bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of key factors driving inflammation-induced sensitization of muscle sensory neurons
Authors: Nagaraja Sridevi , Tewari Shivendra G. , Reifman Jaques
Published: May 2023

Sensory neurons embedded in muscle tissue that initiate pain sensations, i.e., nociceptors, are temporarily sensitized by inflammatory mediators during musculoskeletal trauma. These neurons transduce peripheral noxious stimuli into an electrical signal [i.e., an action potential (AP)] and, when sensitized, demonstrate lower activation thresholds and a heightened AP response. We still do not understand the relative contributions of the various transmembrane proteins and intracellular signaling processes that drive the inflammation-induced hyperexcitability of nociceptors. In this study, we used computational analysis to identify key proteins that could regulate the inflammation-induced increase in the magnitude of AP firing in mechanosensitive muscle nociceptors. First, we extended a previously validated model of a mechanosensitive mouse muscle nociceptor to incorporate two inflammation-activated G protein-coupled receptor (GPCR) signaling pathways and validated the model simulations of inflammation-induced nociceptor sensitization using literature data. Then, by performing global sensitivity analyses that simulated thousands of inflammation-induced nociceptor sensitization scenarios, we identified three ion channels and four molecular processes (from the 17 modeled transmembrane proteins and 28 intracellular signaling components) as potential regulators of the inflammation-induced increase in AP firing in response to mechanical forces. Moreover, we found that simulating single knockouts of transient receptor potential ankyrin 1 (TRPA1) and reducing the rates of Gαq-coupled receptor phosphorylation and Gαq subunit activation considerably altered the excitability of nociceptors (i.e., each modification increased or decreased the inflammation-induced fold change in the number of triggered APs compared to when all channels were present). These results suggest that altering the expression of TRPA1 or the concentration of intracellular Gαq might regulate the inflammation-induced increase in AP response of mechanosensitive muscle nociceptors.
Visual reading for [18F]Florzolotau ([18F]APN-1607) tau PET imaging in clinical assessment of Alzheimer’s disease
Authors: Lin Huan-Chun , Lin Kun-Ju , Huang Kuo-Lun , Chen Shih-Hsin , Ho Tsung-Ying , Huang Chin-Chang , Hsu Jung-Lung , Chang Chiung-Chih , Hsiao Ing-Tsung
Published: May 2023

Introduction

Tau-targeted positron emission tomography (tau-PET) is a potential tool for the differential diagnosis of Alzheimer’s disease (AD) and to clarify the distribution of tau deposition. In addition to the quantitative analysis of tau-PET scans, visual reading supports the assessment of tau loading for clinical diagnosis. This study aimed to propose a method for visually interpreting tau-PET using the [18F] Florzolotau tracer and investigate the performance and utility of the visual reading.

Materials and methods

A total number of 46 individuals with 12 cognitively unimpaired subjects (CU), 20 AD patients with mild cognitive impairment (AD-MCI), and 14 AD with dementia (AD-D) patients with both [18F]Florbetapir amyloid PET and [18F]Florzolotau tau PET scans were included. Clinical information, cognitive assessment, and amyloid PET scan results were recorded. For visual interpretation, a modified rainbow colormap was created and a regional tau uptake scoring system was proposed to evaluate the degree of tracer uptake and its spatial distribution within five cortical regions. Each region was scored on a scale of [0, 2] as compared to the background, and that resulted in a global scale range of [0, 10]. Four readers interpreted [18F]Florzolotau PET using the visual scale. The global and regional standardized uptake value ratios (SUVr) were also calculated for analysis.

Results

The result indicates the average global visual scores were 0 ± 0 in the CU group, 3.43 ± 3.35 in the AD-MCI group, and 6.31 ± 2.97 in the AD-D group (p < 0.001). The consensus among the four observers on image scores was high with an intraclass correlation coefficient of 0.880 (95% CI: 0.767–0.936). The average global visual score was significantly associated with global SUVr (r = 0.884, p < 0.0001) and with the CDR-sum of box (r = 0.677, p < 0.0001).

Conclusion

The visual reading method generated a visual score of [18F]Florzolotau tau-PET with good sensitivity and specificity to identify AD-D or CU individuals from the other patients. The preliminary result also showed that the global visual scores are significantly and reliably correlated with global cortical SUVr, and associated well with the clinical diagnosis and cognitive performance.
Neuromorphic computing facilitates deep brain-machine fusion for high-performance neuroprosthesis
Authors: Qi Yu , Chen Jiajun , Wang Yueming
Published: May 2023

Brain-machine interfaces (BMI) have developed rapidly in recent years, but still face critical issues such as accuracy and stability. Ideally, a BMI system would be an implantable neuroprosthesis that would be tightly connected and integrated into the brain. However, the heterogeneity of brains and machines hinders deep fusion between the two. Neuromorphic computing models, which mimic the structure and mechanism of biological nervous systems, present a promising approach to developing high-performance neuroprosthesis. The biologically plausible property of neuromorphic models enables homogeneous information representation and computation in the form of discrete spikes between the brain and the machine, promoting deep brain-machine fusion and bringing new breakthroughs for high-performance and long-term usable BMI systems. Furthermore, neuromorphic models can be computed at ultra-low energy costs and thus are suitable for brain-implantable neuroprosthesis devices. The intersection of neuromorphic computing and BMI has great potential to lead the development of reliable, low-power implantable BMI devices and advance the development and application of BMI.
Dynamic alterations of spontaneous neural activity in post-stroke aphasia: a resting-state functional magnetic resonance imaging study
Authors: Xu Luyao , Wei Hongchun , Sun Zhongwen , Chu Tongpeng , Li Min , Liu Ruhui , Jiang Li , Liang Zhigang
Published: May 2023

Background and purpose

The dynamic alterations in spontaneous neural activity of the brain during the acute phase of post-stroke aphasia (PSA) remain unclear. Therefore, in this study, dynamic amplitude of low-frequency fluctuation (dALFF) was applied to explore abnormal temporal variability in local functional activity of the brain during acute PSA.

Materials and methods

Resting-state functional magnetic resonance imaging (rs-fMRI) data from 26 patients with PSA and 25 healthy controls (HCs) were acquired. The sliding window method was used to assess dALFF, with the k-means clustering method used to identify dALFF states. The two-sample t-test was applied to compare differences in dALFF variability and state metrics between the PSA and HC groups.

Results

(1) In the PSA group, greater variance of dALFF in the cerebellar network (CBN) and left fronto-temporo-parietal network (FTPN) was observed. (2) Three dALFF states were identified among all subjects. States 1 and 2 were identified in the PSA patients, and the two dALFF states shared a similar proportion. Moreover, the number of transitions between the two dALFF states was higher in the patients compared with that in HCs.

Conclusion

The results of this study provide valuable insights into brain dysfunction that occurs during the acute phase (6.00 ± 3.52 days) of PSA. The observed increase in variability of local functional activities in CBN and left FTPN may be related to the spontaneous functional recovery of language during acute PSA, and it also suggests that cerebellum plays an important role in language.
Transcranial Doppler Ultrasonography detection on cerebrovascular flow for evaluating neonatal hypoxic-ischemic encephalopathy modeling
Authors: Liu Jin-Xiang , Fang Chang-Le , Zhang Kun , Ma Rui-Fang , Zhou Hong-Su , Chen Li , Wang Qiu-Lin , Lu Yu-Xuan , Wang Ting-Hua , Xiong Liu-Lin
Published: May 2023

Objective

This study aimed to investigate the feasibility of Transcranial Doppler Ultrasonography (TCD) in evaluating neonatal hypoxic-ischemic encephalopathy (NHIE) modeling through monitoring the alteration of cerebrovascular flow in neonatal hypoxic-ischemic (HI) rats.

Methods

Postnatal 7-day-old Sprague Dawley (SD) rats were divided into the control group, HI group, and hypoxia (H) group. TCD was applied to assess the changes of cerebral blood vessels, cerebrovascular flow velocity, and heart rate (HR) in sagittal and coronal sections at 1, 2, 3, and 7 days after the operation. For accuracy, cerebral infarct of rats was examined by 2,3,5-Triphenyl tetrazolium chloride (TTC) staining and Nissl staining to simultaneously verify the establishment of NHIE modeling.

Results

Coronal and sagittal TCD scans revealed obvious alteration of cerebrovascular flow in main cerebral vessels. Obvious cerebrovascular back-flow was observed in anterior cerebral artery (ACA), basilar artery (BA), middle cerebral artery (MCA) of HI rats, along with accelerated cerebrovascular flows in the left internal carotid artery (ICA-L) and BA, decreased flows in right internal carotid artery (ICA-R) relative to those in the H and control groups. The alterations of cerebral blood flows in neonatal HI rats indicated successful ligation of right common carotid artery. Besides, TTC staining further validated the cerebral infarct was indeed caused due to ligation-induced insufficient blood supply. Damage to nervous tissues was also revealed by Nissl staining.

Conclusion

Cerebral blood flow assessment by TCD in neonatal HI rats contributed to cerebrovascular abnormalities observed in a real-time and non-invasive way. The present study elicits the potentials to utilize TCD as an effective means for monitoring the progression of injury as well as NHIE modeling. The abnormal appearance of cerebral blood flow is also beneficial to the early warning and effective detection in clinical practice.
Effects of a neurokinin-1 receptor antagonist in the acute phase after thoracic spinal cord injury in a rat model
Authors: Zheng Guoli , Harms Anna-Kathrin , Tail Mohamed , Zhang Hao , Nimmo Alan , Skutella Thomas , Kiening Karl , Unterberg Andreas , Zweckberger Klaus , Younsi Alexander
Published: May 2023

Objective

Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and further neuroinflammation contributes to aggravation of spinal cord injury (SCI). We aimed to observe the effect of antagonizing the binding of the neuropeptide Substance-P (SP) to its neurokinin-1 (NK1) receptor in a rodent SCI model.

Methods

Female Wistar rats were subjected to a T9 laminectomy with or without (Sham) a T9 clip-contusion/compression SCI, followed by the implantation of an osmotic pump for the continuous, seven-day-long infusion of a NK1 receptor antagonist (NRA) or saline (vehicle) into the intrathecal space. The animals were assessed via MRI, and behavioral tests were performed during the experiment. 7 days after SCI, wet & dry weight and immunohistological analyses were conducted.

Results

Substance-P inhibition via NRA showed limited effects on reducing edema. However, the invasion of T-lymphocytes and the number of apoptotic cells were significantly reduced with the NRA treatment. Moreover, a trend of reduced fibrinogen leakage, endothelial and microglial activation, CS-GAG deposition, and astrogliosis was found. Nevertheless, only insignificant general locomotion recovery could be observed in the BBB open field score and the Gridwalk test. In contrast, the CatWalk gait analysis showed an early onset of recovery in several parameters.

Conclusion

Intrathecal administration of NRA might reinforce the integrity of the BSCB in the acute phase after SCI, potentially attenuating aspects of neurogenic inflammation, reducing edema formation, and improving functional recovery.
Vitamin K supplementation and vascular calcification: a systematic review and meta-analysis of randomized controlled trials
Authors: Li Te , Wang Yun , Tu Wei-ping
Published: May 2023

Background

Vascular calcification (VC) is a complex process that has been linked to conditions including cardiovascular diseases and chronic kidney disease. There is an ongoing debate about whether vitamin K (VK) can effectively prevent VC. To assess the efficiency and safety of VK supplementation in the therapies of VC, we performed a systematic review and meta-analysis of recent studies.

Methods

We searched major databases, including PubMed, the Cochrane Library, Embase databases, and Web of Science up until August 2022. 14 randomized controlled trials (RCTs) describing the outcomes of treatment for VK supplementation with VC have been included out of 332 studies. The results were reported in the change of coronary artery calcification (CAC) scores, other artery and valve calcification, vascular stiffness, and dephospho-uncarboxylated matrix Gla protein (dp-ucMGP). The reports of severe adverse events were recorded and analyzed.

Results

We reviewed 14 RCTs, comprising a total of 1,533 patients. Our analysis revealed that VK supplementation has a significant effect on CAC scores, slowing down the progression of CAC [I2 = 34%, MD= −17.37, 95% CI (−34.18, −0.56), p = 0.04]. The study found that VK supplementation had a significant impact on dp-ucMGP levels, as compared to the control group, where those receiving VK supplementation had lower values [I2 = 71%, MD = −243.31, 95% CI (−366.08, −120.53), p = 0.0001]. Additionally, there was no significant difference in the adverse events between the groups [I2 = 31%, RR = 0.92, 95% CI (−0.79,1.07), p = 0.29].

Conclusion

VK may have therapeutic potential for alleviating VC, especially CAC. However, more rigorously designed RCTs are required to verify the benefits and efficacy of VK therapy in VC.
Minimally invasive Ivor Lewis esophagectomy in the elderly patient: a multicenter retrospective matched-cohort study
Authors: Capovilla Giovanni , Uzun Eren , Scarton Alessia , Moletta Lucia , Hadzijusufovic Edin , Provenzano Luca , Salvador Renato , Pierobon Elisa Sefora , Zanchettin Gianpietro , Tagkalos Evangelos , Berlth Felix , Lang Hauke , Valmasoni Michele , Grimminger Peter P.
Published: May 2023

Introduction

Several studies reported the advantages of minimally invasive esophagectomy over the conventional open approach, particularly in terms of postoperative morbidity and mortality. The literature regarding the elderly population is however scarce and it is still not clear whether elderly patients may benefit from a minimally invasive approach as the general population. We sought to evaluate whether thoracoscopic/ laparoscopic (MIE) or fully robotic (RAMIE) Ivor-Lewis esophagectomy significantly reduces postoperative morbidity in the elderly population.

Methods

We analyzed data of patients who underwent open esophagectomy or MIE/RAMIE at Mainz University Hospital and at Padova University Hospital between 2016 and 2021. Elderly patients were defined as those ≥ 75 years old. Clinical characteristics and the postoperative outcomes were compared between elderly patients who underwent open esophagectomy or MIE/RAMIE. A 1-to-1 matched comparison was also performed. Patients < 75 years old were evaluated as a control group.

Results

Among elderly patients MIE/RAMIE were associated with a lower overall morbidity (39.7% vs. 62.7%, p=0.005), less pulmonary complications (32.8 vs. 56.9%, p=0.003) and a shorter hospital stay (13 vs. 18 days, p=0.03). Comparable findings were obtained after matching. Similarly, among < 75 years-old patients, a reduced morbidity (31.2% vs. 43.5%, p=0.01) and less pulmonary complications (22% vs. 36%, p=0.001) were detected in the minimally invasive group.

Discussion

Minimally invasive esophagectomy improves the postoperative course of elderly patients reducing the overall incidence of postoperative complications, particularly of pulmonary complications.
Metastatic insulinoma: exploration from clinicopathological signatures and genetic characteristics
Authors: Zhang Jingcheng , Jiang Rui , Hong Xiafei , Wu Huanwen , Han Xianlin , Wu Wenming
Published: May 2023

Background

Insulinoma is a rare type of pancreatic neuroendocrine tumor with low incidence and low-malignant features. While very few insulinomas present with malignant behaviours, such as lymph node and liver metastasis, only a few studies have focused on this field owing to the limitation of samples. Existing evidence suggests that metastatic insulinoma largely derive from non-functional pancreatic neuroendocrine tumor. However, we found a portion of metastatic insulinomas may derive from non-metastatic insulinomas and explored their clinicopathological signatures and genetic characteristics.

Methods

Four metastatic insulinoma patients with synchronous liver metastasis or lymph node metastasis at the Peking Union Medical College Hospital between October 2016 and December 2018 were enrolled, and whole exon and genome sequencing were performed on fresh frozen tissues and peripheral blood samples. Clinicopathological information and genomic sequencing results were collected and matched to explore the characteristics of the metastatic insulinomas.

Results

These four metastatic insulinoma patients underwent surgery or interventional therapy, and their blood glucose levels immediately increased and maintained within standard range after treatment. For these four patients, the proinsulin/insulin molar ratio <1 and primary tumors were all present as PDX1+, ARX-, and insulin+, which were similar to non-metastatic insulinomas. However, the liver metastasis showed PDX1+ and ARX+, insulin+. Meanwhile, genomic sequencing data showed no recurrently mutations and typical CNV patterns. However, one patient harboured the YY1 T372R mutation, a recurrently mutated gene in non-metastatic insulinomas.

Conclusions

A portion of metastatic insulinomas were largely derived from non-metastatic insulinomas in hormone secretion and ARX/PDX1 expression patterns. Meanwhile, the accumulation of ARX expression may be involved in the progression of metastatic insulinomas.
Combined genetic screening and traditional newborn screening to improve the screening efficiency of congenital hypothyroidism
Authors: Ye Liang , Yin Yifan , Chen Min , Gong Nian , Peng Yong , Liu Hao , Miao Jingkun
Published: May 2023

Background

Congenital hypothyroidism (CH) is an neonatal endocrine disorder. Traditional newborn screening is the mainstream method of CH screening, so as to ensure the early detection and treatment of CH. This method is limited as it has high rates of false positives and negatives. Genetic screening can be used to address the shortcomings of traditional newborn Screening (NBS); however, the comprehensive clinical value of genetic screening is yet to be systematically studied.

Methods

A total of 3,158 newborns who accepted the newborn screening and genetic screening were recruited for this study. Biochemical screening and genetic screening were performed at the same time. The level of TSH with the DBS was detected by time-resolved immunofluorescence assay. High-throughput sequencing technology based on targeted gene capture was used for genetic screening. The suspected neonatal was recalled and tested serum TSH, and FT4. Finally, the effectiveness of traditional NBS and combined screening was compared.

Results

In this study, 16 cases were diagnosed by traditional NBS. 10 cases of DUOX2 mutation were found in newborn CH-related genetic screening, including 5 homozygous and 5 compound heterozygous variations. We found that the c.1588A > T mutations in DUOX2 constituting the predominant site in the present cohort.Compared with NBS and genetic screening, the sensitivity of combined screening increased by 11.1% and 55.6%, respectively. Compared with NBS and genetic screening, the negative predictive value of combined screening increased by 0.1% and 0.4%, respectively.

Conclusions

Combined traditional NBS and genetic screening reduces the false negative rate of CH screening and improves the early and accurate identification of neonates with CH. Our research explains the mutation spectrum of CH in this region, and provisionally demonstrates the necessity, feasibility and significance of genetic screening in newborns and provides a solid basis for future clinical developments.
A specific SNP-based multiplex PCR assay for the simultaneous identification of two biological ingredients for the Chinese patent medicine, Danggui Buxue pill
Authors: Liu Yinrong , Yang Yingying , Zhou Zishan , Fan Jia’er , Diao Jianxin , Chao Zhi , Tian Enwei
Published: May 2023

Background: An increasing number of Chinese patent medicines (CPM) have been widely used in East Asian and North American countries, and the safety and efficacy of CPM have highly attracted public attention. However, it is difficult to supervise the authenticity of multiple biological ingredients within CPM based on microscopic inspection and physical and chemical detection. The raw materials may have similar characteristics of tissue structures and ergastic substances or similar chemical composition and contents when substitutes and/or adulterants are added. DNA molecular markers have been used to distinguish the biological ingredients within CPM based on conventional PCR assay. However, it was proved to be time- and labor-consuming and reagent-wasting, as multiple PCR amplification strategies were required for identifying the complex species composition within CPM. Here, we took the CPM (Danggui Buxue pill) as an example and aimed to establish a specific SNP-based multiplex PCR assay and simultaneously determine the authenticity of the two biological ingredients (Angelicae Sinensis Radix and Astragali Radix) within this CPM.

Methods: We, respectively, designed the species-specific primers based on highly variable nrITS for discriminating Angelicae Sinensis Radix and Astragali Radix from their common substitutes and adulterants. The specificity of the primers was checked through conventional PCR assay and multiplex PCR assay. Furthermore, we used a handcrafted Danggui Buxue pill sample (DGBXP) to optimize annealing temperatures for the primers with multiplex PCR, and the sensitivity was also assessed. Finally, fourteen batches of commercial Danggui Buxue pills were used to verify the stability and practicability of the established multiplex PCR assay.

Results: Two pairs of highly species-specific primers for amplifying Angelicae Sinensis Radix and Astragali Radix were screened, and our established multiplex PCR assay showed high specificity and sensitivity (lowest detection concentration: 4.0 × 10−3 ng/μL) at an optimal annealing temperature of 65°C. The method could simultaneously identify both biological ingredients within the Danggui Buxue pill.

Conclusion: The specific SNP-based multiplex PCR provided a simple, time-, and labor-saving method for the simultaneous identification of the two biological ingredients within Danggui Buxue pills. This study was expected to provide a novel qualitative quality control strategy for CPM.
Efficacy and safety of the herbal formula Naesohwajung-tang for functional dyspepsia: a randomized, double-blind, placebo-controlled, multi-center trial
Authors: Ha Na-Yeon , Ko Seok-Jae , Park Jae-Woo , Kim Jinsung
Published: May 2023

Background: Current treatment and management options for functional dyspepsia (FD) often fail to alleviate symptoms. Naesohwajung-tang (NHT) is a herbal formula frequently used to treat functional dyspepsia in traditional Korean medicine. However, few animal and case reports on the use of Naesohwajung-tang for functional dyspepsia treatment exist, and the clinical evidence remains deficient.

Objectives: This study aimed to evaluate the efficacy of Naesohwajung-tang in patients with functional dyspepsia.

Methods: We enrolled 116 patients with functional dyspepsia at two study sites in this 4 weeks, randomized, double-blind, placebo-controlled trial and randomly assigned them to either the Naesohwajung-tang or placebo group. To evaluate the efficacy of Naesohwajung-tang, the primary endpoint was a score on the total dyspepsia symptom (TDS) scale after treatment. The overall treatment effect (OTE), single dyspepsia symptom (SDS) scale, food retention questionnaire (FRQ), Damum questionnaire (DQ), functional dyspepsia-related quality of life (FD-QoL) questionnaire, and gastric myoelectrical activity measured using electrogastrography were evaluated as secondary outcomes. Laboratory tests were performed to confirm the safety of the intervention.

Results: The 4 weeks administration of Naesohwajung-tang granules demonstrated a significantly higher reduction in the total dyspepsia symptom (p < 0.05) and a higher degree of improvement in the total dyspepsia symptom (p < 0.01) than the placebo group. Patients who underwent Naesohwajung-tang had a significantly higher overall treatment effect and a greater increase in the degree of improvement in scores such as epigastric burning, postprandial fullness, early satiation, functional dyspepsia-related quality of life, and Damum questionnaire (p < 0.05). Additionally, the Naesohwajung-tang group showed a greater effect in preventing a decrease in the percentage of normal gastric slow waves after meals than the placebo group. As a result of subgroup analyses using the degree of improvement in total dyspepsia symptom, Naesohwajung-tang was found to be more effective than placebo in female, younger patients (<65 years), with a high body-mass index (≥22), overlap type, food retention type, and Dampness and heat in the spleen and stomach systems pattern. There was no significant difference in the incidence of adverse events between the two groups.

Conclusion: This is the first randomized clinical trial to verify that Naesohwajung-tang leads on symptom relief in patients with functional dyspepsia.

Clinical Trial Registration:https://cris.nih.go.kr/cris/search/detailSearch.do/17613, identifier KCT0003405
Nirmatrelvir/Ritonavir for hemodialysis patients with COVID-19
Authors: Lu Jiayue , Cai Hong , Hao Yujun , Lin Zhang , Liu Shang , Zhan Yaping , Ding Li , Huang Meilan , Li Zhenyuan , Xu Lan , Yan Xiujuan , Yang Li , Zhang He , Zhang Wei , Zhao Li , Zhao Junli , Wang Ting , Gu Leyi
Published: May 2023

Background: Hemodialysis patients have a high risk of severe/critical COVID-19 and related high mortality, but nirmatrelvir/ritonavir is not recommended for hemodialysis patients with COVID-19 infection because of lack of evidence of safety.

Objectives: Our study aims to evaluate the minimum plasma concentration (Cmin) of nirmatrelvir and its safety of different doses of nirmatrelvir/ritonavir in hemodialysis patients with mild COVID-19.

Method: This was a prospective, two step, nonrandomized, open-label study. Participants were treated with nirmatrelvir 150 mg or 300 mg once a day (another 75 mg or 150 mg supplied after hemodialysis) and ritonavir 100 mg twice daily for 5 days, respectively. The primary outcome was the safety of nirmatrelvir/ritonavir, including the Cmin of nirmatrelvir and the number of adverse events (AE). The secondary outcome was the time of viral elimination in hemodialysis patients.

Results: Adverse events were happened in 3 and 7 participants in the step 1 and step 2 group, respectively (p = 0.025). Among them, 2 and 6 participants were identified as drug-related adverse events (p = 0.054). No SAE or liver function damage happened. The Cmin of nirmatrelvir in step 1 and step 2 group were 5,294.65 ± 2,370.59 ng/mL and 7,675.67 ± 2,745.22 ng/mL (p = 0.125). The Cmin of the control group was 2,274.10 ± 1,347.25 ng/mL (p = 0.001 compared to step 2 and p = 0.059 compared to step 1). Compared to hemodialysis patients without nirmatrelvir/ritonavir, there were no statistical differences in overall viral elimination time (p = 0.232).

Conclusion: In our study, two doses of nirmatrelvir/ritonavir appeared to be excessive for hemodialysis patients. Although all of the patients tolerated 5-day administration, nearly half of the patients experienced drug-related adverse events. In addition, the medication group did not show a significant advantage in the time of viral elimination.
Proarrhythmia associated with antiarrhythmic drugs: a comprehensive disproportionality analysis of the FDA adverse event reporting system
Authors: Wang Feifei , Zhou Bingfeng , Sun Hongwei , Wu Xinan
Published: May 2023

Objective: This study aimed to identify the different associations between antiarrhythmic drugs (AADs) and arrhythmias, and to determine whether pharmacokinetic drug interactions involving AADs increase the risk of AAD-related arrhythmias compared to using AADs alone.

Materials and methods: The disproportionality analysis of AAD-associated cardiac arrhythmias, including AAD monotherapies and concomitant use of pharmacokinetic interacting agents involving AADs, was conducted by using reporting odds ratio (ROR) and information component (IC) as detection of potential safety signals based on FAERS data from January 2016 to June 2022. We compared the clinical features of patients reported with AAD–associated arrhythmias between fatal and non-fatal groups, and further investigated the onset time (TTO) following different AAD regimens.

Results: A total of 11754 AAD–associated cardiac arrhythmias reports were identified, which was more likely to occur in the elderly (52.17%). Significant signals were detected between cardiac arrhythmia and all AAD monotherapies, with ROR ranging from 4.86 with mexiletine to 11.07 with flecainide. Regarding four specific arrhythmias in High Level Term (HLT) level, the AAD monotherapies with the highest ROR were flecainide in cardiac conduction disorders (ROR025 = 21.18), propafenone in rate and rhythm disorders (ROR025 = 10.36), dofetilide in supraventricular arrhythmias (ROR025 = 17.61), and ibutilide in ventricular arrhythmias (ROR025 = 4.91). Dofetilide/ibutilide, ibutilide, mexiletine/ibutilide and dronedarone presented no signal in the above four specific arrhythmias respectively. Compared with amiodarone monotherapy, sofosbuvir plus amiodarone detected the most significantly increased ROR in arrhythmias.

Conclusion: The investigation showed the spectrum and risk of AAD–associated cardiac arrhythmias varied among different AAD therapies. The early identification and management of AAD-associated arrhythmias are of great importance in clinical practice.
Herbal medicine for the treatment of obesity-associated asthma: a comprehensive review
Authors: Das Aparoop , Pathak Manash Pratim , Pathak Kalyani , Saikia Riya , Gogoi Urvashee
Published: May 2023

Obesity is fast growing as a global pandemic and is associated with numerous comorbidities like cardiovascular disease, hypertension, diabetes, gastroesophageal reflux disease, sleep disorders, nephropathy, neuropathy, as well as asthma. Studies stated that obese asthmatic subjects suffer from an increased risk of asthma, and encounter severe symptoms due to a number of pathophysiology. It is very vital to understand the copious relationship between obesity and asthma, however, a clear and pinpoint pathogenesis underlying the association between obesity and asthma is scarce. There is a plethora of obesity-asthma etiologies reported viz., increased circulating pro-inflammatory adipokines like leptin, resistin, and decreased anti-inflammatory adipokines like adiponectin, depletion of ROS controller Nrf2/HO-1 axis, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) associated macrophage polarization, hypertrophy of WAT, activation of Notch signaling pathway, and dysregulated melanocortin pathway reported, however, there is a very limited number of reports that interrelates these pathophysiologies. Due to the underlying complex pathophysiologies exaggerated by obese conditions, obese asthmatics respond poorly to anti-asthmatic drugs. The poor response towards anti-asthmatic drugs may be due to the anti-asthmatics approach only that ignores the anti-obesity target. So, aiming only at the conventional anti-asthmatic targets in obese-asthmatics may prove to be futile until and unless treatment is directed towards ameliorating obesity pathogenesis for a holistic approach towards amelioration of obesity-associated asthma. Herbal medicines for obesity as well as obesity-associated comorbidities are fast becoming safer and more effective alternatives to conventional drugs due to their multitargeted approach with fewer adverse effects. Although, herbal medicines are widely used for obesity-associated comorbidities, however, a limited number of herbal medicines have been scientifically validated and reported against obesity-associated asthma. Notable among them are quercetin, curcumin, geraniol, resveratrol, β-Caryophyllene, celastrol, tomatidine to name a few. In view of this, there is a dire need for a comprehensive review that may summarize the role of bioactive phytoconstituents from different sources like plants, marine as well as essential oils in terms of their therapeutic mechanisms. So, this review aims to critically discuss the therapeutic role of herbal medicine in the form of bioactive phytoconstituents against obesity-associated asthma available in the scientific literature to date.
Fenfluramine: a plethora of mechanisms?
Authors: Sourbron Jo , Lagae Lieven
Published: May 2023

Developmental and epileptic encephalopathies are rare, treatment-resistant epilepsies with high seizure burden and non-seizure comorbidities. The antiseizure medication (ASM) fenfluramine is an effective treatment for reducing seizure frequency, ameliorating comorbidities, and potentially reducing risk of sudden unexpected death in epilepsy (SUDEP) in patients with Dravet syndrome and Lennox-Gastaut syndrome, among other rare epilepsies. Fenfluramine has a unique mechanism of action (MOA) among ASMs. Its primary MOA is currently described as dual-action sigma-1 receptor and serotonergic activity; however, other mechanisms may be involved. Here, we conduct an extensive review of the literature to identify all previously described mechanisms for fenfluramine. We also consider how these mechanisms may play a role in the reports of clinical benefit in non-seizure outcomes, including SUDEP and everyday executive function. Our review highlights the importance of serotonin and sigma-1 receptor mechanisms in maintaining a balance between excitatory (glutamatergic) and inhibitory (γ-aminobutyric acid [GABA]-ergic) neural networks, and suggests that these mechanisms may represent primary pharmacological MOAs in seizures, non-seizure comorbidities, and SUDEP. We also describe ancillary roles for GABA neurotransmission, noradrenergic neurotransmission, and the endocrine system (especially such progesterone derivatives as neuroactive steroids). Dopaminergic activity underlies appetite reduction, a common side effect with fenfluramine treatment, but any involvement in seizure reduction remains speculative. Further research is underway to evaluate promising new biological pathways for fenfluramine. A better understanding of the pharmacological mechanisms for fenfluramine in reducing seizure burden and non-seizure comorbidities may allow for rational drug design and/or improved clinical decision-making when prescribing multi-ASM regimens.
An automated method to discover true events and classification of intracellular Ca2+ profiles for endothelium in situ injury assay
Authors: Sánchez-Tecuatl Marcial , Moccia Francesco , Martínez-Carballido Jorge F. , Berra-Romani Roberto
Published: May 2023

Introduction: Endothelial cells (ECs), being located at the interface between flowing blood and vessel wall, maintain cardiovascular homeostasis by virtue of their ability to integrate chemical and physical cues through a spatio-temporally coordinated increase in their intracellular Ca2+ concentration ([Ca2+]i). Endothelial heterogeneity suggests the existence of spatially distributed functional clusters of ECs that display different patterns of intracellular Ca2+ response to extracellular inputs. Characterizing the overall Ca2+ activity of the endothelial monolayer in situ requires the meticulous analysis of hundreds of ECs. This complex analysis consists in detecting and quantifying the true Ca2+ events associated to extracellular stimulation and classifying their intracellular Ca2+ profiles (ICPs). The injury assay technique allows exploring the Ca2+-dependent molecular mechanisms involved in angiogenesis and endothelial regeneration. However, there are true Ca2+ events of nearly undetectable magnitude that are almost comparable with inherent instrumental noise. Moreover, undesirable artifacts added to the signal by mechanical injury stimulation complicate the analysis of intracellular Ca2+ activity. In general, the study of ICPs lacks uniform criteria and reliable approaches for assessing these highly heterogeneous spatial and temporal events.

Methods: Herein, we present an approach to classify ICPs that consists in three stages: 1) identification of Ca2+ candidate events through thresholding of a feature termed left-prominence; 2) identification of non-true events, known as artifacts; and 3) ICP classification based upon event temporal location.

Results: The performance assessment of true-events identification showed competitive sensitivity = [0.9995, 0.9831], specificity = [0.9946, 0.7818] and accuracy = [0.9978, 0.9579] improvements of 2x and 14x, respectively, compared with other methods. The ICP classifier enhanced by artifact detection showed 0.9252 average accuracy with the ground-truth sets provided for validation.

Discussion: Results indicate that our approach ensures sturdiness to experimental protocol maneuvers, besides it is effective, simple, and configurable for different studies that use unidimensional time dependent signals as data. Furthermore, our approach would also be effective to analyze the ICPs generated by other cell types, other dyes, chemical stimulation or even signals recorded at higher frequency.
Canonical Wnt signaling is not required for Tgfb3 expression in the basal medial edge epithelium during palatogenesis
Authors: Saroya Ghazi-Abdullah , Siismets Erica , Hu Max , Panaretos Christopher , Rice Adam , Reynolds Kurt , Zhou Chengji J. , Kaartinen Vesa
Published: May 2023

The secondary palate forms from two lateral primordia called the palatal shelves which form a contact in the midline, become adherent at the fusing interface (medial edge epithelia, MEE) and subsequently fuse. The gene encoding transforming growth factor-ß3 (Tgfb3) is strongly and specifically expressed in MEE cells. Our previous study suggested that Tgfb3 expression is controlled via upstream cis-regulatory elements in and around the neighboring Ift43 gene. Another study suggested that the canonical Wnt signaling via ß-Catenin is responsible for the MEE-specific Tgfb3 gene expression, since deletion of the Ctnnb1 gene by a commonly used Keratin 14-Cre (K14Cre) mouse line almost completely abolished Tgfb3 expression in the MEE resulting in cleft palate. Here, we wanted to analyze whether Tcf/Lef consensus binding sites located in the previously identified regions of the Ift43 gene are responsible for the spatiotemporal control of Tgfb3 expression during palatogenesis. We show that contrary to the previous report, deletion of the Ctnnb1 gene in basal MEE cells by the K14Cre driver (the same K14Cre mouse line was used as in the previous study referenced above) does not affect the MEE-specific Tgfb3 expression or TGFß3-dependent palatal epithelial fusion. All mutant embryos showed a lack of palatal rugae accompanied by other craniofacial defects, e.g., a narrow snout and a small upper lip, while only a small subset (<5%) of Ctnnb1 mutants displayed a cleft palate. Moreover, the K14Cre:Ctnnb1 embryos showed reduced levels and altered patterns of Shh expression. Our present data imply that epithelial ß-catenin may not be required for MEE-specific Tgfb3 expression or palatal epithelial fusion.
Transcriptome profiling of high and low somatic embryogenesis rate of oil palm (Elaeis guineensis Jacq. var. Tenera)
Authors: Sahara Asri , Roberdi Roberdi , Wiendi Ni Made Armini , Liwang Tony
Published: May 2023

Oil palm micropropagation through tissue culture is a technique to provide elite oil palms to meet the desired traits. This technique is commonly carried out through somatic embryogenesis. However, the oil palm’s somatic embryogenesis rate is quite low. Several approaches have been made to overcome this problem, including transcriptome profiling through RNA-seq to identify key genes involved in oil palm somatic embryogenesis. RNA sequencing was applied in high- and low-embryogenic ortets of Tenera varieties based on the somatic embryoid rate at the callus, globular, scutellar, and coleoptilar embryoid stages. Cellular analysis of embryoid inductions and proliferations showed that high-embryogenic ortets resulted in higher embryoid proliferation and germinations than low-embryogenic ortets. Transcriptome profiling showed that there are a total of 1,911 differentially expressed genes (DEGs) between high- and low-embryogenic ortets. ABA signaling-related genes such as LEA, DDX28, and vicilin-like protein are upregulated in high-embryogenic ortets. Furthermore, DEGs associated with other hormone signaling, such as HD-ZIP associated with brassinosteroids and NPF associated with auxin, are upregulated in high-embryogenic ortets. This result suggests a physiological difference between high- and low-embryogenic ortets that is connected to their capacity for somatic embryogenesis. These DEGs will be used as potential biomarkers for high-embryogenic ortets and will be validated in further studies.
The Bro1-like domain-containing protein, AtBro1, modulates growth and abiotic stress responses in Arabidopsis
Authors: Mehdi Syed Muhammad Muntazir , Szczesniak Michal Wojciech , Ludwików Agnieszka
Published: May 2023

Abscisic acid (ABA) affects plant physiology by altering gene expression, enabling plants to adapt to a wide range of environments. Plants have evolved protective mechanisms to allow seed germination in harsh conditions. Here, we explore a subset of these mechanisms involving the AtBro1 gene, which encodes one of a small family of poorly characterised Bro1-like domain-containing proteins, in Arabidopsis thaliana plants subjected to multiple abiotic stresses. AtBro1 transcripts were upregulated by salt, ABA and mannitol stress, while AtBro1-overexpression lines demonstrated robust tolerance to drought and salt stress. Furthermore, we found that ABA elicits stress-resistance responses in loss-of-function bro1-1 mutant plants and AtBro1 regulates drought resistance in Arabidopsis. When the AtBro1 promoter was fused to the β-glucuronidase (GUS) gene and introduced into plants, GUS was expressed mainly in rosette leaves and floral clusters, especially in anthers. Using a construct expressing an AtBro1-GFP fusion protein, AtBro1 was found to be localized in the plasma membrane in Arabidopsis protoplasts. A broad RNA-sequencing analysis revealed specific quantitative differences in the early transcriptional responses to ABA treatment between wild-type and loss-of-function bro1-1 mutant plants, suggesting that ABA stimulates stress-resistance responses via AtBro1. Additionally, transcripts levels of MOP9.5, MRD1, HEI10, and MIOX4 were altered in bro1-1 plants exposed to different stress conditions. Collectively, our results show that AtBro1 plays a significant role in the regulation of the plant transcriptional response to ABA and the induction of resistance responses to abiotic stress.
Distinguishing features of Lycium L. species (family Solanaceae) distributed in Egypt based on their anatomical, metabolic, molecular, and ecological characteristics
Authors: Ragab Osama G. , Mamdouh Diaa , Bedair Ramadan , Smetanska Iryna , Gruda Nazim S. , Yousif Sawsan K. M. , Omer Rihab M. , Althobaiti Ashwaq T. , Abd El-Raouf Hany S. , El-Taher Ahmed M. , El-Sayed Ashraf S. , Eldemerdash Marwa M.
Published: May 2023

Among the 70–80 species of the genus Lycium (family Solanaceae) disjunctly distributed around the world, only three are frequently distributed in different locations in Egypt. Due to the morphological similarities between these three species, there is a need for alternative tools to distinguish them. Thus, the objective of this study was to revise the taxonomic features of Lycium europaeum L., Lycium shawii Roem. & Schult., and Lycium schweinfurthii var. aschersonii (Dammer) Feinbrun in consideration of their anatomical, metabolic, molecular, and ecological characteristics. In addition to analysis of their anatomical and ecological features, DNA barcoding was performed for molecular characterization through internal transcribed spacer (ITS) sequencing and start codon targeted (SCoT) markers. Furthermore, metabolic profiling of the studied species was conducted based on gas chromatography–mass spectrometry (GC-MS). The observed anatomical features of the adaxial and abaxial epidermal layers, type of mesophyll, crystals, number of palisade and spongy layers, and the vascular system showed variations between the studied species. Beyond this, the anatomy of the leaves showed an isobilateral structure in the studied species, without distinct differences. Species were molecularly identified in terms of ITS sequences and SCoT markers. The ITS sequences were deposited in GenBank with accession numbers ON149839.1, OP597546.1, and ON521125.1 for L. europaeum L., L. shawii, and L. schweinfurthii var. aschersonii, respectively. The sequences showed variations in GC content between the studied species; this was 63.6% in L. europaeum, 61.53% in L. shawii, and 63.55% in L. schweinfurthii var. aschersonii. A total of 62 amplified fragments, including 44 polymorphic fragments with a ratio of 70.97%, were obtained in the SCoT analysis, as well as unique amplicons in L. europaeum L., shawii, and L. schweinfurthii var. aschersonii of 5, 11, and 4 fragments, respectively. Through GC-MS profiling, 38 compounds were identified with clear fluctuations in the extracts of each species. Of these, 23 were distinguishing chemicals that could help in chemical identification of the extracts of the studied species. The present study succeeds in identifying alternative clear and diverse characteristics that can be used to distinguish between L. europaeum, L. shawii, and L. schweinfurthii var. aschersonii.
Brand Love: Role of Online Customer Experience, Value Co-creation, and Relationship Quality
Authors: Mustafa Khurram , Ahmad Farooq , Qaisar Muhammad Nawaz , Zada Shagufta , Jamil Saqib , Anwer Naveed , Khawaja Kausar Fiaz , Vega-Muñoz Alejandro , Contreras-Barraza Nicolás , Hamid Syed Ali Raza , Mariam Shahida
Published: May 2023

Customer experience is a source of retailers’ long-term competitive advantage. This study has examined the relationship between online customer experience and brand love through the mechanism of relationship quality in the context of online shopping in Pakistan. The moderating effect of value co-creation on the relationship of online customer experience with relationship quality and brand love has also been examined. Data were collected from a purposive sampling of 189 online customers in an online survey. Results showed that online customer experience significantly impacts customer relationship quality, which leads to brand love. The relationship between online customer experience and relationship quality is found more robust at high levels of value co-creation. However, we observed a significant negative moderating effect of value co-creation on the direct relationship between online customer experience and brand love. It suggests that including customers in the value co-creation process and affording them a pleasurable online shopping experience may be an excellent way to enhance customer relationship quality and brand love. Theoretical and practical implications of these findings are discussed.