bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of behavioral, neuroinflammatory, and histological responses in a model of rat repetitive mild fluid percussion injury at 2 weeks post-injury
Authors: Fronczak Katherine M. , Roberts Andrea , Svirsky Sarah , Parry Madison , Holets Erik , Henchir Jeremy , Dixon C. Edward , Carlson Shaun W.
Published: October 2022

Repetitive mild traumatic brain injury (rmTBI) is a prominent public health concern, with linkage to debilitating chronic sequelae. Developing reliable and well-characterized preclinical models of rmTBI is imperative in the investigation of the underlying pathophysiological mechanisms, as models can have varying parameters, affecting the overall pathology of the resulting injury. The lateral fluid percussion injury (FPI) model is a reliable and frequently used method of TBI replication in rodent subjects, though it is currently relatively underutilized in rmTBI research. In this study, we have performed a novel description of a variation of the lateral repetitive mild FPI (rmFPI) model, showing the graded acute behavioral impairment and histopathology occurring in response to one, two or four mild FPI (1.25 atm) or sham surgeries, implemented 24h apart. Beam walking performance revealed significant motor impairment in injured animals, with dysfunction increasing with additional injury. Based upon behavioral responses and histological observations, we further investigated the subacute pathophysiological outcomes of the dual FPI (dFPI). Immunoreactivity assessments showed that dFPI led to regionally-specific reductions in the post-synaptic protein neurogranin and increased subcortical white matter staining of the presynaptic protein synaptophysin at 2 weeks following dFPI. Immunohistochemical assessments of the microglial marker Iba-1 showed a striking increase in in several brain regions, and assessment of the astrocytic marker GFAP showed significantly increased immunoreactivity in the subcortical white matter and thalamus. With this study, we have provided a novel account of the subacute post injury outcomes occurring in response to a rmFPI utilizing these injury and frequency parameters, and thereby also demonstrating the reliability of the lateral FPI model in rmTBI replication.
The impact of emotional context on neural substrates of respiratory sensory gating
Authors: Chan Pei-Ying S. , Chang Wen-Pin , Cheng Chia-Hsiung , Liu Chia-Yih , von Leupoldt Andreas , Hsu Ai-Ling , Wu Changwei W.
Published: October 2022

Psychological challenges have been found to impact respiratory symptom perception in healthy individuals as well as in patients with various neurological disorders. Human respiratory sensory gating is an objective measure to examine respiratory sensory information processing of repetitive respiratory mechanical stimuli in the central nervous system. With this electrophysiological method, patients with higher anxiety levels showed reduced respiratory sensory gating function in the cortex, and increased symptom perception. In addition, positive emotional contexts were found to increase the respiratory sensory gating function using RREPs. However, neural substrates related to emotional impacts on respiratory sensory gating remain still unclear. In the present study, we examined the emotion processing of respiratory sensory gating using functional magnetic resonance imaging. We hypothesized that positive compared with neutral stimuli would result in reduced brain activations in cortical areas with the paired occlusion paradigm. Thirty-five healthy adults participated in this event-designed fMRI experiment. Paired inspiratory occlusions (two transient occlusions with a 500 ms inter-stimulus-interval are delivered during one inspiration) were provided using an external trigger outside of the scanner. At least 40 paired inspiratory occlusions were collected for each trial. The experiment contained three runs during which participants underwent 12 min for the paired inspiratory occlusion paradigm while watching a fixation cross (the control condition), neutral and positive emotional picture series. The order of emotional picture series was randomized across the participants. Our results revealed an overall trend of reduction of brain activity from the neutral (minus fixation) condition, to the pleasant (minus fixation) condition. For bilateral thalamus and primary visual cortices, there was no significant difference in neural activation between the two contrasts of pleasant (ContrastP–F) and neutral condition (ContrastN–F). The activation of the mid-cingulate and the orbitofrontal cortex was lower in ContrastP–F compared to ContrastN–F. In conclusion, our results suggest that emotional context, especially positive valence, modulates neural correlates in middle cingulate cortex and orbitofrontal cortex in terms of respiratory sensory gating. Future studies are recommended to test emotional impacts on respiratory sensations in patients with neurological disorders.
Therapeutic applications and potential mechanisms of acupuncture in migraine: A literature review and perspectives
Authors: Chen Ying , Liu Yuhan , Song Yine , Zhao Shaoru , Li Bin , Sun Jingqing , Liu Lu
Published: October 2022

Acupuncture is commonly used as a treatment for migraines. Animal studies have suggested that acupuncture can decrease neuropeptides, immune cells, and proinflammatory and excitatory neurotransmitters, which are associated with the pathogenesis of neuroinflammation. In addition, acupuncture participates in the development of peripheral and central sensitization through modulation of the release of neuronal-sensitization-related mediators (brain-derived neurotrophic factor, glutamate), endocannabinoid system, and serotonin system activation. Clinical studies have demonstrated that acupuncture may be a beneficial migraine treatment, particularly in decreasing pain intensity, duration, emotional comorbidity, and days of acute medication intake. However, specific clinical effectiveness has not been substantiated, and the mechanisms underlying its efficacy remain obscure. With the development of biomedical and neuroimaging techniques, the neural mechanism of acupuncture in migraine has gained increasing attention. Neuroimaging studies have indicated that acupuncture may alter the abnormal functional activity and connectivity of the descending pain modulatory system, default mode network, thalamus, frontal-parietal network, occipital-temporal network, and cerebellum. Acupuncture may reduce neuroinflammation, regulate peripheral and central sensitization, and normalize abnormal brain activity, thereby preventing pain signal transmission. To summarize the effects and neural mechanisms of acupuncture in migraine, we performed a systematic review of literature about migraine and acupuncture. We summarized the characteristics of current clinical studies, including the types of participants, study designs, and clinical outcomes. The published findings from basic neuroimaging studies support the hypothesis that acupuncture alters abnormal neuroplasticity and brain activity. The benefits of acupuncture require further investigation through basic and clinical studies.
New insights in addressing cerebral small vessel disease: Associated with extracellular fluid in white matter
Authors: Lan Haiyuan , Lei Xinjun , Xu Zhihua , Chen Songkuan , Gong Wanfeng , Cai Yunqi
Published: October 2022

Objective

To explore the role of extracellular fluid, assessed by diffusion tensor imaging (DTI) metrics of free water (FW), in the white matter of patients with cerebral small vessel disease (CSVD).

Materials and methods

The baseline clinical and imaging data of 129 patients with CSVD were collected and reviewed. CSVD MR markers, including periventricular white matter hyperintensity (PWMH), deep white matter hyperintensity (DWMH), cerebral microbleed (CMB), enlarged perivascular space (PVS), and lacunar infarction (LI), were identified, and CSVD burden was calculated. According to total CSVD MR marker score, cases were classified as mild, moderate, or severe. The mean FW and fractional anisotropy (FA) values were calculated using DTI images.

Results

The mean white matter FW was associated with the CSVD MR markers, including PWMH, DWMH, LI and PVS (P < 0.05). Moreover, age, hypertension, diabetes mellitus, and FW value were associated with total CSVD MR marker score (P < 0.05). Ordinal logistic regression analysis revealed that FW and age were independently associated with CSVD burden (P < 0.05). Finally, FW in white matter was associated with FA (r = –0.334, P < 0.001).

Conclusion

Extracellular fluid changes, assessed by DTI metrics of FW in white matter, were associated with CSVD markers and burden. An increased extracellular fluid volume in the white matter was associated with lower FA.
Structural consequences of sequence variation in mammalian prion β2α2 loop segments
Authors: Glynn Calina , Hernandez Evelyn , Gallagher-Jones Marcus , Miao Jennifer , Sigurdson Christina J. , Rodriguez Jose A.
Published: October 2022

Sequence variation in the β2α2 loop, residues 165-175 of the mammalian prion protein (PrP), influences its structure. To better understand the consequences of sequence variation in this region of the protein, we biochemically and biophysically interrogate natural and artificial sequence variants of the β2α2 loop of mammalian PrP. Using microcrystal electron diffraction (MicroED), we determine atomic resolution structures of segments encompassing residues 168-176 from the β2α2 loop of PrP with sequences corresponding to human, mouse/cow, bank vole/hamster, rabbit/pig/guinea pig, and naked mole rat (elk-T174S) β2α2 loops, as well as synthetic β2α2 loop sequences. This collection of structures presents two dominant amyloid packing polymorphisms. In the first polymorph, denoted “clasped”, side chains within a sheet form polar clasps by facing each other on the same strand, exemplified by the mouse/cow, human, and bank vole/hamster sequences. Because its stability is derived from within a strand and through polar ladders within a sheet, the sequence requirements for the mating strand are less restrictive. A second polymorph, denoted “interdigitated,” has sidechains interdigitate across mating sheets, exemplified by the elk, naked mole rat (elk T174S), and rabbit sequences. The two types of packing present distinct networks of stabilizing hydrogen bonds. The identity of residue 174 appears to strongly influence the packing adopted in these peptides, but consideration of the overall sequence of a given segment is needed to understand the stability of its assemblies. Incorporation of these β2α2 loop sequences into an 85 residue recombinant segment encoding wild-type bank vole PrP94–178 demonstrates that even single residue substitutions could impact fibril morphology as evaluated by negative stain electron microscopy. This is in line with recent findings supporting the accessibility of different structural geometries by varied mammalian prion sequences, and indicates that sequence-specific polymorphisms may be influenced by residues in the β2α2 loop.
Parkinson’s disease deficits in time perception to auditory as well as visual stimuli – A large online study
Authors: Su Zi H. , Patel Salil , Bredemeyer Oliver , FitzGerald James J. , Antoniades Chrystalina A.
Published: October 2022

Cognitive deficits are common in Parkinson’s disease (PD) and range from mild cognitive impairment to dementia, often dramatically reducing quality of life. Physiological models have shown that attention and memory are predicated on the brain’s ability to process time. Perception has been shown to be increased or decreased by activation or deactivation of dopaminergic neurons respectively. Here we investigate differences in time perception between patients with PD and healthy controls. We have measured differences in sub-second- and second-time intervals. Sensitivity and error in perception as well as the response times are calculated. Additionally, we investigated intra-individual response variability and the effect of participant devices on both reaction time and sensitivity. Patients with PD have impaired sensitivity in discriminating between durations of both visual and auditory stimuli compared to healthy controls. Though initially designed as an in-person study, because of the pandemic the experiment was adapted into an online study. This adaptation provided a unique opportunity to enroll a larger number of international participants and use this study to evaluate the feasibility of future virtual studies focused on cognitive impairment. To our knowledge this is the only time perception study, focusing on PD, which measures the differences in perception using both auditory and visual stimuli. The cohort involved is the largest to date, comprising over 800 participants.
Effects of various degrees of esterification on antioxidant and immunostimulatory activities of okra pectic-polysaccharides
Authors: Li Wei , Li Jie , Wang Jin , He Yuan , Hu Yi-Chen , Wu Ding-Tao , Zou Liang
Published: October 2022

Pectic-polysaccharides are considered as one of the most abundant bioactive components in okra, which possess various promising health-promoting effects. However, the knowledge regarding the structure-bioactivity relationship of okra pectic-polysaccharides (OPP) is still limited. In this study, effects of various degrees of esterification (DEs) on in vitro antioxidant and immunostimulatory activities of OPP were analyzed. Results displayed that OPP with high (42.13%), middle (25.88%), and low (4.77%) DE values were successfully prepared by mild alkaline de-esterification, and their primary chemical structures (compositional monosaccharide and glycosidic linkage) and molecular characteristics (molecular weight distribution, particle size, and rheological property) were overall stable. Additionally, results showed that the notable decrease of DE value did not significantly affect antioxidant activities [2,2’-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) and nitric oxide (NO) radical scavenging abilities as well as ferric reducing antioxidant power (FRAP)] of OPP, suggesting that the DE was not closely related to its antioxidant activity. In fact, the slight decrease of antioxidant activity of OPP after the alkaline de-esterification might be attributed to the slight decrease of uronic acid content. Nevertheless, the immunostimulatory effect of OPP was closely related to its DE, and a suitable degree of acetylation was beneficial to its in vitro immunostimulatory effect. Besides, the complete de-acetylation resulted in a remarkable reduction of immune response. The findings are beneficial to better understanding the effect of DE value on antioxidant and immunomodulatory activities of OPP, which also provide theoretical foundations for developing OPP as functional foods or health products.
Optimisation of the production of a selenium-enriched polysaccharide from Cordyceps cicadae S1 and its structure and antioxidant activity
Authors: Zhuansun Wanwan , Xu Jun , Liu Hengzhao , Zhao Ying , Chen Lulu , Shan Shufang , Song Shiqin , Zhang Haoyu , Dong Tingting , Zeng Huawei , Xu Qinxiang
Published: October 2022

The fermentation medium of a newly identified Cordyceps cicadae S1 was optimized by response surface methodology, with the optimal medium containing sucrose (80 g/L), yeast powder (60 g/L), KH2PO4 (5 g/L), MgSO4·7H2O (1 g/L) and Na2SeO3 (0. 1 g/L). Under these conditions, the extracellular polysaccharide yield was 8.09 g/L. A novel selenium-enriched polysaccharide (PACI-1) was isolated from Cordyceps cicadae, purified and identified as a homofructose polysaccharide with a low average molecular weight of 9.95 × 103 Da. The fine structure of PACI-1 was analyzed using NMR, CD, and AFM. Additionally, the in vitro antioxidant results showed that the PACI-1 had stronger antioxidant capacity than natural polysaccharides. These results provided a candidate strain for producing selenium polysaccharide and a new polysaccharide from C. cicadae, which showed good antioxidant activity.
Nutritional modulation of the gut microbiome in allogeneic hematopoietic stem cell transplantation recipients
Authors: Muratore Edoardo , Leardini Davide , Baccelli Francesco , Venturelli Francesco , Prete Arcangelo , Masetti Riccardo
Published: October 2022

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative strategy for many oncological and non-oncological diseases, but it is associated with marked morbidity and mortality. The disruption of gut microbiota (GM) eubiosis has been linked to major allo-HSCT complications, including infections and acute graft vs. host disease (aGvHD), and correlates with mortality. This increasing knowledge on the role of the GM in the allo-HSCT procedure has led to fascinating ideas for modulating the intestinal ecosystem in order to improve clinical outcomes. Nutritional strategies, either by changing the route of nutritional supplementation or by administering specific molecules, are increasingly being considered as cost- and risk-effective methods of modulating the GM. Nutritional support has also emerged in the past several years as a key feature in supportive care for allo-HSCT recipients, and deterioration of nutritional status is associated with decreased overall survival and higher complication rates during treatment. Herein we provide a complete overview focused on nutritional modulation of the GM in allo-HSCT recipients. We address how pre transplant diet could affect GM composition and its ability to withstand the upsetting events occurring during transplantation. We also provide a complete overview on the influence of the route of nutritional administration on the intestinal ecosystem, with a particular focus on the comparison between enteral and parenteral nutrition (PN). Moreover, as mounting evidence are showing how specific components of post-transplant diet, such as lactose, could drastically shape the GM, we will also summarize the role of prebiotic supplementation in the modulation of the intestinal flora and in allo-HSCT outcomes.
Safety of third dose of COVID-19 vaccination in frail patients: Results from the prospective Italian VAX4FRAIL study
Authors: Di Cosimo Serena , Lupo-Stanghellini Maria Teresa , Costantini Massimo , Mantegazza Renato , Ciceri Fabio , Salvarani Carlo , Zinzani Pier Luigi , Mantovani Alberto , Ciliberto Gennaro , Uccelli Antonio , Baldanti Fausto , Apolone Giovanni , Delcuratolo Sabina , Morrone Aldo , Locatelli Franco , Agrati Chiara , Silvestris Nicola
Published: October 2022

Importance

Despite people with impaired immune competence due to an underlying disease or ongoing therapy, hereinafter frail patients, are (likely to be) the first to be vaccinated, they were usually excluded from clinical trials.

Objective

To report adverse reactions of frail patients after receipt of the third dose (booster) administered after completion of a two-dose mRNA vaccination and to compare with those reported after the receipt of the first two doses.

Design

A multicenter, observational, prospective study aimed at evaluating both the safety profile and the immune response of Pfizer-BioNTech or Moderna vaccines in frail patients.

Setting

National Project on Vaccines, COVID-19 and Frail Patients (VAX4FRAIL)

Participants

People consenting and included in the VAX4FRAIL trial.

Exposure

A series of three doses of COVID-19 mRNA vaccination from the same manufacturer.

Main outcome(s) and measure(s)

Evaluation of a self-assessment questionnaire addressing a predefined list of eight symptoms on a five-item Likert scale. Symptoms were classified as severe if the patient rated them as severe or overwhelming.

Results

Among 320 VAX4FRAIL participants diagnosed/treated for hematological malignancies (N=105; 32.8%), solid tumors (N=48; 15.0%), immune-rheumatological diseases (N=60; 18.8%), neurological diseases (N=107; 33.4%), and receiving the booster dose, 70.3% reported at least one loco-regional or systemic reactions. Adverse events were mostly mild or moderate, none being life-threatening. Only six of the 320 (1.9%) patients had their treatment postponed due to the vaccine. The safety profile of the booster compared to previously administered two doses showed a stable prevalence of patients with one or more adverse events (73.5%, 79.7% and 73.9% respectively), and a slightly increment of patients with one or more severe adverse events (13.4%, 13.9% and 19.2% respectively).

Conclusions and relevance

The booster of the mRNA COVID-19 vaccine was safely administered in the largest prospective cohort of frail patients reported so far. VAX4FRAIL will continue to monitor the safety of additional vaccine doses, especially systemic adverse events that can be easily prevented to avoid interruption of continuity of care.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT04848493, identifier NCT04848493.
Transarterial chemoembolization plus lenvatinib with or without programmed death-1 inhibitors for patients with unresectable hepatocellular carcinoma: A propensity score matching study
Authors: Guo Peng , Pi Xingtao , Gao Feng , Li Qiang , Li Duqiang , Feng Wendong , Cao Wendong
Published: October 2022

Purpose

We conducted a retrospective study to compare transarterial chemoembolization (TACE) plus lenvatinib plus programmed death-1 (PD-1) inhibitors with TACE plus lenvatinib in patients with unresectable hepatocellular carcinoma (HCC).

Patients and methods

Patients with HCC were analyzed from January 2018 to January 2022 in three hospitals. Patients received TACE plus lenvatinib with or without PD-1 inhibitors (TACE+L+PD-1 or TACE+L, respectively). The baseline characteristics of the two groups were compared, and propensity score matching (PSM) was performed. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) of the two groups were compared. Adverse events in the two groups were analyzed.

Results

A total of 166 patients were evaluated (TACE+L+PD-1, n = 75; TACE+L, n = 91). Before PSM, OS was prolonged in the TACE+L+PD-1 group (p = 0.010), but PFS was similar between the two groups (p = 0.18). ORR was higher in the TACE+L+PD-1 group (p = 0.047). After PSM, estimated OS rates at 6, 12, and 24 months were 97.9%, 84.6%, and 74.1%, respectively, in the TACE+L+PD-1 group (n = 48) and 93.1%, 66.1%, and 43.4%, respectively, in the TACE+L group (n = 48). Estimated PFS rates at 3, 6, and 12 months were 81.9%, 61.8%, and 30.9%, respectively, in the TACE+L group and 95.7%, 82.1%, and 68.4%, respectively, in the TACE+L+PD-1 group. OS, PFS, and ORR were improved in the TACE+L+PD-1 group compared to the TACE+L group (p = 0.030; p = 0.027; p = 0.013). The safety of the TACE+L+PD-1 regimen was acceptable.

Conclusions

The addition of PD-1 inhibitors to TACE+L significantly improved clinical outcomes in patients with unresectable HCC. Side effects were manageable.
The role of TGR5 as an onco-immunological biomarker in tumor staging and prognosis by encompassing the tumor microenvironment
Authors: Guan Zhiyuan , Luo Liying , Liu Shengfu , Guan Zhiqiang , Zhang Qinggang , Wu Zhong , Tao Kun
Published: October 2022

The relationship between G protein–coupled bile acid receptor 1 (TGR5, GPBAR1) and, specifically, cancer has been studied in in vivo and in vitro experiments, but there is still a lack of pan-cancer analysis to understand the prognostic significance and functioning mechanism of TGR5 in different cancer-driving oncogenic processes. Here, we used Gene Expression Integration, Human Protein Atlas, and The Cancer Genome Atlas (TCGA) to perform a pan-cancer analysis of the role of TGR5 in all 33 tumors. In all TCGA tumors, the TGR5 gene expression has been assessed, and we found that the high TGR5 gene expression in most cancers is associated with poor prognosis of overall survival for cancers such as glioblastoma multiforme (p = 0.0048), kidney renal papillary cell carcinoma (p = 0.033), lower grade glioma (p = 0.0028), thymoma (p = 0.048), and uveal melanoma (p = 0.004), and then the lower expression of TGR5 was linked with poor prognosis in cervical squamous cell carcinoma and endocervical adenocarcinoma (p = 0.014), malignant mesothelioma (MESO) (p = 0.048), sarcoma (p = 0.018), and skin cutaneous melanoma (p = 0.0085). The TGR5 expression was linked with the immune infiltration level of the macrophage M2_TIDE and was also associated with DNA methylation in ovarian and breast cancers. The regulation of hormone secretion, Rap1 pathway, osteoclast differentiation, and bile acid pathway was involved in the functional mechanism of TGR5. Besides, gene expressions were different in different tumors detected by RT-PCR, and cell activity experiments have also found that TGR5 can increase the activity of renal cell carcinoma and reduce the activity of skin cancer and osteosarcoma cells. In this investigation, the aim was to assess the comprehensive overview of the oncogenic roles of TGR5 in all TCGA tumors using pan-analysis.
Preliminary study on the molecular features of mutation in multiple primary oral cancer by whole exome sequencing
Authors: Li Kan , Gong Jianbin , Zheng Qiuhan , Yang Le , Mei Xueying , Chen Jianghai , Liao Guiqing , Liang Yujie
Published: October 2022

Multiple primary cancers (MPCs) refer to cancers that occur simultaneously or metachronously in the same individual. The incidence of MPC has increased recently, as the survival time of malignant tumor patients has been greatly prolonged. It is difficult to differentiate MPC from primary cancers (PCs) in the same anatomical region from the clinical manifestation alone. However, their biological behaviors appear to be distinct. In this study, we show that the prognosis of multiple primary oral cancers (MP-OCs) is worse than primary oral cancers (P-OCs). To better understand the molecular mechanisms of MP-OC, we used whole exome sequencing (WES) to analyze samples from 9 patients with MP-OC and 21 patients with P-OC. We found more somatic mutations in MP-OC than in P-OC. MP-OC had more complicated mutation signatures, which were associated with age-related and Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) activity-related signatures. Tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH) of MP-OC trended higher compared to P-OC. KEGG and GO analysis showed the differential pathways of MP-OC versus P-OC. In addition, MP-OC took amplification, not loss, as the main pattern of copy number variation (CNV), while P-OC took both. Lastly, we did not find significantly different mutant germline genes, but MSH-6 mutation may be a potential MP-OC driver. In short, our preliminary results show that MP-OC and P-OC have different molecular characteristics.
Case Report: Novel JAG1 gene mutations in two infants with alagille syndrome characterized by cholestasis
Authors: Han Yijiang , Zhu Kun , Wu Hao , Chen Baohai , Hu Shuqi , Lai Dengming , Tou Jinfa
Published: October 2022

Background

Infants with Alagille syndrome (ALGS) need to be promptly differentiated from biliary atresia (BA) at an early stage. ALGS is an autosomal, dominant, multisystem disorder with variable phenotypic penetrance caused by heterozygous mutations in JAG1 or NOTCH2, which encode the Notch signaling pathway.

Case presentation

We report two cases, both with cholestatic jaundice as the main manifestation, in which BA was excluded and finally diagnosed as ALGS based on characteristic facial features, serological tests, imaging, laparoscopic cholangiography, pathology and genetic findings. Both cases are novel mutant genes on chromosome 20 that have not been reported in the literature. The mutation in patient 1 was a novel heterozygous nonsense mutation (NM_000214 exon20, c.2419G > T, p.E807Ter), which was a spontaneous mutation. Followed up to 1 year and 6 months, the symptoms resolved with ursodeoxycholic acid and cholestyramine, and the jaundice has now subsided. Patient 2 was a novel heterozygous frameshift mutation (NM_000214 exon19, c.2367–2368dupTC, p.P790Lfs*31), which was inherited from his mother. This patient was followed up to 9 months and is currently awaiting liver transplantation.

Conclusion

Both cholestatic infants reported combined to exclude BA, avoid Kasai portoenterostomy (KPE), and definitively diagnose ALGS. Broadening the spectrum of JAG1 gene mutations.
Association of duration and etiology with the effect of the artificial liver support system in pediatric acute liver failure
Authors: Yang Chun-Feng , Liu Jing-Wei , Jin Lin-Mei , Li Yu-Mei
Published: October 2022

Background

We aimed to assess the efficacy of the artificial liver support system (ALSS) in pediatric acute liver failure (PALF) patients and to examine the risk factors associated with the effect of ALSS. Similar data are limited in PALF.

Methods

All patients diagnosed with PALF who received ALSS from June 2011 to June 2021 in the pediatric intensive care unit of the First Hospital of Jilin University were included in this retrospective cohort analysis. The effect of ALSS was measured using difference tests before and after treatments. The risk factors associated with the effect of ALSS were evaluated according to whether the total bilirubin (TBIL) and serum ammonia decreased after ALSS (TBIL-unresponsive group vs. TBIL-responsive group, serum ammonia-unresponsive group vs. serum ammonia-responsive group).

Results

Thirty-nine patients who received ALSS during the study period were eligible for inclusion. The most common cause of PALF was undetermined causes (n = 14, 35.9%) followed by infection (n = 11, 28.2%). Four patients received pediatric liver transplantation. The overall survival rate was 76.9% (30/39). Fifteen (38.4%) patients received only one modality, whereas 61.6% patients received hybrid treatments. The most commonly used modality of ALSS was plasma exchange combined with continuous renal replacement therapy (n = 14, 35.9%). Alanine aminotransferase, TBIL, the international normalized ratio, and serum ammonia were significantly decreased after ALSS (P < 0.001). Compared with other causes, more patients with infection and toxication were observed in the TBIL-unresponsive group. A longer ALSS duration was significantly related to blood ammonia reduction.

Conclusions

ALSS can effectively reduce serum alanine aminotransferase, TBIL, international normalized ratio, and serum ammonia and may reduce mortality. The reduction in TBIL levels after ALSS is dependent on etiology. A longer ALSS duration was associated with blood ammonia reduction. Prospective multicenter studies are needed for further validation.
METTL3/m6A/IFIT2 regulates proliferation, invasion and immunity in esophageal squamous cell carcinoma
Authors: Ge Fangfang , Li Zhenyu , Hu Jiaru , Pu Youguang , Zhao Fangfang , Kong Lingsuo
Published: October 2022

Epigenetic regulation plays a critical role in the development, progression, and treatment of tumors. The most common chemical modification of mRNA, called m6A, is essential for controlling mRNA stability, splicing, and translation. Methyltransferase-like 3 (METTL3) is an important m6A methyltransferase. The mechanism of action of METTL3 in esophageal squamous cell carcinoma (ESCC) remains unclear. In this investigation, we sought to clarify the function and clinical importance of METTL3 in ESCC and investigate its underlying mechanisms. We discovered that METTL3 has a significant proliferative effect in ESCC cells by using lentiviral construction of stable cell lines overexpressing METTL3 (METTL3-OE) and knocking down METTL3 (sh-METTL3). To create a xenograft tumor model, we inoculated KYSE510 cells subcutaneously into BALB/c nude mice and discovered that sh-METTL3 inhibited the tumorigenicity of esophageal cancer KYSE510 cells in the nude mouse tumor model. MeRIP-seq and RNA-seq analysis revealed IFIT2 to be a METTL3 target gene. The findings revealed that METTL3 regulates IFIT2 and thus influences malignant biological behaviors such as proliferation, migration, and invasion of ESCC, as well as the immune microenvironment of tumors.
Therapeutics for fulminant hepatitis caused by enteroviruses in neonates
Authors: Wang Li-Chiu , Tsai Huey-Pin , Chen Shun-Hua , Wang Shih-Min
Published: October 2022

Neonatal infection with nonpolio enteroviruses (EVs) causes nonspecific febrile illnesses and even life-threatening multiorgan failure. Hepatitis, which often results in hepatic necrosis followed by disseminated intravascular coagulopathy, is one of the most severe and frequent fatal neonatal EV infection complications. Coxsackievirus B (CVB) 1–5 and many echoviruses have been most commonly identified. Neonatal EV infection treatment has usually involved initial supportive care. Studies for CVB and echovirus infection treatments were developed for more than thirty years. Intravenous immunoglobulin and pleconaril therapy was performed in some clinical trials. Additionally, other studies demonstrated antiviral and/or anti-inflammatory pathogenesis mechanisms of neonatal EV hepatitis in in vitro or in vivo models. These treatments represented promising options for the clinical practice of neonatal EV hepatitis. However, further investigation is needed to elucidate the whole therapeutic potential and safety problems.
Doxycycline for the treatment of breast cancer-related lymphedema
Authors: Brown Stav , Dayan Joseph H. , Coriddi Michelle , McGrath Leslie , Kataru Raghu P. , Mehrara Babak J.
Published: October 2022

Purpose: Secondary lymphedema is a common complication of cancer treatment for which no effective drug treatments yet exist. Level I clinical data suggests that doxycycline is effective for treating filariasis-induced lymphedema, in which it decreases tissue edema and skin abnormalities; however, this treatment has not been tested for cancer-related lymphedema. Over the past year, we used doxycycline in an off-label manner in patients with breast cancer-related secondary lymphedema. The purpose of this report was to retrospectively analyze the efficacy of this treatment.

Methods: Patients who presented to our lymphedema clinic between January 2021 and January 2022 were evaluated, and barring allergies or contraindications to doxycycline treatment, were counseled on the off-label use of this treatment. Patients who wished to proceed were treated with doxycycline (200 mg given orally once daily) for 6 weeks. After IRB approval of this study, lymphedema outcomes were retrospectively reviewed.

Results: Seventeen patients with a mean follow-up of 17.0 ± 13.2 weeks were identified in our retrospective review. Although doxycycline treatment had no significant effect on relative limb volume change or L-Dex scores, we found a significant improvement in patient-reported quality of life. Analysis of patient responses to the Lymphedema Life Impact Scale showed a significant improvement in the total impairment score due to improvements in the physical and psychological well-being subscales (p = 0.03, p = 0.03, p = 0.04, respectively).

Conclusion: This small, retrospective study did not show significant improvements in limb volume or L-Dex scores in patients with breast cancer-related lymphedema treated with doxycycline. However, our patients reported improvements in quality-of-life measures using a validated lymphedema patient-reported outcome instrument. Our results suggest that doxycycline may be of use in patients with breast cancer-related lymphedema; however, larger and more rigorous studies are needed.
Noncoding RNAs as a novel approach to target retinopathy of prematurity
Authors: Kim Hyunjong , Kim Jaesub , Ryu Juhee
Published: October 2022

Retinopathy of prematurity (ROP), a vascular disease characterized by abnormal vessel development in the retina, has become a primary cause of blindness in children around the world. ROP can be developed during two different phases: vessel loss and vessel proliferation. Once preterm infants with immature retinal vessel growth are exposed to high level of oxygen inside the incubator, vessel loss can occur. When infants are exposed to room air, they may experience the proliferation of vessels in the retina. Although multiple factors are reported to be involved in the pathogenesis of ROP, including vaso-endothelial growth factors (VEGFs) and hypoxia-inducible factors, the pathogenesis of ROP is not completely understood. Although laser therapy and pharmacologic agents, such as anti-VEGF agents, have been commonly used to treat ROP, the incidence of ROP is rapidly rising. Given that current therapies can be invasive and long-term effects are not fully known, the search for novel therapeutic targets with less destructive properties needs to be considered. Within the last decade, the field of noncoding RNA therapy has shown potential as next-generation therapy to treat diverse diseases. In this review, we introduce various noncoding RNAs regulating ROP and discuss their role as potential therapeutic targets in ROP.
Role of matrix metalloproteinases in diabetic foot ulcers: Potential therapeutic targets
Authors: Fu Kang , Zheng Xueyao , Chen Yuhan , Wu Liuying , Yang Zhiming , Chen Xu , Song Wei
Published: October 2022

Diabetic foot ulcers (DFUs) are pathological states of tissue destruction of the foot or lower extremity in diabetic patients and are one of the serious chronic complications of diabetes mellitus. Matrix metalloproteinases (MMPs) serve crucial roles in both pathogenesis and wound healing. The primary functions of MMPs are degradation, which involves removing the disrupted extracellular matrix (ECM) during the inflammatory phase, facilitating angiogenesis and cell migration during the proliferation phase, and contracting and rebuilding the tissue during the remodeling phase. Overexpression of MMPs is a feature of DFUs. The upregulated MMPs in DFUs can cause excessive tissue degradation and impaired wound healing. Regulation of MMP levels in wounds could promote wound healing in DFUs. In this review, we talk about the roles of MMPs in DFUs and list potential methods to prevent MMPs from behaving in a manner detrimental to wound healing in DFUs.
A novel method for generating glutamatergic SH-SY5Y neuron-like cells utilizing B-27 supplement
Authors: Martin Emily-Rose , Gandawijaya Josan , Oguro-Ando Asami
Published: October 2022

The human SH-SY5Y neuroblastoma cell line is widely used in neuroscience research as a neuronal cell model. Following differentiation to a neuron-like state, SH-SY5Y cells become more morphologically similar to neurons and form functional synapses. Previous studies have managed to differentiate SH-SY5Y cells towards cholinergic, dopaminergic and adrenergic fates. However, their application in disease modeling remains limited as other neuronal subtypes (e.g., glutamatergic, GABAergic) are also implicated in neurological disorders, and no current protocols exist to generate these subtypes of differentiated SH-SY5Y cells. Our study aimed to evaluate the use of a xeno-free version of B-27, a supplement commonly used in neuronal culture, for SH-SY5Y maintenance and differentiation. To evaluate the proliferative capacity of SH-SY5Y cells cultured in B-27, we performed growth curve analyses, immunocytochemical staining for Ki-67 and qRT-PCR to track changes in cell cycle progression. SH-SY5Y cells cultured in FBS or under serum-starved conditions were used as controls. We observed that SH-SY5Y cells show reduced growth and proliferation rates accompanied by decreased CDK6 and CDK1 expression following 4-day exposure to B-27, suggesting B-27 induces a quiescent state in SH-SY5Y cells. Importantly, this reduced growth rate was not due to increased apoptosis. As cell cycle exit is associated with differentiation, we next sought to determine the fate of SH-SY5Y cells cultured in B-27. B-27-cultured SH-SY5Y cells show changes in cell morphology, adopting pyramidal shapes and extending neurites, and upregulation of neuronal differentiation markers (GAP43, TUBB3, and SYP). B-27-cultured SH-SY5Y cells also show increased expression of glutamatergic markers (GLUL and GLS). These findings suggest that B-27 may be a non-toxic inducer of glutamatergic SH-SY5Y differentiation. Our study demonstrates a novel way of using B-27 to obtain populations of glutamatergic SH-SY5Y cells. As dysregulated glutamatergic signaling is associated with a variety of neuropsychiatric and neurodegenerative disorders, the capability to generate glutamatergic neuron-like SH-SY5Y cells creates endless disease modeling opportunities. The ease of SH-SY5Y culture allows researchers to generate large-scale cultures for high-throughput pharmacological or toxicity studies. Also compatible with the growing popularity of animal-component-free studies, this xeno-free B-27/SH-SY5Y culture system will be a valuable tool to boost the translational potential of preliminary studies requiring glutamatergic neuronal cells of human origin.
Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function
Authors: Yan Yan , Li Ming , Lin Jie , Ji Yanan , Wang Kexin , Yan Dajun , Shen Yuntian , Wang Wei , Huang Zhongwei , Jiang Haiyan , Sun Hualin , Qi Lei
Published: October 2022

Skeletal muscle is one of the largest organs in the body and the largest protein repository. Mitochondria are the main energy-producing organelles in cells and play an important role in skeletal muscle health and function. They participate in several biological processes related to skeletal muscle metabolism, growth, and regeneration. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor and regulator of systemic energy balance. AMPK is involved in the control of energy metabolism by regulating many downstream targets. In this review, we propose that AMPK directly controls several facets of mitochondrial function, which in turn controls skeletal muscle metabolism and health. This review is divided into four parts. First, we summarize the properties of AMPK signal transduction and its upstream activators. Second, we discuss the role of mitochondria in myogenesis, muscle atrophy, regeneration post-injury of skeletal muscle cells. Third, we elaborate the effects of AMPK on mitochondrial biogenesis, fusion, fission and mitochondrial autophagy, and discuss how AMPK regulates the metabolism of skeletal muscle by regulating mitochondrial function. Finally, we discuss the effects of AMPK activators on muscle disease status. This review thus represents a foundation for understanding this biological process of mitochondrial dynamics regulated by AMPK in the metabolism of skeletal muscle. A better understanding of the role of AMPK on mitochondrial dynamic is essential to improve mitochondrial function, and hence promote skeletal muscle health and function.
Time-dependent alteration in the chemoreflex post-acute lung injury
Authors: Kamra Kajal , Karpuk Nikolay , Adam Ryan , Zucker Irving H. , Schultz Harold D. , Wang Han-Jun
Published: October 2022

Acute lung injury (ALI) induces inflammation that disrupts the normal alveolar-capillary endothelial barrier which impairs gas exchange to induce hypoxemia that reflexively increases respiration. The neural mechanisms underlying the respiratory dysfunction during ALI are not fully understood. The purpose of this study was to investigate the role of the chemoreflex in mediating abnormal ventilation during acute (early) and recovery (late) stages of ALI. We hypothesized that the increase in respiratory rate (fR) during post-ALI is mediated by a sensitized chemoreflex. ALI was induced in male Sprague-Dawley rats using a single intra-tracheal injection of bleomycin (Bleo: low-dose = 1.25 mg/Kg or high-dose = 2.5 mg/Kg) (day 1) and respiratory variables- fR, Vt (Tidal Volume), and VE (Minute Ventilation) in response to 10% hypoxia (10% O2, 0% CO2) and 5% hypercapnia/21% normoxia (21% O2, 5% CO2) were measured weekly from W0-W4 using whole-body plethysmography (WBP). Our data indicate sensitization (∆fR = 93 ± 31 bpm, p < 0.0001) of the chemoreflex at W1 post-ALI in response to hypoxic/hypercapnic gas challenge in the low-dose bleo (moderate ALI) group and a blunted chemoreflex (∆fR = −0.97 ± 42 bpm, p < 0.0001) at W1 post-ALI in the high-dose bleo (severe ALI) group. During recovery from ALI, at W3-W4, both low-dose and high-dose groups exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia. We then hypothesized that the blunted chemoreflex at W1 post-ALI in the high-dose bleo group could be due to near maximal tonic activation of chemoreceptors, called the “ceiling effect”. To test this possibility, 90% hyperoxia (90% O2, 0% CO2) was given to bleo treated rats to inhibit the chemoreflex. Our results showed no changes in fR, suggesting absence of the tonic chemoreflex activation in response to hypoxia at W1 post-ALI. These data suggest that during the acute stage of moderate (low-dose bleo) and severe (high-dose bleo) ALI, chemoreflex activity trends to be slightly sensitized and blunted, respectively while it becomes significantly sensitized during the recovery stage. Future studies are required to examine the molecular/cellular mechanisms underlying the time-course changes in chemoreflex sensitivity post-ALI.
An inducible gene from glycoside hydrolase one family of Plutella xylostella decreases larval survival when feeding on host plant
Authors: Chen Wei , Dong Yuhong , Zheng Ling , Lai Yingfang , Li Feifei , Zhou Li , Wang Beibei , You Minsheng , He Weiyi
Published: October 2022

Glycoside hydrolase family 1 (GH1) members exhibit a broad substrate spectrum and play important roles in insect-plant interactions, such as the defensive β-glucosidase and β-thioglucosidase (so-called myrosinase). However, knowledge about the expression profiling and function of glycoside hydrolase family 1 members in a specialist pest of crucifers Plutella xylostella is still limited. In this study, 13 putative glycoside hydrolase family 1 members of P. xylostella were identified based on the sequence characteristics, while no myrosinase activity was detectable in P. xylostella using gas chromatography-mass spectrometry (GC-MS). Expression profiling of these glycoside hydrolase family 1 members identified the midgut-specific gene Px008848 that is induced by host plant. Further experiments revealed that the in vitro expressed Px008848 protein had β-glucosidase activity and the survival rate of the larvae feeding on wounded Arabidopsis thaliana leaves declined when leaves were treated with purified Px008848 protein. When CRISPR/Cas9-based homozygous mutant larvae of Px008848 and wild-type larvae were respectively transferred onto the A. thaliana, the larval survival rate of the mutant larvae was significantly higher than that of the wild-type individuals. Our work showed that certain insect glycoside hydrolase family 1 gene may have negative effect on the development of larvae feeding on the host plant, which broadened our understandings on the evolutionary function of this gene family in the insect-plant interaction.
Functional significance of ion channels during macropinosome resolution in immune cells
Authors: Maekawa Masashi , Natsume Ren , Arita Makoto
Published: October 2022

Macropinocytosis is a unique type of endocytosis accompanied by membrane ruffle formation. Closure of membrane ruffles leads to the uptake of large volumes of fluid phase and, subsequently, the formation of large vacuoles termed macropinosomes. Immune cells, such as dendritic cells, T cells, and macrophages, endocytose the surrounding amino acids and pathogens via macropinocytosis either constitutively or in a stimulus-dependent fashion. This process is critical for cell migration, mammalian target of rapamycin complex 1 (mTORC1) activation, and antigen presentation. Large vacuoles are fragmented into tubules and smaller vesicles during the progression and maturation of macropinosomes in immune cells. This process is called “macropinosome resolution” and requires osmotically driven shrinkage of macropinosomes, which is controlled by ion channels present in them. The crenation of membranes on shrunken macropinosomes is recognized by curvature-sensing proteins and results in intracellular membrane trafficking. In this mini review, we highlight the recent progress in research on macropinosome resolution in macrophages, with a focus on ion channels (TPC1/2 for Na+ and TMEM206 for Cl−) that is required for macropinosome resolution. We also discuss the potential contribution of membrane lipids to this process.