Recent publications
The complex and heterogeneous nature of Parkinson's disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients. Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD. Experimental work performed in induced pluripotent stem cells (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. This was accompanied by increased α-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation - located in the calcium-binding domain of the GTPase - disrupted calcium homeostasis. This resulted in the calcium-dependent activation of calpain proteases and the subsequent cleavage of α-synuclein. Knock-in mice expressing p.R285Q Miro1 (the orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated α-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra, accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.
Long-term alterations of the gut microbiota and host symbiosis after a dietary perturbation remain insufficiently understood and characterized. In this study, we investigate the impact of temporary dietary fiber depletion in mice that received a diet with reduced fiber content (RFD) for 3 weeks followed by a return to a standard chow diet for 6 weeks, compared to mice that only received a chow diet. Fiber deprivation was accompanied by a reduction of microbiota diversity and an increase in mucolytic and sulfate-reducing bacteria. The activities of enzymes targeting glycans from the host mucus were increased accordingly, while those targeting plant fibers were decreased. On the host side, we report transiently higher quantities of host DNA in feces during the RFD suggesting an impaired gut barrier function. Six weeks after the return to the chow diet, lasting changes in microbiota composition were observed, as exemplified by the replacement of durably depleted amplicon sequence variants close to Duncaniella dubosii by other members of the Muribaculaceae family. The observation of two distinct gut microbial communities in mice under identical environmental and alimentary conditions at the end of the experiment suggests the existence of alternative stable microbiota states.
IMPORTANCE
In this article, the authors explore the impact of a diet with reduced fiber content on the gut microbiota-host symbiosis in a mouse model. More importantly, they examine the resilience of the intestinal symbiosis after the return to a standard (chow) diet. Some of the measured parameters (intestinal barrier impairment and bacterial glycan-degrading enzymatic activities) returned to control values. However, this was not the case for bacterial richness—the number of different bacteria observed—which remained durably reduced. Among related bacteria, some groups receded and remained undetected until 6 weeks after the return to the chow diet while others saw their abundance increase in replacement. The authors find that a temporary fiber deprivation lasting as little as 3 weeks can cause a transition to an alternative stable microbiota state, i.e., a lasting change in intestinal microbiota composition.
Background
PQ Grass 27600 SU (PQ Grass) cumulative dose is a pre‐seasonal, six‐injection, aluminium‐free, modified subcutaneous immunotherapy product under development for the treatment of allergic rhinitis (AR). A pivotal Phase III randomised double‐blind, placebo‐controlled clinical trial was performed to evaluate the efficacy and safety of PQ Grass in subjects with seasonal AR.
Methods
An adaptive group sequential trial PQGrass306 (G306) with one pre‐defined interim analysis was designed, using 2 parallel groups applying a 1:1 active versus placebo randomisation of patients aged 18–65. The primary efficacy endpoint was the EAACI (European Academy of Allergy and Clinical Immunology) Combined Symptom and Medication Score (EAACI‐CSMS0–6) averaged over the peak grass pollen season (GPS).
Results
858 subjects were screened and 555 subjects were randomised. Based on the results of the pre‐defined interim analysis, the trial was stopped for success showing superiority in favour of PQ Grass. The primary endpoint EAACI‐CSMS0–6 (peak GPS) demonstrated a highly significant and clinically meaningful point difference of PQ Grass over placebo of −0.27 points (95% CI: −0.42 to −0.12), corresponding to a relative difference of −20.3% (p = 0.0005). Highly consistent and beneficial results were obtained for PQ Grass for all key secondary endpoints. Significant induction of blocking IgG4 and IgA antibody subclasses occurred. PQ Grass was well tolerated, and no unexpected safety signals occurred.
Conclusions
This pivotal Phase III trial demonstrated a significant and clinically meaningful effect on the primary endpoint as well as highly consistent secondary endpoint results and a supportive safety profile.
Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27 Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.
We report a case of wild-type rubella virus (genotype 2B) granuloma in a 29-year-old immunocompromised patient with a full vaccination scheme. He had been followed since his early teens for an unlabeled systemic inflammatory disease. On an inguinal node biopsy, histological analysis revealed a nguudiffuse non-necrotic granulomatous inflammation with no identified conventional infectious agent involved in granuloma formation. Further virological investigation revealed rubella virus (RuV) RNA detected by reverse transcription polymerase chain reaction (RT-PCR). Wild-type viral RNA persistence was documented in plasma samples collected up to 25 months after initial detection and also in different sequential biological samples (cerebrospinal fluid and nasopharyngeal swab). In the context of incomplete rubella eradication, RuV must be added to the list of potential triggers of chronic granuloma in immunodeficient patients.
IMPORTANCE
Rubella has become rare but has not yet disappeared. Rubella virus (RuV) must be added to the list of potential triggers of granuloma, particularly in immunodeficient patients. Diagnosis of RuV granulomas requires molecular testing of biopsy. RuV sequencing distinguishes between wild-type and vaccine-derived viruses and enables epidemiological surveillance.
Growing evidence indicates that type 2 diabetes (T2D) is associated with an increased risk of developing Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism and survival. To investigate insulin resistance caused pathological changes in the human midbrain, which could predispose a healthy midbrain to PD development, we exposed iPSC-derived human midbrain organoids from healthy individuals to either high insulin concentration, promoting insulin resistance, or to more physiological insulin concentration restoring insulin signalling function. We combined experimental methods with metabolic modelling to identify the most insulin resistance-dependent pathogenic processes. We demonstrate that insulin resistance compromises organoid metabolic efficiency, leading to increased levels of oxidative stress. Additionally, insulin-resistant midbrain organoids showed decreased neuronal activity and reduced amount of dopaminergic neurons, highlighting insulin resistance as a significant target in PD prevention.
Background: The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines classify rhinitis as "intermittent" or "persistent" and "mild" or "moderate-severe". Objectives: To assess ARIA classes in a real-world study in terms of phenotypic differences and their association with asthma. Methods: We performed a cross-sectional real-world study based on users of the MASK-air® app who reported data for at least 3 different months. We assessed the frequency of users according to the ARIA classes and compared these classes in terms of rhinitis symptoms, use of comedication, frequency of comorbid asthma, and the association between comorbid asthma and rhinitis control. Results: A total of 2273 users (180 796 days) were assessed. Most users had moderate-severe rhinitis (n=2003; 88.1%) and persistent rhinitis (n=1144; 50.3%). The frequency of patients with probable asthma was 35.7% (95%CI, 34.5%-37.0%) for intermittent rhinitis and 48.5% (95%CI, 47.1%-49.9%) for persistent rhinitis. The maximum values on the visual analog scale (VAS) for rhinitis symptoms and the combined symptom-medication score were lower in patients with mild rhinitis than in those with moderate-severe rhinitis (irrespective of whether they had persistent or intermittent rhinitis). In most ARIA classes, VAS nose and VAS eye and rhinitis comedication were more frequent in patients with rhinitis+asthma than in those with rhinitis alone. Conclusion: This study suggests that the presence of asthma is more closely related to persistence of rhinitis than to severity and that the presence of comorbid asthma may be associated with poorer control of rhinitis across the different ARIA classes.
Limited literature addresses the association between pollution, stress, and obesity, and knowledge synthesis on the associations between these three topics has yet to be made. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases to identify studies dealing with the effects of semi‐volatile organic compounds, pesticides, conservatives, and heavy metals on the psychosocial stress response and adiposity in humans, animals, and cells. The quality of papers and risk assessment were evaluated with ToxRTool, BEES‐C instrument score, SYRCLE's risk of bias tool, and CAMARADES checklist. A protocol for the systematic review was registered on PROSPERO. Of 1869 identified references, 63 were eligible after title and abstract screening, 42 after full‐text reading, and risk of bias and quality assessment. An important body of evidence shows a positive association between pollution, stress response, and obesity. Pollution stimulates the hypothalamic–pituitary–adrenal axis by activating the glucocorticoid receptor signaling and transcriptional factors responsible for adipocyte differentiation, hyperphagia, and obesity. Endocrine‐disrupting chemicals also alter the Peroxisome Proliferator‐activated Receptor gamma pathway to promote adipocyte hyperplasia and hypertrophy. However, these associations depend on sex, age, and pollutant type. Our findings evidence that pollution promotes stress, leading to obesity.
Oxidative stress contributes to the development of cardiometabolic diseases and cancers. Numerous studies have highlighted the adverse effects of high reactive oxygen species (ROS) levels in the progression of chronic noncommunicable diseases and also during infections. On the other hand, antioxidants play a crucial role in preventing oxidative stress or postponing cell damage via the direct scavenging of free radicals or indirectly via the Keap1/Nrf2/ARE pathway, among others. Dietary antioxidants can be obtained from various sources, mainly through a plant-based diet, including fruits and vegetables. The dietary antioxidant index (DAI) has been developed to assess total antioxidant intake from diet. This review delineated the performance of DAI in the risk assessment of different diseases. It is suggested that a high DAI score prevents obesity-related diseases, including diabetes mellitus, hyperuricemia, dyslipidemia, and metabolic (dysfunction)-associated steatotic liver disease (MASLD). Additionally, DAI is negatively associated with Helicobacter pylori and Human papillomavirus infection, thus reducing the risk of gastric and cervical cancer. Also, a high intake of antioxidants prevents the development of osteoporosis, miscarriage, infertility, and mental illnesses. However, further prospective observations and clinical trials are warranted to confirm the application of DAI in preventing diseases that have been studied.
Background
Co‐pathology between Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α‐synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity.
Method
As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers. CSF Aß1‐42, p‐tau181, NfL, and α‐Syn were centrally measured using NeuroToolKit (Roche Diagnostics International Ltd), and clinical data were harmonized. Controls were individuals with normal cognition and normal Aß1‐42. AD was defined as abnormal Aß1‐42 without meeting clinical criteria of DLB or PD. Data were analyzed by general linear models adjusted for age and sex.
Result
38% individuals were female, and mean age was 67 years. 170 individuals had AD, 74 PD, 66 DLB, and 27 were controls (Table 1). AD individuals showed lower Aß1‐42 levels compared to all other groups (Figure 1). DLB individuals had lower Aß1‐42 levels than those with PD, with both groups displaying lower levels than controls. P‐tau181 concentrations were higher in AD relative to DLB and PD (both p<0.001), with DLB showing higher (p=0.013) and PD lower (p=0.007) levels than controls. Relative to controls, α‐Syn levels were lower in AD, DLB and PD (p=0.016, p=0.016, and p=0.019, respectively). NfL levels were higher in AD (p=0.003) and DLB (p=0.009) compared to controls. 80% of DLB and 58% of PD individuals were amyloid‐positive. Compared to amyloid‐negative ones, amyloid‐positive DLB and PD individuals had lower α‐Syn levels (both p<0.001, Figure 2). Amyloid‐positive PD individuals had lower p‐tau181 levels compared to amyloid‐negative ones (p<0.001). No differences were observed between amyloid‐positive and negative DLB and PD individuals regarding NfL levels. Age, sex, APOE‐ε4, MMSE, and MDS‐UPDRS‐III score were not related to amyloid positivity in DLB and PD.
Conclusion
Amyloid pathology is highly prevalent in DLB and PD and associated with lower α‐synuclein levels. α‐Synuclein levels are also decreased in AD. This highlights overlapping pathologies in AD, DLB and PD and has significant implications for clinical trial designs.
Toxoplasma gondii, responsible for toxoplasmosis, is one of the worldwide prevalent parasitic zoonoses infecting warm-blooded animals including humans with cats being the definitive host. Congenital transmission can occur and leads to congenital toxoplasmosis, which may result in foetal or neonatal death, or severe malformations. In this study, we aimed to determine the seroprevalence and associated factors among pregnant women in a rural setting of Burkina Faso. We conducted a cross-sectional study from December 2020 to March 2021 in the Nanoro health district area. Women attending antenatal care for the first time at the selected health centers were enrolled in the study. For each participant, socio-demographic and clinical data were collected through a questionnaire. In addition, venous blood was drawn for the detection and avidity determination of IgG antibodies to T. gondii by enzyme-linked immunosorbent assay. Logistic regression was used to identify factors associated with seropositivity. Out of 416 participants, 37.3% were positive for specific anti-T. gondii IgG antibodies and only two of 149 women with interpretable results (1.3%) had low avidity IgG antibodies suggestive of recent primary infection. Younger age (16–18 years) was significantly associated with seronegativity (OR = 0.48, 95% CI:0.27–0.86, p = 0.013), while multipara (OR = 2.20, 95% CI:1.37–3.76, p value = 0.001) and multigravida (OR = 2.27, 95% CI:1.37–3.76, p = 0.001) were significantly more likely seropositive. The multivariate logistic regression showed that being at the third trimester of pregnancy (OR = 4.17, 95% CI:1.68–10.36, p = 0.002) and being often in contact with a cat (OR = 1.72, 95% CI:1.03–2.37, p = 0.035) were significantly associated with seropositivity. Our findings suggest that Toxoplasma gondii is widespread in the area, resulting in a high exposure risk of pregnant women and we indeed found two women with evidence of recent exposure. To avoid the potentially serious consequences to the foetus, there is an urgent need for systematic screening during antenatal care visits and awareness campaigns.
Loss-of-function mutations in PARK7 , encoding for DJ-1, can lead to early onset Parkinson’s disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. While at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed in 8 month-old males. The affected genes are involved in processes like focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of NRF2. Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male primary astrocytes recapitulated many of the in vivo changes, including downregulation of CYP1B1, an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes through astrocytic alterations in the NRF2-CYP1B1 axis, suggesting higher sensitivity of males to loss of DJ-1.
Background
Despite being the most common cause of dementia worldwide, the mechanisms underlying the progression of Alzheimer’s disease (AD) are not clear and effective treatments are still needed. Hence, further investigation regarding the pathogenesis of AD is required, which might allow for a better understanding of the disease, as well as for an early diagnosis of AD, thus improving the clinical management of AD patients. Here, to identify key proteins in AD pathogenesis, we performed two proteomics strategies, TMT (Tandem Mass Tags) 10‐plex quantitative proteomics and LFQ (Label Free Quantification).
Method
For the TMT analysis, proteins were extracted from frozen left prefrontal cortex brain tissue samples from AD at Braak IV‐VI, and from VD (vascular dementia) and FTD (frontotemporal dementia) patients, and healthy individuals as controls, trypsin digested, differentially labeled with the TMT reagents, and analyzed by tandem mass spectrometry coupled to liquid chromatography (LC‐MS/MS) using a Q‐Exactive mass spectrometer. For the LFQ analysis, a pull‐down with in vitro synthesized Abeta (Amyloid‐beta) fibers incubated with protein extracts from AD patients and healthy individuals was performed, and interacting proteins were analyzed on a Q‐Exactive. Proteomics data were analyzed with MaxQuant and the R program to identify dysregulated proteins.
Result
Among the 3281 proteins quantified by TMT, 15 and 154 proteins were found statistically significant ≥1.5‐fold upregulated and downregulated in AD patients in comparison to controls, respectively. After bioinformatics analysis, 10 candidate dysregulated proteins in AD were selected for further validation by orthogonal techniques to elucidate their role as tissue‐ or blood‐biomarkers, using tissue and plasma samples of AD patients and controls. Regarding the pull‐down, 332 proteins were identified as potential interactors of Abeta fibers, with 23 out of them selected for validation by WB and immunofluorescence.
Conclusion
The dysregulation of selected targets in AD patients was confirmed at protein level in a different cohort of tissue samples. Importantly, two proteins showed potential as blood‐based diagnostic biomarkers of AD, and eighteen candidate proteins were validated as novel Abeta plaques interactors, highlighting a major role of these proteins in AD development and progression.
Background
Individuals with latent tuberculosis infection (LTBI) have a high risk of active infection, morbidity and mortality. Healthcare workers are a group who have increased risk of infection and onward transmission to their patients and other susceptible individuals; however, LTBI is often undiagnosed, and individuals are asymptomatic. Interferon gamma release assays (IGRA) can detect evidence of TB infection in otherwise asymptomatic individuals and are a good indication of LTBI. Laos, a resource limited country in southeast Asia, has limited data on TB prevalence in the general population or in healthcare workers. This study aimed to estimate the prevalence of LTBI in Lao healthcare workers in Vientiane Capital.
Methods
Healthcare workers from high-risk departments from 3 central hospitals in Laos were included (n = 196) and venous blood was tested by IGRA. A questionnaire was administered to determine their knowledge, attitude and practice towards TB and LTBI.
Results
10.2% of the participants were positive by IGRA, none of whom were previously aware of their TB status. The questionnaire revealed that knowledge and awareness of TB and LTBI were low.
Discussion
A significant proportion of healthcare workers in this study had evidence of LTBI infection. These individuals were unaware of their TB status and we suggest that testing and treatment, as well as prevention strategies, should be routinely administered in Lao hospitals.
The coronavirus disease 2019 pandemic substantially impacted the delivery of cancer services and programs. Here we reviewed and synthesized the global scale and impact of pandemic-related delays and disruptions on cancer services, including diagnosis, diagnostic procedures, screening, treatment and supportive and palliative care. Based on data from 245 articles in 46 countries, we observed declines in the number of cancer screening participation (39.0%), diagnoses (23.0%), diagnostic procedures (24.0%) and treatment (28.0%), ranging from a 15.0% decline for radiotherapy to a 35.0% decline for systemic treatment during the pandemic compared to during the prepandemic period. Medium-human development index (HDI) category countries experienced greater reductions than high- and very-high-HDI countries. Missing data from low-HDI countries emphasize the need for increased investments in cancer surveillance and research in these settings. PROSPERO registration: CRD42022301816
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