Leveraging dendritic properties to advance machine learning and neuro-inspired computing.

The brain is a remarkably capable and efficient system. It can process and store huge amounts of noisy and unstructured information, using minimal energy. In contrast, current artificial intelligence (AI) systems require vast resources for training while still struggling to compete in tasks that are trivial for biological agents. Thus, brain-inspired engineering has emerged as a promising new avenue for designing sustainable, next-generation AI systems. Here, we describe how dendritic mechanisms of biological neurons have inspired innovative solutions for significant AI problems, including credit assignment in multi-layer networks, catastrophic forgetting, and high-power consumption. These findings provide exciting alternatives to existing architectures, showing how dendritic research can pave the way for building more powerful and energy efficient artificial learning systems.

Dendrites and efficiency: Optimizing performance and resource utilization.

The brain is a highly efficient system that has evolved to optimize performance under limited resources. In this review, we highlight recent theoretical and experimental studies that support the view that dendrites make information processing and storage in the brain more efficient. This is achieved through the dynamic modulation of integration versus segregation of inputs and activity within a neuron. We argue that under conditions of limited energy and space, dendrites help biological networks to implement complex functions such as processing natural stimuli on behavioral timescales, performing the inference process on those stimuli in a context-specific manner, and storing the information in overlapping populations of neurons. A global picture starts to emerge, in which dendrites help the brain achieve efficiency through a combination of optimization strategies that balance the tradeoff between performance and resource utilization.

Dendrites and Efficiency: Optimizing Performance and Resource Utilization.

The brain is a highly efficient system evolved to achieve high performance with limited resources. We propose that dendrites make information processing and storage in the brain more efficient through the segregation of inputs and their conditional integration via nonlinear events, the compartmentalization of activity and plasticity and the binding of information through synapse clustering. In real-world scenarios with limited energy and space, dendrites help biological networks process natural stimuli on behavioral timescales, perform the inference process on those stimuli in a context-specific manner, and store the information in overlapping populations of neurons. A global picture starts to emerge, in which dendrites help the brain achieve efficiency through a combination of optimization strategies balancing the tradeoff between performance and resource utilization.

Leveraging dendritic properties to advance machine learning and neuro-inspired computing.

The brain is a remarkably capable and efficient system. It can process and store huge amounts of noisy and unstructured information using minimal energy. In contrast, current artificial intelligence (AI) systems require vast resources for training while still struggling to compete in tasks that are trivial for biological agents. Thus, brain-inspired engineering has emerged as a promising new avenue for designing sustainable, next-generation AI systems. Here, we describe how dendritic mechanisms of biological neurons have inspired innovative solutions for significant AI problems, including credit assignment in multilayer networks, catastrophic forgetting, and high energy consumption. These findings provide exciting alternatives to existing architectures, showing how dendritic research can pave the way for building more powerful and energy-efficient artificial learning systems.

RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation.

TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival.

Bone conducted responses in the neonatal rat auditory cortex.

Rats are born deaf and start hearing at the end of the second postnatal week, when the ear canals open and low-intensity sounds start to evoke responses in the auditory cortex. Here, using µECoG electrode arrays and intracortical silicon probe recordings, we found that bone-conducted (BC) sounds evoked biphasic responses in the auditory cortex starting from postnatal day (P) 8. The initial phase of these responses, generated by thalamocortical input, was followed by intracortical propagation within supragranular layers. BC-evoked responses co-localized with the responses evoked by electrical stimulation of the cochlea and the deepest layers of the inferior colliculus prior to onset of low-threshold hearing (P13), as well as with the responses evoked by high-frequency (30 kHz) low-intensity (70 dB) air-conducted sounds after that. Thus, BC signals reach high-frequency processing regions of the auditory cortex well before the onset of low-threshold hearing, reflecting early integrity of the auditory system.

TNF Is Partially Required for Cell-Death-Triggered Skin Inflammation upon Acute Loss of cFLIP.

cFLIP is required for epidermal integrity and skin inflammation silencing via protection from TNF-induced keratinocyte apoptosis. Here, we generated and analyzed cFLIP epidermal KO mice with additional TNF deficiency. Intriguingly, the ablation of TNF rescued the pathological phenotype of epidermal cFLIP KO from characteristic weight loss and increased mortality. Moreover, the lack of TNF in these animals strongly reduced and delayed the epidermal hyperkeratosis and the increased apoptosis in keratinocytes. Our data demonstrate that TNF signaling in cFLIP-deficient keratinocytes is the critical factor for the regulation of skin inflammation via modulated cytokine and chemokine expression and, thus, the attraction of immune cells. Our data suggest that autocrine TNF loop activation upon cFLIP deletion is dispensable for T cells, but is critical for neutrophil attraction. Our findings provide evidence for a negative regulatory role of cFLIP for TNF-dependent apoptosis and partially for epidermal inflammation. However, alternative signaling pathways may contribute to the development of the dramatic skin disease upon cFLIP deletion. Our data warrant future studies of the regulatory mechanism controlling the development of skin disease upon cFLIP deficiency and the role of cFLIP/TNF in a number of inflammatory skin diseases, including toxic epidermal necrolysis (TEN).

A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in Keratinocytes.

The ubiquitin-editing protein A20 (TNFAIP3) is a known key player in the regulation of immune responses in many organs. Genome-wide associated studies (GWASs) have linked A20 with a number of inflammatory and autoimmune disorders, including psoriasis. Here, we identified a previously unrecognized role of A20 as a pro-apoptotic factor in TNF-induced cell death in keratinocytes. This function of A20 is mediated via the NF-κB-dependent alteration of cIAP1/2 expression. The changes in cIAP1/2 protein levels promote NIK stabilization and subsequent activation of noncanonical NF-κB signaling. Upregulation of TRAF1 expression triggered by the noncanonical NF-κB signaling further enhances the NIK stabilization in an autocrine manner. Finally, stabilized NIK promotes the formation of the ripoptosome and the execution of cell death. Thus, our data demonstrate that A20 controls the execution of TNF-induced cell death on multiple levels in keratinocytes. This signaling mechanism might have important implications for the development of new therapeutic strategies for the treatment of A20-associated skin diseases.

Emergence of Coordinated Activity in the Developing Entorhinal-Hippocampal Network.

Correlated activity in the entorhinal-hippocampal neuronal networks, supported by oscillatory and intermittent population activity patterns is critical for learning and memory. However, when and how correlated activity emerges in these networks during development remains largely unknown. Here, we found that during the first postnatal week in non-anaesthetized head-restrained rats, activity in the superficial layers of the medial entorhinal cortex (MEC) and hippocampus was highly correlated, with intermittent population bursts in the MEC followed by early sharp waves (eSPWs) in the hippocampus. Neurons in the superficial MEC layers fired before neurons in the dentate gyrus, CA3 and CA1. eSPW current-source density profiles indicated that perforant/temporoammonic entorhinal inputs and intrinsic hippocampal connections are co-activated during entorhinal-hippocampal activity bursts. Finally, a majority of the entorhinal-hippocampal bursts were triggered by spontaneous myoclonic body movements, characteristic of the neonatal period. Thus, during the neonatal period, activity in the entorhinal cortex (EC) and hippocampus is highly synchronous, with the EC leading hippocampal activation. We propose that such correlated activity is embedded into a large-scale bottom-up circuit that processes somatosensory feedback resulting from neonatal movements, and that it is likely to instruct the development of connections between neocortex and hippocampus.

cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis.

FADD, caspase-8, and cFLIP regulate the outcome of cell death signaling. Mice that constitutively lack these molecules die at an early embryonic age, whereas tissue-specific constitutive deletion of FADD or caspase-8 results in inflammatory skin disease caused by increased necroptosis. The function of cFLIP in the skin in vivo is unknown. In contrast to tissue-specific caspase-8 knockout, we show that mice constitutively lacking cFLIP in the epidermis die around embryonic days 10 and 11. When cFLIP expression was abrogated in adult skin of cFLIPfl/fl-K14CreERtam mice, severe inflammation of the skin with concomitant caspase activation and apoptotic, but not necroptotic, cell death developed. Apoptosis was dependent of autocrine tumor necrosis factor production triggered by loss of cFLIP. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. Our data demonstrate the importance of cFLIP for the integrity of the epidermis and for silencing of spontaneous skin inflammation.

Genome sequence analysis of the Vibrio parahaemolyticus lytic bacteriophage VPMS1.

VPMS1 is a Vibrio parahaemolyticus lytic phage isolated from a marine clam. The 42.3-kb genome was predicted to encode 53 proteins. Comparison of the VPMS1 DNA genome with known phage genomes revealed no similarity; hence, it represents a new VP phage, organized into three differently oriented modules. The module for packaging covers 12 % of the genome, the module for structure covers 31 %, and the module for replication and regulation covers 48 %. The G + C content was 44.67 %. The coding region corresponds to 91 % of the genome, and 9 % apparently does not encode any protein. Thirty genes, constituting 57 % of the genome, had significant similarity to some reported proteins in the protein database; 23 genes, constituting 43 % of the genome, showed no significant homology to any reported protein, and these could be new proteins whose hypothetical functions can be deduced from their position in the genome.

Cell death in the skin: how to study its quality and quantity?

The characterization of the quality and quantity of cell death has gained substantial interest over the past decades. More recently necroptosis as a programmed form of necrosis has been identified as an important additional form of cell death with relevance in the skin. Understanding how to assay cell death in specific is of critical importance for cancer research and treatment. Here we describe six different methods that can be used to assay cell viability and to study the quality or quantity of cultured human keratinocytes in vitro. These methods include crystal violet assay, hypodiploidy analysis, caspase-8 cleavage, release of HMGB1, annexin V/propidium iodide co-staining, and Hoechst/SYTOX green co-staining.

The impact of CFNS-causing EFNB1 mutations on ephrin-B1 function.

BACKGROUND: Mutations of EFNB1 cause the X-linked malformation syndrome craniofrontonasal syndrome (CFNS). CFNS is characterized by an unusual phenotypic pattern of inheritance, because it affects heterozygous females more severely than hemizygous males. This sex-dependent inheritance has been explained by random X-inactivation in heterozygous females and the consequences of cellular interference of wild type and mutant EFNB1-expressing cell populations. EFNB1 encodes the transmembrane protein ephrin-B1, that forms bi-directional signalling complexes with Eph receptor tyrosine kinases expressed on complementary cells. Here, we studied the effects of patient-derived EFNB1 mutations predicted to give rise to truncated ephrin-B1 protein or to disturb Eph/ephrin-B1 reverse ephrin-B1 signalling. Five mutations are investigated in this work: nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT, splice-site mutation c.406 + 2T > C and two missense mutations p.P54L and p.T111I. Both missense mutations are located in the extracellular ephrin domain involved in Eph-ephrin-B1 recognition and higher order complex formation. METHODS: Nonsense mutation c.196C > T/p.R66X, frameshift mutation c.614_615delCT and splice-site mutation c.406+2T > C were detected in the primary patient fibroblasts by direct sequencing of the DNA and were further analysed by RT-PCR and Western blot analyses.The impact of missense mutations p.P54L and p.T111I on cell behaviour and reverse ephrin-B1 cell signalling was analysed in a cell culture model using NIH 3T3 fibroblasts. These cells were transfected with the constructs generated by in vitro site-directed mutagenesis. Investigation of missense mutations was performed using the Western blot analysis and time-lapse microscopy. RESULTS AND DISCUSSION: Nonsense mutation c.196C > T/p.R66X and frameshift mutation c.614_615delCT escape nonsense-mediated RNA decay (NMD), splice-site mutation c.406+2T > C results in either retention of intron 2 or activation of a cryptic splice site in exon 2. However, c.614_615delCT and c.406+2T > C mutations were found to be not compatible with production of a soluble ephrin-B1 protein. Protein expression of the p.R66X mutation was predicted unlikely but has not been investigated.Ectopic expression of p.P54L ephrin-B1 resists Eph-receptor mediated cell cluster formation in tissue culture and intracellular ephrin-B1 Tyr324 and Tyr329 phosphorylation. Cells expressing p.T111I protein show similar responses as wild type expressing cells, however, phosphorylation of Tyr324 and Tyr329 is reduced. CONCLUSIONS: Pathogenic mechanisms in CFNS manifestation include impaired ephrin-B1 signalling combined with cellular interference.

Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic.

Craniofrontonasal syndrome (CFNS) is an X-linked malformation syndrome with variable phenotype that is caused by mutations in the ephrin-B1 gene (EFNB1). Over 50% of EFNB1 mutations result in premature termination codons that may elicit mRNA degradation by the nonsense-mediated decay pathway. To assess the effects of various mutations at the transcript level, expression of EFNB1 mRNA was studied by RT-PCR in fibroblast cultures established from CFNS female patients. Compared to the wild-type and two missense mutation alleles, severe depletion of transcripts was observed for mutant alleles harbouring either splice site mutation c.407-2A>T at the exon 2/3 boundary or frameshift mutation c.377_384delTCAAGAAG in exon 2. In contrast, escape from mRNA decay was observed for mutation c.614_615delCT, which generates a premature termination codon close to the 3'-end of the penultimate exon 4 disobeying the '50-55 bp' rule. These results suggest differential degradation of mutant EFNB1 transcripts by the nonsense-mediated mRNA decay pathway. Although the clinical phenotypes of the patients were not highly suggestive of a phenotype-genotype correlation, the two female patients were diagnosed with diaphragmatic hernia harbouring putative ephrin-B1 truncating mutations. Previously, disease manifestation in heterozygous females had been attributed mainly to cellular interference of divergent cell populations expressing wild-type or mutant EFNB1, depending on the pattern of X-inactivation. Upon clonal expansion of patient cells with either the wild-type or mutant EFNB1 on the active X-chromosome, we were able to separate mutant and wild-type EFNB1-expressing cells in vitro, further supporting the concept of cellular interference in CFNS.