bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of sloping bottom on river plume dynamics on a laboratory-scale rotating table
Authors: Yuan Yeping , Tan Xinyu , Lin Ying-Tien
Published: March 2023

In nature, plumes usually enter the coastal ocean after they leave the estuary, and most of them interact with the continental shelf slope. To understand plume dynamics, laboratory experiments were carried out on a rotating table to simulate the evolution of plumes over a sloping bottom. We modified reduced gravity g’, Coriolis parameter f, and shelf slope α to study their impacts on plume characteristics and freshwater fate, and used the optical thickness method to obtain the depth field. We found that with the increasing g’ or decreasing f, plume maximum depth hmax decreases and plume maximum width Wmax increases. We proposed a method to determine plume types based on their attachment to the shelf slope: when PCN (plume classification number) > 1.6, the plume is bottom-attached; when PCN< 1.6, the plume is surface-advected. In addition, we found the bulge will become unstable when BIN (bulge instability number)< 0.8. Our analysis shows that the sloping bottom is the most significant factor determining the ratio of freshwater accumulated in the bulge over transported with coastal currents. Generally, bottom-attached plume trapped near the coast inhibits offshore freshwater transport and promotes coastal current transport, while baroclinic instability tends to produce a large cyclonic vortex over a gentle slope which strongly enhances the offshore transport.
Pathophysiology and clinical manifestations of immune complex vasculitides
Authors: Sunderkötter Cord , Golle Linda , Pillebout Evangéline , Michl Christiane
Published: March 2023

Immune complex (IC) vasculitides present inflammations of vessel walls associated with perivascular deposition of immunoglobulins (Igs), mostly ICs. They encompass systemic and skin-limited variants of IgA vasculitis (IgAV), cryoglobulinemic vasculitis (CV), rheumatoid, lupus, and hypocomplementemic vasculitides, serum sickness cutaneous IgM/IgG (non-IgA) vasculitis, and recurrent macular (hypergammaglobulinemic or exertion-induced) vasculitis. Serum sickness and CV fulfill the criteria of a type III hypersensitivity immune reaction as large lattices of the IC precipitate at vessel walls and activate polymorphonuclear neutrophils (PMNs). Immunoglobulin-A vasculitis differs with regard to the causes of perivascular deposition of ICs since here many IgA1 molecules are hypoglycosylated (Gd-IgA1), which appears to facilitate their perivascular deposition in skin and mesangium (via e.g. CD71). The reasons for increased generation of immunoglobulins or formation of IC and their perivascular deposition in either skin or systemic organs are different and not fully explored. A common denominator of OC vasculitides is the activation of PMNs near the vessel wall via Fcy or Fcα receptors. Acute episodes of IgAV additionally require PMNs to become preactivated by IgA1 or by IC already in circulation. This intravascular priming results in increased adherence and subsequently vessel-destructive NETosis when they encounter IgA deposited at the vessel walls. Binding of IgA1 to PMNs in blood stream is associated with increased serum levels of hypogalactosidated IgA1. The characteristic clinical picture of IgAV (and also of so-called IgG/IgM vasculitis) comprises palpable or retiform purpura with a clear predilection for lower legs, probably due to stasis-related reduction in blood velocity, while in other IC vasculitides, additional factors influence the sites of vasculitides. Our knowledge of distinct forms and different pathophysiological pathways of IC vasculitides may lead to in efficacious or targeted therapies. Antibodies to complement components or intestinal budesonide for IgAV are promising agents (the latter suppresses the pathophysiologically related IgA nephropathy by reducing the generation of mucosal IgA.
Application of prophage sequence analysis to investigate a disease outbreak involving Salmonella Adjame, a rare serovar and implications for the population structure
Authors: Gao Ruimin , Duceppe Marc-Olivier , Chattaway Marie Anne , Goodridge Lawrence , Ogunremi Dele
Published: March 2023

Introduction

Outbreak investigation of foodborne salmonellosis is hindered when the food source is contaminated by multiple strains of Salmonella, creating difficulties matching an incriminated organism recovered from patients with the specific strain in the suspect food. An outbreak of the rare Salmonella Adjame was caused by multiple strains of the organism as revealed by single-nucleotide polymorphism (SNP) variation. The use of highly discriminatory prophage analysis to characterize strains of Salmonella should enable a more precise strain characterization and aid the investigation of foodborne salmonellosis.

Methods

We have carried out genomic analysis of S. Adjame strains recovered during the course of a recent outbreak and compared them with other strains of the organism (n = 38 strains), using SNPs to evaluate strain differences present in the core genome, and prophage sequence typing (PST) to evaluate the accessory genome. Phylogenetic analyses were performed using both total prophage content and conserved prophages.

Results

The PST analysis of the S. Adjame isolates showed a high degree of strain heterogeneity. We observed small clusters made up of 2-6 isolates (n = 27) and singletons (n = 11) in stark contrast with the three clusters observed by SNP analysis. In total, we detected 24 prophages of which only four were highly prevalent, namely: Entero_p88 (36/38 strains), Salmon_SEN34 (35/38 strains), Burkho_phiE255 (33/38 strains) and Edward_GF (28/38 strains). Despite the marked strain diversity seen with prophage analysis, the distribution of the four most common prophages matched the clustering observed using core genome.

Discussion

Mutations in the core and accessory genomes of S. Adjame have shed light on the evolutionary relationships among the Adjame strains and demonstrated a convergence of the variations observed in both fractions of the genome. We conclude that core and accessory genomes analyses should be adopted in foodborne bacteria outbreak investigations to provide a more accurate strain description and facilitate reliable matching of isolates from patients and incriminated food sources. The outcomes should translate to a better understanding of the microbial population structure and an 46 improved source attribution in foodborne illnesses.
Brain network analysis for the discrimination of dementia disorders using electrophysiology signals: A systematic review
Authors: Adebisi Abdulyekeen T. , Veluvolu Kalyana C.
Published: March 2023

Background

Dementia-related disorders have been an age-long challenge to the research and healthcare communities as their various forms are expressed with similar clinical symptoms. These disorders are usually irreversible at their late onset, hence their lack of validated and approved cure. Since their prodromal stages usually lurk for a long period of time before the expression of noticeable clinical symptoms, a secondary prevention which has to do with treating the early onsets has been suggested as the possible solution. Connectivity analysis of electrophysiology signals has played significant roles in the diagnosis of various dementia disorders through early onset identification.

Objective

With the various applications of electrophysiology signals, the purpose of this study is to systematically review the step-by-step procedures of connectivity analysis frameworks for dementia disorders. This study aims at identifying the methodological issues involved in such frameworks and also suggests approaches to solve such issues.

Methods

In this study, ProQuest, PubMed, IEEE Xplore, Springer Link, and Science Direct databases are employed for exploring the evolution and advancement of connectivity analysis of electrophysiology signals of dementia-related disorders between January 2016 to December 2022. The quality of assessment of the studied articles was done using Cochrane guidelines for the systematic review of diagnostic test accuracy.

Results

Out of a total of 4,638 articles found to have been published on the review scope between January 2016 to December 2022, a total of 51 peer-review articles were identified to completely satisfy the review criteria. An increasing trend of research in this domain is identified within the considered time frame. The ratio of MEG and EEG utilization found within the reviewed articles is 1:8. Most of the reviewed articles employed graph theory metrics for their analysis with clustering coefficient (CC), global efficiency (GE), and characteristic path length (CPL) appearing more frequently compared to other metrics.

Significance

This study provides general insight into how to employ connectivity measures for the analysis of electrophysiology signals of dementia-related disorders in order to better understand their underlying mechanism and their differential diagnosis.
Brain inspired path planning algorithms for drones
Authors: Chao Yixun , Augenstein Philipp , Roennau Arne , Dillmann Ruediger , Xiong Zhi
Published: March 2023

Introduction

With the development of artificial intelligence and brain science, brain-inspired navigation and path planning has attracted widespread attention.

Methods

In this paper, we present a place cell based path planning algorithm that utilizes spiking neural network (SNN) to create efficient routes for drones. First, place cells are characterized by the leaky integrate-and-fire (LIF) neuron model. Then, the connection weights between neurons are trained by spike-timing-dependent plasticity (STDP) learning rules. Afterwards, a synaptic vector field is created to avoid obstacles and to find the shortest path.

Results

Finally, simulation experiments both in a Python simulation environment and in an Unreal Engine environment are conducted to evaluate the validity of the algorithms.

Discussion

Experiment results demonstrate the validity, its robustness and the computational speed of the proposed model.
Case report: Neonatal diabetes mellitus caused by KCNJ11 mutation presenting with intracranial hemorrhage
Authors: Wu Bo , Xu Wei
Published: March 2023

Neonatal diabetes mellitus (NDM) is a rare type of monogenic diabetes. At present, most published studies have focused on the types of gene mutations associated with NDM and the therapeutic effect of sulfonylureas (SUs) on the disease; few studies on NDM-associated intracranial hemorrhage (ICH) exist. In addition, p.V59M mutations generally lead to intermediate DEND (iDEND: intermediate developmental delay and neonatal diabetes) syndrome without epilepsy. Here, we present a case of a 1-month-old male infant who was diagnosed with NDM caused by a KCNJ11 missense mutation (p.V59M), presenting with cerebral injury. In the early stage of the disease, continuous insulin dose adjustment did not achieve an ideal level of blood glucose. Although blood glucose was subsequently controlled by oral SUs, which were administered after the genetic test result, the patient still displayed epilepsy and developmental delay. In this case report, we present our experience in the treatment of the infant, switching from insulin to oral SUs and we thought that SUs have limited effects on improving the prognosis of neurodevelopmental disturbances in NDM with foci of encephalomalacia. In addition, there may be a relationship between KCNJ11 missense mutations and cerebral injury, and further research must be carried out to confirm these points.
Association between brain structures and migraine: A bidirectional Mendelian randomization study
Authors: Guo Xiaoming , Wang Dingkun , Ying Caidi , Hong Yuan
Published: March 2023

Background

Accumulating evidence of clinical and neuroimaging studies indicated that migraine is related to brain structural alterations. However, it is still not clear whether the associations of brain structural alterations with migraine are likely to be causal, or could be explained by reverse causality confounding.

Methods

We carried on a bidirectional Mendelian randomization analysis in order to identify the causal relationship between brain structures and migraine risk. Summary-level data and independent variants used as instruments came from large genome-wide association studies of total surface area and average thickness of cortex (33,992 participants), gray matter volume (8,428 participants), white matter hyperintensities (50,970 participants), hippocampal volume (33,536 participants), and migraine (102,084 cases and 771,257 controls).

Results

We identified suggestive associations of the decreased surface area (OR = 0.85; 95% CI, 0.75–0.96; P = 0.007), and decreased hippocampal volume (OR = 0.74; 95% CI, 0.55–1.00; P = 0.047) with higher migraine risk. We did not find any significant association of gray matter volume, cortical thickness, or white matter hyperintensities with migraine. No evidence supporting the significant association was found in the reverse MR analysis.

Conclusion

We provided suggestive evidence that surface area and hippocampal volume are causally associated with migraine risk.
Visually evoked potentials (VEPs) across the visual field in hearing and deaf cats
Authors: Mitzelfelt Thomas , Bao Xiaohan , Barnes Paisley , Lomber Stephen G.
Published: March 2023

Introduction

Congenitally deaf cats perform better on visual localization tasks than hearing cats, and this advantage has been attributed to the posterior auditory field. Successful visual localization requires both visual processing of the target and timely generation of an action to approach the target. Activation of auditory cortex in deaf subjects during visual localization in the peripheral visual field can occur either via bottom-up stimulus-driven and/or top-down goal-directed pathways.

Methods

In this study, we recorded visually evoked potentials (VEPs) in response to a reversing checkerboard stimulus presented in the hemifield contralateral to the recorded hemisphere in both hearing and deaf cats under light anesthesia.

Results

Although VEP amplitudes and latencies were systematically modulated by stimulus eccentricity, we found little evidence of changes in VEP in deaf cats that can explain their behavioral advantage. A statistical trend was observed, showing larger peak amplitudes and shorter peak latencies in deaf subjects for stimuli in the near- and mid-peripheral field. Additionally, latency of the P1 wave component had a larger inter-sweep variation in deaf subjects.

Discussion

Our results suggested that cross-modal plasticity following deafness does not play a major part in cortical processing of the peripheral visual field when the “vision for action” system is not recruited.
Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model
Authors: Fu Yan , Sun Liting , Zhu Fengting , Xia Wei , Wen Ting , Xia Ruilong , Yu Xin , Xu Dan , Peng Changgeng
Published: March 2023

Neuropathic pain (NP) induced by spinal cord injury (SCI) often causes long-term disturbance for patients, but the mechanisms behind remains unclear. Here, our study showed SCI-induced ectopic expression of Nav1.7 in abundant neurons located in deep and superficial laminae layers of the spinal dorsal horn (SDH) and upregulation of Nav1.7 expression in dorsal root ganglion (DRG) neurons in mice. Pharmacologic studies demonstrated that the efficacy of the blood–brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771. Moreover, more than 20% of Nav1.7-expressing SDH neurons in SCI mice were activated to express FOS when there were no external stimuli, suggesting that the ectopic expression of Nav1.7 made SDH neurons hypersensitive and Nav1.7-expressing SDH neurons participated in central sensitization and in spontaneous pain and/or walking-evoked mechanical pain. Further investigation showed that NGF, a strong activator of Nav1.7 expression, and its downstream JUN were upregulated after SCI in SDH neurons with similar distribution patterns and in DRG neurons too. In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP.
Mechanism of skeletal muscle atrophy after spinal cord injury: A narrative review
Authors: Xu Xin , Talifu Zuliyaer , Zhang Chun-Jia , Gao Feng , Ke Han , Pan Yun-Zhu , Gong Han , Du Hua-Yong , Yu Yan , Jing Ying-Li , Du Liang-Jie , Li Jian-Jun , Yang De-Gang
Published: March 2023

Spinal cord injury leads to loss of innervation of skeletal muscle, decreased motor function, and significantly reduced load on skeletal muscle, resulting in atrophy. Factors such as braking, hormone level fluctuation, inflammation, and oxidative stress damage accelerate skeletal muscle atrophy. The atrophy process can result in skeletal muscle cell apoptosis, protein degradation, fat deposition, and other pathophysiological changes. Skeletal muscle atrophy not only hinders the recovery of motor function but is also closely related to many systemic dysfunctions, affecting the prognosis of patients with spinal cord injury. Extensive research on the mechanism of skeletal muscle atrophy and intervention at the molecular level has shown that inflammation and oxidative stress injury are the main mechanisms of skeletal muscle atrophy after spinal cord injury and that multiple pathways are involved. These may become targets of future clinical intervention. However, most of the experimental studies are still at the basic research stage and still have some limitations in clinical application, and most of the clinical treatments are focused on rehabilitation training, so how to develop more efficient interventions in clinical treatment still needs to be further explored. Therefore, this review focuses mainly on the mechanisms of skeletal muscle atrophy after spinal cord injury and summarizes the cytokines and signaling pathways associated with skeletal muscle atrophy in recent studies, hoping to provide new therapeutic ideas for future clinical work.
Crosstalk between melatonin and reactive oxygen species in fruits and vegetables post-harvest preservation: An update
Authors: Li Na , Zhai Kefeng , Yin Qin , Gu Quan , Zhang Xingtao , Melencion Merced G. , Chen Ziping
Published: March 2023

Fruits and vegetables contain numerous nutrients, such as vitamins, minerals, phenolic compounds, and dietary fibers. They reduce the incidence of cardiovascular diseases and the risk of certain chronic diseases, and improve the antioxidant and anti-inflammatory capacity. Moreover, melatonin was found in various fruits and vegetables species. Melatonin acts as a multifunctional compound to participate in various physiological processes. In recent years, many advances have been found that melatonin is also appraised as a key modulator on the fruits and vegetables post-harvest preservation. Fruits and vegetables post-harvest usually elicit reactive oxygen species (ROS) generation and accumulation. Excess ROS stimulate cell damage, protein structure destruction, and tissue aging, and thereby reducing their quality. Numerous studies find that exogenous application of melatonin modulates ROS homeostasis by regulating the antioxidant enzymes and non-enzymatic antioxidants systems. Further evidences reveal that melatonin often interacts with hormones and other signaling molecules, such as ROS, nitric oxide (NO), hydrogen sulfide (H2S), and etc. Among these ‘new’ molecules, crosstalks of melatonin and ROS, especially the H2O2 produced by RBOHs, are provided in fruits and vegetables post-harvest preservation in this review. It will provide reference for complicated integration of both melatonin and ROS as signal molecules in future study.
Chemoradiotherapy in geriatric patients with squamous cell carcinoma of the esophagus: Multi-center analysis on the value of standard treatment in the elderly
Authors: Bostel Tilman , Akbaba Sati , Wollschläger Daniel , Mayer Arnulf , Nikolaidou Eirini , Murnik Markus , Kirste Simon , Rühle Alexander , Grosu Anca-Ligia , Debus Jürgen , Fottner Christian , Moehler Markus , Grimminger Peter , Schmidberger Heinz , Nicolay Nils Henrik
Published: March 2023

Background and purpose

To evaluate the tolerability and outcomes of chemoradiation in elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Materials and methods

This multi-center retrospective analysis included 161 patients with SCC of the esophagus with a median age of 73 years (range 65-89 years) treated with definitive or neoadjuvant (chemo)radiotherapy between 2010 and 2019 at 3 large comprehensive cancer centers in Germany. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities were analyzed, and parameters determining patient outcomes and treatment tolerance were assessed.

Results

The delivery of radiotherapy without dose reduction was possible in 149 patients (93%). In 134 patients (83%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 41% of these patients (n = 55) required chemotherapy de-escalation due to treatment-related toxicities. Fifty-two patients (32%) experienced higher-grade acute toxicities, and 22 patients (14%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS rates amounted to 67.5%, 33.8%, 31.4%, and 40.4%, respectively. Upon multivariate analysis, full-dose concomitant chemotherapy (vs. no or modified chemotherapy) was associated with significantly better DMFS (p=0.005), PFS (p=0.005) and OS (p=0.001). Furthermore, neoadjuvant chemoradiotherapy followed by tumor resection (vs. definitive chemoradiotherapy or definitive radiotherapy alone) significantly improved PFS (p=0.043) and OS (p=0.049). We could not identify any clinico-pathological factor that was significantly associated with LRC. Furthermore, definitive (chemo)radiotherapy, brachytherapy boost and stent implantation were significantly associated with higher-grade acute toxicities (p<0.001, p=0.002 and p=0.04, respectively). The incidence of higher-grade late toxicities was also significantly associated with the choice of therapy, with a higher risk for late toxicities when treatment was switched from neoadjuvant to definitive (chemo)radiotherapy compared to primary definitive (chemo)radiotherapy (p<0.001).

Conclusions

Chemoradiation with full-dose and unmodified concurrent chemotherapy has a favorable prognostic impact in elderly ESCC patients; however, about half of the analyzed patients required omission or adjustment of chemotherapy due to comorbidities or toxicities. Therefore, the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly ESCC patients requires further exploration to optimize treatment in this vulnerable patient cohort.
Survival analyses of different treatment modalities and clinical stage for hypopharyngeal carcinoma
Authors: Lin Tian-Yun , Lee Tsung-Lun , Hsu Yen-Bin , Tai Shyh-Kuan , Wang Ling-Wei , Yang Muh-Hwa , Chu Pen-Yuan
Published: March 2023

Objective

We investigated the effects of different treatment modalities and clinical stage for hypopharyngeal carcinoma (HPC) patients.

Methods

Between February 2004 and December 2012, 167 HPC patients were reviewed. We calculated overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis failure-free survival (DMFFS) using the Kaplan–Meier method and compared various survival outcomes between definitive chemoradiotherapy (CRT) and surgery-based therapy (SBT).

Results

There were no significant differences in baseline characteristics between SBT (n = 102) and definitive CRT (n = 65) groups. The 5-year rates of OS (59.7% vs. 24.0%, p < 0.0001) and PFS (49.9% vs. 22.6%, p = 0.0002) were significantly better in patients who received SBT than in those who received definitive CRT. The SBT group also obtained better LFFS (p < 0.0001), RFFS (p = 0.0479), and DMFFS (p = 0.0110). We did similar analyses by different T-classification (T1–2, T3, and T4) and found that SBT had better OS (p < 0.0001 and p = 0.0020), PFS (p < 0.0001 and p = 0.0513), LFFS (p = 0.0002 and p = 0.0075), RFFS (p = 0.1949 and p = 0.0826), and DMFFS (p = 0.0248 and p = 0.0436) in the T4 and T1–2 subgroups but similar OS (p = 0.9598), PFS (p = 0.5052), RFFS (p = 0.9648), and DMFFS (p = 0.8239) in T3 patients. Analyses by different overall stages revealed no differences between definitive CRT and SBT for stage III patients but significantly better results for stage IV patients who received SBT.

Conclusions

SBT can obtain significant survival benefits when compared with definitive CRT for the whole cohort of patients. Definitive CRT has similar survival outcomes compared with SBT only for T3 tumors or overall stage III disease.
Platelets in the tumor microenvironment and their biological effects on cancer hallmarks
Authors: Chen Lilan , Zhu Chunyan , Pan Fan , Chen Ying , Xiong Lei , Li Yan , Chu Xiaoyuan , Huang Guichun
Published: March 2023

The interplay between platelets and tumors has long been studied. It has been widely accepted that platelets could promote tumor metastasis. However, the precise interactions between platelets and tumor cells have not been thoroughly investigated. Although platelets may play complex roles in multiple steps of tumor development, most studies focus on the platelets in the circulation of tumor patients. Platelets in the primary tumor microenvironment, in addition to platelets in the circulation during tumor cell dissemination, have recently been studied. Their effects on tumor biology are gradually figured out. According to updated cancer hallmarks, we reviewed the biological effects of platelets on tumors, including regulating tumor proliferation and growth, promoting cancer invasion and metastasis, inducing vasculature, avoiding immune destruction, and mediating tumor metabolism and inflammation.
First-line pembrolizumab plus androgen deprivation therapy for locally advanced microsatellite instability-high prostate cancer in a patient with Muir-Torre syndrome: A case report
Authors: Atiq Mohammad O. , Pastor Danielle M. , Karzai Fatima , Hankin Amy R. , Turkbey Baris , Cordes Lisa M. , Brownell Isaac , Liu Yi , Chesnut Gregory T. , Madan Ravi A.
Published: March 2023

The risks of development of colorectal and endometrial cancers in individuals with Lynch syndrome (LS) are well known and have been widely studied. In recent years, the potential association of other malignancies, including prostate cancer, with LS has been considered. Decision-making regarding screening for prostate cancer in the generalized population can be complicated; accounting for the possibility of a higher risk of cancer conferred by a potential genetic predisposition confounds the creation of salient guidelines even further. Although tissue-agnostic treatment approvals have been granted to several immune checkpoint inhibitors (ICIs) for their use in the treatment of subsets of patients whose tumors exhibit high levels of microsatellite instability or high tumor mutational burden, a paucity of data exists regarding the use of ICIs in the first line treatment of patients with locally advanced prostate cancer harboring these features. A significant reduction in tumor volume in response to the combination of immune checkpoint inhibition and androgen deprivation therapy is described in this report of a male with Muir-Torre syndrome who was found to have locally advanced adenocarcinoma of the prostate. While anecdotal, the anti-tumor activity of this combination of therapy is notable and calls attention to the importance of considering further investigation of the use of immune checkpoint blockade as a primary therapeutic option in patients with localized prostate cancer.
FBXO43 increases CCND1 stability to promote hepatocellular carcinoma cell proliferation and migration
Authors: Li Chun-Ming , Zhang Jie , Wu Wu , Zhu Zhu , Li Feng , Wu Di , Wang Xiao-Jun , Xie Chuan-Ming , Gong Jian-Ping
Published: March 2023

Background and Aims

Abnormal expression of E3 ubiquitin ligase plays an important role in the development and progression of hepatocellular carcinoma (HCC), although the mechanism has remained elusive. This study aimed to investigate the biological function and potential mechanism of FBXO43 in HCC.

Methods

FBXO43 expression in tissues and cells were detected by quantitative real-time PCR (qRT−PCR), Western blot, and immunohistochemistry (IHC). The Kaplan-Meier method and Cox regression analysis were used to explore the correlation between the expression level of FBXO43 and the clinical survival. MTT assay, EdU incorporation, colony formation, Transwell, and wound healing assays were performed to evaluate the function of FBXO43 in cell proliferation and migration in vitro. The interaction between FBXO43 and cyclin D1 (CCND1) was assessed by co-immunoprecipitation (Co-IP) assay and in vivo ubiquitination assay.

Results

We found that FBXO43 was upregulated in HCC patient tissues and positively associated with poor clinicopathological features. Meanwhile, HCC patients with high expression of FBXO43 had shorter overall survival (OS) and disease-free survival (DFS). Furthermore, knockdown of FBXO43 inhibited HCC cell proliferation, migration and epithelial-mesenchymal transition (EMT) in HCC cells. Mechanistically, FBXO43 interacted with CCND1 and promoted its stability by polyubiquitination, leading to HCC cell proliferation, migration and EMT. Functional rescue experiments demonstrated that knockdown of CCND1 blocks FBXO43-mediated cell proliferation and metastasis.

Conclusions

FBXO43, as an independent prognostic biomarker, promotes HCC cell proliferation, metastasis and EMT by stability of CCND1, which provides a new potential strategy for HCC treatment by targeting FBXO43-CCND1 axis.
A review of Gabonese gorillas and their pathogens: Diversity, transfer and One Health approach to avoid future outbreaks?
Authors: Boundenga Larson , Makouloutou-Nzassi Patrice , Ngoubangoye Barthelemy
Published: March 2023

In Africa, great apes, among which gorillas, are the reservoir of several infectious agents, some of which have zoonotic potential. However, scientific reports summarizing data on the pathogens harbored by some primate species still need to be published for the scientific community, conservation, and public health actors. In the case of Gabon, despite its outstanding biodiversity, particularly in great apes, and the history of outbreaks involving wildlife, there is a lack of reports on pathogens found in some ape species living in the vicinity of the human being. Thus, it is becoming urgent for us to synthesize the available data on pathogens (parasites, bacteria, and viruses) identified in gorillas living in different ecosystems of Gabon to assess the risks for the human population. Therefore, this review article presents the diversity of pathogens identified in gorillas in Gabon, their impact on primates’ health, the cases of transfer between gorillas and humans, and the interest in a One Health approach for prevention and a better understanding of the ecology of gorilla’s diseases infection in Gabon.
Case report: High-dose epoprostenol therapy in pediatric patients with pulmonary hypertension and developmental lung disease
Authors: Fukasawa Yoshie , Yamamoto Hidenori , Ito Miharu , Saito Akiko , Go Kiyotaka , Morimoto Yoshihito , Yasuda Kazushi , Sato Yoshiaki , Hayakawa Masahiro , Kato Taichi
Published: March 2023

Pulmonary hypertension (PH) with developmental lung disease is a life-threatening disease and accounts for 10%–12% of pediatric PH patients. Administration of specific pulmonary vasodilators to pediatric PH patients has brought about improvement of their long-term prognosis. Intravenous epoprostenol therapy is a gold standard therapy for severe idiopathic pulmonary arterial hypertension (IPAH), but there are few reports demonstrating the efficacy of epoprostenol for pediatric PH patients with developmental lung disease, especially when treating with high doses of epoprostenol. Two cases of pediatric PH patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) and congenital diaphragmatic hernia (CDH) with bronchopulmonary dysplasia (BPD), respectively, treated with epoprostenol above 100 ng/kg/min are presented. In these two cases, severe PH was improved significantly by an aggressive increase of the epoprostenol infusion rate with administration of oral pulmonary vasodilators and appropriate respiratory management, without any significant adverse effects. High-dose epoprostenol therapy may be one of the therapeutic options in pediatric PH patients with developmental lung disease.
SeDeM expert system with I-optimal mixture design for oral multiparticulate drug delivery: An encapsulated floating minitablets of loxoprofen Na and its in silico physiologically based pharmacokinetic modeling
Authors: Rauf-ur-Rehman  , Shoaib Muhammad Harris , Ahmed Farrukh Rafiq , Yousuf Rabia Ismail , Siddiqui Fahad , Saleem Muhammad Talha , Qazi Faaiza , Khan Momina Zarish , Irshad Asma , Bashir Lubna , Naz Shazia , Farooq Muhammad , Mahmood Zafar Alam
Published: March 2023

Introduction: A SeDeM expert tool-driven I-optimal mixture design has been used to develop a directly compressible multiparticulate based extended release minitablets for gastro-retentive drug delivery systems using loxoprofen sodium as a model drug.

Methods: Powder blends were subjected to stress drug-excipient compatibility studies using FTIR, thermogravimetric analysis, and DSC. SeDeM diagram expert tool was utilized to assess the suitability of the drug and excipients for direct compression. The formulations were designed using an I-optimal mixture design with proportions of methocel K100M, ethocel 10P and NaHCO3 as variables. Powder was compressed into minitablets and encapsulated. After physicochemical evaluation lag-time, floating time, and drug release were studied. Heckel analysis for yield pressure and accelerated stability studies were performed as per ICH guidelines. The in silico PBPK Advanced Compartmental and Transit model of GastroPlus™ was used for predicting in vivo pharmacokinetic parameters.

Results: Drug release follows first-order kinetics with fickian diffusion as the main mechanism for most of the formulations; however, a few formulations followed anomalous transport as the mechanism of drug release. The in-silico-based pharmacokinetic revealed relative bioavailability of 97.0%.

Discussion: SeDeM expert system effectively used in QbD based development of encapsulated multiparticulates for once daily administration of loxoprofen sodium having predictable in-vivo bioavailability.
Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy
Authors: Lohman Rink-Jan , Reddy Tupally Karnaker , Kandale Ajit , Cabot Peter J. , Parekh Harendra S.
Published: March 2023

Kappa opioid receptors have exceptional potential as an analgesic target, seemingly devoid of many problematic Mu receptor side-effects. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side-effects limit clinical translation. We modify endogenous dynorphin peptides to improve drug-likeness and develop safer KOP receptor agonists for clinical use. Using rational, iterative design, we developed a series of potent, selective, and metabolically stable peptides from dynorphin 1–7. Peptides were assessed for in vitro cAMP-modulation against three opioid receptors, metabolic stability, KOP receptor selectivity, desensitisation and pERK-signalling capability. Lead peptides were evaluated for in vivo efficacy in a rat model of inflammatory nociception. A library of peptides was synthesised and assessed for pharmacological and metabolic stability. Promising peptide candidates showed low nanomolar KOP receptor selectivity in cAMP assay, and improved plasma and trypsin stability. Selected peptides showed bias towards cAMP signalling over pERK activity, also demonstrating reduced desensitisation. In vivo, two peptides showed significant opioid-like antinociception comparable to morphine and U50844H. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are somewhat biased peptide Kappa agonists they may lack many significant side-effects, such as tolerance, addiction, sedation, and euphoria/dysphoria, common to opioid analgesics.
Edge-enhancement cascaded network for lung lobe segmentation based on CT images
Authors: Bao Nan , Yuan Ye , Luo Qingyao , Li Qiankun , Zhang Li-Bo
Published: March 2023

In order to reduce postoperative complications, it is required that the puncture needle should not pass through the lung lobe without tumor as far as possible in lung biopsy surgery. Therefore, it is necessary to accurately segment the lung lobe on the lung CT images. This paper proposed an automatic lung lobe segmentation method on lung CT images. Considering the boundary of the lung lobe is difficult to be identified, our lung lobe segmentation network is designed to be a multi-stage cascade network based on edge enhancement. In the first stage, the anatomical features of the lung lobe are extracted based on the generative adversarial network (GAN), and the lung lobe boundary is Gaussian smoothed to generate the boundary response map. In the second stage, the CT images and the boundary response map are used as input, and the dense connection blocks are used to realize deep feature extraction, and finally five lung lobes are segmented. The experiments indicated that the average value of Dice coefficient is 0.9741, which meets the clinical needs.
Gel growth and characterization of Cs3Bi2Br9 perovskite single crystals for radiation detection
Authors: Alshogeathri Saqr , Cao Da , Kim Doup , Yang Ge
Published: March 2023

Metal halide perovskites have been sought for ionizing radiation detection due to their tunable bandgap, high quantum yield, high absorption coefficient, excellent charge transport properties, flexible chemistry synthesis and cost-effective manufacturing. Among the family of perovskites, bismuth-based halide perovskites have attracted a rapidly growing interest as possible alternatives to lead-based halide perovskites in the development of nontoxic perovskites for opto-electronic devices. Herein, bismuth-based inorganic perovskite Cs3Bi2Br9 single crystals were successfully grown using an innovative dual-diffusion gel growth technique for the first time. Silica gel has been developed as an enabling medium for gel growth of single crystals due to its transparency and easy control of nucleation sites. The UV-vis transmission spectrum was recorded using a light source of deuterium and halogen lamps and a Tauc plot was obtained, which gave an estimate of the bandgap energy, 2.54 eV. Silver electrodes were used on the top surface and the bottom surface of Cs3Bi2Br9 single crystals for material characterization and detector tests. Current-voltage (I-V) measurements gave a room-temperature resistivity of 1.79×1011 Ω•cm. The Cs3Bi2Br9 single crystals were then tested for X-ray response using ON\OFF testing which revealed attractive responsiveness for X-ray photons (rise and fall time: ≈0.3 s ). Using the net current (IXray−Idark), which can be extracted from the X-ray response measurements at varied applied voltages, a modified Hecht fitting was applied to estimate the mobility-lifetime product of electrons, μτ=5.12×10−4 ±6.70×10−5 cm2/V for a Ag/Cs3Bi2Br9/Ag device. This study shows that our innovative crystal growth method, enabled by the unique gel growth process, can be used as an appealing technique to grow functional crystals for opto-electronic devices. Meanwhile, Cs3Bi2Br9 has shown great potential as a promising candidate for X-ray detection applications. The efforts in this work will serve as a metric for growing halide perovskites in the gel for opto-electronic devices.
Methods: Aortic wall deformation assessment by ultrafast ultrasound imaging: Application to bicuspid aortic valve associated aortopathy
Authors: Goudot Guillaume , Cheng Charles , Guédon Alexis F. , Mirault Tristan , Pedreira Olivier , Dahan Alexandre , Wang Louise Z. , Pernot Mathieu , Messas Emmanuel
Published: March 2023

Purpose: Aortic maximal rate of systolic distention (MRSD) is a prognosis factor of ascending aorta dilatation with magnetic resonance imaging. Its calculation requires precise continuous tracking of the aortic diameter over the cardiac cycle, which is not feasible by focused ultrasound. We aimed to develop an automatic aortic acquisition using ultrafast ultrasound imaging (UUI) to provide access to the aortic MRSD.

Methods: A phased array probe and developed sequences at 2000 frames/s were used. A created interface automatically tracked the anterior and posterior aortic walls over the cardiac cycle. Tissue Doppler allowed a precise estimation of the walls’ movements. MRSD was the maximum derivative of the aortic diameter curve over time. To assess its feasibility, 34 patients with bicuspid aortic valve (BAV) and 31 controls were consecutively included to evaluate the BAV-associated aortopathy at the sinus of Valsalva, the tubular ascending aorta, and the aortic arch.

Results: UUI acquisitions and the dedicated interface allow tracking of the aortic diameter and calculating the MRSD for the BAV patients and controls (mean age of 34 vs. 43 years, p = 0.120). A trend toward lower deformation in the different aortic segments was observed, as expected. Still, only the MRSD with UUI was significantly different at the sinus of Valsalva in this small series: (0.61 .103.s–1 [0.37–0.72] for BAV patients vs. 0.92 .103.s–1 [0.72–1.02] for controls, p = 0.025).

Conclusion: Aortic deformation evaluated with UUI deserves attention with a simple and automated measurement technique that could assess the segmental aortic injury associated with BAV.
Acute oxygen sensing by vascular smooth muscle cells
Authors: Moreno-Domínguez Alejandro , Colinas Olaia , Smani Tarik , Ureña Juan , López-Barneo José
Published: March 2023

An adequate supply of oxygen (O2) is essential for most life forms on earth, making the delivery of appropriate levels of O2 to tissues a fundamental physiological challenge. When O2 levels in the alveoli and/or blood are low, compensatory adaptive reflexes are produced that increase the uptake of O2 and its distribution to tissues within a few seconds. This paper analyzes the most important acute vasomotor responses to lack of O2 (hypoxia): hypoxic pulmonary vasoconstriction (HPV) and hypoxic vasodilation (HVD). HPV affects distal pulmonary (resistance) arteries, with its homeostatic role being to divert blood to well ventilated alveoli to thereby optimize the ventilation/perfusion ratio. HVD is produced in most systemic arteries, in particular in the skeletal muscle, coronary, and cerebral circulations, to increase blood supply to poorly oxygenated tissues. Although vasomotor responses to hypoxia are modulated by endothelial factors and autonomic innervation, it is well established that arterial smooth muscle cells contain an acute O2 sensing system capable of detecting changes in O2 tension and to signal membrane ion channels, which in turn regulate cytosolic Ca2+ levels and myocyte contraction. Here, we summarize current knowledge on the nature of O2 sensing and signaling systems underlying acute vasomotor responses to hypoxia. We also discuss similarities and differences existing in O2 sensors and effectors in the various arterial territories.
Genome-wide characterization and identification of Trihelix transcription factors and expression profiling in response to abiotic stresses in Chinese Willow (Salix matsudana Koidz)
Authors: Yang Jie , Tang Zhixuan , Yang Wuyue , Huang Qianhui , Wang Yuqing , Huang Mengfan , Wei Hui , Liu Guoyuan , Lian Bolin , Chen Yanhong , Zhang Jian
Published: March 2023

Trihelix transcription factors (TTF) are a class of light-responsive proteins with a typical triple-helix structure (helix-loop-helix-loop-helix). Members of this gene family play an important role in plant growth and development, especially in various abiotic stress responses. Salix matsudana Koidz is an allotetraploid ornamental forest tree that is widely planted for its excellent resistance to stress, but no studies on its Trihelix gene family have been reported. In this study, the Trihelix gene family was analyzed at the genome-wide level in S. matsudana. A total of 78 S. matsudana Trihelix transcription factors (SmTTFs) were identified, distributed on 29 chromosomes, and classified into four subfamilies (GT-1, GT-2, SH4, SIP1) based on their structural features. The gene structures and conserved functional domains of these Trihelix genes are similar in the same subfamily and differ between subfamilies. The presence of multiple stress-responsive cis-elements on the promoter of the S. matsudana Trihelix gene suggests that the S. matsudana Trihelix gene may respond to abiotic stresses. Expression pattern analysis revealed that Trihelix genes have different functions during flooding stress, salt stress, drought stress and low temperature stress in S. matsudana. Given that SmTTF30, as a differentially expressed gene, has a faster response to flooding stress, we selected SmTTF30 for functional studies. Overexpression of SmTTF30 in Arabidopsis thaliana (Arabidopsis) enhances its tolerance to flooding stress. Under flooding stress, the leaf cell activity and peroxidase activity (POD) of the overexpression strain were significantly higher than the leaf cell activity and POD of the wild type, and the malondialdehyde (MDA) content was significantly lower than the MDA content of the wild type. Thus, these results suggest that SmTTF30 enhances plant flooding tolerance and plays a positive regulatory role in plant flooding tolerance.