bluuebunny/crossref_metadata_2025 huggingface dataset:
A crosstalk between gut and brain in sepsis-induced cognitive decline
Authors: Giridharan Vijayasree V. , Generoso Jaqueline S. , Lence Leonardo , Candiotto Gabriela , Streck Emílio , Petronilho Fabricia , Pillai Anilkumar , Sharshar Tarek , Dal-Pizzol Felipe , Barichello Tatiana
Published: May 2022

Background

Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors.

Methods

To test our hypothesis, adult Wistar rats were subjected to cecal–ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [11C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after CLP and non-CLP surgeries. At 24 h and 10 days after surgery, we evaluated the gut microbiome, bacterial metabolites, cytokines, microglia, and astrocyte markers. Ten days after sepsis induction, the animals were subjected to the novel object recognition (NOR) and the Morris water maze (MWM) test to assess their learning and memory.

Results

Compared to the control group, the 24-h and 10-day CLP groups showed increased [11C]PBR28 uptake, glial cells count, and cytokine levels in the brain. Results show that sepsis modulates the gut villus length and crypt depth, alpha and beta microbial diversities, and fecal short-chain fatty acids (SCFAs). In addition, sepsis surviving animals showed a significant cognitive decline compared with the control group.

Conclusions

Since several pharmacological studies have failed to prevent cognitive impairment in sepsis survivors, a better understanding of the function of glial cells and gut microbiota can provide new avenues for treating sepsis patients.
Poly-γ-glutamic acid/Alum adjuvanted pH1N1 vaccine-immunized aged mice exhibit a significant increase in vaccine efficacy with a decrease in age-associated CD8+ T cell proportion in splenocytes
Authors: Yang Jihyun , Kim Jaemoo , Kwak Chaewon , Poo Haryoung
Published: May 2022

Background

Highly contagious respiratory diseases caused by viral infections are a constantly emerging threat, particularly the elderly with the higher risk of developing serious complications. Vaccines are the best strategy for protection against influenza-related diseases. However, the elderly has lower vaccine efficacy than young population and the age-driven decline of the influenza vaccine efficacy remains unresolved.

Objectives

This study investigates the effect of an adjuvant, poly-γ-glutamic acid and alum (PGA/Alum) on vaccine efficacy in aged mice (18-months) and its mechanism is investigated using ovalbumin as a model antigen and a commercial pandemic H1N1 (pH1N1) flu vaccine. Antigen trafficking, dendritic cell (DC) activation, and the DC-mediated T cell activation were analyzed via in vivo imaging and flow cytometry. Antigen-specific humoral and cellular immune responses were evaluated in sera and splenocytes from the vaccinated mice. Also, we analyzed gene expression profiles of splenocytes from the vaccinated mice via single-cell transcriptome sequencing and evaluated the protective efficacy against pH1N1 virus challenge.

Results

Aged mice had lower antigen trafficking and DC activation than younger mice (6-weeks), which was ameliorated by PGA/Alum with increased antigen uptake and DC activation leading to improved antigen-specific IFN-γ+CD8+ T lymphocyte frequencies higher in the vaccinated aged mice, to a similar extent as PGA/Alum adjuvanted vaccine-immunized young mice. The results of single-cell transcriptome sequencing display that PGA/Alum also reduced the proportion of age-associated CD8+ T cell subsets and gene levels of inhibitory regulators in CD8+ T cells, which may play a role in the recovery of CD8+ T cell activation. Finally, PGA/Alum adjuvanted pH1N1 vaccine-immunized aged mice were completely protected (100% survival) compared to aged mice immunized with vaccine only (0% survival) after pH1N1 virus challenge, akin to the efficacy of the vaccinated young mice (100% survival).

Conclusions

PGA/Alum adjuvanted pH1N1 vaccine-immunized aged mice showed a significant increase in vaccine efficacy compared to aged mice administered with vaccine only. The enhanced vaccine efficacy by PGA/Alum is associated with significant increases of activation of DCs and effector CD8+ T cells and a decrease in age-associated CD8+ T cell proportion of splenocytes. Collectively, PGA/Alum adjuvanted flu vaccine may be a promising vaccine candidate for the elderly.
In vitro anti-influenza assessment of anionic compounds ascorbate, acetate and citrate
Authors: Shokouhi Targhi Hadiseh , Mehrbod Parvaneh , Fotouhi Fatemeh , Amininasab Mehriar
Published: May 2022

Background

Influenza A virus (IAV) infection remains a serious public health threat. Due to drug resistance and side effects of the conventional antiviral drugs, repurposing the available natural compounds with high tolerability and fewer side effects has attracted researchers’ attention. The aim of this study was to screen in vitro anti-influenza activity of three anionic compounds ascorbate, acetate, and citrate.

Methods

The non-cytotoxic concentration of the compounds was determined by MTT assay and examined for the activity against IAV in simultaneous, pre-, and post-penetration combination treatments over 1 h incubation on Madin-Darby Canine Kidney (MDCK) cell line. The virus titer and viral load were determined using hemagglutination assay (HA) and qPCR, respectively. Few pro-inflammatory and anti-inflammatory cytokines were evaluated at RNA and protein levels by qPCR and ELISA, respectively.

Results

The non-cytotoxic concentrations of the ascorbate (200 mg/ml), acetate and citrate (both 3 mg/ml) reduced the viral titer by 6.5, 4.5, and 1.5 logs in the simultaneous combination treatment. The M protein gene copy number decreased significantly in simultaneous treatment (P < 0.01). The expression of cytokines was also affected by the treatment of these compounds.

Conclusions

These anionic compounds could affect the influenza virus load, thereby reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines levels.
Robust network topologies for temperature-inducible bioswitches
Authors: Wu Di , Wang Hongli , Ouyang Qi
Published: May 2022

Background

Thermoinducible bioswitches are unique in that the all-or-none switch response is triggered by temperature, which is a global factor that impacts all biochemical reaction processes. To date, temperature-inducible bioswitches rely exclusively on special thermal sensing biomolecules of DNA, RNA, proteins and lipids whose conformations are critically temperature dependent.

Method

This paper extends the traditional thermal switch by utilizing purposely designed network topologies of biomolecular interactions to achieve the switching function. By assuming the general Arrhenius law for biochemical reactions, we explore the full space of all three-node genetic interaction networks to screen topologies capable of thermal bioswitches. Three target bioswitches, i.e., thermal-inducible Off–On, cold-inducible On–Off, and hybrid Off–On-Off double switches, are considered separately.

Conclusions

We identify the minimal and core network skeletons that are basic and essential for building robust high-performance bioswitches: three Off–On motifs, three On–Off motifs, and an incoherent feedforward motif for an Off–On-Off double switch. Functional topologies are implicitly preferential in choosing parameter values to achieve the target functions. The scenario of the topology-based bioswitch we propose here is an extension of molecule-based bioswitches and would be valuable in aiding the rational design and synthesis of efficient high-performance thermal bioswitches.
Circulating Th2 cell reduction and Th1/Th2 imbalance are correlated with primary Sjogren’s syndrome-associated interstitial lung disease
Authors: Shi Lei , Wang Jia , Guo Hong-Xia , Han Xiao-Lei , Tang Yu-Ping , Liu Guang-Ying
Published: May 2022

Objective

Primary Sjogren’s syndrome (pSS) is a heterogeneous chronic autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands and the involvement and dysfunction of multiple organs and tissues. Interstitial lung disease (ILD) is the most common type of respiratory system damage. This study ascertained the factors related to ILD in patients with pSS (pSS-ILD), such as altered levels of circulating lymphocyte subtypes.

Methods

Eighty healthy controls and 142 patients diagnosed with pSS were included. The pSS patients were classified into groups with pSS-ILD or pSS without ILD (pSS-non-ILD). Baseline clinical and laboratory data were collected for all subjects, including the levels of lymphocytes measured by modified flow cytometry.

Results

The pSS-ILD patients were older, had higher ESSDAI scores, had higher positivity rates for anti-SSB and anti-Ro52 antibodies, and had more frequent symptoms of respiratory system involvement than pSS-non-ILD patients. pSS-ILD patients had the lowest Th2 cell counts among the three groups. Although the absolute numbers of Treg and NK cells were lower in pSS patients with and without ILD than in the healthy controls, there was no significant difference between the two pSS groups. The Th1/Th2 ratio was significantly higher in patients with ILD than in patients without ILD. Further analysis showed that older age (OR=1.084), lower Th2 count (OR=0.947), higher Th1/Th2 ratio (OR=1.021), and positivity for anti-SSB (OR=3.620) and anti-Ro52 (OR=5.184) antibodies were associated with the occurrence of ILD in patients with pSS.

Conclusion

Decreased circulating Th2 cells and an elevated Th1/Th2 ratio may be the immunological mechanism underlying the development of ILD in pSS patients.
DNA methylation and expression profiles of placenta and umbilical cord blood reveal the characteristics of gestational diabetes mellitus patients and offspring
Authors: Lu Sha , Wang Jiahao , Kakongoma Nisile , Hua Wen , Xu Jiahui , Wang Yunfei , He Shutao , Gu Hongcang , Shi Jiantao , Hu Wensheng
Published: May 2022

Background

Gestational diabetes mellitus (GDM) is a common pregnancy-specific disease and is growing at an alarming rate worldwide, which can negatively affect the health of pregnant women and fetuses. However, most studies are limited to one tissue, placenta or umbilical cord blood, usually with one omics assay. It is thus difficult to systematically reveal the molecular mechanism of GDM and the key influencing factors on pregnant women and offspring.

Results

We recruited a group of 21 pregnant women with GDM and 20 controls without GDM. For each pregnant woman, reduced representation bisulfite sequencing and RNA-seq were performed using the placenta and paired neonatal umbilical cord blood specimens. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were identified with body mass index as a covariate. Through the comparison of GDM and control samples, 2779 and 141 DMRs, 1442 and 488 DEGs were identified from placenta and umbilical cord blood, respectively. Functional enrichment analysis showed that the placenta methylation and expression profiles of GDM women mirrored the molecular characteristics of “type II diabetes” and “insulin resistance.” Methylation-altered genes in umbilical cord blood were associated with pathways “type II diabetes” and “cholesterol metabolism.” Remarkably, both DMRs and DEGs illustrated significant overlaps among placenta and umbilical cord blood samples. The overlapping DMRs were associated with “cholesterol metabolism.” The top-ranking pathways enriched in the shared DEGs include “growth hormone synthesis, secretion and action” and “type II diabetes mellitus.”

Conclusions

Our research demonstrated the epigenetic and transcriptomic alternations of GDM women and offspring. Our findings emphasized the importance of epigenetic modifications in the communication between pregnant women with GDM and offspring, and provided a reference for the prevention, control, treatment, and intervention of perinatal deleterious events of GDM and neonatal complications.
Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer
Authors: Zhou Rui , Xie Fuli , Liu Kuncai , Zhou Xuee , Chen Xuemei , Chen Jinzhang , Xi Shaoyan , Huang Zhenhua , Rong Xiaoxiang
Published: May 2022

Background

Alterations in histone modifications have been reported to be related to tumorigenicity and tumor progression. However, whether histone modification can aid the classification of patients or influence clinical behavior in patients with colon cancer remains unclear. Therefore, this study aimed to evaluate histone modifier expression patterns using the unsupervised clustering of the transcriptomic expressions of 88 histone acetylation and methylation regulators.

Results

In this study, by consensus clustering analysis based on the transcriptome data of 88 histone modification regulators, we identified four distinct expression patterns of histone modifiers associated with different prognoses, intrinsic fluorouracil sensitivities, biological pathways, and tumor microenvironment characteristics among 1372 colon cancer samples. In these four clusters, the HMC4 cluster represented a stroma activation phenotype characterized by both the worst prognosis and lowest response rates to fluorouracil treatment. Then, we established a scoring scheme comprising 155 genes designated as “HM_score” by using the Boruta algorithm to distinguish colon cancer patients within the HMC4 cluster. Patients with a high HM_score were considered to have high stromal pathway activation, high stromal fraction, and an unfavorable prognosis. Further analyses indicated that a high HM_score also correlated with reduced therapeutic benefits from fluorouracil chemotherapy. Moreover, through CRISPR library screening, ZEB2 was found to be a critical driver gene that mediates fluorouracil resistance, which is associated with histone modifier expression patterns.

Conclusions

This study highlights that characterizing histone modifier expression patterns may help better understand the epigenetic mechanisms underlying tumor heterogeneity in patients with colon cancer and provide more personalized therapeutic strategies.
Genome-wide promoter methylation profiling in a cellular model of melanoma progression reveals markers of malignancy and metastasis that predict melanoma survival
Authors: Rius Flávia E. , Papaiz Debora D. , Azevedo Hatylas F. Z. , Ayub Ana Luísa P. , Pessoa Diogo O. , Oliveira Tiago F. , Loureiro Ana Paula M. , Andrade Fernando , Fujita André , Reis Eduardo M. , Mason Christopher E. , Jasiulionis Miriam G.
Published: May 2022

The epigenetic changes associated with melanoma progression to advanced and metastatic stages are still poorly understood. To shed light on the CpG methylation dynamics during melanoma development, we analyzed the methylome profiles of a four-stage cell line model of melanoma progression: non-tumorigenic melanocytes (melan-a), premalignant melanocytes (4C), non-metastatic melanoma cells (4C11−), and metastatic melanoma cells (4C11+). We identified 540 hypo- and 37 hypermethylated gene promoters that together characterized a malignancy signature, and 646 hypo- and 520 hypermethylated promoters that distinguished a metastasis signature. Differentially methylated genes from these signatures were correlated with overall survival using TCGA-SKCM methylation data. Moreover, multivariate Cox analyses with LASSO regularization identified panels of 33 and 31 CpGs, respectively, from the malignancy and metastasis signatures that predicted poor survival. We found a concordant relationship between DNA methylation and transcriptional levels for genes from the malignancy (Pyroxd2 and Ptgfrn) and metastasis (Arnt2, Igfbp4 and Ptprf) signatures, which were both also correlated with melanoma prognosis. Altogether, this study reveals novel CpGs methylation markers associated with malignancy and metastasis that collectively could improve the survival prediction of melanoma patients.
Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease: a discovery cohort study
Authors: Vrillon Agathe , Mouton-Liger François , Martinet Matthieu , Cognat Emmanuel , Hourregue Claire , Dumurgier Julien , Bouaziz-Amar Elodie , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Hugon Jacques , Paquet Claire
Published: May 2022

Background

Synaptic dysfunction is an early core feature of Alzheimer’s disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest.

Objective

To measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers.

Methods

This retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD-MCI,n= 27) and at dementia stage (n= 35), non-AD dementia (n= 26, Aβ-negative), non-AD MCI (n= 19), and neurological controls (n=20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho-tau, and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP-43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP-25.

Results

Plasma NRG1 concentration was higher in AD-MCI and AD dementia patients compared with neurological controls (respectivelyP =0.005 andP< 0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β= 0.372,P= 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ-positive patients (β= −0.197–0.423). Plasma NRG1 correlated with CSF GAP-43, neurogranin, and SNAP-25 (β= 0.278–0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ-positive patients (all,β= −0.188,P= 0.038; Aβ+:β= −0.255,P= 0.038).

Conclusion

Plasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers and cognitive status. Thus, plasma NRG1 is a promising non-invasive biomarker to monitor synaptic impairment in AD.
Interventions for the management of Pain and Sedation in Newborns undergoing Therapeutic hypothermia for hypoxic-ischemic encephalopathy (IPSNUT): protocol of a systematic review
Authors: Bäcke Pyrola , Bruschettini Matteo , Blomqvist Ylva Thernström , Olsson Emma
Published: May 2022

Background

Clinical research has shown that therapeutic hypothermia after neonatal hypoxic-ischemic injury improves survival without disability. There is no consensus regarding pain relief or sedation during therapeutic hypothermia in newborns; however, therapeutic hypothermia seems to be associated with pain and stress, and adequate analgesia and sedation are central to maximize the effect of therapeutic hypothermia. Pain needs to be adequately managed in all patients, especially the newborn infant due to the potential short- and long-term negative effects of inadequately treated pain in this population.

Methods

We will perform a systematic review of pharmacological and non-pharmacological interventions for the management of pain and sedation in newborn infants undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy. We will include randomized, quasi-randomized controlled trials and observational studies. The use of pharmacological or non-pharmacological interventions will be compared to other pharmacological and or non-pharmacological interventions or no intervention/placebo. The primary outcomes for this review will be analgesia and sedation assessed with validated pain scales, circulatory instability, mortality to discharge, and moderate-to-severe neurodevelopmental disability. We will search the following databases: CINAHL, ClinicalTrials.gov, Cochrane Library, Embase, PubMed, Scopus, and Web of Science. Two independent researchers will screen the records for inclusion, extract data using a data extraction form, and assess the risk of bias in the included trials.

Discussion

The result of this review will summarize the knowledge regarding the management of pain and sedation in infants treated with therapeutic hypothermia and potentially provide clinicians with guidance on the effective and safe methods.

Systematic review registration

PROSPERO CRD42020205755
Optimal control of stochastic singular affine systems with Markovian jumps
Authors: Wang Xin , Wang Lisha , Liu Yuxiang
Published: May 2022

We consider an optimal control problem for a class of stochastic singular affine systems with Markovian jumps. We establish the existence and uniqueness of the solution to stochastic singular affine systems with Markovian jumps for the first time. Via square completion technique and the generalized Itô’s formula, we derive new kinds of generalized differential Riccati equations (GDREs) and generalized backward differential equations (GBDEs), which give sufficient conditions for the well-posedness of the optimal control problem, and present an explicit representation of optimal control. Also, we discuss the solvability of the GDREs in two cases. As an application, we present a leader-follower differential game to demonstrate the practicability of our results.
An uncertain production-inventory problem with deteriorating items
Authors: Shen Jiayu , Jin Yueqiang , Liu Bing , Lu Ziqiang , Chen Xin
Published: May 2022

The uncertain production-inventory problem with deteriorating items is investigated and an optimal control model is developed in the present paper. The uncertain production-inventory problem is perturbed by an uncertain canonical process. Based on uncertainty theory, an optimistic-value optimal-based control model is established. The present study aims to find the optimistic value of revenue at a certain confidence level. The uncertainty theory is used to obtain the equation of optimality. Using the Hamilton–Jacobi–Bellman principle, a nonlinear partial differential equation that has to be satisfied by a value function is obtained. Assuming a specific form of the solution, backsubstituting the partial differential equation to find functions of time is conducted, and the functions are then used to solve the partial differential equation. Numerical experiments with different demand functions are used to assess the feasibility of this model and this method.
Factors affecting intention to screen after being informed of benefits and harms of breast cancer screening: a study in 5 European countries in 2021
Authors: Ritchie David , Van Hal Guido , Van den Broucke Stephan
Published: May 2022

Background

Participation in mammography screening comes with harms alongside benefits. Information about screening provided to women should convey this information yet concerns persist about its effect on participation. This study addressed factors that may influence the intention to screen once a woman has been informed about benefits and harms of participation.

Methods

A cross-sectional survey of women from five countries (Belgium, France, Italy, Spain, and the United Kingdom) was performed in January 2021. The survey contained a statement regarding the benefits and harms of mammography screening along with items to measure cognitive variables from the theory of planned behaviour and health belief model and the 6-item version of the European Health Literacy Survey Questionnaire (HLS-EU-Q6). Logistic regression and mediation analysis were performed to investigate the effect of cognitive and sociodemographic variables.

Results

A total of 1180 participants responded to the survey. 19.5% of participants (n = 230) were able to correctly identify that mammography screening carries both benefits and harms. 56.9% of participants (n = 672) responded that they would be more likely to participate in screening in the future after being informed about the benefits and harms of mammography screening. Perceived behavioural control and social norms demonstrated were significant in predicting intention, whereas, the effect of health literacy was limited.

Conclusions

Informing women about the presence of benefits and harms of in mammography screening participation did not negatively impact upon intention to be screened. Information should also address perception on implementation factors alongside messages on benefits and harms. Overall, screening programme managers should not be discouraged by the assumption of decreased participation through increasing efforts to address the lack of knowledge on benefits and harms.
Fungi associated with the potato taste defect in coffee beans from Rwanda
Authors: Hale Amanda R. , Ruegger Paul M. , Rolshausen Philippe , Borneman James , Yang Jiue-in
Published: May 2022

Background

Potato taste defect (PTD) of coffee is characterized by a raw potato like smell that leads to a lower quality taste in the brewed coffee, and harms the commercial value of some East African coffees. Although several causes for PTD have been proposed, none of them have been confirmed. Recently, high throughput sequencing techniques and bioinformatic analysis have shown great potential for identifying putative causal agents of plant diseases. Toward the goal of determining the cause of PTD, we examined raw coffee beans from Rwanda exhibiting varying PTD scores using an Illumina-based sequence analysis of the fungal rRNA ITS region.

Results

Six fungal amplicon sequence variants (ASVs) with high relative abundances correlated with coffee taste scores. Four of these ASVs exhibited negative correlations – Aspergillus versicolor, Penicillium cinnamopurpureum, Talaromyces radicus, and Thermomyces lanuginosus – indicating that they might be causing PTD. Two of these fungi exhibited positive correlations – Kazachstania humilis and Clavispora lusitaniae – indicating that they might be inhibiting organisms that cause PTD.

Conclusions

This study addressed PTD causality from a new angle by examining fungi with high throughput sequencing. To our knowledge, this is the first study characterizing fungi associated with PTD, providing candidates for both causality and biocontrol.
Issues related to velocity structure estimation in small coastal sedimentary plains: case of Tottori plain facing the Sea of Japan
Authors: Kagawa Takao , Noguchi Tatsuya
Published: May 2022

Issues of predominant period of ground motion and derived underground velocity structure model are investigated in the coastal plains affected by the shallow soft sedimentary layer after the last ice age. It is found that two predominant periods due to the shallow soft layer and deeper drastic sedimentary boundaries are close in a small plain such as the Tottori plain, Japan as an example. This study analyzes the underground velocity structure derived from EHVSR (H/V spectrum ratio of earthquake ground motions) with the diffuse field theory. It is considered that the interaction of close predominant periods due to the different layer boundaries with high contrast may amplify the seismic ground motion in the period range that affects building structures in small plains in coastal area.

Graphical Abstract
Trialling a microbiome-targeted dietary intervention in children with ADHD—the rationale and a non-randomised feasibility study
Authors: Lawrence Kate , Myrissa Kyriaki , Toribio-Mateas Miguel , Minini Lori , Gregory Alice M.
Published: May 2022

Background

Dietary interventions have been previously explored in children with ADHD. Elimination diets and supplementation can produce beneficial behaviour changes, but little is known about the mechanisms mediating change. We propose that these interventions may work, in part, by causing changes in the gut microbiota. A microbiome-targeted dietary intervention was developed, and its feasibility assessed.

Methods

A non-randomised feasibility study was conducted on nine non-medicated children with ADHD, aged 8–13 years (mean 10.39 years), using a prospective one-group pre-test/post-test design. Participants were recruited from ADHD support groups in London and took part in the 6-week microbiome-targeted dietary intervention, which was specifically designed to impact the composition of gut bacteria. Children were assessed pre- and post-intervention on measures of ADHD symptomatology, cognition, sleep, gut function and stool-sample microbiome analysis. The primary aim was to assess the study completion rate, with secondary aims assessing adherence, adverse events (aiming for no severe and minimal), acceptability and suitability of outcome measures.

Results

Recruitment proved to be challenging and despite targeting 230 participants directly through support groups, and many more through social media, nine families (of the planned 10) signed up for the trial. The completion rate for the study was excellent at 100%. Exploration of secondary aims revealed that (1) adherence to each aspect of the dietary protocol was very good; (2) two mild adverse events were reported; (3) parents rated the treatment as having good acceptability; (4) data collection and outcome measures were broadly feasible for use in an RCT with a few suggestions recommended; (5) descriptive data for outcome measures is presented and suggests that further exploration of gut microbiota, ADHD symptoms and sleep would be helpful in future research.

Conclusions

This study provides preliminary evidence for the feasibility of a microbiome-targeted dietary intervention in children with ADHD. Recruitment was challenging, but the diet itself was well-tolerated and adherence was very good. Families wishing to trial this diet may find it an acceptable intervention. However, recruitment, even for this small pilot study, was challenging. Because of the difficulty experienced recruiting participants, future randomised controlled trials may wish to adopt a simpler dietary approach which requires less parental time and engagement, in order to recruit the number of participants required to make meaningful statistical interpretations of efficacy.

Trial registration

ClinicalTrials.gov Identifier: NCT03737877. Registered 13 November 2018—retrospectively registered, within 2 days of the first participant being recruited.
Two new species of Dugesia (Platyhelminthes, Tricladida, Dugesiidae) from the subtropical monsoon region in Southern China, with a discussion on reproductive modalities
Authors: Chen Guang-wen , Wang Lei , Wu Fan , Sun Xiao-juan , Dong Zi-mei , Sluys Ronald , Yu Fei , Yu-wen Yan-qing , Liu De-zeng
Published: May 2022

Background

Freshwater planarians of the genus Dugesia (Platyhelminthes, Tricladida, Dugesiidae) are distributed in a major part of the Old World and Australia, although until recently only very few species were known from China.

Results

Two new species of Dugesia from Southern China are described on the basis of an integrative taxonomic approach. BI and ML phylogenetic trees based on the independent genes and on the concatenated dataset had similar topologies, only differing in some nodes that were weakly supported. Phylogenetic trees based on the concatenated dataset revealed that D. adunca Chen & Sluys, sp. nov. and D. tumida Chen & Sluys, sp. nov. are not closely related and belong to different clades. The two new species occupy separate long branches with high support values and, thus, are well-differentiated from their congeners. Separate species status of D. adunca and D. tumida is supported also by the genetic distances between the species included in our analysis, albeit that COI distances varied greatly among species. Dugesia adunca from Guangxi Province is characterized by the following features: living mature animals rather small; asymmetrical openings of the oviducts into the bursal canal; penis papilla with shape of an aquiline bill, albeit with a blunt tip; asymmetrical penis papilla, with a large antero-dorsal lip and a much smaller ventro-posterior lip; very large seminal vesicle, provided with trabeculae; small diaphragm; mixoploid karyotype with diploid complements of 2n = 2x = 16 and triploid complements of 2n = 3x = 24, with all chromosomes being metacentric. Dugesia tumida from Guangdong Province is characterized by a penis papilla provided with a large, symmetrical penial valve from the middle of which arises the small, distal section of the papilla; a duct intercalated between the seminal vesicle and the small diaphragm; ventrally displaced ejaculatory duct curving upwards before opening to the exterior; penis papilla highly asymmetrical, having a slim and long ventral portion and a short and stubby dorsal part; vasa deferentia separately opening into antero-dorsal portion of seminal vesicle; oviducts openings symmetrically into ventral portion of the bursal canal, near its opening into the atrium; mixoploid karyotype, with diploid chromosome portraits of 2n = 2x = 16, and triploid complements of 2n = 3x = 24, with all chromosomes being metacentric. In the context of the various kinds of mixoploidy and the sexualization of specimens, reproductive modalities within the genus Dugesia are shortly discussed.

Conclusion

Molecular, morphological, and karyological markers show that the two populations examined represent members of the genus Dugesia and constitute two new, distinct species.
Utilizing cross-product prior knowledge to rapidly de-risk chemical liabilities in therapeutic antibody candidates
Authors: Jacobitz Alex W. , Rodezno Wilfredo , Agrawal Neeraj J.
Published: May 2022

There is considerable pressure in the pharmaceutical industry to advance better molecules faster. One pervasive concern for protein-based therapeutics is the presence of potential chemical liabilities. We have developed a simple methodology for rapidly de-risking specific chemical concerns in antibody-based molecules using prior knowledge of each individual liability at a specific position in the molecule’s sequence. Our methodology hinges on the development of sequence-aligned chemical liability databases of molecules from different stages of commercialization and on sequence-aligned experimental data from prior molecules that have been developed at Amgen. This approach goes beyond the standard practice of simply flagging all instances of each motif that fall in a CDR. Instead, we de-risk motifs that are common at a specific site in commercial mAb-based molecules (and therefore did not previously pose an insurmountable barrier to commercialization) and motifs at specific sites for which we have prior experimental data indicating acceptably low levels of modification. We have used this approach successfully to identify candidates in a discovery phase program with exclusively very low risk potential chemical liabilities. Identifying these candidates in the discovery phase allowed us to bypass protein engineering and accelerate the program’s timeline by 6 months.
A dengue-like outbreak of unknown aetiology in Pakistan
Authors: Merchant Hamid A.
Published: May 2022

There were recent reports of a mysterious virus spreading in Pakistan causing dengue-like illness with hundreds of cases admitted to hospitals over the winter. The mysterious virus was touted as a new variant of the dengue virus by the local health experts in Pakistan as most patients were tested negative for the dengue virus test despite presenting with dengue-like symptoms. In this letter, we have critically appraised the current situation in Pakistan in an attempt to explain the science and mechanism behind recent dengue-like outbreak, offered suggestions on diagnostic tests and provided recommendations to improve medication safety in Pakistan.
Efficacy and safety of oral pharmacological and supplementary therapies in bladder pain syndrome: a systematic review
Authors: Widyadharma I Putu Eka , Dewi Valentina Tjandra , Wijayanti Ida Ayu Sri , Santosa Kadek Budi
Published: May 2022

Treatment goals in bladder pain syndrome (BPS) or interstitial cystitis (IC) focusing on relieving symptoms to improve quality of life and avoiding adverse events (AEs) since curative treatment for BPS/IC is not available. The readily available pharmacologic options for BPS/IC including oral, intravesical, and transdermal therapy. The purpose of this study is to review randomized trial studies over the last 15 years examining the efficacy and safety of oral pharmacological and supplementary therapies for BPS/IC. A systematic search was conducted in PubMed and Medline Library. Only randomized-controlled trials and randomized comparative trials published between 2005 and 2020 on the efficacy and safety of oral therapies for BPS/IC were included. The keywords used were “bladder pain syndrome”, or “interstitial cystitis”, and “random” or “trial”. From 629 articles, nine were included in this review. Oral therapies included consist of cyclosporine A (CyA), amitriptyline, amitriptyline plus alpha lipoic acid (ALA) and omega-3 fatty acids (n-3 PUFA), PD-0299685, sildenafil, pentosan polysulfate sodium (PPS), AQX-1125, and hydrogen-rich water. Among retrieved trials, amitriptyline in combination with ALA and n-3 PUFA, sildenafil, and cyclosporine A proved their efficacy for BPS/IC. Sildenafil was generally well tolerated, while amitriptyline and CyA must be used with caution, the supplementation of ALA/n-3 PUFAs possibly lower dosage of amitriptyline, subsequently reduce its AEs. CyA was superior to PPS but possessed greater AEs. Further studies focusing on etiopathology and phenotype differentiation of this syndrome will greatly contribute to the development of effective therapy.
Anticonvulsant activity and mechanism of actions of fractions of Ipomoea asarifolia (Desr) (Convolvulaceae) ethanol leaf extract
Authors: Chiroma Samaila S. , Nazifi Abdullahi B. , Jamilu Ya’u , Musa Aliyu , Bichi Lawal A. , Chiroma Samaila M.
Published: May 2022

Background

Preparation of Ipomoea asarifolia (Desr) (Convolvulaceae) is widely used in traditional African medicine for the treatments of different kinds of ailments such as syphilis, malaria, convulsions and rheumatism.

Aim

The anticonvulsant properties of fractions of leaf of Ipomoea asarifolia (Desr); n-butanol (BF), chloroform, n-hexane and residual aqueous fractions (RAF) were evaluated on animals.

Results

The RAF at dose of 75 mg/kg (P < 0.01) with 33% quantal protection and 83% protection against mortality is the most active fraction when compared with BF at 300 mg/kg (P < 0.01) with no quantal protection and 83% protection against mortality; the anti-seizure activity could be because of the presence of saponins (23.3%) and flavonoids (43.92%). The RAF may also owes its anticonvulsant activity via GABAergic pathway as flumazenil at 2 mg/kg significantly (P < 0.05) blocked the activity of RAF, via glutamatergic pathway with RAF (P < 0.05) significantly reversing the proconvulsive activity of ketamine at 200 mg/kg as compared to ketamine alone. Opioidergic pathway may also be implicated as naloxone 1 mg/kg significantly (P < 0.05) reduced the anticonvulsant effect of RAF.

Conclusions

BF and RAF of leaf of Ipomoea asarifolia have shown anticonvulsants activities in PTZ-induced seizures. RAF was observed to be the most active fraction of Ipomoea asarifolia extract which probably exerts its action through GABAergic, glutamatergic and opioidergic pathways.
Isothermal microcalorimetry (IMC) calscreener: automated peculiarities of antimicrobial therapy and metabolism depth of multidrug resistant bacteria
Authors: Bayode Michael Tosin , Alabi Mercy Adewumi , Babatunde Olamide Joshua , Sadibo Muyideen Enitan , Lawani Blessing Temitope , Okiti Ayomide Faith , Elabiyi Michael Omoniyi , Lawrence Damilola Israel
Published: May 2022

Background

The global development of innovative antimicrobial drugs and drug design techniques has been necessitated by the persistent increase of multidrug resistant infections. Regardless of advances in technology for detecting pathogenic bacteria and their resistance genes (DNA-based assays), most bacteriological studies of infections still use conventional cultural techniques and susceptibility testing as reference standards. Commonly used conventional assays such as the disc diffusion test and broth micro-dilution have been effective in defining pathogen susceptibility and determining the minimum inhibitory concentration of antimicrobial agents. However, they are still prone to error and time consuming, hence, not sufficient in the face of the urgent need for answers to sporadic worldwide disease maladies.

Main body

In this review, we describe a developing but promising method for gauging/measuring the amount of energy released when a cell is actively metabolizing, which may then be used to calculate the bacterial cell's growth rate. The isothermal microcalorimetry (IMC) calscreener translate heat production of cellular metabolism which is pertinent to the operation of all biological life in demonstrating a more advanced technique for drug design and discovery, especially in the area of pathogen-specific chemotherapy.

Conclusion

The IMC calscreener technology is sacrosanct in establishing the heat levels in microwatt to read the metabolic kinematics of biological specimens with emphasis on medically-relevant bacteria within a closed scheme. The application of this technology also looks promising in antimicrobial chemotherapy and metal recovery.
High parasitaemia correlates with malaria episodes and the socioeconomic impact of recurrent malaria infection in high-transmission zone of Nigeria
Authors: Babamale Abdulkareem Olarewaju , Abdulkareem Adam Olaitan , Yinka Oyewole Jamiu , Folasade Kolawole , Olatundun Babawale Oluwapelumi , Ayodipo Onitayo Faith , Uddin Mohammad Mosleh , Ugbomoiko Uade Samuel
Published: May 2022

Background

Recurrent malaria infection is a major phenomenon in a hightransmission zone with deplorable health and socioeconomic consequences on individuals and the public. However, the association between parasitaemia, repeated episodes of the infection, and its socioeconomic impact is less studied. Therefore, this study aimed at bridging this research gap by conducting an epidemiological survey in selected malaria-endemic settings of Kwara state, Nigeria.

Results

High prevalence and intensity of infection were observed, 56.6% of 572 study participants were infected with average parasitaemia of 3022.25 ± 1001.51 per µl of blood and the majority of heavy infection was due toPlasmodium falciparum. The heavily asymptomatic infected participants were among the younger age group particularly ≤ 20 years, and infection decreases with increasing age. Parasitaemia and the number of episodes of malaria attacks were positively correlated (R2 = 0.2388,p < 0.0001). Highrecurrent malaria was associated with male (p = 0.001), younger age (p = 0.0012), low-income status (p = 0.0004), bush around habitation (0.0014), and unavoidability of preventive strategies and treatment (p < 0.0001) of malaria. Our study further revealed socioeconomic factors as cause and/or consequence of recurrent malaria infection. Low income individuals (aOR 1.948 95%CI 0.945–2.512) and illiterates (aOR 1.920 95%CI 1.470–2.149), those living close to bush (aOR 2.501 95%CI 2.033–3.714) and dumpsite (aOR 2.718 95%CI 1.661–3.118) are at least twice likely to have recurrent infection. The socioeconomic consequence of recurrent malaria episodes includes reduced economic activities, personal savings, and change of lifestyle in adults, while infected children suffered declined academic performance and sports activities.

Conclusions

This study underscores high malaria intensity as a prevalent health problem in our study location and demonstrates a positive correlation between malaria episodes and parasitaemia which can be explored in the clinic for the screening of suitable antimalarial drugs that cure beyond a single infection. Our finding also advocates for mass distribution of insecticide-treated nets, provision of socio-infrastructural amenities such as medical centers, good drainage system and highly subsidized malaria treatment in endemic endemic rural communities
Effect of biological disease-modifying antirheumatic drugs on body composition in patients with rheumatoid arthritis: a systematic review and meta-analysis
Authors: de Souza Mariana Peixoto Guimarães Ubirajara , Guimarães Nathalia Sernizon , de Resende Guimarães Maria Fernanda Brandão , de Souza Viviane Angelina , Kakehasi Adriana Maria
Published: May 2022

Background

Rheumatoid arthritis (RA) generates an inflammatory profile that predisposes to total and visceral fatty accumulation and reduced fat free mass (FFM). This metabolic disorder contributes to poor functionality, increased cardiovascular risk and higher mortality. This study aimed to address a systematic review with meta-analysis to determine the effect of biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) on body composition (BC) of patients with RA.

Methods

The search was conducted at the electronic databases PubMed, Cochrane Library, Embase, Lilacs and grey literature. This investigation was carried until July 2021. Outcomes of interest were total weight, body mass index (BMI), fat mass (FM) and FFM. A meta-analysis comparing these outcomes in RA patients under bDMARD treatment versus controls was performed.

Results

Out of 137 studies reviewed, 18 were selected: fifteen prospective cohorts, two retrospective cohorts, and one cross-sectional study. The studies comprised 1221 patients, 778 on bDMARD treatment and 443 controls, which included RA patients under conventional synthetic DMARD (csDMARD). No study addressing BC analysis in patients using tsDMARD was found. The mean age and duration of the disease was 56.7 years and 6.77 years, respectively. Ten studies demonstrated a significant increase of total weight in 88.2% of patients and 42.3% for BMI. In studies that analyzed BC by double X-ray absorptiometry (DXA), the increase in total weight and BMI correlated positively to the increase in FFM. The meta-analysis carried out in five studies showed no significant difference of the mean difference for total weight 0.12 kg (95% CI − 5.58, 5.82), BMI 0.08 kg/m2 (95% CI − 1.76, 1.92), FM − 0.08 kg (95% IC − 5.31, 5.14), and FFM − 2.08 kg (95% CI − 7.37, 3.21).

Conclusion

This systematic review suggests a possible impact of bDMARDs on BC of RA patients, even though, the meta-analysis carried out in a small part of these studies was not able to confirm significant variation in BC components.

Trial registration: PROSPERO code: CRD42020206949.