Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. ...How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI.
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•OPCs need primary cilia for proliferation in development and white matter injury•The primary cilium is not required for canonical Hh signaling in OPCs•A cAMP/CREB signaling axis initiated within the primary cilium regulates OPC proliferation
Hoi et al. find that deletion of Ift88 in OPCs leads to loss of their primary cilia. OPCs require these cilia for proliferation in development and white matter injury. It is not required for canonical Hh signaling, and they propose that a primary cilium-initiated GPCR/cAMP/CREB signaling axis orchestrates OPC proliferation.
Aim
To establish groups of people with chronic non‐cancer pain according to the impairment caused by pain and to identify factors associated with the group with a higher level of impairment.
...Background
Knowing the profiles of people who suffer from chronic non‐cancer pain could make it possible to direct their treatment and to detect associated risks.
Design
A cross‐sectional study.
Methods
A sample of 395 people with chronic non‐cancer pain was collected in Pain Units and Primary Healthcare Centres in southern Spain (January to March 2020). A cluster analysis was performed to divide the population into groups and a binary logistic regression model was established to determine factors associated with the group with a higher level of impairment.
Results
Two groups were identified: lower level of impairment due to pain, characterized by being 45–65 years old, not medicated with opioids or anxiolytics, employed and with a mild level of impact on daily life; and higher level of impairment characterized by being older than 65 years old, medicated with opioids and anxiolytics, retired or on medical leave and with a severe impact on daily life. In addition, among women, being widowed, single or a smoker are risk factors for belonging to the group with a higher level of impairment; being smokers or consuming alcohol three or less times a week would be risk factors in men.
Conclusions
Age, chronic non‐cancer pain impact on daily life, work situation and the consumption of opioid drugs and/or anxiolytics are factors that appear to influence the level of impairment due to chronic pain.
Impact
These findings could help detect impairment due to pain in its early stages, determining the specific needs of each person.
Effective testing is essential to control the coronavirus disease 2019 (COVID-19) transmission. Here we report a-proof-of-concept study on hyperspectral image analysis in the visible and ...near-infrared range for primary screening at the point-of-care of SARS-CoV-2. We apply spectral feature descriptors, partial least square-discriminant analysis, and artificial intelligence to extract information from optical diffuse reflectance measurements from 5 µL fluid samples at pixel, droplet, and patient levels. We discern preparations of engineered lentiviral particles pseudotyped with the spike protein of the SARS-CoV-2 from those with the G protein of the vesicular stomatitis virus in saline solution and artificial saliva. We report a quantitative analysis of 72 samples of nasopharyngeal exudate in a range of SARS-CoV-2 viral loads, and a descriptive study of another 32 fresh human saliva samples. Sensitivity for classification of exudates was 100% with peak specificity of 87.5% for discernment from PCR-negative but symptomatic cases. Proposed technology is reagent-free, fast, and scalable, and could substantially reduce the number of molecular tests currently required for COVID-19 mass screening strategies even in resource-limited settings.
Abstract
Optical spectroscopic techniques have been commonly used to detect the presence of biofilm-forming pathogens (bacteria and fungi) in the agro-food industry. Recently, near-infrared (NIR) ...spectroscopy revealed that it is also possible to detect the presence of viruses in animal and vegetal tissues. Here we report a platform based on visible and NIR (VNIR) hyperspectral imaging for non-contact, reagent free detection and quantification of laboratory-engineered viral particles in fluid samples (liquid droplets and dry residue) using both partial least square-discriminant analysis and artificial feed-forward neural networks. The detection was successfully achieved in preparations of phosphate buffered solution and artificial saliva, with an equivalent pixel volume of 4 nL and lowest concentration of 800 TU·
$$\upmu$$
μ
L
−1
. This method constitutes an innovative approach that could be potentially used at point of care for rapid mass screening of viral infectious diseases and monitoring of the SARS-CoV-2 pandemic.
Extracellular vesicles (EVs) are emerging as powerful players in cell‐to‐cell communication both in healthy and diseased brain. In Parkinson's disease (PD)—characterized by selective dopaminergic ...neuron death in ventral midbrain (VMB) and degeneration of their terminals in striatum (STR)—astrocytes exert dual harmful/protective functions, with mechanisms not fully elucidated. Here, this study shows that astrocytes from the VMB‐, STR‐, and VMB/STR‐depleted brains release a population of small EVs in a region‐specific manner. Interestingly, VMB‐astrocytes secreted the highest rate of EVs, which is further exclusively increased in response to CCL3, a chemokine that promotes robust dopaminergic neuroprotection in different PD models. The neuroprotective potential of nigrostriatal astrocyte‐EVs is investigated in differentiated versus undifferentiated SH‐SY5Y cells exposed to oxidative stress and mitochondrial toxicity. EVs from both VMB‐ and STR‐astrocytes counteract H2O2‐induced caspase‐3 activation specifically in differentiated cells, with EVs from CCL3‐treated astrocytes showing a higher protective effect. High resolution respirometry further reveals that nigrostriatal astrocyte‐EVs rescue neuronal mitochondrial complex I function impaired by the neurotoxin MPP+. Notably, only EVs from VMB‐astrocyte fully restore ATP production, again specifically in differentiated SH‐SY5Y. These results highlight a regional diversity in the nigrostriatal system for the secretion and activities of astrocyte‐EVs, with neuroprotective implications for PD.
Astrocytes from the main brain regions affected by Parkinson's disease (PD) secrete different levels of extracellular vesicles (EVs). CCL3‐EVs better protect neurons from apoptosis and only ventral midbrain‐derived EVs ameliorate ATP production in neurotoxin‐injured neurons. These data demonstrate the importance of the brain region for the neuroprotection mediated by astrocyte‐EVs, with implications for PD diagnosis and treatment.
Phase angle (PhA) is a valuable tool for evaluating the nutritional and inflammatory status, which can accompany acute and severe disorders. PhA is a cellular health biomarker, whose value is ...particularly substantial due to the negative consequences of these situations in the pediatric population. Relevant literature was collected with the aim of comprehensively analysing the evidence on the association between an altered PhA can serve as a predictive-marker for mortality and poor-outcomes in at-risk-pediatric patients. Understanding this relationship could have significant implications for identifying high-risk individuals and implementing timely interventions. A systematic review with meta-analysis was conducted in the primary electronic databases from inception until January 2023. Overall, four studies with a total of 740 patients were eligible for our analysis. Evidence demonstrates that PhA is associated with nutritional status, reflecting undernutrition and changes in body composition related to illness. This review suggests that PhA can indeed be used as an indicator of nutritional status and a tool for predicting prognosis, including mortality and poor-outcomes, in hospitalized pediatric patients. A low PhA was associated with a significant mortality risk RR:1.51;95%CI (1.22–1.88),p = 0.0002;I2 = 0%,(p = 0.99) and an increased complications risk OR:8.17;95%CI (2.44–27.4),p = 0.0007;I2 = 44%,(p = 0.18). These findings highlight the importance of taking a comprehensive approach to clinical nutrition, integrating multiple evaluation aspects to establish an accurate diagnosis and personalized therapeutic plans. While PhA emerges as a valuable tool for assessing the risk of malnutrition and as a prognostic-indicator for poor-outcomes in pediatric patients. Further future studies are needed to focus on investigating this relationship in larger and diverse population to strengthen the evidence base.
Graphical Abstract
•Mueller reflected polarimetric imaging detects SARS-CoV-2 models in dry droplets.•Initial proof-of-concept, two synthetic viral models in artificial saliva.•Polarization features quantified at ...per-pixel and per-droplet levels.•Potential to improve fast, non-contact analysis of multiple samples simultaneously.
To conduct a proof-of-concept study of the detection of two synthetic models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using polarimetric imaging.
Two SARS-CoV-2 models were prepared as engineered lentiviruses pseudotyped with the G protein of the vesicular stomatitis virus, and with the characteristic Spike protein of SARS-CoV-2. Samples were prepared in two biofluids (saline solution and artificial saliva), in four concentrations, and deposited as 5-µL droplets on a supporting plate. The angles of maximal degree of linear polarization (DLP) of light diffusely scattered from dry residues were determined using Mueller polarimetry from87 samples at 405 nm and 514 nm. A polarimetric camera was used for imaging several samples under 380–420 nm illumination at angles similar to those of maximal DLP. Per-pixel image analysis included quantification and combination of polarization feature descriptors in 475 samples.
The angles (from sample surface) of maximal DLP were 3° for 405 nm and 6° for 514 nm. Similar viral particles that differed only in the characteristic spike protein of the SARS-CoV-2, their corresponding negative controls, fluids, and the sample holder were discerned at 10-degree and 15-degree configurations.
Polarimetric imaging in the visible spectrum may help improve fast, non-contact detection and identification of viral particles, and/or other microbes such as tuberculosis, in multiple dry fluid samples simultaneously, particularly when combined with other imaging modalities. Further analysis including realistic concentrations of real SARS-CoV-2 viral particles in relevant human fluids is required. Polarimetric imaging under visible light may contribute to a fast, cost-effective screening of SARS-CoV-2 and other pathogens when combined with other imaging modalities.
The individual influence of a variety of comorbidities on COVID-19 patient outcomes has already been analyzed in previous works in an isolated way. We aim to determine if different associations of ...diseases influence the outcomes of inpatients with COVID-19.
Retrospective cohort multicenter study based on clinical practice. Data were taken from the SEMI-COVID-19 Registry, which includes most consecutive patients with confirmed COVID-19 hospitalized and discharged in Spain. Two machine learning algorithms were applied in order to classify comorbidities and patients (Random Forest -RF algorithm, and Gaussian mixed model by clustering -GMM-). The primary endpoint was a composite of either, all-cause death or intensive care unit admission during the period of hospitalization. The sample was randomly divided into training and test sets to determine the most important comorbidities related to the primary endpoint, grow several clusters with these comorbidities based on discriminant analysis and GMM, and compare these clusters.
A total of 16,455 inpatients (57.4% women and 42.6% men) were analyzed. According to the RF algorithm, the most important comorbidities were heart failure/atrial fibrillation (HF/AF), vascular diseases, and neurodegenerative diseases. There were six clusters: three included patients who met the primary endpoint (clusters 4, 5, and 6) and three included patients who did not (clusters 1, 2, and 3). Patients with HF/AF, vascular diseases, and neurodegenerative diseases were distributed among clusters 3, 4 and 5. Patients in cluster 5 also had kidney, liver, and acid peptic diseases as well as a chronic obstructive pulmonary disease; it was the cluster with the worst prognosis.
The interplay of several comorbidities may affect the outcome and complications of inpatients with COVID-19.
We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-3-(triethoxysilyl)propylcarbamateplatinum(IV) (Pt(IV)-biSi-1) and ...cis-dichloro(diisopropylamine)-trans-3-(triethoxysilyl) propyl carbamateplatinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.
Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic ...effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.
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