bluuebunny/crossref_metadata_2025 huggingface dataset:
Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma
Authors: Umeyama Yasuhiro , Taniguchi Hirokazu , Gyotoku Hiroshi , Senju Hiroaki , Tomono Hiromi , Takemoto Shinnosuke , Yamaguchi Hiroyuki , Tagod Mohammed S. O. , Iwasaki Masashi , Tanaka Yoshimasa , Mukae Hiroshi
Published: March 2023

Introduction

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive thoracic tumor with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors exhibit a promising effect in some patients with unresectable MPM in clinical trials, the majority of MPM patients show only modest response rates to the currently available treatments. It is thus imperative to develop novel and innovative therapeutic modalities for MPM, including immune effector cell-based therapies.

Methods

γδ T cells were expanded using tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2, and the therapeutic potential of γδ T cells was examined through analyzing cell surface markers and cellular cytotoxicity against MPM in vitro using a europium chelate-based time-resolved fluorescence assay system and a luciferase-based luminescence assay system.

Results and discussion

We successfully expanded γδ T cells from peripheral blood mononuclear cells of healthy donors and MPM patients. γδ T cells expressed natural killer receptors such as NKG2D and DNAM-1 and exhibited a moderate level of cytotoxicity to MPM cells in the absence of antigens. The inclusion of PTA, (E)-4-hydroxy-3- methylbut-2-enyl diphosphate (HMBPP) or zoledronic acid (ZOL) induced a TCR-dependent cytotoxicity in γδ T cells and secreted interferon-γ (IFN-γ). In addition, γδ T cells expressing CD16 exhibited a significant level of cytotoxicity against MPM cells in the presence of an anti-epidermal growth factor receptor (EGFR) mAb, at lower concentrations than in clinical settings, whereas a detectable level of IFN-γ was not produced. Taken together, γδ T cells showed cytotoxic activity against MPM in three distinct mechanisms through NK receptors, TCRs and CD16. Since major histocompatibility complex (MHC) molecules are not involved in the recognition, both autologous and allogeneic γδ T cells could be used for the development of γδ T cell-based adoptive immunotherapy for MPM.
BTG2 and SerpinB5, a novel gene pair to evaluate the prognosis of lung adenocarcinoma
Authors: Yang Wanting , Wei Chunli , Cheng Jingliang , Ding Ran , Li Yan , Wang Yonghua , Yang Yinfeng , Wang Jinghui
Published: March 2023

Introduction

Lung adenocarcinoma (LUAD), as the most frequent pathological subtype of non−small cell lung cancer, is often characterized by poor prognosis and low 5-year survival rate. Exploriton of new biomarkers and accurate molecular mechanisms for effectively predicting the prognosis of LUAD patients is still necessary. Presently, BTG2 and SerpinB5, which play important roles in tumors, are studied as a gene pair for the first time with the aim of exploring whether they can be used as potential prognostic markers.

Methods

Using the bioinformatics method to explore whether BTG2 and SerpinB5 can become independent prognostic factors, and explore their clinical application value and whether they can be used as immunotherapeutic markers. In addition, we also verify the conclusions obtained from external datasets, molecular docking, and SqRT-PCR.

Results

The results show that compared with normal lung tissue, BTG2 expression level was down-regulated and SerpinB5 was up-regulated in LUAD. Additionally, Kaplan–Meier survival analysis demonstrate that the prognosis of low expression level of BTG2 was poor, and that of high expression level of SerpinB5 was poor, suggesting that both of them can be used as independent prognostic factors. Moreover, the prognosis models of the two genes were constructed respectively in this study, and their prediction effect was verified by external data. Besides, ESTIMATE algorithm reveals the relationship between this gene pair and the immune microenvironment. Furthermore, patients with a high expression level of BTG2 and a low expression level of SerpinB5 have higher immunophenoscore for CTLA-4 and PD-1 inhibitors than patients with a low expression level of BTG2 and a high expression level of SerpinB5, indicating that such patients have a more obvious effect of immunotherapy.

Discussion

Collectively, all the results demonstrate that BTG2 and SerpinB5 might serve as potential prognostic biomarkers and novel therapeutic targets for LUAD.
Habitat changes and catch rate variability for greater amberjack in the Taiwan Strait: The effects of El Niño–southern oscillation events
Authors: Mammel Mubarak , Lee Ming-An , Naimullah Muhamad , Liao Cheng-Hsin , Wang Yi-Chen , Semedi Bambang
Published: March 2023

El Niño–Southern Oscillation (ENSO) is a crucial oceanographic phenomenon that leads to interannual fluctuations in the climate and ecosystem productivity of tropical and subtropical areas. These fluctuations affect the suitability of habitats for many commercial fish species. However, detailed information on the effects of this major phenomenon and the resulting environmental changes on the habitat and catch rates of the economically and ecologically crucial species of the greater amberjack (Seriola dumerili) in the Taiwan Strait (TS) is lacking. In this study, we employed a weighted habitat suitability index (HSI) modeling method and used remotely sensed marine environmental data as well as data from recorders in Taiwanese fishing vessels (in 2014–2019) to understand the effects of ENSO events on the habitat suitability and catch rates for greater amberjack in the TS. Analysis of variance revealed that environmental factors substantially influenced greater amberjack habitats and catch rates during ENSO events across seasons. The catch rates were high in spring and summer in the southern and northern TS and in autumn and winter in the southern TS. The catch rates were higher in spring, summer, and autumn (>9.0 kg/h) in El Niño years, and in winter, the catch rates were higher in normal years (>12.0 kg/h) and lower in La Niña years. The predicted HSI for the southern and northern TS revealed that greater amberjack populations were predominantly distributed at 20–24°N and 24–28°N, respectively. Opposite habitat suitability was synchronously found in spring and summer during ENSO events, with higher HSI values recorded in spring in El Niño and normal years and higher HSI values recorded in summer in La Niña years. In winter, the HSI values of the southern and northern TS were higher in El Niño and normal years and substantially lower in La Niña years. Habitat suitability was extremely low in autumn. These findings imply that ENSO events play a key role in regulating environmental conditions and affect the catch rates and habitat suitability for the greater amberjack in the TS.
Assessment of the bycatch level for the Black Sea harbour porpoise in the light of new data on population abundance
Authors: Popov Dimitar , Meshkova Galina , Vishnyakova Karina , Ivanchikova Julia , Paiu Marian , Timofte Costin , Amaha Öztürk Ayaka , Tonay Arda M. , Dede Ayhan , Panayotova Marina , Düzgüneş Ertuğ , Gol’din Pavel
Published: March 2023

Incidental catch in fishing gear (often known as bycatch) is a major mortality factor for the Black Sea harbour porpoise (Phocoena phocoena relicta), an endemic subspecies listed as Endangered in the IUCN Red List. The primary gear, responsible for porpoise bycatch in the Black Sea are bottom gillnets and trammel nets targeting turbot (Scophthalmus spp.), the most valuable commercial fish species in the Black Sea. From 2019 to 2021, a study was conducted in Bulgaria, Romania, Türkiye and Ukraine, to estimate the bycatch level in light of new information on porpoise distribution and abundance obtained from aerial surveys (CeNoBS) undertaken in 2019 as part of ACCOBAMS Survey Initiative (ASI). Bycatch data were collected by independent observers onboard turbot fishing boats (Bulgaria and Romania), complemented by questionnaire surveys and examination of stranded carcasses (in all countries). Some 48 monitoring trips took place (63 hauls by 11 different vessels). Cetaceans were caught on just over half of the trips (55%): 182 harbour porpoises, 4 bottlenose dolphins and 3 common dolphins. The median number of porpoises bycaught per trip was 1 (maximum 41) and the number of porpoises per km of net varied between 0 and 3.66 (median 0.1). Bycatch rates showed seasonal variation with marked increase in summer, compared to spring. The total annual bycatch of harbour porpoises in the Black Sea was roughly estimated as between 11 826 and 16 200 individuals. These numbers were the product of median values for effort (days/trips and vessels) and bycatch rate. Given the new estimates of porpoise abundance based on the CeNoBS survey of 2019 and reconciling abundance and bycatch estimates, harbour porpoise bycatch in the Black Sea represents between 4.6% - 17.2% of the estimated total population, depending on assumptions used. Even the most conservative estimate is among the highest worldwide and far exceeds the probable sustainable levels of around 1.0-1.7%. This study confirms that bycatch poses the most serious threat to the Black Sea harbour porpoises and that all riparian countries engaged in turbot fisheries must implement urgent measures to reduce it immediately, if the population is to survive in the long-term.
Processes controlling the distributions and cycling of dissolved aluminum and manganese in the northeastern Indian Ocean
Authors: Yang Yichao , Li Lei , Ren Jingling , Jiang Shuo , Zhang Jing
Published: March 2023

Aluminum and manganese are both key parameters in the GEOTRACES program. Data on dissolved aluminum (dAl) and dissolved manganese (dMn) relative to their geochemical behavior remain limited in the northeastern Indian Ocean (IO; including the Bay of Bengal (BoB) and equatorial Indian Ocean (Eq. IO)). Seawater samples collected in the BoB and Eq. IO during the spring inter-monsoon period (7 March to 9 April) of 2017 were analyzed to investigate the behavior and main processes controlling the distributions of dAl and dMn in the northeastern IO. The average concentrations of dAl and dMn in the mixed layer of the BoB were 16.6 and 6.7 nM, respectively. A modified 1-D box-model equation was utilized to estimate the contributions of different sources to dAl and dMn in the mixed layer. Al released from the desorption of and/or dissolution of the lithogenic sediments discharged by the Ganga–Brahmaputra (G-B) river system predominantly controlled the dAl distributions in the mixed layer of the BoB, while the desorption from the lithogenic sediments only contributed approximately 13%–21% dMn. Additional dMn input from the advection of Andaman Sea water and photo-reduction–dissolution of particulate Mn(IV) contributed more than 60% dMn in the mixed layer of the BoB. dAl and dMn in the surface mixed layer of the Eq. IO were mainly affected by the mixing of dAl- and dMn-enriched BoB surface water and low-dAl, low-dMn southern Arabian Sea surface water. Considering water mass properties and dAl concentrations, the distributions of dAl in the intermediate water (750–1,500 m) of northeastern IO were controlled by the mixing of Red Sea Intermediate Water, Indonesian Intermediate Water, and intermediate water of the BoB. Different from dAl, the apparent oxygen utilization relationship with dMn concentrations indicated that the regeneration of lithogenic particles under hypoxic conditions played a more important role than the remineralization of settling organic particles in controlling dMn distributions in the subsurface and intermediate water body (100–1,000 m) of the BoB and that remineralization of biogenic particles mattered to dMn in the subsurface of the Eq. IO.
Ecological carrying capacity and carbon sequestration potential of bivalve shellfish in marine ranching: A case study in Bohai Bay, China
Authors: Li Zepeng , Chen Yan , Wang Gang , Mu Jiandong , Sun Yanfeng , Yu Haolin , Xu Jiangling , Yan Ying , Luo Shuangyue , Han Fuqiang , Feng Jie , Pan Zhe
Published: March 2023

Introduction

Shellfish play an important role in ecological restoration and as carbon (C) sinks, but studies on their ecological carrying capacity (ECC) and C sequestration potential are sparse.

Methods

In this study, we selected a 57-hectare artificial oyster reef in a typical marine ranching in Bohai Bay, China, to evaluate the ECC and their C sequestration potential of bivalve shellfish, and projecting their impact on functional groups in the system, with an Ecopath with Ecosim (EwE) food web model. We conducted four biological surveys to obtain the biomass measurements, with one conducted in each of the summer, autumn, and winter of 2019 and one in the spring of 2020; and the functional groups included in the surveys comprised fish, cephalopods, crustaceans, snails, bivalve shellfish, annelids, other macrobenthos, meiobenthos, starfish, sea cucumbers, zooplankton, phytoplankton, and detritus.

Results and Discussion

The EwE model prediction results showed that the ECC of bivalve shellfish was established to be 282.66 t/km2, far more than the existing quantity of 187.76 t/km2. Therefore, at present, the ecosystem of the study marine ranching is not yet mature. Moreover, our ecological network analysis parameters indicated that the marine ranching ecosystem will be mature and stable when the bivalve shellfish population reaches its ECC. However, the increase in bivalve shellfish biomass will result in a decrease in the population sizes of species competing for food resources with bivalve shellfish, mainly gobiid fish such as Tridentiger bifasciatus, Tridentiger trigonocephalus, Tridentiger barbatus. Simultaneously, when the bivalve shellfish reach their ECC, 29.23 t of CO2 can be sequestrated by bivalve shellfish, comprising 14.32 t being removed from the ecosystem as prey and 14.91 t being stored on the seafloor through biodeposition.

Conclusion

Therefore, the research demonstrated that, within the scope of ECC, the increasing bivalve shellfish can improve the C sequestration capacity of the marine ranch ecosystem, and effective management of bivalve shellfish in marine ranching can improve the economic benefits and C sink service functions of marine ranching.
D-dimer trends elaborate the heterogeneity of risk in hospitalized patients with COVID-19: A multi-national case series from different waves
Authors: Ronderos Botero Diana Maria , Omar Alaa Mabrouk Salem , Pengo Martino F. , Haider Syed Waqas , Latif Hira , Parati Gianfranco , Pengo Vittorio , Cañas Arboleda Alejandra , Díaz Melissa , Villaquirán-Torres Claudio , Contreras Johanna , Chilimuri Sridhar
Published: March 2023

Introduction

Variable D-dimer trends during hospitalization reportedly result in distinct in-hospital mortality. In this multinational case series from the first and second waves, we show the universality of such D-dimer trends.

Methods

We reviewed 405 patients with COVID-19 during the first wave admitted to three institutions in the United States, Italy, and Colombia, and 111 patients admitted to the U.S. site during the second wave and 55 patients during the third wave. D-dimer was serially followed during hospitalization.

Results

During the first wave, 66 (15%) patients had a persistently-low pattern, 33 (8%) had early-peaking, 70 (16%) had mid-peaking, 94 (22%) had fluctuating, 30 (7%) had late-peaking, and 112 (26%) had a persistently-high pattern. During the second and third waves, similar patterns were observed. D-dimer patterns were significantly different in terms of in-hospital mortality similarly in all waves. Patterns were then classified into low-risk patterns (persistently-low and early-peaking), where no deaths were observed in both waves, high-risk patterns (mid-peaking and fluctuating), and malignant patterns (late-peaking and persistently-high). Overall, D-dimer trends were associated with an increased risk for in-hospital mortality in the first wave (overall: HR: 1.73) and stayed the same during the second (HR: 1.67, p < 0.001) and the third (HR: 4.4, p = 0.001) waves.

Conclusion

D-dimer behavior during COVID-19 hospitalization yielded universal categories with distinct mortality risks that persisted throughout all studied waves of infection. Monitoring D-dimer behavior may be useful in the management of these patients.
Increased zinc levels facilitate phenotypic detection of ceftazidime-avibactam resistance in metallo-β-lactamase-producing Gram-negative bacteria
Authors: Simon Michaela , Gerlach Roman G. , Pfeifer Yvonne , Pfennigwerth Niels , Gatermann Sören G. , Schröder Agnes , Hiergeist Andreas , Hamprecht Axel , Rügamer Tamara , Gessner André , Jantsch Jonathan
Published: March 2023

Ceftazidime-avibactam is one of the last resort antimicrobial agents for the treatment of carbapenem-resistant, Gram-negative bacteria. Metallo-β-lactamase-producing bacteria are considered to be ceftazidime-avibactam resistant. Here, we evaluated a semi-automated antimicrobial susceptibility testing system regarding its capability to detect phenotypic ceftazidime-avibactam resistance in 176 carbapenem-resistant, metallo-β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa isolates. Nine clinical isolates displayed ceftazidime-avibactam susceptibility in the semi-automated system and six of these isolates were susceptible by broth microdilution, too. In all nine isolates, metallo-β-lactamase-mediated hydrolytic activity was demonstrated with the EDTA-modified carbapenemase inactivation method. As zinc is known to be an important co-factor for metallo-β-lactamase activity, test media of the semi-automated antimicrobial susceptibility testing system and broth microdilution were supplemented with zinc. Thereby, the detection of phenotypic resistance was improved in the semi-automated system and in broth microdilution. Currently, ceftazidime-avibactam is not approved as treatment option for infections by metallo-β-lactamase-producing, Gram-negative bacteria. In infections caused by carbapenem-resistant Gram-negatives, we therefore recommend to rule out the presence of metallo-β-lactamases with additional methods before initiating ceftazidime-avibactam treatment.
Domestication and microbiome succession may drive pathogen spillover
Authors: Apari Péter , Földvári Gábor
Published: March 2023

Emerging infectious diseases have posed growing medical, social and economic threats to humanity. The biological background of pathogen spillover or host switch, however, still has to be clarified. Disease ecology finds pathogen spillovers frequently but struggles to explain at the molecular level. Contrarily, molecular biological traits of host-pathogen relationships with specific molecular binding mechanisms predict few spillovers. Here we aim to provide a synthetic explanation by arguing that domestication, horizontal gene transfer even between superkingdoms as well as gradual exchange of microbiome (microbiome succession) are essential in the whole scenario. We present a new perspective at the molecular level which can explain the observations of frequent pathogen spillover events at the ecological level. This proposed rationale is described in detail, along with supporting evidence from the peer-reviewed literature and suggestions for testing hypothesis validity. We also highlight the importance of systematic monitoring of virulence genes across taxonomical categories and in the whole biosphere as it helps prevent future epidemics and pandemics. We conclude that that the processes of domestication, horizontal gene transfer and microbial succession might be important mechanisms behind the many spillover events driven and accelerated by climate change, biodiversity loss and globalization.
3D electron microscopy and volume-based bouton sorting reveal the selectivity of inputs onto geniculate relay cell and interneuron dendrite segments
Authors: Maher Erin E. , Briegel Alex C. , Imtiaz Shahrozia , Fox Michael A. , Golino Hudson , Erisir Alev
Published: March 2023

Introduction

The visual signals evoked at the retinal ganglion cells are modified and modulated by various synaptic inputs that impinge on lateral geniculate nucleus cells before they are sent to the cortex. The selectivity of geniculate inputs for clustering or forming microcircuits on discrete dendritic segments of geniculate cell types may provide the structural basis for network properties of the geniculate circuitry and differential signal processing through the parallel pathways of vision. In our study, we aimed to reveal the patterns of input selectivity on morphologically discernable relay cell types and interneurons in the mouse lateral geniculate nucleus.

Methods

We used two sets of Scanning Blockface Electron Microscopy (SBEM) image stacks and Reconstruct software to manually reconstruct of terminal boutons and dendrite segments. First, using an unbiased terminal sampling (UTS) approach and statistical modeling, we identified the criteria for volume-based sorting of geniculate boutons into their putative origins. Geniculate terminal boutons that were sorted in retinal and non-retinal categories based on previously described mitochondrial morphology, could further be sorted into multiple subpopulations based on their bouton volume distributions. Terminals deemed non-retinal based on the morphological criteria consisted of five distinct subpopulations, including small-sized putative corticothalamic and cholinergic boutons, two medium-sized putative GABAergic inputs, and a large-sized bouton type that contains dark mitochondria. Retinal terminals also consisted of four distinct subpopulations. The cutoff criteria for these subpopulations were then applied to datasets of terminals that synapse on reconstructed dendrite segments of relay cells or interneurons.

Results

Using a network analysis approach, we found an almost complete segregation of retinal and cortical terminals on putative X-type cell dendrite segments characterized by grape-like appendages and triads. On these cells, interneuron appendages intermingle with retinal and other medium size terminals to form triads within glomeruli. In contrast, a second, presumed Y-type cell displayed dendrodendritic puncta adherentia and received all terminal types without a selectivity for synapse location; these were not engaged in triads. Furthermore, the contribution of retinal and cortical synapses received by X-, Y- and interneuron dendrites differed such that over 60% of inputs to interneuron dendrites were from the retina, as opposed to 20% and 7% to X- and Y-type cells, respectively.

Conclusion

The results underlie differences in network properties of synaptic inputs from distinct origins on geniculate cell types.
Examining four blood biomarkers for the detection of acute intracranial abnormalities following mild traumatic brain injury in older adults
Authors: Iverson Grant L. , Minkkinen Mira , Karr Justin E. , Berghem Ksenia , Zetterberg Henrik , Blennow Kaj , Posti Jussi P. , Luoto Teemu M.
Published: March 2023

Blood-based biomarkers have been increasingly studied for diagnostic and prognostic purposes in patients with mild traumatic brain injury (MTBI). Biomarker levels in blood have been shown to vary throughout age groups. Our aim was to study four blood biomarkers, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light (NF-L), and total tau (t-tau), in older adult patients with MTBI. The study sample was collected in the emergency department in Tampere University Hospital, Finland, between November 2015 and November 2016. All consecutive adult patients with head injury were eligible for inclusion. Serum samples were collected from the enrolled patients, which were frozen and later sent for biomarker analyses. Patients aged 60 years or older with MTBI, head computed tomography (CT) imaging, and available biomarker levels were eligible for this study. A total of 83 patients (mean age = 79.0, SD = 9.58, range = 60–100; 41.0% men) were included in the analysis. GFAP was the only biomarker to show statistically significant differentiation between patients with and without acute head CT abnormalities [U(83) = 280, p < 0.001, r = 0.44; area under the curve (AUC) = 0.79, 95% CI = 0.67–0.91]. The median UCH-L1 values were modestly greater in the abnormal head CT group vs. normal head CT group [U (83) = 492, p = 0.065, r = 0.20; AUC = 0.63, 95% CI = 0.49–0.77]. Older age was associated with biomarker levels in the normal head CT group, with the most prominent age associations being with NF-L (r = 0.56) and GFAP (r = 0.54). The results support the use of GFAP in detecting abnormal head CT findings in older adults with MTBIs. However, small sample sizes run the risk for producing non-replicable findings that may not generalize to the population and do not translate well to clinical use. Further studies should consider the potential effect of age on biomarker levels when establishing clinical cut-off values for detecting head CT abnormalities.
A risk-predictive model for obstructive sleep apnea in patients with chronic obstructive pulmonary disease
Authors: Peng Tianfeng , Yuan Shan , Wang Wenjing , Li Zhuanyun , Jumbe Ayshat Mussa , Yu Yaling , Hu Zhenghao , Niu Ruijie , Wang Xiaorong , Zhang Jinnong
Published: March 2023

Background

Obstructive sleep apnea syndrome (OSA) is increasingly reported in patients with chronic obstructive pulmonary disease (COPD). Our research aimed to analyze the clinical characteristics of patients with overlap syndrome (OS) and develop a nomogram for predicting OSA in patients with COPD.

Methods

We retroactively collected data on 330 patients with COPD treated at Wuhan Union Hospital (Wuhan, China) from March 2017 to March 2022. Multivariate logistic regression was used to select predictors applied to develop a simple nomogram. The area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA) were used to assess the value of the model.

Results

A total of 330 consecutive patients with COPD were enrolled in this study, with 96 patients (29.1%) confirmed with OSA. Patients were randomly divided into the training group (70%, n = 230) and the validation group (30%, n = 100). Age [odds ratio (OR): 1.062, 1.003–1.124], type 2 diabetes (OR: 3.166, 1.263–7.939), neck circumference (NC) (OR: 1.370, 1.098–1,709), modified Medical Research Council (mMRC) dyspnea scale (OR: 0.503, 0.325–0.777), Sleep Apnea Clinical Score (SACS) (OR: 1.083, 1.004–1.168), and C-reactive protein (CRP) (OR: 0.977, 0.962–0.993) were identified as valuable predictors used for developing a nomogram. The prediction model performed good discrimination [AUC: 0.928, 95% confidence interval (CI): 0.873–0.984] and calibration in the validation group. The DCA showed excellent clinical practicability.

Conclusion

We established a concise and practical nomogram that will benefit the advanced diagnosis of OSA in patients with COPD.
Potential health benefits of Nigella sativa on diabetes mellitus and its complications: A review from laboratory studies to clinical trials
Authors: Adam Siti Hajar , Mohd Nasri Noor , Kashim Mohd Izhar Ariff Mohd , Abd Latib Erny Haslina , Ahmad Juhari Muhammad Amirul Aiman , Mokhtar Mohd Helmy
Published: March 2023

This review aims to gather and summarize up-to-date information on the potential health benefits of Nigella sativa (NS) on diabetes mellitus (DM) and its complications from different animal models, clinical trials and in vitro studies. DM is one of the most prevalent metabolic disorders resulting from chronic hyperglycaemia due to problems in insulin secretion, insulin action or both. It affects people regardless of age, gender and race. The main consequence of DM development is the metabolic dysregulation of glucose homeostasis. Current treatments for DM include pharmacological therapy, insulin and diabetic therapy targeting β cells. Some of these therapeutic approaches are promising; however, their safety and effectiveness remain elusive. Since ancient times, medicinal plants have been used and proven effective against diseases. These plants are believed to be effective and benefit physiological and pathological processes, as they can be used to prevent, reduce or treat multiple diseases. Nigella sativa Linn. is an annual indigenous herbaceous plant belonging to Ranunculaceae, the buttercup family. NS exhibits multifactorial activities; it could ameliorate oxidative, inflammatory, apoptotic and insulinotropic effects and inhibit carbohydrate digestive enzymes. Thus, this review demonstrates the therapeutic potential of NS that could be used as a complement or adjuvant for the management of DM and its complications. However, future research should be able to replicate and fill in the gaps of the study conducted to introduce NS safely to patients with DM.
Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment
Authors: Xia Jin-kun , Tang Ning , Wu Xing-yu , Ren Hao-zhen
Published: March 2023

Bile acids (BAs) are physiological detergents that can not only promote the digestion and absorption of lipids, but also may be a potential carcinogen. The accumulation of BAs in the body can lead to cholestatic liver cirrhosis and even liver cancer. Recently, studies demonstrated that BAs are highly accumulated in metastatic lymph nodes, but not in normal healthy lymph nodes or primary tumors. Lymph node metastasis is second only to hematogenous metastasis in liver cancer metastasis, and the survival and prognosis of hepatocellular carcinoma (HCC) patients with lymph node metastasis are significantly worse than those without lymph node metastasis. Meanwhile, component of BAs was found to significantly enhance the invasive potential of HCC cells. However, it is still poorly understood how deregulated BAs fuel the metastasis process of liver cancer. The tumor microenvironment is a complex cellular ecosystem that evolves with and supports tumor cells during their malignant transformation and metastasis progression. Aberrant BAs metabolism were found to modulate tumor immune microenvironment by preventing natural killer T (NKT) cells recruitment and increasing M2-like tumor-associated macrophages (TAMs) polarization, thus facilitate tumor immune escape and HCC development. Based on these available evidence, we hypothesize that a combination of genetic and epigenetic factors in cancerous liver tissue inhibits the uptake and stimulates the synthesis of BAs by the liver, and excess BAs further promote liver carcinogenesis and HCC metastasis by inducing immunosuppressive microenvironment.
The role of physics in multiomics and cancer evolution
Authors: Gourmet Lucie E. , Walker-Samuel Simon
Published: March 2023

Complex interactions between the physical environment and phenotype of a tumour, and genomics, transcriptomics, proteomics and epigenomics, are increasingly known to have a significant influence on cancer development, progression and evolution. For example, mechanical stress can alter both genome maintenance and histone modifications, which consequently affect transcription and the epigenome. Increased stiffness has been linked to genetic heterogeneity and is responsible for heterochromatin accumulations. Stiffness thereby leads to deregulation in gene expression, disrupts the proteome and can impact angiogenesis. Several studies have shown how the physics of cancer can influence diverse cancer hallmarks such as resistance to cell death, angiogenesis and evasion from immune destruction. In this review, we will explain the role that physics of cancer plays in cancer evolution and explore how multiomics are being used to elucidate the mechanisms underpinning them.
CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring
Authors: Vergani Stefano , Bagnara Davide , Agathangelidis Andreas , Ng Anita Kar Yun , Ferrer Gerardo , Mazzarello Andrea N. , Palacios Florencia , Yancopoulos Sophia , Yan Xiao-Jie , Barrientos Jaqueline C. , Rai Kanti R. , Stamatopoulos Kostas , Chiorazzi Nicholas
Published: March 2023

Introduction

The leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, “stereotyped BCRs”. The B-cell receptors (BCRs) on CLL cells are also distinctive in often deriving from autoreactive B lymphocytes, leading to the assumption of a defect in immune tolerance.

Results

Using bulk and single-cell immunoglobulin heavy and light chain variable domain sequencing, we enumerated CLL stereotype-like IGHV-IGHD-IGHJ sequences (CLL-SLS) in B cells from cord blood (CB) and adult peripheral blood (PBMC) and bone marrow (BM of healthy donors. CLL-SLS were found at similar frequencies among CB, BM, and PBMC, suggesting that age does not influence CLL-SLS levels. Moreover, the frequencies of CLL-SLS did not differ among B lymphocytes in the BM at early stages of development, and only re-circulating marginal zone B cells contained significantly higher CLL-SLS frequencies than other mature B-cell subpopulations. Although we identified CLL-SLS corresponding to most of the CLL major stereotyped subsets, CLL-SLS frequencies did not correlate with those found in patients. Interestingly, in CB samples, half of the CLL-SLS identified were attributed to two IGHV-mutated subsets. We also found satellite CLL-SLS among the same normal samples, and they were also enriched in naïve B cells but unexpectedly, these were ~10-fold higher than standard CLL-SLS. In general, IGHV-mutated CLL-SLS subsets were enriched among antigen-experienced B-cell subpopulations, and IGHV-unmutated CLL-SLS were found mostly in antigen-inexperienced B cells. Nevertheless, CLL-SLS with an IGHV-mutation status matching that of CLL clones varied among the normal B-cell subpopulations, suggesting that specific CLL-SLS could originate from distinct subpopulations of normal B cells. Lastly, using single-cell DNA sequencing, we identified paired IGH and IGL rearrangements in normal B lymphocytes resembling those of stereotyped BCRs in CLL, although some differed from those in patients based on IG isotype or somatic mutation.

Discussion

CLL-SLS are present in normal B-lymphocyte populations at all stages of development. Thus, despite their autoreactive profile they are not deleted by central tolerance mechanisms, possibly because the level of autoreactivity is not registered as dangerous by deletion mechanisms or because editing of L-chain variable genes occurred which our experimental approach could not identify.
Long-term outcome after combined or sequential liver and kidney transplantation in children with infantile and juvenile primary hyperoxaluria type 1
Authors: Loos Sebastian , Kemper Markus J. , Schmaeschke Kaja , Herden Uta , Fischer Lutz , Hoppe Bernd , Levart Tanja Kersnik , Grabhorn Enke , Schild Raphael , Oh Jun , Brinkert Florian
Published: March 2023

Introduction

Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare.

Methods

All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively.

Results

Eighteen patients (infantile PH1 n = 10, juvenile PH1 n = 8) underwent transplantation (CLKT n = 17, SLKT n = 1) at a median age of 5.4 years (1.5–11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4–11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4–2.4) vs. 12.8 years (8.4–14.1), P = 0.003). Median follow-up was 11.0 years (6.8–11.6) in patients with infantile PH1 vs. 6.9 years (5.7–9.9) in juvenile PH1 (P = 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8, P = 0.59).

Discussion

In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1.
Doxofylline ameliorates liver fibrosis by regulating the ferroptosis signaling pathway
Authors: Xu Lenan , Zhang Meiling , Pan Junzhi , Xu Xiangwei , Zhang Yawen , Han Xue , Yin Lina , Chen Lingfeng , Ren Juan , Yu Jie , Zhang Yanmei , Liang Guang , Zhang Yi
Published: March 2023

Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and phenotypic transformation are regarded as key events in its progression. Ferroptosis, a novel form of programmed cell death, is also closely related to different pathological processes, including those associated with liver diseases. Here, we investigated the effect of doxofylline (DOX), a xanthine derivative with potent anti-inflammatory activity, on liver fibrosis as well as the associated mechanism. Our results indicated that in mice with CCl4-induced liver fibrosis, DOX attenuated hepatocellular injury and the levels of liver fibrosis indicators, inhibited the TGF-β/Smad signaling pathway, and significantly downregulated the expression of HSC activation markers, both in vitro and in vivo. Furthermore, inducing ferroptosis in activated HSCs was found to be critical for its anti-liver fibrosis effect. More importantly, ferroptosis inhibition using the specific inhibitor, deferoxamine (DFO) not only abolished DOX-induced ferroptosis, but also led to resistance to the anti-liver fibrosis effect of DOX in HSCs. In summary, our results showed an association between the protective effect of DOX against liver fibrosis and HSC ferroptosis. Thus, DOX may be a promising anti-hepatic fibrosis agent.
Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice
Authors: Wu Jingyi , Jia Shu , Xu Benhong , Yao Xiaokun , Shao Jingping , Yao Jianzuo , Cen Danwei , Yao Xiaomin
Published: March 2023

Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.

Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.

Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).

Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.
Quantitative and qualitative analyses of the mKdV equation and modeling nonlinear waves in plasma
Authors: Arif Kanza , Ehsan Tayyaba , Masood W. , Asghar S. , Alyousef Haifa A. , Tag-Eldin Elsayed , El-Tantawy S. A.
Published: March 2023

In this paper, nonlinear electrostatic structures on the ion time scale in plasma consisting of two populations of electrons (cold and hot), positrons, and warm adiabatic ions are investigated. The multiple scale method is used to derive the modified Korteweg–de Vries equation (mKdVE). The Jacobi elliptic function expansion method (JEFEM) is employed to find some exact analytical solutions such as periodic, solitonic, and shock solutions. It is shown that the variation in the plasma parameters of interest, for our model, allows the existence of solitary and periodic structures and no shocks. It is also shown that the most important plasma parameters for the plasma model under consideration are positron concentration, α, and the percentage of cold and hot electrons, represented by the parameters μ and ν, respectively. Additionally, the qualitative behavior of the mKdVE is studied using dynamical system theory. The topological structure of the solution is discussed in the phase plane. In this work, the phase plane analysis, which is restricted to the discrete values of the parameter, is extended to the continuous range of the parameter using a bifurcation diagram. Bifurcation diagrams are drawn to forecast the behavior of the solution for specifically chosen essential plasma parameters. The analytical solution and the qualitative behavior of the solution presented in this paper are shown to be compatible with each other. The results presented here are general and can be gainfully employed to study a variety of nonlinear waves in space, laboratory plasmas, and astrophysical plasmas.
Marker-assisted introgression of wild chromosome segments conferring resistance to fungal foliar diseases into peanut (Arachis hypogaea L.)
Authors: Moretzsohn Márcio de Carvalho , Santos João Francisco dos , Moraes Andrea Rocha Almeida , Custódio Adriana Regina , Michelotto Marcos Doniseti , Maharjan Namrata , Leal-Bertioli Soraya Cristina de Macedo , Godoy Ignácio José , Bertioli David John
Published: March 2023

Introduction

Fungal foliar diseases can severely affect the productivity of the peanut crop worldwide. Late leaf spot is the most frequent disease and a major problem of the crop in Brazil and many other tropical countries. Only partial resistance to fungal diseases has been found in cultivated peanut, but high resistances have been described on the secondary gene pool.

Methods

To overcome the known compatibility barriers for the use of wild species in peanut breeding programs, we used an induced allotetraploid (Arachis stenosperma × A. magna)4x, as a donor parent, in a successive backcrossing scheme with the high-yielding Brazilian cultivar IAC OL 4. We used microsatellite markers associated with late leaf spot and rust resistance for foreground selection and high-throughput SNP genotyping for background selection.

Results

With these tools, we developed agronomically adapted lines with high cultivated genome recovery, high-yield potential, and wild chromosome segments from both A. stenosperma and A. magna conferring high resistance to late leaf spot and rust. These segments include the four previously identified as having QTLs (quantitative trait loci) for resistance to both diseases, which could be confirmed here, and at least four additional QTLs identified by using mapping populations on four generations.

Discussion

The introgression germplasm developed here will extend the useful genetic diversity of the primary gene pool by providing novel wild resistance genes against these two destructive peanut diseases.
Bioactive secondary metabolites from endophytic strains of Neocamarosporium betae collected from desert plants
Authors: Liu Peng , Tan Yue , Yang Jian , Wang Yan-Duo , Li Qi , Sun Bing-Da , Xing Xiao-Ke , Sun Di-An , Yang Sheng-Xiang , Ding Gang
Published: March 2023

Endophytic fungi from desert plants belong to a unique microbial community that has been scarcely investigated chemically and could be a new resource for bioactive natural products. In this study, 13 secondary metabolites (1–13) with diverse carbon skeletons, including a novel polyketide (1) with a unique 5,6-dihydro-4H,7H-2,6-methanopyrano[4,3-d][1,3]dioxocin-7-one ring system and three undescribed polyketides (2, 7, and 11), were obtained from the endophytic fungus Neocamarosporium betae isolated from two desert plant species. Different approaches, including HR-ESI-MS, UV spectroscopy, IR spectroscopy, NMR, and CD, were used to determine the planar and absolute configurations of the compounds. The possible biosynthetic pathways were proposed based on the structural characteristics of compounds 1–13. Compounds 1, 3, 4, and 9 exhibited strong cytotoxicity toward HepG2 cells compared with the positive control. Several metabolites (2, 4–5, 7–9, and 11–13) were phytotoxic to foxtail leaves. The results support the hypothesis that endophytic fungi from special environments, such as desert areas, produce novel bioactive secondary metabolites.
Impact of COVID-19 lockdown on match performances in the National Basketball Association
Authors: Lu Peng , Zhang Shaoliang , Ding Jie , Wang Xing , Gomez Miguel Angel
Published: March 2023

This study aimed to compare differences in the match performances between home and away games during pre- and post-COVID-19 lockdown and to identify the key factors to match success with and without spectators. The sample consisted of 1,549 basketball matches including 971 games of the 2019–2020 regular season before the COVID-19 lockdown and 578 ghost matches of the 2020–2021 regular season after the COVID-19 pandemic. The independent t-test was used to explore the differences before and after COVID-19 while univariate and multivariable logistic regression models were used to identify the key factors to match success between matches with and without spectators. Our study identified that offensive rebounds were the only indicator differentiating between home and away games after the COVID-19 lockdown. Furthermore, home teams won more matches than away matches before the COVID-19 whereas home advantage had no impact on winning matches after the COVID-19. Our study suggested that crowd support may play a key role in winning games in the NBA. Furthermore, independently of the pre-and post-COVID19 pandemic, free throws made, three-point field goals made, defensive rebounds, assists, steals, personal fouls, and opponent quality were key factors differentiating between win and loss. Coaches and coaching staff can make informed decisions and well prepare for basketball match strategies.