Engineered Neuronal Circuits: A New Platform for Studying the Role of Modular Topology

Neuron–glia cultures serve as a valuable model system for exploring the bio-molecular activity of single cells. Since neurons in culture can be conveniently recorded with great fidelity from many sites simultaneously, it has long been suggested that uniform cultured neurons may also be used to investigate network-level mechanisms pertinent to information processing, activity propagation, memory, and learning. But how much of the functionality of neural circuits can be retained in vitro remains an open question. Recent studies utilizing patterned networks suggest that they provide a most useful platform to address fundamental questions in neuroscience. Here we review recent efforts in the realm of patterned networks’ activity investigations. We give a brief overview of the patterning methods and experimental approaches commonly employed in the field, and summarize the main results reported in the literature. The general picture that emerges from these reports indicates that patterned networks with uniform connectivity do not exhibit unique activity patterns. Rather, their activity is very similar to that of unpatterned uniform networks. However, by breaking the connectivity homogeneity, using a modular architecture, it is possible to introduce pronounced topology-related gating and delay effects. These findings suggest that patterned cultured networks may serve as a new platform for studying the role of modularity in neuronal circuits

The Future of Medicine is Digital: Developing Educational Materials to Explore the Ethics of Digital Pills.

Digital Pills are a drug-device technology that permit to combine traditional medications with a monitoring system that automatically records data about medication adherence and patients’ physiological data. They are a promising innovation in digital medicine, however their use has raised a number of ethical concerns. In this paper, we outline some of the main Digital Pills technologies and explore key ethical challenges surrounding their use. In this paper, we introduce educational materials we have developed that provide an insight into the technologies and ethical aspects that underpin Digital Pills

Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats

Stroke is a leading cause of mortality and morbidity worldwide. Few therapeutic options with proven efficacy are available for the treatment of this disabling disease. Lithium is the gold standard treatment for bipolar disorder. Moreover, lithium has been shown to exhibit neuroprotective effects and therapeutic efficacy as a treatment of other neurological disorders. This study was undertaken to examine the effects of lithium on brain inflammatory mediators levels, fever, and mortality in postischemic stroke rats. Ischemic stroke was induced by occlusion of the mid cerebral artery (MCAO). Pretreatment with a single dose of lithium at 2 hours before MCAO induction significantly reduced the elevation in interleukin- (IL-) 6 and prostaglandin E2 levels in brain of post-MCAO rats, as compared to vehicle-treated animals. On the other hand, lithium did not affect the elevation in IL-1α, IL-10, IL-12, and tumor necrosis factor-α levels in brain of post-MCAO rats. Moreover, pretreatment with lithium did not alter post-MCAO fever and mortality. These results suggest that acute pretreatment with a single dose of lithium did not markedly affect post-MCAO morbidity and mortality in rats

White Matter Hyperintensities in Parkinson’s Disease: Do They Explain the Disparity between the Postural Instability Gait Difficulty and Tremor Dominant Subtypes?

Background: Brain white matter hyperintensities (WMHs) commonly observed on brain imaging of older adults are associated with balance and gait impairment and have also been linked to cognitive deficits. Parkinson’s disease (PD) is traditionally sub-classified into the postural instability gait difficulty (PIGD) sub-type, and the tremor dominant (TD) sub-type. Considering the known association between WMHs and axial symptoms like gait disturbances and postural instability, one can hypothesize that WMHs might contribute to the disparate clinical sub-types of patients with PD. Methods: 110 patients with PD underwent a clinical evaluation and a 3T MRI exam. Based on the Unified Parkinson Disease Rating Scale, the patients were classified into motor sub-types, i.e., TD or PIGD, and scores reflecting PIGD and TD symptoms were computed. We compared white matter burden using three previously validated methods: one using a semi-quantitative visual rating scale in specific brain regions and two automated methods. Results: Overall, MRI data were obtained in 104 patients. The mean WMHs scores and the percent of subjects with lesions in specific brain regions were similar in the two subtypes, p = 0.678. The PIGD and the TD scores did not differ even when comparing patients with a relatively high burden of WMHs to patients with a relatively low burden. Across most of the brain regions, mild to moderate correlations between WMHs and age were found (r = 0.23 to 0.41; p<0.021). Conversely, no significant correlations were found between WMHs and the PIGD score or disease duration. In addition, depressive symptoms and cerebro-vascular risk factors were similar among the two subtypes. Conclusions: In contrast to what has been reported previously among older adults, the present study could not demonstrate any association between WMHs and the PIGD or TD motor sub-types in patients with PD

The DNA damage response pathway regulates the expression of the immune checkpoint CD47

CD47 is a cell surface ligand expressed on all nucleated cells. It is a unique immune checkpoint protein acting as “don’t eat me” signal to prevent phagocytosis and is constitutively overexpressed in many tumors. However, the underlying mechanism(s) for CD47 overexpression is not clear. Here, we show that irradiation (IR) as well as various other genotoxic agents induce elevated expression of CD47. This upregulation correlates with the extent of residual double-strand breaks (DSBs) as determined by γH2AX staining. Interestingly, cells lacking mre-11, a component of the MRE11-RAD50-NBS1 (MRN) complex that plays a central role in DSB repair, or cells treated with the mre-11 inhibitor, mirin, fail to elevate the expression of CD47 upon DNA damage. On the other hand, both p53 and NF-κB pathways or cell-cycle arrest do not play a role in CD47 upregualtion upon DNA damage. We further show that CD47 expression is upregulated in livers harvested from mice treated with the DNA-damage inducing agent Diethylnitrosamine (DEN) and in cisplatin-treated mesothelioma tumors. Hence, our results indicate that CD47 is upregulated following DNA damage in a mre-11-dependent manner. Chronic DNA damage response in cancer cells might contribute to constitutive elevated expression of CD47 and promote immune evasion.</p

Treat-to-target in dermatology:A scoping review and International Eczema Council survey on the approach in atopic dermatitis

Treat-to-target (T2T) is a pragmatic therapeutic strategy being gradually introduced into dermatology after adoption in several other clinical areas. Atopic dermatitis (AD), one of the most common inflammatory skin diseases, may also benefit from this structured and practical therapeutic approach. We aimed to evaluate existing data regarding the T2T approach in dermatology, with a specific focus on AD, as well as the views of International Eczema Council (IEC) members on the potential application of a T2T approach to AD management. To do so, we systematically searched for peer-reviewed publications on the T2T approach for any skin disease in the PubMed and Scopus databases up to February 2022 and conducted a survey among IEC members regarding various components to potentially include in a T2T approach in AD. We identified 21 relevant T2T-related reports in dermatology, of which 14 were related to psoriasis, five to AD, one for juvenile dermatomyositis and one for urticaria. In the IEC member survey, respondents proposed treatable traits (with itch, disease severity and sleep problems getting the highest scores), relevant comorbidities (with asthma being selected most commonly, followed by anxiety and depression in adults), recommended specialists that should define the approach in AD (dermatologists, allergists and primary care physicians were most commonly selected in adults), and applicable assessment tools (both physician- and patient-reported), in both adult and paediatric patients, for potential future utilization of the T2T approach in AD. In conclusion, while the T2T approach may become a useful tool to simplify therapeutic goals and AD management, its foundation in AD is only starting to build. A multidisciplinary approach, including a wide range of stakeholders, including patients, is needed to further define the essential components needed to utilize T2T in AD.</p

Long-ranged attraction between disordered heterogeneous surfaces

Long-ranged attractions across water between two surfaces that are randomly covered with (mobile) positive and negative charge domains have been attributed to induced correlation of the charges (positive lining up with negative) as the surfaces approach. Here we show, by directly measuring normal forces under a rapid shear field, that these attractions may not in fact be due to such correlations. It is rather the inherent interaction-asymmetry between equally- and between oppositely-charged domains that results in the long-ranged attraction even in the complete absence of any charge correlation

Gene Essentiality Analyzed by In Vivo Transposon Mutagenesis and Machine Learning in a Stable Haploid Isolate of Candida albicans

This work was supported by European Research Council Advanced Award 340087 (RAPLODAPT) to J.B., the Dahlem Centre of Plant Sciences (DCPS) of the Freie Universität Berlin (R.K.), Israel Science Foundation grant no. 715/18 (R.S.), the Wellcome Trust (grants 086827, 075470, 101873, and 200208) and the MRC Centre for Medical Mycology (N006364/1) (N.A.R.G.). Data availability.All of the code and required dependencies for analysis of the TnSeq data are available at https://github.com/berman-lab/transposon-pipeline. Library insertion sequences are available at NCBI under project PRJNA490565 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA490565). Datasets S1 through S9 are available at https://doi.org/10.6084/m9.figshare.c.4251182.Peer reviewedPublisher PD