An analog-AI chip for energy-efficient speech recognition and transcription.

Models of artificial intelligence (AI) that have billions of parameters can achieve high accuracy across a range of tasks1,2, but they exacerbate the poor energy efficiency of conventional general-purpose processors, such as graphics processing units or central processing units. Analog in-memory computing (analog-AI)3-7 can provide better energy efficiency by performing matrix-vector multiplications in parallel on 'memory tiles'. However, analog-AI has yet to demonstrate software-equivalent (SWeq) accuracy on models that require many such tiles and efficient communication of neural-network activations between the tiles. Here we present an analog-AI chip that combines 35 million phase-change memory devices across 34 tiles, massively parallel inter-tile communication and analog, low-power peripheral circuitry that can achieve up to 12.4 tera-operations per second per watt (TOPS/W) chip-sustained performance. We demonstrate fully end-to-end SWeq accuracy for a small keyword-spotting network and near-SWeq accuracy on the much larger MLPerf8 recurrent neural-network transducer (RNNT), with more than 45 million weights mapped onto more than 140 million phase-change memory devices across five chips.

Intra-articular administration of xenogeneic neonatal Mesenchymal Stromal Cells early after meniscal injury down-regulates metalloproteinase gene expression in synovium and prevents cartilage degradation in a rabbit model of osteoarthritis.

OBJECTIVE: The anti-inflammatory and anti-catabolic effects of neonatal Mesenchymal Stromal Cell (MSC) were investigated in a xenogeneic model of mild osteoarthritis (OA). The paracrine properties of MSC on synoviocytes were further investigated in vitro. STUDY DESIGN: OA was induced by medial meniscal release (MMR) in 30 rabbit knees. A single early (day 3) or delayed (day 15) intra-articular (IA) injection of MSC isolated from equine Umbilical Cord Wharton's jelly (UC-MSC) was performed. Rabbits were euthanized on days 15 or 56. OA grading was performed and gene expression of inflammatory cytokines and metalloproteinases was measured in synovial tissue. Paracrine effects of UC-MSC were investigated using UC-conditioned vs control medium on rabbit primary synoviocytes stimulated with interleukin 1 beta in vitro. RESULTS: No adverse local or systemic responses were observed clinically after xenogeneic UC-MSC injection. At study end point, cartilage fibrillation was lower in early treatment than in delayed treatment group. Cellular infiltrate was observed in the synovium of both UC-MSC groups. OA synovium exhibited a reduced expression of metalloproteinases-1, -3, -13 in the early cell-treated group at d56. In vitro, UC-conditioned medium exerted anti-inflammatory and anti-catabolic effects on synoviocytes exposed to pro-inflammatory stimulus. CONCLUSIONS: Early IA injection of equine UC-MSC was effective in preventing OA signs in rabbit knees following MMR. UC-MSC target the synovium and modulate the gene expression pattern of synoviocytes to promote an anti-catabolic environment. This confirms the synovium is a major target and mediator of MSC therapy, modulating the expression of matrix-degrading enzymes.

cDNA-microarray analysis as a new tool to predict lymph node metastasis in gastric cancer.

BACKGROUND: The aim of the present study was to investigate whether microarray gene expression analysis can be used to predict lymph node status in gastric cancer. METHODS: Twenty-nine patients undergoing gastrectomy for cancer were enrolled and subdivided according to the pathologic nodal involvement of their disease (N+ vs. N0). Molecular profiling was performed by cDNA microarray on tumor tissue and healthy mucosa. Data were processed to identify differently expressed genes. Selected genes were categorized with gene ontology. RESULTS: Compared to healthy gastric mucosa, 52 genes were differently expressed in N+ patients, and 50 genes in N0 patients. Forty-five genes were similarly regulated in N+ and N0 patients, whereas 12 genes were differently expressed between N+ and N0 patients. Seven genes were exclusively expressed in N+ patients: Egr-1 was upregulated; Claudin-18, AKR1C2, Cathepsin E, CA II, TFF 1, and progastricsin were downregulated. Five genes were exclusively expressed in N0 patients: Complement C5 receptor 1, PLA2/VII, and MMP- 9 were upregulated; MAO-A and ID-4 were downregulated. CONCLUSIONS: Microarray analysis could be a valuable tool to identify genes associated with lymph node metastasis in gastric cancer. This technique could improve the selection of patients with locally advanced disease who are candidates for extended lymph node dissection, multimodal treatment options, or alternative therapeutic strategies.

Placenta-derived mesenchymal stromal cells as a treatment for refractory chronic gingivostomatitis in cats: eight cases (2018).

OBJECTIVES: The aim of this case series was to collect preliminary data on safety and efficacy of treating cats suffering from refractory feline chronic gingivostomatitis with a single intravenous therapy of cryopreserved placenta-derived mesenchymal stromal cells. MATERIALS AND METHODS: We planned the prospective inclusion of cats suffering from refractory chronic gingivostomatitis in three veterinary clinics. All cats received a single infusion of 10×106 cryopreserved cells. Follow-up evaluations were done at day 15 and at 2-, 3- and 6-months following infusion. Clinical disease severity was evaluated by dental specialists using a published stomatitis disease activity index scoring system coupled with an owners' assessment questionnaire. RESULTS: All eight cats attended all follow up visits. Cryopreserved ready-to-use placenta-derived cells administered systemically were safe and resulted in notable clinical improvement in all cats as reported by stomatitis disease activity index scoring and owner's survey. CLINICAL SIGNIFICANCE: Infusion of cryopreserved freshly thawed placenta-derived mesenchymal stromal cells appears to promote clinical and consequently behavioural benefits in cats with refractory chronic gingivostomatitis after having undergone full-mouth or premolar-molar tooth extraction. Future randomised studies are required to confirm safety and efficacy of this treatment.

Gene expression profiling of patients with latex and/or vegetable food allergy.

BACKGROUND: The prevalence of individuals allergic to latex, exhibiting cross-hypersensitivity with plant-derived food has been frequently reported as the so-called latex-fruit syndrome. Nonetheless, molecular mechanisms underlying allergy to latex and/or fruit are poorly understood. AIM: The aims of this study were to identify candidate genes that may be associated with the pathogenesis of allergy to latex and/or vegetable food, and to assess if similar molecular pathways are involved in both types of hypersensitivity. MATERIALS AND METHODS: DNA microarray analysis was performed to screen the molecular profiles of peripheral blood mononuclear cells isolated from patients with allergy to latex, to fruit, or with latex-fruit syndrome, and from control healthy subjects. RESULTS: Molecular profiling identified an overlapping dataset of genes commonly regulated in all the atopic patients enrolled in this study, suggesting that similar molecular mechanisms are involved in the pathogenesis of allergy to the fruit and/or latex. Several regulators of the innate and acquired immunity reported to polarize the immunological response towards a Th2-mediated immune response were overexpressed in the patients. Evidences suggested that the expression of T-regulatory cells might be defective in allergic patients, as a consequence of a dysregulation of some inflammatory cytokines. Finally, several transcription factors that may be responsible for the Th1/Th2 imbalance were modulated in allergic patients. CONCLUSIONS: This study identified relevant genes that may help to elucidate the molecular mechanisms underlying allergic disease. Knowledges of critical targets, along with transcription factors regulating gene activity may facilitate the development of new therapeutic options.

Adipose tissue-derived mesenchymal stem cells and hepatic differentiation: old concepts and future perspectives.

Mesenchymal stem cells (MSCs) are multipotent cells, able to differentiate into elements of the mesodermal lineage. Bone marrow and adipose tissue represent the main sources for MSC isolation. In the last decade, several studies have reported the plasticity of MSCs toward a hepatocyte-like phenotype. The use of MSCs to generate hepatocyte-like cells holds great promises to overcome the scarcity of available organs for transplantation. However, little is known about the molecular pathways involved in lineage cross-differentiation and several issues remain to be answered before MSC application in clinical settings. Aim of this review is to critically analyze the possible sources of MSCs suitable for liver repopulation and the molecular mechanisms underlying MSC hepatic differentiation.

Mesenchymal stromal cells multipotency and plasticity: induction toward the hepatic lineage.

BACKGROUND: Human mesenchymal stromal cells (MSCs) can be isolated from a variety of adult and perinatal tissues and exert multipotency and self renewal properties which make them suitable for cell-based therapy. Their potential plasticity extended to non-mesodermal-derived tissues has been indicated, although it is still a debated issue. In this study we have isolated MSCs from both adult and fetal tissues. Their growth, immunophenotype and multi-lineage differentiation potentials have been analyzed, focusing, in particular, on the hepatic differentiation. METHODS: Cells were isolated from bone marrow (BMSC), adipose tissue (ATSC) and second trimester amniotic fluid (AFSC), upon a written informed consent obtained from donor patients. Cells were expanded and growth kinetics was assessed by means of proliferation assay. Their immunophenotype was analyzed using cytometry and multi-lineage differentiation potential was evaluated by means of in vitro differentiation assays. Finally, the expression of tissue-specific markers was also assessed by mean of semi-quantitative PCR. RESULTS: Bipolar spindle-shaped cells were successfully isolated from all these tissues. Interestingly, ATSCs and AFSCs showed a higher proliferation potential than BMSCs. Mesodermal differentiation capacity was verified in all MSC populations, even if AFSCs were not able to undergo adipogenesis in our culture conditions. Furthermore, we showed that MSC cultured in appropriate conditions were able to induce hepatic-associated genes, such as ALB and TDO2. CONCLUSION: Taken together the data here reported suggest that MSCs from both adult and fetal tissues are capable of tissue-specific commitment along mesodermal and non-mesodermal lineages. In particular we have demonstrated that a specific hepatogenic commitment can be efficiently induced, proposing these cells as suitable tool for cell-based applications aimed at liver regeneration.

Isolation and characterization of CD133+ cell population within human primary and metastatic colon cancer.

BACKGROUND: "Cancer stem cells" (CSC) have been identified as a minority of cancer cells responsible for tumor initiation, maintenance and spreading. Although a universal marker for CSC has not yet been identified, CD133 has been proposed as the hallmark of CSC in colon cancer. The aim of our study was to assess the presence of a CD133+ cell fraction in samples of colon cancer and liver metastasis from colon cancer and evaluate their potential as tumor-initiating cells. METHODS: Tissue samples from 17 colon cancers and 8 liver metastasis were fragmented and digested using collagenase. Cell suspensions were characterized by flow cytometry using anti-CD133, CD45 and CD31 antibodies. CD133+ cells were also isolated by magnetic cell sorting and their tumor-initiating potential was assessed versus the remaining CD133- fraction by soft-agar assay. RESULTS: Our results confirmed the existence of a subset of CD133+ tumor cells within human colon cancers. Interestingly, CD133+ cells were detectable in liver metastasis at a higher percentage when compared to primary tumors. Soft-agar assay showed that CD133+ cell fraction was able to induce larger and more numerous colonies than CD133-cells. CONCLUSION: Our findings data that the CD133+ colon cancer cells might play an important role in both primary tumors as well as in metastatic lesions thus warranting further studies on the role(s) of this subset of cells in the metastatic process.

Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure.

BACKGROUND/AIM: We aimed to evaluate safety and efficacy of granulocyte-colony stimulating factor treatment in patients with acute on chronic liver failure and the effect of granulocyte-colony stimulating factor on the expression level of CXCR4, vascular endothelial growth factor receptor and very late activation antigen 4. METHODS: Twenty-four patients with acute on chronic liver failure were randomised to receive standard therapy, standard therapy+granulocyte-colony stimulating factor (5 microg/kg/day for 6 days) and standard therapy+granulocyte-colony stimulating factor (15 microg/kg/day s.c. for 6 days). Data on CD34+cell mobilisation were compared to age-matched peripheral blood haematopoietic stem cell donors treated with granulocyte-colony stimulating factor. On day third of treatment, the expression level of CXCR4, vascular endothelial growth factor receptor and very late activation antigen 4 was analysed in mobilised CD34+ cells. RESULTS: CD34 cell count increased after the second day of granulocyte-colony stimulating factor injection in both treatment groups compared to the linear increase observed in control. After the fifth day the increase was significantly higher in healthy donors versus patients with acute on chronic liver failure. A decrease in the expression of CXCR4, very late activation antigen 4 and vascular endothelial growth factor receptor compared to premobilisation values was observed. No major side effects were observed. CONCLUSIONS: Granulocyte-colony stimulating factor treatment is able to induce CD34 mobilisation in patients with acute on chronic liver failure. The expression pattern of CXCR4, very late activation antigen 4 and vascular endothelial growth factor receptor suggests that these molecules are involved in the granulocyte-colony stimulating factor-induced stem cell mobilisation.

Characterization of gene expression profile in rat Kupffer cells stimulated with IFN-alpha or IFN-gamma.

BACKGROUND AND AIM: Kupffer cells are intrasinusoidal space located macrophages with phagocytic capacity. Interferons are cytokines with antiviral, antiproliferative and immunomodulatory activities which may influence the activity of Kupffer cells. Aim of this study was to evaluate Kupffer cell gene expression after interferon-alpha or interferon-gamma stimulation in order to investigate a link between these cytokines and macrophage activation. METHODS: Rat Kupffer cells were cultured for 24 h and divided into three groups: unstimulated; stimulated with interferon-alpha and stimulated with interferon-gamma. After 8 h stimulation total RNA was extracted and processed according to Affymetrix protocols and hybridised on R34A microarray gene set. Data analyses was performed using Microarray Analysis Suite 5.0 software. Genes showing remarkably different expression in microarray analysis were confirmed by real-time PCR. RESULTS: Nearly 4000 out of the 8800 genes represented in the array were expressed by Kupffer cells. Among these, interferon-alpha up-regulates 91 genes by over two-fold (antiviral, antigen processing and presentation, and tumour suppressor/proapoptotic genes) and down-regulates 72 genes by 50% or more. Interferon-gamma up-regulates 70 genes by over two-fold and down-regulates 78 genes by 50% or more. Most of the genes induced by interferon-alpha are also induced by interferon-gamma. Down-regulated genes include growth factors and genes involved in cell cycle/proliferation. Real-time PCR confirms the results of the array. CONCLUSION: Interferons directly target rat Kupffer cells and are involved in the regulation of a wide variety of genes. Their expression profile shed light onto molecular mechanism of Kupffer cells activation in specific pathways such as antiviral and antitumour processes.

From stem cell to solid organ. Bone marrow, peripheral blood or umbilical cord blood as favorable source?

Adult stem cells (ASC) have becoming a great domain of research by their promising interest for the regenerative medicine. For some years, the number of publications has been increasing, displaying the potential of ASC to differentiate in all tissue-lineages, challenging the previous dogma that ASC were restricted to give rise only to specific cells from their tissue of origin. Among the diversity of ASC, hematopoietic stem cells (HSC) have been the most studied and their use in the clinical setting is largely documented. Commonly, HSC have been harvested from the bone marrow, but for some years, two others sources, the peripheral blood and the umbilical cord blood have been introduced. All these HSC posses their own molecular characteristics and degree of maturity and represent a more or less good candidate to participate in the cellular-based tissue regeneration. We have reviewed the different parameters allowing to define which subset could be the more favorable such as the accessibility to the pool of HSC; the quantity of available cells; the tolerability of host-engraftment and the capacity of the cells to home correctly to the required site of damaged. Besides, recently, the molecular profiling of HSC has allowed identifying which subset posses the more promising characteristics.

Probiotics and small bowel mucosa: Molecular aspects of their interactions.

Probiotics are described as "friendly bacteria" that could improve the intestine defense by interacting with the resident microflora. There is a large body of evidence suggesting that consumption of functional food containing probiotics exerts positive effects on human health. Several clinical trials have highlighted the efficiency of probiotics in the prevention and treatment of different gastrointestinal disorders including the prevention of antibiotic associated diarrhea, the remission in patients with inflammatory bowel disease, beneficial effects against Helicobacter pylori infection, positive effects in patients affected by allergies and atopic diseases. The clinical benefits of probiotics use are mainly attributed to their antimicrobial substances production and their positive interactions with the enterocytes to reinforce the intestinal epithelial barrier. Moreover, there is evidence suggesting that probiotics stimulate both specific and non-specific host immune responses. Recently, have been published some experiments performed with the DNA microarray technology which provided a global gene screening of the complex bacteria-host interplay. Nevertheless, the molecular mechanisms by which probiotics enhance the intestinal host defense are still not completely elucidated. Here, we review the experiments and clinical studies to date on the complex mechanisms regulating the communication between probiotics and their hosts.