognosis of Pain After Stroke During Rehabilitation Depends on the Pain Quality
Authors: Uragami Shinji , Osumi Michihiro , Sumitani Masahiko , Fuyuki Masanori , Igawa Yuki , Iki Shinya , Koga Masayuki , Tanaka Yoichi , Sato Gosuke , Morioka Shu 
Published: April 2024

Abstract

Objective
Pain after a stroke interferes with daily life and the rehabilitation process. This study aimed to clarify the prognosis of pain in subgroups of patients with pain after a stroke using pain quality data.

Methods
The study included 85 patients with pain after stroke undergoing exercise-based rehabilitation. Items of the Neuropathic Pain Symptom Inventory (NPSI) were used, and patients with pain after stroke were clustered according to their scores of NPSI. Other clinical assessments, such as physical and psychological conditions, were assessed by interviews and questionnaires, and then these were compared among subgroups in a cross-sectional analysis. Longitudinal pain intensity in each subgroup was recorded during 12 weeks after the stroke and the patients’ pain prognoses were compared between subgroups.

Results
Four distinct subgroups were clustered: cluster 1 (cold-evoked pain and tingling), cluster 2 (tingling only), cluster 3 (pressure-evoked pain), and cluster 4 (deep muscle pain with a squeezing and pressure sensation). The cross-sectional analysis showed varying clinical symptoms among the subgroups, with differences in the prevalence of joint pain, limited range of motion, somatosensory dysfunction, and allodynia. There were no significant differences in pain intensity at baseline among the subgroups. A longitudinal analysis showed divergent prognoses of pain intensity among the subgroups. The pain intensity in cluster 4 was significantly alleviated, which suggested that musculoskeletal pain could be reduced with conventional exercise-based rehabilitation. However, the pain intensity of patients in clusters 1 and 2 remained over 12 weeks.

Conclusion
The study classified patients into clinically meaningful subgroups using pain quality data and provided insight into their prognosis of pain. The findings could be useful for guiding personalized rehabilitation strategies for pain management.

Impact
Assessment of pain quality in patients with pain after stroke leads to personalized rehabilitation for pain management.
Long-term clinical outcomes in early rheumatoid arthritis that was treated-to-target in the BeSt and IMPROVED studies
Authors: Heckert Sascha Louise , Maassen Johanna M , Nevins Isabell , Baudoin Paul , Steup-Beekman Gerda M , Huizinga Tom W J , Bergstra Sytske Anne , Allaart Cornelia F 
Published: April 2024

Abstract

Objectives
To assess disease outcomes after 20 and 12 years of patients with RA or undifferentiated arthritis (UA), treated-to-target in the BeSt and IMPROVED trials.

Methods
In BeSt (inclusion 2000–02, duration 10 years), 508 patients with early RA were randomized to: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial csDMARD combination therapy, 4. initial bDMARD/csDMARD combination therapy. The treatment target was low disease activity (DAS ≤ 2.4).
In IMPROVED (inclusion 2007–10, duration 5 years), 610 patients with early RA/UA started MTX with prednisone bridging. The treatment target was remission (DAS &lt; 1.6). Patients not in early remission were randomized to 1. csDMARD combination therapy or 2. bDMARD/csDMARD combination therapy.
Between 2019 and 22, these patients were invited for long-term follow-up.

Results
One-hundred-fifty-three ex-Best and 282 ex-IMPROVED patients participated in the follow-up study after a median of 12 and 20 years since the study started.
In ex-BeSt and ex-IMPROVED patients, the rate of low disease activity was 91%, and 68% were in DAS remission. Median SHS was 14.0 in ex-BeSt (IQR 6.0–32.5; progression since end BeSt 6.0, IQR 2.0–12.5) and 8 in ex-IMPROVED participants (IQR 3–16; progression since end IMPROVED 4, IQR 2–9). Mean HAQ was 0.8 ± 0.6 in ex-BeSt (change since end BeSt: 0.3 ± 0.5) and 0.6 ± 0.6 in ex-IMPROVED participants (change since end IMPROVED: 0.06 ± 0.5).

Conclusion
At 12/20 years after treatment started, the majority of RA and UA patients who had been treated to target low DAS or DAS remission were in DAS remission and had limited functional disability. Radiographic damage progression was mild although not completely suppressed.
Tackling the environmental cost of digital technology: Some reflections on a soft law instrument on sustainability in contracts
Authors: Feleppa Margherita 
Published: April 2024

Abstract
This article explores the convergence of digital innovation and its negative consequences (such as e-waste) with modern sustainability goals by looking at contracts. Specifically, it discusses the use of sustainability contract clauses (SCCs) in business contracts as an expression of corporate social responsibility and of self-regulation. It suggests that there is potential in promoting the use of sustainable obligations in the electronics supply chain (the generator of the fastest growing waste source). As little guidance exists on sustainable obligations, this article discusses the possibility of establishing a new soft law instrument that could tackle some of the described legal challenges in the current use of SCCs. In doing so, it reflects on the possible issues of the proposed instrument.
Nonclinical Investigation of Cytokine Mitigation Strategies for T-cell–Engaging Bispecifics in the Cynomolgus Macaque
Authors: Kamperschroer Cris , Guffroy Magali , Shen Amy , Dokmanovich Melba , Stubbs Makeida , O’Donnell Lynn M. 
Published: April 2024

Summary:
T-cell–directed cancer therapies such as T-cell–engaging bispecifics (TCBs) are commonly associated with cytokine release syndrome and associated clinical signs that can limit their tolerability and therapeutic benefit. Strategies for reducing cytokine release are therefore needed. Here, we report on studies performed in cynomolgus monkeys to test different approaches for mitigating cytokine release with TCBs. A “priming dose” as well as subcutaneous dosing reduced cytokine release compared with intravenous dosing but did not affect the intended T-cell response to the bispecific. As another strategy, cytokines or cytokine responses were blocked with an anti-IL-6 antibody, dexamethasone, or a JAK1/TYK2-selective inhibitor, and the effects on toxicity as well as T-cell responses to a TCB were evaluated. The JAK1/TYK2 inhibitor and dexamethasone prevented CRS-associated clinical signs on the day of TCB administration, but the anti-IL-6 had little effect. All interventions allowed for functional T-cell responses and expected damage to target-bearing tissues, but the JAK1/TYK2 inhibitor prevented the upregulation of activation markers on T cells, suggesting the potential for suppression of T-cell responses. Our results suggest that short-term prophylactic dexamethasone treatment may be an effective option for blocking cytokine responses without affecting desired T-cell responses to TCBs.
Characterizing the “HIV Care Adherence Journey” for Persons With HIV in the Philippines: Conceptual Foundation for Person-Centered Intervention
Authors: De Torres Ryan Q. , Operario Don 
Published: April 2024

AbstractPromoting adherence to HIV care among persons with HIV (PWH) is a key component to addressing the rising HIV epidemic in the Philippines. HIV care adherence is a complex process that may change throughout an individual's life course or “journey” living with HIV. This qualitative study aimed to explore the HIV care adherence journey of PWH. Maximum variation sampling was used to select 12 PWH and 3 health care providers for in-depth online interviews, which were analyzed using thematic analysis. The four themes that emerged to describe the HIV care adherence journey are integration, relation, navigation, and manifestation. Each theme corresponds to a unique set of activities and goals related to PWH's lived experiences as they initiate, practice, and maintain care adherence. This study provides a preliminary framework to characterize the HIV care adherence journey as a dynamic, complex, and multifaceted phenomenon, which can help to inform holistic interventions to support PWH.
Association between neutrophil-to-lymphocyte ratio and outcomes in hospitalized patients with left ventricular thrombus
Authors: Che Yingxia , Huang Shenglan , Zhou Wei , Shi Shunyi , Ye Fei , Ji Yuan , Huang Jun 
Published: April 2024

Background
Left ventricular thrombus (LVT) is a severe cardiovascular complication occurring in approximately 10% of patients with acute anterior ST-segment elevation myocardial infarction. This study aimed to evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) in patients with LVT.

Material and methods
This multicenter retrospective study was conducted between January 2000 and June 2022 in hospitalized patients with LVT. The outcome included in-hospital MACCE. The association between NLR and in-hospital MACCE was measured by odds ratios (ORs). The restricted cubic spline model was used for dose-response analysis.

Results
A total of 197 LVT patients from four centers were included for analysis in this study. MACCE occurred in 13.7% (27/197) of the patients. After adjusting for estimated glomerular filtration rate (eGFR), D-dimer, and age, the OR for MACCE comparing first to the third tertile of NLR was 13.93 [95% confidence interval: 2.37–81.77, P = 0.004, P-trend = 0.008]. When further adjusting for etiology and heart failure with reduced ejection fraction (HFrEF), the association remained statistically significant. Spline regression models showed an increasing trend in the incidence of MACCEs with NLR both in crude and adjusted models. Subgroup analyses showed that a high NLR may be correlated with poorer outcomes for LVT patients older than 65 years, or with hypertension, dyslipidemia, low ejection fraction, liver, and renal dysfunctions.

Conclusion
In conclusion, these findings suggested that higher NLR may be associated with an increased risk of in-hospital MACCE in patients with LVT.