bluuebunny/crossref_metadata_2025 huggingface dataset:
Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques
Authors: Srinivasula Sharat , Degrange Paula , Perazzolo Simone , Bonvillain Andrew , Tobery Amanda , Kaplan Jacob , Jang Hyukjin , Turnier Refika , Davies Michael , Cottrell Mackenzie , Ho Rodney J. Y. , Di Mascio Michele
Published: September 2023

Introduction and methods

To understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months.

Results

The intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments.

Conclusion

These observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments.
Soluble biomarkers of HIV-1-related systemic immune activation are associated with high plasma levels of growth factors implicated in the pathogenesis of Kaposi sarcoma in adults
Authors: Nana Benderli Christine , Esemu Livo Forgu , Besong Michael Ebangha , Atchombat Derrick Hyacinthe Nyasse , Ogai Kazuhiro , Sobgui Thérèse M. Patricia , Nana Chris Marco Mbianda , Seumko’o Reine Medouen Ndeumou , Awanakan Honoré , Ekali Gabriel Loni , Leke Rose Gana Fomban , Okamoto Shigefumi , Ndhlovu Lishomwa C. , Megnekou Rosette
Published: September 2023

Background

Human Herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi’s sarcoma (KS), a multicentric angio-proliferative cancer commonly associated with Human Immunodeficiency Virus (HIV) infection. KS pathogenesis is a multifactorial condition hinged on immune dysfunction yet the mechanisms underlying the risk of developing KS in HHV-8 seropositive adults remains unclear. Here we explored whether soluble markers of HIV-1-related systemic immune activation (SIA) and angiogenesis (VEGF and FGF acidic) are involved in the pathogenesis of KS in adults with HHV8.

Methodology

Blood samples from 99 HIV-1 infected and 60 HIV-1 uninfected adults were collected in Yaoundé, Cameroon. CD3+/CD4+ T cell counts and HIV-1 plasma viral load were determined using the Pima Analyzer and the RT-PCR technique, respectively. Plasma levels of SIA biomarkers (sCD163, sCD25/IL-2Rα, and sCD40/TNFRSF5) and biomarkers of progression to KS (VEGF and FGF acidic) were measured using the Luminex assay. Seropositivity (IgG) for HHV-8 was determined using the ELISA method.

Results

Overall, 20.2% (20/99) of HIV-1 infected and 20% (12/60) of HIV-1 uninfected participants were seropositive for HHV8. Levels of sCD163, sCD25/IL-2Rα, sCD40/TNFRSF5, and FGF acidic were higher in the HIV-1 and HHV8 co-infection groups compared to the HIV-1 and HHV8 uninfected groups (all P <0.05). In addition, Higher plasma levels of VEGF correlated with sCD163 (rs = 0.58, P =0.0067) and sCD40/TNFRSF5 (rs = 0.59, P = 0.0064), while FGF acidic levels correlated with sCD40/TNFRSF5 (rs = 0.51, P = 0.022) in co-infected. In HIV-1 mono-infected donors, VEGF and FGF acidic levels correlated with sCD163 (rs =0.25, P = 0.03 and rs = 0.30, P = 0.006 respectively), sCD25/IL-2Rα (rs = 0.5, P <0.0001 and rs = 0.55, P <0.0001 respectively) and sCD40/TNFRSF5 (rs = 0.7, P <0.0001 and rs = 0.59, P <0.0001 respectively) and even in patients that were virally suppressed sCD25/IL-2Rα (rs = 0.39, P = 0.012 and rs = 0.53, P = 0.0004 respectively) and sCD40/TNFRSF5 (rs = 0.81, P <0.0001 and rs = 0.44, P = 0.0045 respectively).

Conclusion

Our findings suggest that although the development of KS in PLWH is multifactorial, HIV-associated SIA might be among the key drivers in coinfections with HHV8 and is independent of the patients’ viremic status.
Severe autoimmune hemolytic anemia; epidemiology, clinical management, outcomes and knowledge gaps
Authors: Mulder Femke V. M. , Evers Dorothea , de Haas Masja , Cruijsen Marjan J. , Bernelot Moens Sophie J. , Barcellini Wilma , Fattizzo Bruno , Vos Josephine M. I.
Published: September 2023

Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic disorder, mediated by auto-antibodies, and has a variable clinical course ranging from fully compensated low grade hemolysis to severe life-threatening cases. The rarity, heterogeneity and incomplete understanding of severe AIHA complicate the recognition and management of severe cases. In this review, we describe how severe AIHA can be defined and what is currently known of the severity and outcome of AIHA. There are no validated predictors for severe clinical course, but certain risk factors for poor outcomes (hospitalisation, transfusion need and mortality) can aid in recognizing severe cases. Some serological subtypes of AIHA (warm AIHA with complement positive DAT, mixed, atypical) are associated with lower hemoglobin levels, higher transfusion need and mortality. Currently, there is no evidence-based therapeutic approach for severe AIHA. We provide a general approach for the management of severe AIHA patients, incorporating monitoring, supportive measures and therapeutic options based on expert opinion. In cases where steroids fail, there is a lack of rapidly effective therapeutic options. In this era, numerous novel therapies are emerging for AIHA, including novel complement inhibitors, such as sutimlimab. Their potential in severe AIHA is discussed. Future research efforts are needed to gain a clearer picture of severe AIHA and develop prediction models for severe disease course. It is crucial to incorporate not only clinical characteristics but also biomarkers that are associated with pathophysiological differences and severity, to enhance the accuracy of prediction models and facilitate the selection of the optimal therapeutic approach. Future clinical trials should prioritize the inclusion of severe AIHA patients, particularly in the quest for rapidly acting novel agents.
Distinct SARS-CoV-2 specific NLRP3 and IL-1β responses in T cells of aging patients during acute COVID-19 infection
Authors: Mahalingam Shanmuga Sundaram , Jayaraman Sangeetha , Arunkumar Adhvika , Dudley Holly M. , Anthony Donald D. , Shive Carey L. , Jacobson Jeffrey M. , Pandiyan Pushpa
Published: September 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19) that presents with varied clinical manifestations ranging from asymptomatic or mild infections and pneumonia to severe cases associated with cytokine storm, acute respiratory distress syndrome (ARDS), and even death. The underlying mechanisms contributing to these differences are unclear, although exacerbated inflammatory sequelae resulting from infection have been implicated. While advanced aging is a known risk factor, the precise immune parameters that determine the outcome of SARS-CoV-2 infection in elderly individuals are not understood. Here, we found aging-associated (age ≥61) intrinsic changes in T cell responses when compared to those from individuals aged ≤ 60, even among COVID-positive patients with mild symptoms. Specifically, when stimulated with SARS-CoV-2 peptides in vitro, peripheral blood mononuclear cell (PBMC) CD4+ and CD8+ T cells from individuals aged ≥61 showed a diminished capacity to produce IFN-γ and IL-1β. Although they did not have severe disease, aged individuals also showed a higher frequency of PD-1+ cells and significantly diminished IFN-γ/PD-1 ratios among T lymphocytes upon SARS-CoV-2 peptide stimulation. Impaired T cell IL-1β expression coincided with reduced NLRP3 levels in T lymphocytes. However, the expression of these molecules was not affected in the monocytes of individuals aged ≥61. Together, these data reveal SARS-CoV-2-specific CD4+ and CD8+ T-cell intrinsic cytokine alterations in the individuals older than 61 and may provide new insights into dysregulated COVID-directed immune responses in the elderly.
Novel quantitative immunohistochemical analysis for evaluating PD-L1 expression with phosphor-integrated dots for predicting the efficacy of patients with cancer treated with immune checkpoint inhibitors
Authors: Ohkuma Ryotaro , Miura Sakiko , Muto Satoshi , Toyomasu Yoshitaka , Fujimoto Yuki , Ieguchi Katsuaki , Onishi Nobuyuki , Shimizu Takashi , Watanabe Makoto , Takayanagi Daisuke , Goshima Tsubasa , Horiike Atsushi , Hamada Kazuyuki , Ariizumi Hirotsugu , Shimokawa Masahiro , Hirasawa Yuya , Ishiguro Tomoyuki , Suzuki Risako , Iriguchi Nana , Tsurui Toshiaki , Mura Emiko , Takenoshita Sachiko , Numajiri Kazuki , Okabe Naoyuki , Yoshimura Kiyoshi , Tsuji Mayumi , Kiuchi Yuji , Yajima Toshiki , Ishida Hideyuki , Suzuki Hiroyuki , Yamochi Toshiko , Kobayashi Shinichi , Tsunoda Takuya , Wada Satoshi
Published: September 2023

Introduction

Programmed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method.

Methods

In total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression.

Results

PD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group.

Conclusion

Quantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.
Oyster reef restoration - aquaculture interactions: maximizing positive synergies
Authors: Bishop Melanie J. , Lanham Brendan S. , Esquivel-Muelbert Juan R. , Cole Victoria J. , Faelnar Kristine M. , Jenkins Charlotte , Keating Jillian , Martínez-Baena Francisco , O’Connor Wayne A.
Published: September 2023

Globally, oyster reef restoration is on the rise. In many instances, restoration is occurring alongside established oyster aquaculture industries that grew to prominence following oyster reef demise. This paper examines the potential positive and negative interactions between the two industries and identifies key factors that may promote positive interactions. Interactions between the two industries result from shared resource requirements (e.g., space, clean water, brood-stock, breeding programs), shared knowledge requirements (e.g. around threats and their mitigation, factors optimizing growth/survival) and biological interactions (e.g. over-catch, disease spill-over, competition for resources). Many of these interactions are reciprocated, and can shift from positive to negative depending on environmental, biological and socio-economic conditions. From our examination, three key factors emerge as shaping the strength and direction (positive or negative) of interactions: (1) whether the focal species is common or different between the two industries; (2) the physicochemical and socio-economic environment in which the two industries are occurring; and (3) whether there is open dialogue and consultation between the two industries and relevant stakeholders. Positive interactions can be maximized where the two industries are able to co-invest in and share infrastructure (e.g. hatcheries, breeding programs), resources (e.g. spat, broodstock, shell) and knowledge (e.g. optimal conditions of growth) – an easier task where the target oyster species is in common. Positive interactions may also be maximized by utilizing marine spatial planning tools, such as suitability modelling, to inform optimal siting of the two industries. As the two industries continue to grow, open and inclusive dialogue between these and key stakeholders will be essential for mitigating risk and maximising positive synergies.
Zhishi Daozhi decoction alleviates constipation induced by a high-fat and high-protein diet via regulating intestinal mucosal microbiota and oxidative stress
Authors: Peng Xinxin , Yi Xin , Deng Na , Liu Jing , Tan Zhoujin , Cai Ying
Published: September 2023

Background

A growing body of evidence has demonstrated that a high-fat and high-protein diet (HFHPD) causes constipation. This study focuses on understanding how the use of Zhishi Daozhi decoction (ZDD) affects the intricate balance of intestinal microorganisms. The insights gained from this investigation hold the potential to offer practical clinical approaches to mitigate the constipation-related issues associated with HFHPD.

Materials and methods

Mice were randomly divided into five groups: the normal (MN) group, the natural recovery (MR) group, the low-dose ZDD (MLD) group, the medium-dose ZDD (MMD) group, and the high-dose ZDD (MHD) group. After the constipation model was established by HFHPD combined with loperamide hydrochloride (LOP), different doses of ZDD were used for intervention. Subsequently, the contents of cholecystokinin (CCK) and calcitonin gene-related peptide (CGRP) in serum, superoxide dismutase (SOD), and malondialdehyde (MDA) in the liver were determined. The DNA of intestinal mucosa was extracted, and 16S rRNA amplicon sequencing was used to analyze the changes in intestinal mucosal microbiota.

Results

After ZDD treatment, CCK content in MR group decreased and CGRP content increased, but the changes were not significant. In addition, the SOD content in MR group was significantly lower than in MLD, MMD, and MHD groups, and the MDA content in MR group was significantly higher than in MN, MLD, and MHD groups. Constipation modeling and the intervention of ZDD changed the structure of the intestinal mucosal microbiota. In the constipation induced by HFHPD, the relative abundance of pathogenic bacteria such as Aerococcus, Staphylococcus, Corynebacterium, Desulfovibrio, Clostridium, and Prevotella increased. After the intervention of ZDD, the relative abundance of these pathogenic bacteria decreased, and the relative abundance of Candidatus Arthromitus and the abundance of Tropane, piperidine, and pyridine alkaloid biosynthesis pathways increased in MHD group.

Conclusion

Constipation induced by HFHPD can increase pathogenic bacteria in the intestinal mucosa, while ZDD can effectively relieve constipation, reduce the relative abundance of pathogenic bacteria, and alleviate oxidative stress injury. In addition, high-dose ZDD can increase the abundance of beneficial bacteria, which is more conducive to the treatment of constipation.
PtrA regulates prodigiosin synthesis and biological functions in Serratia marcescens FZSF02
Authors: Lin Junjie , Yu Yanshuang , Zhao Ke , Zhao Jie , Rensing Christopher , Chen Jichen , Jia Xianbo
Published: September 2023

Serratia marcescens is a gram-negative bacterium that is able to produce many secondary metabolites, such as the prominent red pigment prodigiosin (PG). In this work, a ptrA-disrupted mutant strain with reduced PG production was selected from Tn5 transposon mutants. RT–qPCR results indicated that ptrA promoted elevated transcription of the pig gene cluster in S. marcescens FZSF02. Furthermore, we found that ptrA also controls several other important biological functions of S. marcescens, including swimming and swarming motilities, biofilm formation, hemolytic activity, and stress tolerance. In conclusion, this study demonstrates that ptrA is a PG synthesis-promoting factor in S. marcescens and provides a brief understanding of the regulatory mechanism of ptrA in S. marcescens cell motility and hemolytic activity.
Dissecting the association between gut microbiota and liver cancer in European and East Asian populations using Mendelian randomization analysis
Authors: Jiang Hua , Song Tianjun , Li Zhongyi , An Lingxuan , He Chiyi , Zheng Kai
Published: September 2023

Background

Ample evidence suggests an important role of the gut microbiome in liver cancer, but the causal relationship between gut microbiome and liver cancer is unclear. This study employed Mendelian randomization (MR) analysis to examine the causal relationship between the gut microbiome and liver cancer in European and East Asian populations.

Methods

We sourced genetic variants linked to gut microbiota from the MiBioGen consortium meta-analysis, and procured liver cancer genome-wide association study (GWAS) summary data from the FinnGen consortium and Biobank Japan. We employed the inverse variance weighted method for primary statistical analysis, fortified by several sensitivity analyses such as MR-PRESSO, MR-Egger regression, weighted median, weighted mode, and maximum likelihood methods for rigorous results. We also evaluated heterogeneity and horizontal pleiotropy.

Results

The study examined an extensive set of gut microbiota, including 131 genera, 35 families, 20 orders, 16 classes, and 9 phyla. In Europeans, ten gut microbiota types displayed a suggestive association with liver cancer (p < 0.05). Notably, Oscillospira and Mollicutes RF9 exhibited a statistically significant positive association with liver cancer risk, with odds ratios (OR) of 2.59 (95% CI 1.36–4.95) and 2.03 (95% CI 1.21–3.40), respectively, after adjusting for multiple testing. In East Asians, while six microbial types demonstrated suggestive associations with liver cancer, only Oscillibacter displayed a statistically significant positive association (OR = 1.56, 95% CI 1.11–2.19) with an FDR < 0.05. Sensitivity analyses reinforced these findings despite variations in p-values.

Conclusion

This study provides evidence for a causal relationship between specific gut microbiota and liver cancer, enhancing the understanding of the role of the gut microbiome in liver cancer and may offer new avenues for preventive and therapeutic strategies.
Development and characterization of rice bran-gum Arabic based encapsulated biofertilizer for enhanced shelf life and controlled bacterial release
Authors: Kaur Rajinder , Kaur Sukhminderjit , Dwibedi Vagish , Kaur Charanjit , Akhtar Nadeem , Alzahrani Abdulhakeem
Published: September 2023

Introduction

Currently, microbe-based approaches are being tested to address nutrient deficiencies and enhance nutrient use efficiency in crops. However, these bioinoculants have been unsuccessful at the commercial level due to differences in field andin-vivoconditions. Thus, to enhance bacterial stability, microbial formulations are considered, which will provide an appropriate microenvironment and protection to the bacteria ensuring better rhizospheric-colonization.

Methods

The present study aimed to develop a phosphobacterium-based encapsulated biofertilizer using the ion-chelation method, wherein a bacterial strain,Myroid gitamensiswas mixed with a composite solution containing rice bran (RB), gum Arabic (GA), tricalcium phosphate, and alginate to develop low-cost and slow-release microbeads. The developed microbead was studied for encapsulation efficiency, shape, size, external morphology, shelf-life, soil release behavior, and biodegradability and characterized using SEM, FTIR, and XRD. Further, the wheat growth-promoting potential of microbeads was studied.

Results

The developed microbeads showed an encapsulation efficiency of 94.11%. The air-dried beads stored at 4°C were favorable for bacterial survival for upto 6 months. Microbeads showed 99.75% degradation within 110 days of incubation showing the bio-sustainable nature of the beads. The application of dried formulations to the pot-grown wheat seedlings resulted in a higher germination rate, shoot length, root length, fresh weight, dry weight of the seedlings, and higher potassium and phosphorus uptake in wheat.

Discussion

This study, for the first time, provides evidence that compared to liquid biofertilizers, the RB-GA encapsulated bacteria have better potential of enhancing wheat growth and can be foreseen as a future fertilizer option for wheat.
Characterization of an archaeal virus-host system reveals massive genomic rearrangements in a laboratory strain
Authors: Mercier Coraline , Thies Daniela , Zhong Ling , Raftery Mark J. , Erdmann Susanne
Published: September 2023

Halophilic archaea (haloarchaea) are known to exhibit multiple chromosomes, with one main chromosome and one or several smaller secondary chromosomes or megaplasmids. Halorubrum lacusprofundi, a model organism for studying cold adaptation, exhibits one secondary chromosome and one megaplasmid that include a large arsenal of virus defense mechanisms. We isolated a virus (Halorubrum tailed virus DL1, HRTV-DL1) infecting Hrr. lacusprofundi, and present an in-depth characterization of the virus and its interactions with Hrr. lacusprofundi. While studying virus-host interactions between Hrr. lacusprofundi and HRTV-DL1, we uncover that the strain in use (ACAM34_UNSW) lost the entire megaplasmid and about 38% of the secondary chromosome. The loss included the majority of virus defense mechanisms, making the strain sensitive to HRTV-DL1 infection, while the type strain (ACAM34_DSMZ) appears to prevent virus replication. Comparing infection of the type strain ACAM34_DSMZ with infection of the laboratory derived strain ACAM34_UNSW allowed us to identify host responses to virus infection that were only activated in ACAM34_UNSW upon the loss of virus defense mechanisms. We identify one of two S-layer proteins as primary receptor for HRTV-DL1 and conclude that the presence of two different S-layer proteins in one strain provides a strong advantage in the arms race with viruses. Additionally, we identify archaeal homologs to eukaryotic proteins potentially being involved in the defense against virus infection.
Association of age-related hearing loss with cognitive impairment and dementia: an umbrella review
Authors: Ying Guo , Zhao Guangran , Xu Xianpeng , Su Su , Xie Xin
Published: September 2023

Background

Hearing loss, cognitive impairment and dementia have become common problems for older adults. Currently, systematic reviews and meta-analyses of the association between age-related hearing loss (ARHL) with cognitive impairment and dementia may have inconsistent results. To explore and validate the association between ARHL with cognitive impairment and dementia through summarizing and evaluating existing evidence.

Methods

From inception to February 01, 2023, PubMed, Web of Science, Embase, and Cochrane Library databases were systematically searched. AMSTAR 2 was used to evaluate methodological quality and GRADE system was used to evaluate evidence quality. We summarized the basic characteristics of the included studies and extracted effect data for ARHL with cognitive impairment and dementia. Forest plots were used to describe the relative risk associated with ARHL and cognitive impairment, and the relative risk associated with ARHL and dementia, respectively.

Results

A total of 11 systematic reviews and meta-analyses met the inclusion criteria. Overall, the methodological quality of the included SRs/MAs was moderate and the quality of the evidence was low. The combined results found that the pooled risk ratio of ARHL and cognitive impairment was 1.30 (random-effects; 95% CI 1.16 to 1.45), and the pooled risk ratio of ARHL and dementia was 1.59 (random-effects; 95% CI 1.34 to 1.90).

Conclusion

Based on the evidence reported in this umbrella review, age-related hearing loss is significantly associated with cognitive impairment and dementia. Hearing loss may be a high risk factor for cognitive impairment and dementia in older adults.
Efficacy of a strength-based exercise program in patients with chronic tension type headache: a randomized controlled trial
Authors: Martín-Vera Daniel , Sánchez-Sierra Alberto , González-de-la-Flor Ángel , García-Pérez-de-Sevilla Guillermo , Domínguez-Balmaseda Diego , del-Blanco-Muñiz Jose Ángel
Published: September 2023

Background

Strength-based exercise is widely used to treat tension-type headache, but the evidence of its benefit is unclear. This study aims to analyze the efficacy of a strength-based exercise program in patients with chronic tension-type headaches.

Methods

A randomized controlled trial with a 12-week strength-based exercise program, with chronic tension-type headache. The headache characteristics (which were the primary outcomes: frequency, duration, and intensity), cervical muscle thickness at rest or contraction of multifidus and longus-colli muscle, cervical range of motion, pain pressure threshold of temporalis, upper trapezius, masseter, tibialis muscle and median nerve, and cervical craniocervical flexion test were assessed at baseline and 12-weeks of follow-up in the intervention group (n = 20) and the control group (n = 20) was performed on 40 patients (85% women, aged 37.0 ± 13.3 years).

Results

Between baseline and week-12 of follow-up the intervention group showed statistically significant differences compared to control group in the following primary outcomes: duration and intensity of headaches. In addition, the intervention group improved the thickness of deep cervical muscles, reduced the peripheral sensitization, and improved the strength of deep cervical flexors.

Conclusion

A 12-week strength training of neck and shoulder region induced changes in pain intensity and duration, and physical-related factors in patients with TTH. Future interventions are needed to investigate if normalization of pain characteristics and physical factors can lead to an increase of headache-related impact.
Can developmental trajectories in gait variability provide prognostic clues in motor adaptation among children with mild cerebral palsy? A retrospective observational cohort study
Authors: Visscher Rosa M. S. , Gwerder Michelle , Viehweger Elke , Taylor William R. , Brunner Reinald , Singh Navrag B.
Published: September 2023

Aim

To investigate whether multiple domains of gait variability change during motor maturation and if this change over time could differentiate children with a typical development (TDC) from those with cerebral palsy (CwCP).

Methods

This cross-sectional retrospective study included 42 TDC and 129 CwCP, of which 99 and 30 exhibited GMFCS level I and II, respectively. Participants underwent barefoot 3D gait analysis. Age and parameters of gait variability (coefficient of variation of stride-time, stride length, single limb support time, walking speed, and cadence; as well as meanSD for hip flexion, knee flexion, and ankle dorsiflexion) were used to fit linear models, where the slope of the models could differ between groups to test the hypotheses.

Results

Motor-developmental trajectories of gait variability were able to distinguish between TDC and CwCP for all parameters, except the variability of joint angles. CwCP with GMFCS II also showed significantly higher levels of gait variability compared to those with GMFCS I, these levels were maintained across different ages.

Interpretation

This study showed the potential of gait variability to identify and detect the motor characteristics of high functioning CwCP. In future, such trajectories could provide functional biomarkers for identifying children with mild movement related disorders and support the management of expectations.
CLET: Computation of Latencies in Event-related potential Triggers using photodiode on virtual reality apparatuses
Authors: Swami Piyush , Gramann Klaus , Vonstad Elise Klæbo , Vereijken Beatrix , Holt Alexander , Holt Tomas , Sandstrak Grethe , Nilsen Jan Harald , Su Xiaomeng
Published: September 2023

To investigate event-related activity in human brain dynamics as measured with EEG, triggers must be incorporated to indicate the onset of events in the experimental protocol. Such triggers allow for the extraction of ERP, i.e., systematic electrophysiological responses to internal or external stimuli that must be extracted from the ongoing oscillatory activity by averaging several trials containing similar events. Due to the technical setup with separate hardware sending and recording triggers, the recorded data commonly involves latency differences between the transmitted and received triggers. The computation of these latencies is critical for shifting the epochs with respect to the triggers sent. Otherwise, timing differences can lead to a misinterpretation of the resulting ERPs. This study presents a methodical approach for the CLET using a photodiode on a non-immersive VR (i.e., LED screen) and an immersive VR (i.e., HMD). Two sets of algorithms are proposed to analyze the photodiode data. The experiment designed for this study involved the synchronization of EEG, EMG, PPG, photodiode sensors, and ten 3D MoCap cameras with a VR presentation platform (Unity). The average latency computed for LED screen data for a set of white and black stimuli was 121.98 ± 8.71 ms and 121.66 ± 8.80 ms, respectively. In contrast, the average latency computed for HMD data for the white and black stimuli sets was 82.80 ± 7.63 ms and 69.82 ± 5.52 ms. The codes for CLET and analysis, along with datasets, tables, and a tutorial video for using the codes, have been made publicly available.
The ameliorative effects of choline on ethanol-induced cell death in the neural tube of susceptible BXD strains of mice
Authors: Xu Fannia , Thomas Jennifer D. , Goldowitz Dan , Hamre Kristin M.
Published: September 2023

Introduction

Fetal alcohol spectrum disorders (FASD) are the leading preventable cause of intellectual disability, providing the impetus for evaluating various potential treatments to ameliorate ethanol’s teratogenic effects, particularly in the nervous system. One treatment is the dietary supplement choline which has been shown to mitigate at least some of ethanol’s teratogenic effects. The present study was designed to investigate the effects of genetics on choline’s efficacy in ameliorating cell death in the developing neural tube. Previously, we examined BXD recombinant inbred mice, and their parental C57BL/6 J (B6) and DBA/2 J strains, and identified strains that were sensitive to ethanol’s teratogenic actions. Thus, we used these strains to identify response to choline treatment.

Materials and methods

Timed pregnant mice from 4 strains (B6, BXD51, BXD73, BXD2) were given either ethanol or isocaloric maltose-dextrin (5.8 g/kg in two administrations separated by 2 h) with choline at one of 3 doses: 0, 100 or 250 mg/kg. Subjects were exposed via intragastric gavage on embryonic day 9 and embryos were collected 7 h after the initial ethanol administrations. Cell death was analyzed using TUNEL staining in the developing forebrain and brainstem.

Results

Choline ameliorated the ethanol-induced cell death across all 4 strains without causing enhanced cell death in control mice. Choline was effective in both the developing telencephalon and in the brainstem. Both doses diminished cell death, with some differences across strains and brain regions, although the 100 mg/kg dose was most consistent in mitigating ethanol-related cell death. Comparisons across strains showed that there was an effect of strain, particularly in the forebrain at the higher dose.

Discussion

These results show that choline is effective in ameliorating ethanol-induced cell death at this early stage of nervous system development. However, there were some strain differences in its efficacy, especially at the high dose, providing further evidence of the importance of genetics in influencing the ability of choline to protect against prenatal alcohol exposure.
Adaptations of the balloon analog risk task for neuroimaging settings: a systematic review
Authors: Compagne Charline , Mayer Juliana Teti , Gabriel Damien , Comte Alexandre , Magnin Eloi , Bennabi Djamila , Tannou Thomas
Published: September 2023

Introduction

The Balloon Analog Risk Task (BART), a computerized behavioral paradigm, is one of the most common tools used to assess the risk-taking propensity of an individual. Since its initial behavioral version, the BART has been adapted to neuroimaging technique to explore brain networks of risk-taking behavior. However, while there are a variety of paradigms adapted to neuroimaging to date, no consensus has been reached on the best paradigm with the appropriate parameters to study the brain during risk-taking assessed by the BART. In this review of the literature, we aimed to identify the most appropriate BART parameters to adapt the initial paradigm to neuroimaging and increase the reliability of this tool.

Methods

A systematic review focused on the BART versions adapted to neuroimaging was performed in accordance with PRISMA guidelines.

Results

A total of 105 articles with 6,879 subjects identified from the PubMed database met the inclusion criteria. The BART was adapted in four neuroimaging techniques, mostly in functional magnetic resonance imaging or electroencephalography settings.

Discussion

First, to adapt the BART to neuroimaging, a delay was included between each trial, the total number of inflations was reduced between 12 and 30 pumps, and the number of trials was increased between 80 and 100 balloons, enabling us to respect the recording constraints of neuroimaging. Second, explicit feedback about the balloon burst limited the decisions under ambiguity associated with the first trials. Third, employing an outcome index that provides more informative measures than the standard average pump score, along with a model incorporating an exponential monotonic increase in explosion probability and a maximum explosion probability between 50 and 75%, can yield a reliable estimation of risk profile. Additionally, enhancing participant motivation can be achieved by increasing the reward in line with the risk level and implementing payment based on their performance in the BART. Although there is no universal adaptation of the BART to neuroimaging, and depending on the objectives of a study, an adjustment of parameters optimizes its evaluation and clinical utility in assessing risk-taking.
Decoding the role of gut microbiota in Alzheimer’s pathogenesis and envisioning future therapeutic avenues
Authors: Liang Junyi , Liu Bin , Dong Xiaohong , Wang Yueyang , Cai Wenhui , Zhang Ning , Zhang Hong
Published: September 2023

Alzheimer’s disease (AD) emerges as a perturbing neurodegenerative malady, with a profound comprehension of its underlying pathogenic mechanisms continuing to evade our intellectual grasp. Within the intricate tapestry of human health and affliction, the enteric microbial consortium, ensconced within the milieu of the human gastrointestinal tract, assumes a role of cardinal significance. Recent epochs have borne witness to investigations that posit marked divergences in the composition of the gut microbiota between individuals grappling with AD and those favored by robust health. The composite vicissitudes in the configuration of the enteric microbial assembly are posited to choreograph a participatory role in the inception and progression of AD, facilitated by the intricate conduit acknowledged as the gut-brain axis. Notwithstanding, the precise nature of this interlaced relationship remains enshrouded within the recesses of obscurity, poised for an exhaustive revelation. This review embarks upon the endeavor to focalize meticulously upon the mechanistic sway exerted by the enteric microbiota upon AD, plunging profoundly into the execution of interventions that govern the milieu of enteric microorganisms. In doing so, it bestows relevance upon the therapeutic stratagems that form the bedrock of AD’s management, all whilst casting a prospective gaze into the horizon of medical advancements.
Real-world predictors of survival in patients with extensive-stage small-cell lung cancer in Manitoba, Canada: a retrospective cohort study
Authors: Dawe David E. , Rittberg Rebekah , Syed Iqra , Shanahan Mary Kate , Moldaver Daniel , Bucher Oliver , Galloway Katie , Reynolds Kayla , Paul James T. , Harlos Craig , Kim Julian O. , Banerji Shantanu
Published: September 2023

Background

Extensive-stage small-cell lung cancer (ES-SCLC) is an incurable cancer with poor prognosis in which characteristics predictive of long-term survival are debated. The utility of agents such as immune checkpoint inhibitors highlights the importance of identifying key characteristics and treatment strategies that contribute to long-term survival and could help guide therapeutic decisions.

Objective

This real-world analysis examines the characteristics, treatment patterns, and clinical outcomes of patients receiving chemotherapy without immunotherapy for ES-SCLC in Manitoba, Canada.

Methods

A retrospective cohort study assessed patient characteristics, treatment, and survival duration (short: <6 months; medium: 6–24 months; long: >24 months) using the Manitoba Cancer Registry and CancerCare Manitoba records. Eligible patients were aged >18 years with cytologically confirmed ES-SCLC diagnosed between January 1, 2004, and December 31, 2018, and received cytotoxic chemotherapy (CT). The one-, two-, and five-year probabilities of overall survival (OS) were assessed relative to patient, disease, and treatment characteristics using Kaplan-Meier methods and Cox proportional hazards models.

Results

This analysis included 537 patients. Cisplatin was used in 56.1% of patients, 45.6% received thoracic radiotherapy (RT), and few received prophylactic cranial irradiation (PCI). In the overall cohort, one-, two- and five-year OS rates were 26%, 8%, and 3%, respectively. For patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, OS rates at one, two, and five years were 43%, 17%, and 10%, respectively, vs. 27%, 8%, and 2% for those with ECOG PS 1–2, and 16%, 3%, and 3% for those with ECOG PS 3–4. In long-term survivors, ECOG PS scores were lower and abnormal laboratory test results were less frequent. Overall, 74.4% of long-term survivors received thoracic RT and 53.5% received PCI. Known poor prognostic factors – including brain/liver metastases, high lactate dehydrogenase (LDH), abnormal sodium, and low hemoglobin levels – were less common but still seen in long-term survivors.

Conclusion

Although rare, patients with ES-SCLC may experience long-term survival with CT ± thoracic RT ± PCI. Factors predicting long-term survival include traditional prognostic factors such as ECOG PS, LDH level, and receipt of thoracic RT or PCI. These findings support current treatment algorithms for ES-SCLC and provide baseline survival estimates to assess the real-world impact of adding immune checkpoint inhibitors in the future.
Cell-in-cell structure in cancer: evading strategies from anti-cancer therapies
Authors: Okuyama Kohei , Fukushima Hiromasa , Naruse Tomofumi , Yanamoto Souichi
Published: September 2023

One of the regulated forms of cell death is the cell-in-cell (CIC) structure, in which a surviving cell is engulfed by another cell, a mechanism that causes the death of the engulfed cell by an adjacent cell. Several investigators have previously shown that the presence of CICs is an independent risk factor significantly associated with decreased survival in patients with various types of cancer. In this review, we summarize the role of CIC in the tumor microenvironment (TME), including changes and crosstalk of molecules and proteins in the surrounding CIC, and the role of these factors in contributing to therapeutic resistance acquisition. Moreover, CIC structure formation is influenced by the modulation of TME, which may lead to changes in cellular properties. Future use of CIC as a clinical diagnostic tool will require a better understanding of the effects of chemotherapy on CIC, biomarkers for each CIC formation process, and the development of automated CIC detection methods in tissue sections of tumor specimens.
Cellular specificity of lactate metabolism and a novel lactate-related gene pair index for frontline treatment in clear cell renal cell carcinoma
Authors: Li Xiangsheng , Du Guangsheng , Li Liqi , Peng Ke
Published: September 2023

Background

Although lactate metabolism-related genes (LMRGs) have attracted attention for their effects on cancer immunity, little is known about their function in clear cell renal cell carcinoma (ccRCC). The aim of this study was to examine the cellular specificity of lactate metabolism and how it affected the first-line treatment outcomes in ccRCC.

Methods

GSE159115 was used to examine the features of lactate metabolism at the single-cell level. Utilizing the transcriptome, methylation profile, and genomic data from TCGA-KIRC, a multi-omics study of LMRG expression characteristics was performed. A prognostic index based on a gene-pair algorithm was created to assess how LMRGs affected patients’ clinical outcomes. To simulate the relationship between the prognostic index and the frontline treatment, pRRophetic and Subclass Mapping were used. E-MTAB-1980, E-MTAB-3267, Checkmate, and Javelin-101 were used for external validation.

Results

The variable expression of some LMRGs in ccRCC can be linked to variations in DNA copy number or promoter methylation levels. Lactate metabolism was active in tumor cells and vSMCs, and LDHA, MCT1, and MCT4 were substantially expressed in tumor cells, according to single-cell analysis. The high-risk patients would benefit from immune checkpoint blockade monotherapy (ICB) and ICB plus tyrosine kinase inhibitors (TKI) therapy, whereas the low-risk individuals responded to mTOR-targeted therapy.

Conclusions

At the single-cell level, our investigation demonstrated the cellular specificity of lactate metabolism in ccRCC. We proposed that the lactate-related gene pair index might be utilized to identify frontline therapy responders in ccRCC patients as well as predict prognosis.
Assessing the safety and use of medicinal herbs during pregnancy: a cross-sectional study in São Paulo, Brazil
Authors: Im Hyea Bin , Ghelman Ricardo , Portella Caio Fábio Schlechta , Hwang Jung Hye , Choi Dain , Kunwor Sangita Karki , Moraes Sandra Dircinha Teixeira de Araújo , Han Dongwoon
Published: September 2023

Background: Despite the lack of evidence supporting the safety and clinical efficacy of herbal medicine (HM), its use among pregnant women continues to increase. Given the high prevalence of contraindicated herbs among the pregnant population in Brazil, it is crucial to examine the use of HM and evaluate its safety based on the current scientific literature to ensure that women are using HM appropriately.

Methods: A cross-sectional study was conducted from October 2022 to January 2023 at a public teaching hospital in São Paulo, Brazil. A total of 333 postpartum women in the postnatal wards and postnatal clinic were interviewed using a semi-structured questionnaire. The survey instrument consisted of 51 items covering the use of HM during pregnancy, sociodemographic and health-related characteristics, COVID-19 experiences, and pregnancy outcomes. For data analysis, chi-square and multivariate logistic regression were conducted using SPSS ver. 26.0.

Results: Approximately 20% of respondents reported using HM during their most recent pregnancy, with a higher use observed among women from ethnic minority groups and those with prior HM experience. Among the 20 medicinal herbs identified, 40% were found to be contraindicated or recommended for use with caution during pregnancy. However, only half of the women discussed their HM use with obstetric care providers.

Conclusion: This study emphasizes the continued public health concern regarding the use of contraindicated or potentially harmful HM among pregnant women in Brazil, highlighting the need for sustained efforts to reduce the risk of inappropriate HM use. By updating antenatal care guidelines based on the latest scientific evidence, healthcare providers can make informed clinical decisions and effectively monitor pregnant women’s HM use, ultimately promoting safer and more effective healthcare practices.
Functional consequences of a rare human serotonergic 5-HT1A receptor variant
Authors: Tauber Merav , Ben-Chaim Yair
Published: September 2023

Serotonin (5-HT) plays a central role in various brain functions via the activation of a family of receptors, most of them G protein coupled receptors (GPCRs). 5-HT1A receptor, the most abundant 5-HT receptors, was implicated in many brain dysfunctions and is a major target for drug discovery. Several genetic polymorphisms within the 5-HT1A receptor gene were identified and linked to different conditions, including anxiety and depression. Here, we used Xenopus oocytes to examine the effects of one of the functional polymorphism, Arg220Leu, on the function of the receptor. We found that the mutated receptor shows normal activation of G protein and normal 5-HT binding. On the other hand, the mutated receptor shows impaired desensitization, probably due to impairment in activation of β arrestin-dependent pathway. Furthermore, while the 5-HT1A receptor was shown to exhibit voltage dependent activation by serotonin and by buspirone, the mutated receptor was voltage-independent. Our results suggest a pronounced effect of the mutation on the function of the 5-HT1A receptor and add to our understanding of the molecular mechanism of its voltage dependence. Moreover, the findings of this study may suggest a functional explanation for the possible link between this variant and brain pathologies.