bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples
Authors: St-Pierre Marie-Kim , Carrier Micaël , González Ibáñez Fernando , Šimončičová Eva , Wallman Marie-Josée , Vallières Luc , Parent Martin , Tremblay Marie-Ève
Published: September 2022

A diverse heterogeneity of microglial cells was previously described in Alzheimer’s disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1stratum lacunosum-moleculareof 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aβ) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aβ plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.
The reference ranges and characteristics of lymphocyte parameters and the correlation between lymphocyte parameters and routine health indicators in adults from China
Authors: Liu Wei , Xu Jie , Pu Qiyao , Lan Mingwei , Zhang Xiaolu , Gu Yufeng , Wang Ying , Zheng Fan , Qian Jingjing , Fan Chunxue , Sui Jun , Xu Yanli , Zhang Yongchen , Luo Jing , Lin Xiangyang , Shi Shaorui , Wang Liying , Sun Chengming , Zhou Maohua , Yue Baohong , Wang Feng
Published: September 2022

Background

Assessment of immune function is of key importance in recognition of disease or healthy status, which still faces challenge in clinical practice. We conducted a 10-center study to investigate lymphocyte parameters including the number, phenotype and IFN-γ-producing ability, and routine laboratory indicators by using the standard method.

Results

Although the heterogeneity of lymphocyte parameters was widely found, we have established the normal ranges of these parameters by using pooled data which showed no significant difference among centers. Cluster analysis of 35 parameters found 3 interesting clusters which represented different immunological status. Cluster 1 (parameters: IFN-γ+CD4+T cell percentage and IFN-γ+CD8+T cell percentage) represented current lymphocyte function, which was associated with indicators such as body mass index and red blood cell; Cluster 2 (parameters: NK cell number and CD45RA+CD4+T cell percentage) represented potential of lymphocytes, which was associated with indicators such as albumin and high-density lipoprotein. Cluster 3 (parameters: HLA-DR+CD8+T cell percentage) represented inflammatory status, which was associated with indicators such as low-density lipoprotein, globulin and age. Correlation analysis found that nutritional indicator albumin is significantly positively correlated with lymphocyte potential. Triglyceride and body mass index were positively correlated with current lymphocyte function rather than lymphocyte potential. The loss of CD8+T cells was extremely pronounced with increasing age and was one of the most important factors to cause immunosenescence, which may be associated with increased glucose.

Conclusions

We have established the normal ranges of lymphocyte parameters in different areas. This study elucidates the key indicators used to reflect the current function or potential of lymphocytes, which may provide a valuable clue for how to keep immunity healthy.
Antimicrobial treatment improves tryptophan metabolism and mood of patients with small intestinal bacterial overgrowth
Authors: Chojnacki Cezary , Popławski Tomasz , Konrad Paulina , Fila Michał , Błasiak Janusz , Chojnacki Jan
Published: September 2022

Background

Optimal composition of intestinal bacteria is an essential condition for good health. Excessive growth of these bacteria can cause various ailments. The aim of this study was to assess the mental state and gastrointestinal complaints of patients with small intestinal bacterial overgrowth (SIBO) in relation to tryptophan metabolism and rifaximin treatment.

Methods

120 subjects, aged 23–61 years, were enrolled in the study, and divided into 3 groups, 40 individuals each: healthy subjects (Controls), patients with SIBO and chronic diarrhea (SIBO-D), and with chronic constipation (SIBO-C). The lactulose hydrogen breath test (LHBT) was performed to diagnose SIBO. The mental state of patients was assessed using the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D). L-tryptophan (TRP) and its metabolites: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), xanthurenic acid (XA) and quinolinic acid (QA) were measured in urine by liquid-chromatography-tandem mass spectrometry and related to creatinine level. Patients with SIBO were recommended to take rifaximin for 10 days at daily dose 1200 mg, and this cycle was repeated in subsequent two months.

Results

Mild and moderate anxiety, as well as mild depression were diagnosed in all SIBO patients. Changes in TRP metabolism were also observed in these patients. Specifically, an increase in the activity of the serotonin pathway of TRP metabolism in the group SIBO-D was observed. The SIBO-C patients showed an increase in the concentration of KYN, XA and QA. 5-HIAA/TRP and KYN/TRP ratios significantly decreased in group SIBO-D, and KYN and QA levels decreased in group SIBO-C after treatment with rifaximin. The levels of anxiety and depression decreased in both groups.

Conclusion

Rifaximin treatment of SIBO patients ameliorated their mood disorders and gastrointestinal aliments underlined by changes in tryptophan metabolism.

Trial registration Retrospectively registered (if applicable).
The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy
Authors: Qian Kewen , Fu Wenyan , Li Tian , Zhao Jian , Lei Changhai , Hu Shi
Published: September 2022

Extracellular vesicles (EVs) facilitate the extracellular transfer of proteins, lipids, and nucleic acids and mediate intercellular communication among multiple cells in the tumour environment. Small extracellular vesicles (sEVs) are defined as EVs range in diameter from approximately 50 to 150 nm. Tumour-derived sEVs (TDsEVs) and immune cell-derived sEVs have significant immunological activities and participate in cancer progression and immune responses. Cancer-specific molecules have been identified on TDsEVs and can function as biomarkers for cancer diagnosis and prognosis, as well as allergens for TDsEVs-based vaccination. Various monocytes, including but not limited to dendritic cells (DCs), B cells, T cells, natural killer (NK) cells, macrophages, and myeloid-derived suppressor cells (MDSCs), secrete sEVs that regulate immune responses in the complex immune network with either protumour or antitumour effects. After engineered modification, sEVs from immune cells and other donor cells can provide improved targeting and biological effects. Combined with their naïve characteristics, these engineered sEVs hold great potential as drug carriers. When used in a variety of cancer therapies, they can adjunctly enhance the safety and antitumor efficacy of multiple therapeutics. In summary, both naïve sEVs in the tumour environment and engineered sEVs with effector cargoes are regarded as showing promising potential for use in cancer diagnostics and therapeutics.
The clinical evaluation of electroacupuncture combined with mindfulness meditation for overweight and obesity: study protocol for a randomized sham-controlled clinical trial
Authors: Chung Ching Yee , Yang Angela Wei Hong , Foe Alexander , Li Mingdi , Lenon George Binh
Published: September 2022

Background

Overweight and obesity have reached an epidemic level which impacts individual health and creates a financial burden worldwide. Evidence has shown that electroacupuncture is effective for weight loss when combined with lifestyle intervention, while mindfulness meditation can enhance the outcome of weight loss programs. This study aims to evaluate the safety and the add-on effect of electroacupuncture and mindfulness meditation for weight management in overweight and obesity.

Methods/design

This is a sham-controlled, three-armed randomized clinical trial. A total of 165 participants with BMI between 25 and 39.99 and aged between 18 and 60 who meet the inclusion and exclusion criteria will be randomized into [1] electroacupuncture plus mindfulness meditation group, [2] sham electroacupuncture plus mindfulness meditation group, and [3] electroacupuncture only group. The total duration of this study will be 22 weeks, which consists of a 2-week run-in period, a 12-week intervention period, and an 8-week follow-up period. Participants will receive 12 weekly treatments during the intervention period. Primary outcomes will include body mass index, waist and hip ratio, and body composition. Secondary outcomes will be measured by the Weight-Related Symptom Measure, Obesity and Weight Loss Quality of Life, the Power of Food Scale, and the Chinese medicine differential diagnosis questionnaire. Outcomes will be assessed at the baseline, and endpoints of the 3rd, 6th, 9th, 12th, 14th, 16th, and 20th week.

Discussion

This clinical trial will investigate the add-on effect of two combined interventions for weight loss treatment. The findings of this study may contribute to the development of a cost-effective and multidisciplinary weight management approach.

Trial registration

Australia and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000964213. Registered on 07 June 2018.
A single-center, randomized, parallel design study to evaluate the efficacy of donepezil in improving visuospatial abilities in patients with mild cognitive impairment using eye-tracker: the COG-EYE study protocol for a phase II trial
Authors: Kim Ko Woon , Wang Qi , Koo Se Hee , Shin Byoung-Soo
Published: September 2022

Background

Cholinesterase inhibitors (ChEIs) decrease long-term cognitive decline in patients with Alzheimer’s disease (AD); however, there is little evidence that ChEIs affect cognitive test scores in patients with mild cognitive impairment (MCI). Conventional endpoints, such as cognitive tests or clinical rating scores, may lack the sensitivity to subtle treatment effects in participants with MCI. Therefore, there is an immediate need to refocus on direct physiological assessments to detect the effects of ChEIs in patients with MCI due to AD.

Methods

We propose a randomized controlled trial to evaluate the effect of donepezil, a ChEI, on patients with MCI due to AD. We plan to recruit 78 participants (39 in each arm) with MCI who had amyloid positron emission tomography (PET)-positive results for this open-label study. To evaluate subtle differences, we will measure eye-tracking metrics and digital pen data while participants perform the simplified Rey Complex Figure (RCFT) and clock drawing tests. The primary outcome is a change in the ratio of the number of fixations (working space/perceptual space) performed using the simplified RCFT, from baseline to 12 weeks, as assessed using eye-tracking metrics. The secondary outcomes are changes in general cognition, clinical severity, activities of daily living, and visuospatial function assessed using standard rating scores and digital pen data. The analyses of the primary and secondary outcomes will be based on the difference in changes during follow-up between the donepezil and control groups using the t-test or Mann–Whitney U test, as well as adjusting for baseline values.

Discussion

This study is designed to determine whether eye-tracking metrics can detect the effect of donepezil on visuospatial dysfunction more sensitively in patients with MCI. It is expected that multimodal data, such as eye-tracking and digital pen data, may provide helpful biomarkers for identifying subtle changes that are difficult to measure using conventional methods.

Trial registration

Clinical Research Information Service, Republic of Korea (CRIS, cris.nih.go.kr) KCT0006236. Registered on June 10, 2021.
Technological advances in the serological diagnosis of Chagas disease in dogs and cats: a systematic review
Authors: Freitas Natália Erdens Maron , Habib Fernanda Lopes , Santos Emily Ferreira , Silva Ângelo Antônio Oliveira , Fontes Natália Dantas , Leony Leonardo Maia , Sampaio Daniel Dias , de Almeida Marcio Cerqueira , Dantas-Torres Filipe , Santos Fred Luciano Neves
Published: September 2022

Background

Chagas disease (CD) is caused byTrypanosoma cruzi, which is transmitted mainly through the feces/urine of infected triatomine bugs. The acute phase lasts 2–3 months and is characterized by high parasitemia and nonspecific symptoms, whereas the lifelong chronic phase features symptoms affecting the heart and/or digestive tract occurring in 30–40% of infected individuals. As in humans, cardiac abnormalities are observed inT. cruzi-infected dogs and cats. We reviewed the technological advances in the serological diagnosis of CD in dogs and cats.

Methods

A review of the published literature during the last 54 years (1968–2022) on the epidemiology, clinical features, diagnosis, treatment and prevention of CD in dogs and cats was conducted.

Results

Using predefined eligibility criteria for a search of the published literature, we retrieved and screened 436 publications. Of these, 84 original studies were considered for inclusion in this review. Dogs and cats are considered as sentinels, potentially indicating an activeT. cruzitransmission and thus the risk for human infection. Although dogs and cats are reputed to be important for maintaining theT. cruzidomestic transmission cycle, there are no commercial tests to detect past or active infections in these animals. Most published research on CD in dogs and cats have used in-house serological tests prepared with native and/or full-length recombinant antigens, resulting in variable diagnostic performance. In recent years, chimeric antigens have been used to improve the diagnosis of chronic CD in humans with encouraging results. Some of them have high performance values (> 95%) and extremely low cross-reactivity rates forLeishmaniaspp., especially the antigens IBMP-8.1 to IBMP-8.4. The diagnostic performance of IBMP antigens was also investigated in dogs, showing high diagnostic performance with negligible cross-reactivity with anti-Leishmania infantumantibodies.

Conclusions

The development of a commercial immunodiagnostic tool to identify past or activeT. cruziinfections in dogs and cats is urgently needed. The use of chimeric recombinantT. cruziantigens may help to fill this gap and is discussed in this review.

Graphical Abstract
Identification of Jingmen tick virus (JMTV) in Amblyomma testudinarium from Fujian Province, southeastern China
Authors: Zhang Yuli , Li Zhenfeng , Pang Zheng , Wu Zhen , Lin Zhijuan , Niu Guoyu
Published: September 2022

Background

Jingmen tick virus (JMTV) is a newly discovered tick-borne virus that can cause disease in humans. This virus has been authenticated as being extremely widespread worldwide and as posing a significant threat to public health and safety.

Methods

We collected 35 ticks belonging to two tick species from wild boars in Nanping, Fujian Province, China. JMTV-specific genes were amplified by qRT-PCR and nested PCR to confirm the presence of this pathogen.

Results

More than one third of of all ticks collected (11/35) were positive for JMTV. Viral sequences were obtained from three of the JMTV-positive ticks, including the complete genomic sequence from one tick. This was the first time that JMTV was identified in the hard-bodied tick Amblyomma testudinarium. Phylogenetic analysis revealed that JMTV from Fujian Province shared > 90% identity with other isolates derived from China, but was distinct from those reported in France and Cambodia.

Conclusions

JMTV is characterized by relatively low mutations and has its own local adaptive characteristics in different regions. Our findings provide molecular evidence of the presence of JMTV in an overlooked tick species from an area not unrecognized as being endemic. They also suggest that JMTV occupies a wider geographical distribution than currently believed and is a potential disease vector.

Graphical abstract
Understanding reasons and factors for participation and non-participation to a medication adherence program for patients with diabetic kidney disease in Switzerland: a mixed methods study
Authors: Bandiera Carole , Lam Liliane , Locatelli Isabella , Dotta-Celio Jennifer , Duarte Dina , Wuerzner Gregoire , Pruijm Menno , Zanchi Anne , Schneider Marie P.
Published: September 2022

Background

An interprofessional medication adherence intervention led by pharmacists, combining motivational interviews and feedback with electronic monitor (EM) drug assessment, was offered to all consecutive patients with diabetic kidney disease (DKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m2) visiting their nephrologist or endocrinologist. Approximately 73% (202/275) of eligible patients declined to participate, and the factors and reasons for refusal were investigated.

Methods

Sociodemographic and clinical data of included patients and those who refused were collected retrospectively for those who had previously signed the general consent form. Multivariate logistic regression analysis was performed to identify independent variables associated with non-participation. Patients who refused or accepted the adherence study were invited to participate in semi-structured interviews. Verbatim transcription, thematic analysis, and inductive coding were performed.

Results

Patients who refused to participate were older (n = 123, mean age 67.7 years, SD:10.4) than those who accepted (n = 57, mean age 64.0 years, SD:10.0, p = 0.027) and the proportion of women was higher among them than among patients who accepted it (30.9% vs 12.3%, p = 0.007). The time from diabetes diagnosis was longer in patients who refused than in those who accepted (median 14.2 years IQR 6.9–22.7 vs. 8.6 years, IQR 4.5–15.9, p = 0.003). Factors associated with an increased risk of non-participation were female sex (OR 3.8, 95% CI 1.4–10.0, p = 0.007) and the time from diabetes diagnosis (OR 1.05, 95% CI 1.01–1.09, p = 0.019).

The included patients who were interviewed (n = 14) found the interprofessional intervention useful to improve their medication management, support medication literacy, and motivation.

Patients who refused to participate and who were interviewed (n = 16) explained no perceived need, did not agree to use EM, and perceived the study as a burden and shared that the study would have been beneficial if introduced earlier in their therapeutic journey. Other barriers emerged as difficult relationships with healthcare providers, lack of awareness of the pharmacist’s role, and negative perception of clinical research.

Conclusions

Investigating the factors and reasons for participation and non-participation in a study helps tailor intervention designs to the needs of polypharmacy patients. Patients who refused the adherence intervention may not be aware of the benefits of medication management and medication literacy. There is an urgent need to advocate for interprofessional outpatient collaborations to support medication adherence in patients with DKD.

Trial registrationClinicaltrials.gov NCT04190251_PANDIA IRIS.
High-normal serum carcinoembryonic antigen levels and increased risk of diabetic peripheral neuropathy in type 2 diabetes
Authors: Wang Chun-hua , Yu Chao , Zhuang Lei , Xu Feng , Zhao Li-hua , Wang Xiao-hua , Ning Li-yan , Zhang Xiu-lin , Zhang Dong-mei , Wang Xue-qin , Su Jian-bin
Published: September 2022

Background

Increased serum carcinoembryonic antigen (CEA) levels are reported to be associated with various metabolic and inflammatory diseases. This study assessed whether high-normal serum CEA is related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D).

Methods

All subjects received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate compositeZscores of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum CEA levels and other clinical indices were also synchronously detected. Multivariable linear regression analyses were used to determine the independent effects of serum CEA levels on nerve conduction indices, multivariable logistic regression analyses were used to determine the independent impact of CEA levels on the risk of DPN, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic capability of CEA levels to discriminate DPN.

Results

We ultimately recruited 402 eligible subjects with normal ranges of serum CEA for this study, and 25.4% (n = 102) were determined to have DPN. After adjusting for other clinical covariates, serum CEA levels were independently associated with the compositeZscore for latency (β = 0.132,t = 2.330,p = 0.021), amplitude (β = − 0.164,t = − 2.838,p = 0.005) and NCV (β = − 0.210,t = − 3.662,p < 0.001). Moreover, the prevalence of DPN in the first, second, third and fourth quartiles of CEA level was 12.9%, 19.0%, 29.4% and 40.4%, respectively (p for trend < 0.001); the corresponding adjusted odds ratios and 95% CIs for DPN in CEA quartiles were 1, 1.47 (0.45–4.82), 1.72 (0.54–5.53) and 4.58 (1.39–15.06), respectively. Furthermore, the optimal cut-off value of high-normal serum CEA to discriminate DPN was ≥ 2.66 ng/mL, with a Youden index of 0.28, sensitivity of 66.67% and specificity of 61.00%.

Conclusions

Increased serum CEA levels within the normal range are closely linked to dysfunction of peripheral nerve conduction and the risk of DPN, and high-normal serum CEA levels are a potential risk factor for DPN in T2D.
Healthy beverages may reduce the genetic risk of abdominal obesity and related metabolic comorbidities: a gene-diet interaction study in Iranian women
Authors: Gholami Fatemeh , Samadi Mahsa , Soveid Neda , Mirzaei Khadijeh
Published: September 2022

Background & aims

The nutrition transition in developing countries like Iran causes the increasing rise of obesity and abdominal obesity rates. However, it is not yet well proven that environmental modifications like improving the quality of beverage intake can be effective in people who have a genetic predisposition to obesity. So, in the present study, we examine the interaction between genetic predisposition and healthy beverage index (HBI) with abdominal obesity and obesity-related metabolic risk factors in overweight and obese women.

Method

Based on inclusion and exclusion criteria, 202 overweight or obese females were chosen for this cross-sectional study. Body composition, anthropometric measures, physical activity, and beverage intake data were collected and analyzed using recognized and trustworthy methodologies. Biochemical tests were performed on serum samples. A genetic risk score (GRS) was calculated based on the results of genetic tests. The predetermined HBI was calculated based on previous studies. A generalized linear model was used to estimate the interactions between GRS and HBI (GLM).

Results

We found significant interactions between GRS and HBI on WHR (β = − 0.39, CI: -0.07 to 0.001, P = 0.05) and WC (β = − 6.18, CI: − 13.41 to 1.05, P = 0.09). Also, there were significant gene-diet interactions for HBI and GRS on HDL (β = 7.09, CI: − 0.73 to 14.92, P = 0.07) and FBS (β = − 9.07, CI: − 18.63 to 0.47, P = 0.06).

Conclusions

These findings emphasize the HBI considering genetics appears to protect against the risks of abdominal obesity and metabolic associated obesity markers.
Applicability of devices available for the measurement of intracompartmental pressures: a cadaver study
Authors: Vogels Sanne , Ritchie Ewan D. , de Vries Djuna , Kleinrensink Gert-Jan , Verhofstad Michiel H. J. , Hoencamp Rigo
Published: September 2022

Purpose

The indication for surgical treatment of the chronic exertional compartment syndrome is evaluated by measuring intracompartmental pressures. The validity of these invasive intracompartmental pressure measurements are increasingly questioned in the absence of a standardized test protocol and uniform cut-off values. The aim of the current study was to test compartment pressure monitors and needles for uniformity, thereby supporting the physician’s choice in the selection of appropriate test materials.

Methods

A compartment syndrome was simulated in embalmed above-knee cadaveric leg specimen. Four different terminal devices (Compass manometer, Stryker device, Meritrans transduce, and arterial line) were tested with 22 different needle types. Legs were pressurized after introduction of the four terminal devices in the anterior compartment, using the same needle type. Pressure was recorded at a 30-second interval for 11 minutes in total. Before and after pressurization, the intravenous bag of saline was weighed.

Results

The simulation of a compartment syndrome resulted in intracompartmental pressure values exceeding 100 mmHg in 17 of the 22 legs (77%). In the other five legs, a smaller built-up of pressure was seen, although maximum intracompartmental pressure was in between 70 and 100 mmHg. The intraclass correlation coefficient was above 0.700 for all possible needle types. Excellent to good resemblance was seen in 16 out of 22 instrumental setups (73%). The mean volume of saline infusion required in runs that exceeded 100 mmHg (309 ± 116 ml) was significantly lower compared to the legs in which 100 mmHg was not achieved (451 ± 148 ml; p = 0.04).

Conclusion

The intracompartmental pressure recordings of the four terminal devices were comparable, when tested with a standardized pressurization model in a human cadaver model. None of the included terminal devices or needle types were found to be superior. The results provide evidence for more diverse material selection when logistic choices for intracompartmental pressure measurement devices are warranted.

Level of evidence

Level IV.
Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability
Authors: Ma Zhi-Qiang , Feng Ying-Tong , Guo Kai , Liu Dong , Shao Chang-Jian , Pan Ming-Hong , Zhang Yi-Meng , Zhang Yu-Xi , Lu Di , Huang Di , Zhang Fan , Wang Jin-Liang , Yang Bo , Han Jing , Yan Xiao-Long , Hu Yi
Published: September 2022

Background

Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.

Methods

ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes’ expression and prognosis of ESCC.

Results

Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan–Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.

Conclusions

Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.
CCR5 as a prognostic biomarker correlated with immune infiltrates in head and neck squamous cell carcinoma by bioinformatic study
Authors: Li Chunhong , Chen Shanlin , Liu Chuanyu , Mo Chune , Gong Weiwei , Hu Jiahua , He Min , Xie Lei , Hou Xianliang , Tang Jianhong , Ou Minglin
Published: September 2022

Background

C-C chemokine receptor 5 (CCR5) has recently been recognized as an underlying therapeutic target for various malignancies. However, the association of CCR5 with prognosis in the head and neck squamous cell carcinoma (HNSC) patients and tumor-infiltrating lymphocytes (TILs) is unclear.

Methods

In the current experiment, methods such as the Tumor Immune Estimation Resource Analysis (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier plotter Analysis were used to comprehensively evaluate the expression of CCR5 in human various malignancies and the clinical prognosis in HNSC patients. Subsequently, we used the TIMER database and the TISIDB platform to investigate the correlation between CCR5 expression levels and immune cell infiltration in the HNSC tumor microenvironment. Furthermore, immunomodulatory and chemokine profiling were performed using the TISIDB platform to analyse the correlation between CCR5 expression levels and immunomodulation in HNSC patients.

Results

We found that CCR5 expression in HNSC tumor tissues was significantly upregulated than in normal tissues. In HNSC, patients with high CCR5 expression levels had worse overall survival (OS, HR = 0.59, p = 0.00015) and worse recurrence-free survival (RFS, HR = 3.27, p = 0.00098). Upregulation of CCR5 expression is closely associated with immunomodulators, chemokines, and infiltrating levels of CD4+ T cells, neutrophils, macrophages, and myeloid dendritic cells. Furthermore, upregulated CCR5 was significantly associated with different immune markers in the immune cell subsets of HNSC.

Conclusions

High expression of CCR5 plays an important prognostic role in HNSC patients and may serve as a prognostic biomarker correlated with immune infiltration, and further studies are still needed to investigate therapeutic targeting HNSC patients in the future.
Quality control of [177Lu]Lu-PSMA preparations using HPLC: effect of sample composition and ligand on recovery
Authors: Aalbersberg Else A. , Cao Tammie T. , Geluk-Jonker Martine M. , Hendrikx Jeroen J. M. A.
Published: September 2022

Background

[177Lu]Lu-PSMA is used for the treatment of metastatic castration-resistant prostate cancer. For in-house productions, quality control methods are essential for ensuring product quality, and thus patient safety. During HPLC method development for quality control of [177Lu]Lu-PSMA-I&T, we noticed an unpredictable variability in peak area and height with replicate measurements. After a run, irremovable radioactivity was measured over the whole the length of the HPLC column, with slightly higher activity at the beginning and end of the column. The uniform distribution suggests that [177Lu]Lu-PSMA-I&T interacts with the column. As a result of the interaction, incomplete and variable recovery of injected activity was observed leading to the variability in peak area and height. Therefore the aim of this study was to (1) investigate the effect of sample composition on the interaction of [177Lu]Lu-PSMA-I&T to the HPLC column (measured as recovery, peak area, and peak height), and (2) to compare this with same concentrations of the well-known [177Lu]Lu-PSMA-617.

Results

Sample composition significantly affects recovery of [177Lu]Lu-PSMA-I&T, leading to a change in peak area and height. Recovery was 24% when diluted with 0.1 mM octreotide, 38% with water, and increased to 95% when diluted with 0.7 mM unlabeled PSMA-I&T. Peak area and height decreased to 26% and 17% when diluted in octreotide and to 41% and 29% when diluted in water, compared to a dilution in PSMA-I&T. Further experiments showed that recovery (and consequently peak area and peak height) reached a plateau of > 99% at concentrations of 0.27 mM and higher. [177Lu]Lu-PSMA-617 also interacts with the HPLC column, leading to lower, but less variable, recovery (9%). The low recovery of [177Lu]Lu-PSMA-617 could not be prevented with addition of unlabeled PSMA-617.

Conclusion

[177Lu]Lu-PSMA-I&T can undergo an irreversible binding with an HPLC column resulting in a decreased recovery. The recovery is can be highly dependent on sample composition. The addition of a surplus of unlabeled PSMA-I&T leads to an accurate analysis of [177Lu]Lu-PSMA-I&T.
Polymorphisms of nicotinic acetylcholine receptors in Alzheimer’s disease: a systematic review and data analysis
Authors: Mohammadi Solmaz , Mahmoudi Javad , Farajdokht Fereshteh , Asadi Milad , Pirsarabi Parya , Kazeminiaei Seyedeh Farrokh , Parvizpour Sepideh , Sadigh-Eteghad Saeed
Published: September 2022

Objective

This study was conducted to accomplish a better insight into the impact of single nucleotide polymorphisms (SNPs) of nicotinic acetylcholine receptors (nAChR) at the risk of Alzheimer’s disease (AD) and their possible pathogenicity.

Methods

We carried out a systemic review of accessible studies. The case–control studies were assessed by an electronic search of international and local databases to identify relevant studies on SNPs relating to nAChR genes in AD. Two reviewers evaluated the inclusion/exclusion criteria, summarized, and analyzed the extracted data. We used odds ratios (ORs) with 95% confidence intervals (CIs) for reporting our data. Online databases were checked for possible pathogenicity of statistically significant SNPs. Also, online databases, including NCBI, NIH, ClinVar, RegulomeDB, and Ensemble, were used to analyze and identify structure and function, DNA features, and flank sequencing in SNPs.

Results

Among all collected SNPs, rs4779978 and rs1827294 on CHRNA7, rs1044394 on CHRNA4, and rs1127314 on CHRNB2 showed statistically significant between AD cases and controls.

Conclusions

Some SNPs from the reviewed reports show evidence supporting their possible involvement in AD pathology. However, more comprehensive studies are necessary to identify the exact correlation and their role on the pathogenicity of disease.
Microplastics in Namibian river sediments – a first evaluation
Authors: Faulstich L. , Prume J. A. , Arendt R. , Reinhardt-Imjela Ch. , Chifflard P. , Schulte A.
Published: September 2022

The African continent is rarely the focus of microplastics research, although the ubiquity of microplastics in the environment is undisputed and still increasing. Due to the high production and use of plastic products and the partial lack of recycling systems in many parts of the African continent, it can be assumed that microplastic particles are already present in limnic and terrestrial ecosystems. Few studies, mainly from South Africa and the Northern African region, show a contamination with microplastics, especially in marine environments. This study aims to explore the presence and composition of microplastics in fluvial sediments of the major catchments in Namibia with a regional focus on the Iishana system in Northern Namibia, as one of the most densely populated areas in the country. In March 2019 and March 2021, at the end of the rainy seasons, sediments from the Iishana system and of the largest river catchments were sampled. Extraction was performed by density separation using the Microplastic Sediment Separator (MPSS) with the separation solution sodium chloride (density of 1.20 g/cm3). The particle size was determined by filtration and fractionation, and the polymer type by measurement with ATR-FTIR spectroscopy (minimum particle size 0.3 mm). Microplastics were found in the sediments of each river system, most of the particles in the Iishana system (average of 13.2 particles/kg dry weight). The perennial, the ephemeral rivers, and the Iishana system are similar concerning polymer type and particle size. Polyethylene and polypropylene were the dominant polymer types. Most of the particles were found in the size fractions 0.3 – 0.5 mm and 0.5 – 1.0 mm. The particles were found mainly as fragments and films, the majority transparent and brown.
Reservoir multiparameter prediction method based on deep learning for CO2 geologic storage
Authors: Li Dong , Peng Suping , Guo Yinling , Lu Yongxu , Cui Xiaoqin , Du Wenfeng
Published: September 2022

Time-lapse seismic difference refers to the comprehensive response of fluid saturation, pore pressure, and porosity. However, the contribution of different parameters to the seismic response is difficult to distinguish. The high-precision prediction of these reservoir parameters is of great significance in CO2 geologic storage and oil and gas development. Therefore, a simultaneous time-lapse reservoir multiparameter prediction method based on a multitask learning network is proposed. Combined with CO2 geologic storage monitoring, the process of generating training data is described, involving numerical simulation, petrophysical models, and seismic forward modeling. Moreover, the Hertz-Mindlin formula, which considers pressure changes, is used to establish the relationship between formation elasticity and physical parameters in CO2 storage. The effects of fluid saturation, pressure, and porosity on P- and S-wave velocities and densities are analyzed, and the amplitude-variation-with-offset response characteristics of fluid saturation, pressure, and porosity changes are discussed. In total, 4700 and 300 sets of reservoir parameters and seismic angle gather data are used for network training and testing, respectively. The prediction results of synthetic and field data find that the time-lapse reservoir multiparameter prediction method based on multitask learning can effectively distinguish changes in each parameter and simultaneously obtain high-precision prediction results of fluid saturation, pressure, and porosity. Once the network is constructed, the prediction will take only a few seconds, which will promote the further development of the CO2 geologic storage theory and technology.
Improving sparse representation with deep learning: A workflow for separating strong background interference
Authors: Liu Dawei , Wang Wei , Wang Xiaokai , Shi Zhensheng , Sacchi Mauricio D. , Chen Wenchao
Published: September 2022

Revealing hidden reservoirs that are severely shielded by strong background interference (SBI) is critical to subsequent refined interpretation. To enhance the characterization of these reservoirs, current interpretation workflows merge multiple attribute information, necessitating intensive human expertise. As an alternative, we regard SBI suppression as a signal separation problem and develop a workflow to suppress SBI by cascading a sparse representation method and deep learning. SBI has coherent morphological characteristics in seismic sections; reservoir seismic responses, such as channels and karst caves, have a narrow spatial distribution, exhibiting abrupt morphological characteristics. As their morphologies differ, we select two 2D sparse representation dictionaries to identify their individual components. Through the morphological component analysis (MCA) technique, we can obtain adequate SBI separation results. However, the MCA separation is inevitably limited because 2D dictionaries cannot adequately represent 3D structures, but 3D dictionaries are not viable due to computing constraints. As an extension, we use 3D deep learning to improve the separation results based on the 2D MCA results. Specifically, the network is fed with training samples from a region with better SBI suppression results obtained by the MCA method. After learning a direct mapping from noisy data to SBI, the network can improve the separation results and remove more SBI than the previous conventional method. Field data experiments demonstrate that our separation workflow successfully enhances reservoir structures after removing SBI.
Longitudinal comparisons of mental health, burnout and well-being in patient-facing, non-patient-facing healthcare professionals and non-healthcare professionals during the COVID-19 pandemic: findings from the CoPE-HCP study
Authors: Kapil Vikas , Collett George , Godec Thomas , Gupta Jaya , Maniero Carmela , Ng Sher M. , McIntosh Iris , Kumar Abhishek , Nair Satheesh , Kotecha Ashish , Janmohamed Azara , Antoniou Sotiris , Khan Rehan , Khanji Mohammed Y. , Siddiqui Imrana , Gupta Ajay
Published: September 2022

Background

The COVID-19 pandemic may disproportionately affect the mental health of healthcare professionals (HCPs), especially patient-facing HCPs.

Aims

To longitudinally examine mental health in HCPs versus non-HCPs, and patient-facing HCPs versus non-patient-facing HCPs.

Method

Online surveys were distributed to a cohort at three phases (baseline, July to September 2020; phase 2, 6 weeks post-baseline; phase 3, 4 months post-baseline). Each survey contained validated assessments for depression, anxiety, insomnia, burnout and well-being. For each outcome, we conducted mixed-effects logistic regression models (adjusted for a priori confounders) comparing the risk in different groups at each phase.

Results

A total of 1574 HCPs and 147 non-HCPs completed the baseline survey. Although there were generally higher rates of various probable mental health issues among HCPs versus non-HCPs at each phase, there was no significant difference, except that HCPs had 2.5-fold increased risk of burnout at phase 2 (emotional exhaustion: odds ratio 2.50, 95% CI 1.15–5.46, P = 0.021), which increased at phase 3 (emotional exhaustion: odds ratio 3.32, 95% CI 1.40–7.87, P = 0.006; depersonalisation: odds ratio 3.29, 95% CI 1.12–9.71, P = 0.031). At baseline, patient-facing HCPs (versus non-patient-facing HCPs) had a five-fold increased risk of depersonalisation (odds ratio 5.02, 95% CI 1.65–15.26, P = 0.004), with no significant difference in the risk for other outcomes. The difference in depersonalisation reduced over time, but patient-facing HCPs still had a 2.7-fold increased risk of emotional exhaustion (odds ratio 2.74, 95% CI 1.28–5.85, P = 0.009) by phase 3.

Conclusions

The COVID-19 pandemic had a huge impact on the mental health and well-being of both HCPs and non-HCPs, but there is disproportionately higher burnout among HCPs, particularly patient-facing HCPs.
Defining the unknowns for cell therapies in Parkinson's disease
Authors: Lane Emma L. , Lelos Mariah J.
Published: September 2022

First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD.
Creating connections: developing an online space for cross-regional mentorship and network building in the dementia research field
Authors: Fullerton Josie , Bettencourt Conceicao , Daniels Michael , Mclean Fiona , Simpson Susan , Smith Adam , Woodling Nathan , Kerr Fiona
Published: September 2022

Background

Effective development and retention of talented early-career researchers (ECRs) is essential to the continued success of biomedical science research fields. To this end, formal mentorship programmes (where researchers are paired with one or more mentors beyond their direct manager) have proven to be successful in providing support and expanding career development opportunities. However, many programmes are limited to pools of mentors and mentees within one institute or geographical area, highlighting that cross-regional connections may be a missed opportunity in many mentorship schemes.

Methods

Here, we aimed to address this limitation through our pilot cross-regional mentorship scheme, creating reciprocal mentor-mentee pairings between two pre-established networks of Alzheimer’s Research UK (ARUK) Network-associated researchers. We carefully created 21 mentor-mentee pairings between the Scotland and University College London (UCL) networks in 2021, with surveys conducted to assess mentor/mentee satisfaction with the programme.

Results

Participants reported very high satisfaction with the nature of the pairings and the mentors’ contribution to the career development of mentees; a majority also reported that the mentorship scheme increased their connections outside of their home network. Our assessment of this pilot programme is that it supports the utility of cross-regional mentorship schemes for ECR development. At the same time, we highlight the limitations of our programme and recommend areas for improvement in future programmes, including greater consideration of support for minoritized groups and the need for additional training for mentors.

Conclusions

In conclusion, our pilot scheme generated successful and novel mentor-mentee pairings across pre-existing networks; both of which reported high satisfaction with pairings, ECR career and personal development, and the formation of new cross-network connections. This pilot may serve as a model for other networks of biomedical researchers, where existing networks within medical research charities can act as a scaffold to build new cross-regional career development opportunities for researchers.