Pluripotent stem cell derived inhibitory interneurons–principles and applications in health and disease

Inhibitory interneurons are gamma-aminobutyric acid-ergic (GABAergic) nerve cells that act to maintain the appropriate excitation-inhibition balance, and synchronise the output of principle cells to generate rhythmic patterns of firing (Kessaris et al., 2014). This critical role, along with their brain-wide distribution, has led to the implication of interneurons in many neuropathologies, including schizophrenia, autism, dystonia and epilepsies (Marín, 2012).

Data and subject heterogeneity and data sharing:keys to translational success in spinal cord injury research?

Spinal cord injury(SCI)is a highly devastating and com plex inj u ry with many seconda ry consequences.Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys.As a matter of fact,there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage.

Understanding the pathophysiology of postpartum psychosis: Challenges and new approaches

Postpartum psychosis is a severe psychiatric condition which affects 1-2 of every 1000 mothers shortly after childbirth. Whilst there is convincing evidence that the condition is precipitated by a complex combination of biological and environmental factors, as yet the pathophysiological mechanisms remain extremely poorly defined. Here, I critically review approaches that have been, or are being, employed to identify and characterise such mechanisms; I also review a recent animal model approach, and describe a novel biological risk model that it suggests. Clarification of biological risk mechanisms underlying disorder risk should permit the identification of relevant predictive biomarkers which will ensure that "at risk" subjects receive prompt clinical intervention if required.

How random is the random forest ? Random forest algorithm on the service of structural imaging biomarkers for Alzheimer's disease: from Alzheimer's disease neuroimaging initiative(ADNI) database

Neuroinformatics is a fascinating research field that applies computational models and analytical tools to high dimensional experimental neuroscience data for a better understanding of how the brain functions or dysfunctions in brain diseases. Neuroinformaticians work in the intersection of neuroscience and informatics supporting the integration of various sub-disciplines（behavioural neuroscience, genetics, cognitive psychology, etc.） working on brain research. Neuroinformaticians are the pathway of information exchange between informaticians and clinicians for a better understanding of the outcome of computational models and the clinical interpretation of the analysis. Machine learning is one of the most significant computational developments in the last decade giving tools to neuroinformaticians and finally to radiologists and clinicians for an automatic and early diagnosis-prognosis of a brain disease. Random forest（RF） algorithm has been successfully applied to high-dimensional neuroimaging data for feature reduction and also has been applied to classify the clinical label of a subject using single or multi-modal neuroimaging datasets. Our aim was to review the studies where RF was applied to correctly predict the Alzheimer＇s disease（AD）, the conversion from mild cognitive impairment（MCI） and its robustness to overfitting, outliers and handling of non-linear data. Finally, we described our RF-based model that gave us the 1 ^（st） position in an international challenge for automated prediction of MCI from MRI data.

High mobility group box protein 1 and white matter injury following traumatic brain injury: perspectives on mechanisms and therapeutic strategies

Traumatic brain injury(TBI)is a major cause of morbidity and mortality worldwide.Despite significant medical advances over recent decades,many survivors of TBI develop long term neuro-cognitive deficits.Previously,only moderate and severe injuries were thought to account for the devastating consequences of TBI.However,there is increasing evidence that even milder injuries may result in problematic lifelong cognitive and affective disturbances.TBI is typically characterized by an an acute physical injury followed by a protracted innate neuro-inflammatory response.These reponses,mediated via neuronal,astrocyte and microglial cells,amongst others,and may result in widespread neuronal death and a micro-environment that is not conducive to brain repair(Manivannan et al.,2021).Whilst the primary physical injury often evades intervention from a medical perspective,the subsequent neuro-inflammatory response offers a potential therapeutic target.Nonetheless,effective pharmacological strategies continue to elude clinicians and scientists due to the complex underlying pathogenesis and difficulties of modelling such a heterogeneous disease.However,the majority of research to date has focused on investigating the effects of post-traumatic neuro-inflammation on grey matter injury rather than the consequences upon white matter(WM),which contributes greatly to cognitive dysfunction across many neurological diseases(Filly and Kelly,2018).Herein,we will briefly discuss:(i)high mobility group box protein 1(HMGB1)as a potential therapeutic target;(ii)the relevance of WM injury in TBI and current understanding of WM repair following injury;and(iii)perspectives on how HMGB1 may play a role.

Cognitive, behavioural and psychiatric phenotypes associated with steroid sulfatase deficiency

The enzyme steroid sulfatase(STS)desulfates a variety of steroid compounds thereby altering their activity.STS is expressed in the skin,and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis.STS is also highly expressed in the developing and adult human brain,and in a variety of steroidogenic organs(including the placenta and gonads);therefore it has the potential to influence brain development and function directly and/or indirectly(through influencing the hormonal milieu).In this review,we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders.We subsequently discuss potential mechanisms that may underlie these vulnerabilities.The data described herein have potential implications for understanding the complete spectrum ofclinical phenotypes associated with X-linked ichthyosis,and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.

Deriving striatal projection neurons from human pluripotent stem cells with Activin A

The striatum is the main input structure of the basal ganglia and is involved in voluntary motor control,habit learning and reward processing.Medium spiny neurons（MSNs）comprise80%and 95%of striatal neurons in primates and rodents,respectively.

Significance of native PLGA nanoparticles in the treatment of Alzheimer’s disease pathology

Alzheimer’s disease (AD) is believed to be triggered by increased levels/aggregation of β-amyloid (Aβ) peptides. At present, there is no effective disease-modifying treatment for AD. Here, we evaluated the therapeutic potential of FDA-approved native poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles on Aβ aggregation and in cellular/ animal models of AD. Our results showed that native PLGA can not only suppress the spontaneous aggregation but can also trigger disassembly of preformed Aβ aggregates. Spectroscopic studies, molecular dynamics simu-lations and biochemical analyses revealed that PLGA, by interacting with the hydrophobic domain of Aβ1-42, prevents a conformational shift towards the β-sheet structure, thus precluding the formation and/or triggering disassembly of Aβ aggregates. PLGA-treated Aβ samples can enhance neuronal viability by reducing phosphor-ylation of tau protein and its associated signaling mechanisms. Administration of PLGA can interact with Aβ aggregates and attenuate memory deficits as well as Aβ levels/deposits in the 5xFAD mouse model of AD. PLGA can also protect iPSC-derived neurons from AD patients against Aβ toxicity by decreasing tau phosphorylation. These findings provide unambiguous evidence that native PLGA, by targeting different facets of the Aβ axis, can have beneficial effects in mouse neurons/animal models as well as on iPSC-derived AD neurons - thus signifying its unique therapeutic potential in the treatment of AD pathology.

Cardiac natriuretic peptides for diagnosis of covert atrial fibrillation after acute ischaemic stroke: a meta-analysis of diagnostic accuracy studies

Background and purpose Detection of atrial fibrillation(AF)after acute ischaemic stroke is pivotal for the timely initiation of anticoagulation to prevent recurrence.Besides heart rhythm monitoring,various blood biomarkers have been suggested as complimentary diagnostic tools for AF.We aimed to summarise data on the performance of cardiac natriuretic peptides for the diagnosis of covert AF after acute ischaemic stroke and to assess their potential clinical utility.Methods We searched PubMed and Embase for prospective studies reporting the performance of B-type natriuretic peptide(BNP)or N-terminal pro-BNP(NT-proBNP)for the diagnosis of covert AF after acute ischaemic stroke.Summary diagnostic performance measures were pooled using bivariate meta-analysis with a random-effect model.Results We included six studies focusing on BNP(n=1930)and three studies focusing on NT-proBNP(n=623).BNP had a sensitivity of 0.83(95% CI 0.64 to 0.93),a specificity of 0.74(0.67 to 0.81),a positive likelihood ratio of 3.2(2.6 to 4.0)and a negative likelihood ratio of 0.23(0.11 to 0.49).NT-proBNP had a sensitivity of 0.91(0.65 to 0.98),a specificity of 0.77(0.52 to 0.91),a positive likelihood ratio of 3.9(1.8 to 8.7)and a negative likelihood ratio of 0.12(0.03 to 0.48).Considering a pretest probability of 20%,BNP and NT-proBNP had post-test probabilities of 45%and 50%.Conclusions NT-proBNP has a better performance than BNP for the diagnosis of covert AF after acute ischaemic stroke.Both biomarkers have low post-test probabilities and may not be used as a stand-alone decision-making tool for the diagnosis of covert AF in patients with acute ischaemic stroke.However,they may be useful for a screening strategy aiming to select patients for long-term monitoring of the heart rhythm.