bluuebunny/crossref_metadata_2025_split huggingface dataset:
Регламентація кримінальної відповідальності комбатантів у міжнародному гуманітарному праві
Authors: Мельничук А. І. 
Published: April 2023

У статті розглянуто питання регламентації кримінальної відповідальності комбатантів у міжнародному гуманітарному праві. Методологічною основою наукової роботи стали філософські, загальнонаукові концептуальні підходи, а також характерні для сучасної юридичної науки підходи і методи, відповідно до проблеми. У ході дослідження з’ясовано, що кримінальна відповідальність комбатантів закріплена як у конвенціях, так і в статутних документах, які в сукупності складають основу міжнародного гуманітарного права. Аналіз норм міжнародного гуманітарного права дав змогу встановити, що конвенційні норми містять заборони щодо вчинення дій-воєнних злочинів комбатантами в межах збройних конфліктів, недотримання яких визнається серйозними порушеннями міжнародного гуманітарного права. Індивідуальна відповідальність окреслюється через встановлення обмежувальних механізмів, спрямованих на захист осіб, які не беруть участі або припинили участь у збройних конфліктах, регламентацію ведення збройного конфлікту, обмеження насильства під час збройного конфлікту. Такі норми мають високий рівень узагальнення та не містять належного механізму притягнення до кримінальної відповідальності комбатантів, конкретних зобов’язань держав-учасників і механізмів контролю за їх виконанням, що потребує системної розробки, зокрема уточнення складу злочинів, визначення ступеня їх суспільної небезпеки тощо національним правом. З’ясовано, що принцип індивідуальної відповідальності комбатантів, як і юрисдикція стосовно воєнних злочинів, їх зміст міститься в статутах Міжнародних військових трибуналів та Міжнародного кримінального суду, на основі яких вони функціонують. Діяльність Трибуналів сприяла появі прецедентних рішень, які є ефективним правовим засобом реалізації міжнародного гуманітарного права в частині припинення його порушень, з огляду на визнані юридичні підстави кваліфікації певної поведінки, як міжнародне правопо-рушення, встановлені елементи міжнародних правопорушень, склади міжнародних злочинів тощо.
Neutrophil extracellular traps promote bronchopulmonary dysplasia-like injury in neonatal mice via the WNT/β-catenin pathway
Authors: Sun Liujuan , Zhang Meiyu , Jiang Jin , Liu Wanjiao , Zhao Wenhao , Li Fang 
Published: April 2023

BackgroundBronchopulmonary dysplasia (BPD) is one of the most common and severe chronic diseases in preterm infants. Premature infants are susceptible to BPD due to immature lungs and adverse perinatal episodes of infection, hyperoxia, and mechanical ventilation.MethodsNeutrophils are the first line of host defence, and the release of neutrophil extracellular traps (NETs) is an important strategy to immobilize and kill invading microorganisms. This study examined whether NETs were associated with BPD in preterm infants and contributed to hyperoxia-induced lung injury in neonatal mice via the WNT/β-catenin pathway.ResultsIn this study, we found that preterm infants with BPD had higher levels of NETs in their tracheal aspirates than those without BPD. Neonatal mice treated with NETs after birth exhibited BPD-like changes in their lungs. Furthermore, the levels of Aquaporin 5 (AQP5) and surfactant-associated protein C (SPC), which represent alveolar differentiation and development, were significantly lower than those in the controls. The WNT/β-catenin pathway is one of the most well-known signalling pathways involved in lung growth. We found that the expression of the target genes c-MYC, cyclin D, and vascular endothelial growth factor (VEGF) and the important proteins WNT3a and β-catenin significantly decreased. Moreover, heparin, which is a NET inhibitor, attenuated changes in gene and protein expression, thereby attenuating BPD-like changes.DiscussionThis finding indicates that NETs are associated with BPD and can induce BPD-like changes in neonatal mice via the WNT/β-catenin pathway.
Serum level of S100A8/A9 as a biomarker for establishing the diagnosis and severity of community-acquired pneumonia in children
Authors: Xie Si , Wang Jun , Tuo Wenbin , Zhuang Shihao , Cai Qinzhen , Yao Cong , Han Feng , Zhu Hongmin , Xiang Yun , Yuan Chunhui 
Published: April 2023

BackgroundS100A8/A9, which is a member of S100 proteins, may be involved in the pathophysiology of Community-acquired pneumonia (CAP) that seriously threatens children’s health. However, circulating markers to assess the severity of pneumonia in children are yet to be explored. Therefore, we aimed to investigate the diagnostic performance of serum S100A8/A9 level in determining the severity of CAP in children.MethodsIn this prospective and observational study, we recruited 195 in-hospital children diagnosed with CAP. In comparison, 63 healthy children (HC) and 58 children with non-infectious pneumonia (pneumonitis) were included as control groups. Demographic and clinical data were collected. Serum S100A8/A9 levels, serum pro-calcitonin concentrations, and blood leucocyte counts were quantified.ResultsThe serum S100A8/A9 levels in patients with CAP was 1.59 ± 1.32 ng/mL, which was approximately five and two times higher than those in healthy controls and those in children with pneumonitis, respectively. Serum S100A8/A9 was elevated parallelly with the clinical pulmonary infection score. The sensitivity, specificity, and Youden’s index of S100A8/A9 ≥1.25 ng/mL for predicting the severity of CAP in children was optimal. The area under the receiver operating characteristic curve of S100A8/A9 was the highest among the indices used to evaluate severity.ConclusionsS100A8/A9 may serve as a biomarker for predicting the severity of the condition in children with CAP and establishing treatment grading.
Cellular and transcriptional impacts of Janus kinase and/or IFN-gamma inhibition in a mouse model of primary hemophagocytic lymphohistiocytosis
Authors: Albeituni Sabrin , Oak Ninad , Tillman Heather S. , Stroh Alexa , Keenan Camille , Bloom Mackenzie , Nichols Kim E. 
Published: April 2023

BackgroundPrimary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T cells. Towards this end, ruxolitinib treatment or IFNg neutralization (aIFNg) lessens immunopathology in a model of pHLH in which perforin-deficient mice (Prf1–/–) are infected with Lymphocytic Choriomeningitis virus (LCMV). However, neither agent completely eradicates inflammation. Two studies combining ruxolitinib with aIFNg report conflicting results with one demonstrating improvement and the other worsening of disease manifestations. As these studies used differing doses of drugs and varying LCMV strains, it remained unclear whether combination therapy is safe and effective.MethodsWe previously showed that a ruxolitinib dose of 90 mg/kg lessens inflammation in Prf1–/– mice infected with LCMV-Armstrong. To determine whether this dose controls inflammation induced by a different LCMV strain, we administered ruxolitinib at 90mg/kg to Prf1–/– mice infected with LCMV-WE. To elucidate the impacts of single agent versus combination therapy, Prf1–/– animals were infected with LCMV, treated or not with ruxolitinib, aIFNg or both agents, and analyzed for disease features and the transcriptional impacts of therapy within purified CD8 T cells.ResultsRuxolitinib is well-tolerated and controls disease regardless of the viral strain used. aIFNg, administered alone or with ruxolitinib, is most effective at reversing anemia and reducing serum IFNg levels. In contrast, ruxolitinib appears better than aIFNg, and equally or more effective than combination therapy, at lessening immune cell expansion and cytokine production. Each treatment targets distinct gene expression pathways with aIFNg downregulating IFNg, IFNa, and IL-6-STAT3 pathways, and ruxolitinib downregulating IL-6-STAT3, glycolysis, and reactive oxygen species pathways. Unexpectedly, combination therapy is associated with upregulation of genes driving cell survival and proliferation.ConclusionsRuxolitinib is tolerated and curtails inflammation regardless of the inciting viral strain and whether it is given alone or in combination with aIFNg. When administered at the doses used in this study, the combination of ruxolitinb and aIFNg appears no better than treatment with either drug alone in lessening inflammation. Further studies are warranted to elucidate the optimal doses, schedules, and combinations of these agents for the treatment of patients with pHLH.
Demethylating therapy increases cytotoxicity of CD44v6 CAR-T cells against acute myeloid leukemia
Authors: Tang Ling , Kong Yingjie , Wang Haobing , Zou Ping , Sun Ting , Liu Ying , Zhang Juan , Jin Na , Mao Hanwen , Zhu Xiaojian , Wang Jue , Meng Fankai , You Yong 
Published: April 2023

BackgroundCD44v6 chimeric antigen receptor T (CD44v6 CAR-T) cells demonstrate strong anti-tumor ability and safety in acute myeloid leukemia (AML). However, the expression of CD44v6 on T cells leads to transient fratricide and exhaustion of CD44v6 CAR-T cells, which affect the application of CD44v6 CAR-T. The exhaustion and function of T cells and CD44v6 expression of AML cells are associated with DNA methylation. Hypomethylating agents (HAMs) decitabine (Dec) and azacitidine (Aza) have been widely used to treat AML. Therefore, there may be synergy between CD44v6 CAR-T cells and HAMs in the treatment of AML.MethodsCD44v6 CAR-T cells pretreated with Dec or Aza were co-cultured with CD44v6+ AML cells. Dec or aza pretreated AML cells were co-cultured with CD44v6 CAR-T cells. The cytotoxicity, exhaustion, differentiation and transduction efficiency of CAR-T cells, and CD44v6 expression and apoptosis in AML cells were detected by flow cytometry. The subcutaneous tumor models were used to evaluate the anti-tumor effect of CD44v6 CAR-T cells combined with Dec in vivo. The effects of Dec or Aza on gene expression profile of CD44v6 CAR-T cells were analyzed by RNA-seq.ResultsOur results revealed that Dec and Aza improved the function of CD44v6 CAR-T cells through increasing the absolute output of CAR+ cells and persistence, promoting activation and memory phenotype of CD44v6 CAR-T cells, and Dec had a more pronounced effect. Dec and Aza promoted the apoptosis of AML cells, particularly with DNA methyltransferase 3A (DNMT3A) mutation. Dec and Aza also enhanced the CD44v6 CAR-T response to AML by upregulating CD44v6 expression of AML cells regardless of FMS-like tyrosine kinase 3 (FLT3) or DNMT3A mutations. The combination of Dec or Aza pretreated CD44v6 CAR-T with pretreated AML cells demonstrated the most potent anti-tumor ability against AML.ConclusionDec or Aza in combination with CD44v6 CAR-T cells is a promising combination therapy for AML patients.
Excessive BMI is associated with higher C-peptide level at recognition but also with its greater loss in two years clinical observation in children with new onset type 1 diabetes
Authors: Kurpiewska Emilia , Ciężki Sebastian , Jamiołkowska-Sztabkowska Milena , Polkowska Agnieszka , Starosz Aleksandra , Grubczak Kamil , Moniuszko Marcin , Bossowski Artur , Głowińska-Olszewska Barbara 
Published: April 2023

IntroductionThe prevalence of obesity in general pediatric population increases without sparing children with T1D. We intended to find factors associated with the possibility of preserving endogenous insulin secretion in individuals with long-standing T1D. At onset, higher BMI is associated with higher C-peptide level, which may indicate to be one of the favorable factors involved in preserving residual β-cell function. The study determines the influence of BMI on C-peptide secretion in children newly diagnosed with T1D in two years observation.MethodsWe assessed the possible relationship between selected pro- and anti-inflammatory cytokines, body mass at recognition and β-cell function status. 153 pediatric patients with newly diagnosed T1D were divided into quartiles according to BMI-SDS index. We separated a group consisted of patients with BMI-SDS &gt;1. Participants were followed up for two years and examined for changes in body weight, HbA1c, and insulin requirement. C-peptide was assessed at baseline and after two years. We evaluated the patients’ levels of selected inflammatory cytokines at baseline.ResultsSubjects with higher BMI-SDS presented higher serum C-peptide levels and lower insulin requirements at diagnosis than children with lower body weight. The two-year follow-up showed that C-peptide levels of obese patients dropped more rapidly than in children with BMI-SDS within normal limits. The group with BMI-SDS &gt;1 showed the greatest decrease in C-peptide level. Despite statistically insignificant differences in HbA1c at diagnosis between the study groups, in the fourth quartile and BMI-SDS &gt;1 groups, HbA1c as well as insulin requirements increased after two years. The levels of cytokines varied the most between BMI-SDS &lt;1 and BMI-SDS &gt;1 groups and were significantly higher within BMI-SDS &gt;1 group.DiscussionHigher BMI, associated with enhanced levels of inflammatory cytokines, relates to preservation of C-peptide at T1D recognition in children but is not beneficial in the long term. A decrease in C-peptide levels combined with an increase in insulin requirements and in HbA1c among patients with high BMI occur, which may indicate a negative effect of excessive body weight on the long term preservation of residual β-cell function. The process seems to be mediated by inflammatory cytokines.
Effect of Cu addition on sedimentary bacterial community structure and heavy metal resistance gene abundance in mangrove wetlands
Authors: Liao Junxian , Xu Ying , Zhang Zuye , Zeng Linfang , Qiao Yue , Guo Zhipeng , Chen Jun , Jia Bin , Shang Chenjing , Chen Si 
Published: April 2023

IntroductionMangroves are a unique ecosystem, but are often affected by heavy metal pollution. Bacterial communities in mangrove sediments usually respond to heavy-metal pollution stress by expressing specific heavy-metal resistance genes (HMRGs).MethodsMultivariate statistics were performed on Metagenomics as well as environmental data to evaluated the effects of Cu addition on the sedimentary bacterial community structure.Results and discussionUsing metagenomics technology, we found that the Shannon andChao1 indices of natural sediments were significantly higher than in sediments with artificially added Cu. Addition of Cu significantly altered bacterial community structure and diversity at the phylum, class and order levels in sediments. The relative abundance of HMRGs in Cuadded sediments was lower than that in natural sediments. Environmental factors that affect bacterial communities also affect HMRGs. However, the contribution of heavy-metal pollution to the change in HMRG abundance was much lower than its contribution to the change in the bacterial community, indicating that the relationship between HMRG abundance and heavy-metal pollution is complex and needs to be comprehensively studied.
Multiplex LNA probe-based RAP assay for rapid and highly sensitive detection of rifampicin-resistant Mycobacterium tuberculosis
Authors: Zhang Ruiqing , Ou Xichao , Sun Xiuli , Fan Guohao , Zhao Bing , Tian Fengyu , Li Fengyu , Shen Xinxin , Zhao Yanlin , Ma Xuejun 
Published: April 2023

ObjectivesThe World Health Organization (WHO) Global tuberculosis Report 2021 stated that rifampicin-resistant tuberculosis (RR-TB) remains a major public health threat. However, the in-practice diagnostic techniques for RR-TB have a variety of limitations including longer time, lack of sensitivity, and undetectable low proportion of heterogeneous drug resistance.MethodsHere we developed a multiplex LNA probe-based RAP method (MLP-RAP) for more sensitive detection of multiple point mutations of the RR-TB and its heteroresistance. A total of 126 clinical isolates and 78 sputum samples collected from the National Tuberculosis Reference Laboratory, China CDC, were tested by MLP-RAP assay. In parallel, qPCR and Sanger sequencing of nested PCR product assay were also performed for comparison.ResultsThe sensitivity of the MLP-RAP assay could reach 5 copies/μl using recombinant plasmids, which is 20 times more sensitive than qPCR (100 copies/μl). In addition, the detection ability of rifampicin heteroresistance was 5%. The MLP-RAP assay had low requirements (boiling method) for nucleic acid extraction and the reaction could be completed within 1 h when placed in a fluorescent qPCR instrument. The result of the clinical evaluation showed that the MLP-RAP method could cover codons 516, 526, 531, and 533 with good specificity. 41 out of 78 boiled sputum samples were detected positive by MLP-RAP assay, which was further confirmed by Sanger sequencing of nested PCR product assay, on the contrary, qPCR was able to detect 32 samples only. Compared with Sanger sequencing of nested PCR product assay, both the specificity and sensitivity of the MLP-RAP assay were 100%.ConclusionMLP-RAP assay can detect RR-TB infection with high sensitivity and specificity, indicating that this assay has the prospect of being applied for rapid and sensitive RR-TB detection in general laboratories where fluorescent qPCR instrument is available.
Serum zinc deficiency could be associated with dementia conversion in Parkinson’s disease
Authors: Lee Jieun , Park Suyeon , Jang Wooyoung 
Published: April 2023

BackgroundAssociation between heavy metals and Parkinson’s disease (PD) is well noted, but studies regarding heavy metal levels and non-motor symptoms of PD, such as PD’s dementia (PD-D), are lacking.MethodsIn this retrospective cohort study, we compared five serum heavy metal levels (Zn, Cu, Pb, Hg, and Mn) of newly diagnosed PD patients (n = 124). Among 124 patients, 40 patients were later converted to Parkinson’s disease dementia (PD-D), and 84 patients remained without dementia during the follow-up time. We collected clinical parameters of PD and conducted correlation analysis with heavy metal levels. PD-D conversion time was defined as the initiation time of cholinesterase inhibitors. Cox proportional hazard models were used to identify factors associated with dementia conversion in PD subjects.ResultsZn deficiency was significant in the PD-D group than in the PD without dementia group (87.53 ± 13.20 vs. 74.91 ± 14.43, p &lt; 0.01). Lower serum Zn level was significantly correlated with K-MMSE and LEDD at 3 months (r = −0.28, p &lt; 0.01; r = 0.38, p &lt; 0.01). Zn deficiency also contributed to a shorter time to dementia conversion (HR 0.953, 95% CI 0.919 to 0.988, p &lt; 0.01).ConclusionThis clinical study suggests that a low serum Zn level can be a risk factor for developing PD-D and could be used as a biological marker for PD-D conversion.
Polypyrimidine tract binding protein knockdown reverses depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons
Authors: Zhou Yiying , Zhang Ke , Wang Fangmin , Chen Jiali , Chen Shanshan , Wu Manqing , Lai Miaojun , Zhang Yisheng , Zhou Wenhua 
Published: April 2023

Background and objectivesDepression is a common comorbidity of dementia and may be a risk factor for dementia. Accumulating evidence has suggested that the cholinergic system plays a central role in dementia and depression, and the loss of cholinergic neurons is associated with memory decline in aging and Alzheimer’s patients. A specific loss of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) is correlated with depression and dysfunction of cognition in mice. In this study, we examined the potential regenerative mechanisms of knockdown the RNA-binding protein polypyrimidine tract binding protein (PTB) in reversing depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons.MethodsWe lesioned cholinergic neurons in mice induced by injection of 192 IgG-saporin into HDB; then, we injected either antisense oligonucleotides or adeno-associated virus-shRNA (GFAP promoter) into the injured area of HDB to deplete PTB followed by a broad range of methodologies including behavioral examinations, Western blot, RT-qPCR and immunofluorescence.ResultsWe found that the conversion of astrocytes to newborn neurons by using antisense oligonucleotides on PTB in vitro, and depletion of PTB using either antisense oligonucleotides or adeno-associated virus-shRNA into the injured area of HDB could specifically transform astrocytes into cholinergic neurons. Meanwhile, knockdown of PTB by both approaches could relieve the depression-like behaviors shown by sucrose preference, forced swimming or tail-suspension tests, and alleviate cognitive impairment such as fear conditioning and novel object recognition in mice with lesioned cholinergic neurons.ConclusionThese findings suggest that supplementing cholinergic neurons after PTB knockdown may be a promising therapeutic strategy to revert depression-like behaviors and cognitive impairment.
Connection between right-to-left shunt and photosensitivity: a community-based cross-sectional study
Authors: Dong Bosi , Ji Shuming , Li Yajiao , Li Hua , Yang Ruiqi , Yang Na , Liu Zhu , Zhu Chenxing , Wang Hui , Tang Yusha , Peng Anjiao , Chen Lei 
Published: April 2023

BackgroundHypersensitivity to light is a common symptom associated with dysfunction of the occipital region. Earlier studies also suggested that clinically significant right-to-left shunt (RLS) could increase occipital cortical excitability associated with the occurrence of migraine. The aim of this study was to investigate the relationship between RLS and photosensitivity.MethodsThis cross-sectional observational study included the residents aged 18–55 years living in the Mianzhu community between November 2021 and October 2022. Photosensitivity was evaluated using the Photosensitivity Assessment Questionnaire along with baseline clinical data through face-to-face interviews. After the interviews, contrast-transthoracic echocardiography (cTTE) was performed to detect RLS. Inverse probability weighting (IPW) was used to reduce selection bias. Photosensitivity score was compared between individuals with and without significant RLS using multivariable linear regression based on IPW.ResultsA total of 829 participants containing 759 healthy controls and 70 migraineurs were finally included in the analysis. Multivariable linear regression analysis showed that migraine (β = 0.422; 95% CI: 0.086–0.759; p = 0.014) and clinically significant RLS (β = 1.115; 95% CI: 0.760–1.470; p &lt; 0.001) were related to higher photosensitivity score. Subgroup analysis revealed that clinically significant RLS had a positive effect on hypersensitivity to light in the healthy population (β = 0.763; 95% CI: 0.332–1.195; p &lt; 0.001) or migraineurs (β = 1.459; 95% CI: 0.271–2.647; p = 0.010). There was also a significant interaction between RLS and migraine for the association with photophobia (pinteraction = 0.009).ConclusionRLS is associated with photosensitivity independently and might exacerbate photophobia in migraineurs. Future studies with RLS closure are needed to validate the findings.Trial registrationThis study was registered at the Chinese Clinical Trial Register, Natural Population Cohort Study of West China Hospital of Sichuan University, ID: ChiCTR1900024623, URL: https://www.chictr.org.cn/showproj.html?proj=40590.