CAR-T cell therapy for breast cancer: Current status and future perspective.

Within the expanding therapeutic landscape for breast cancer (BC), metastatic breast cancer (MBC) remains virtually incurable and tend to develop resistance to conventional treatments ultimately leading to metastatic progression and death. Cellular immunotherapy (CI), particularly chimeric antigen receptor-engineered T (CAR-T) cells, has emerged as a promising approach for addressing this challenge. In the wake of their striking efficacy against hematological cancers, CAR-T cells have also been used where the clinical need is greatest - in patients with aggressive BCs.

Producing agri-food derived composts from coffee husk as primary feedstock at different temperature conditions.

There is a great global concern about agricultural wastes from food and feed crop processing that have significant environmental impacts. Composting is the most environmentally friendly, cost-effective, and efficient processes that can solve the problems of accumulation and toxicity of agricultural waste. The aim of this study is the detoxification of coffee husk by composting at two temperature conditions ("warm" and "cold").

Functional effects of mutations in proteins can be predicted and interpreted by guided selection of sequence covariation information.

Predicting the effects of one or more mutations to the in vivo or in vitro properties of a wild-type protein is a major computational challenge, due to the presence of epistasis, that is, of interactions between amino acids in the sequence. We introduce a computationally efficient procedure to build minimal epistatic models to predict mutational effects by combining evolutionary (homologous sequence) and few mutational-scan data. Mutagenesis measurements guide the selection of links in a sparse graphical model, while the parameters on the nodes and the edges are inferred from sequence data.

Propofol sedation does not improve measures of colonoscopy quality but increase cost - findings from a large population-based cohort study.

Background: Propofol is often used for sedation during colonoscopy. We assessed the impact of propofol sedation on colonoscopy related quality metrics and cost in a population-based cohort study.

Methods: All colonoscopies performed at 21 hospitals in the province of Ontario, Canada, during an 18-month period, from April 1, 2017 to October 31, 2018, using either propofol or conscious sedation were evaluated.

Computational design of novel Cas9 PAM-interacting domains using evolution-based modelling and structural quality assessment.

We present here an approach to protein design that combines (i) scarce functional information such as experimental data (ii) evolutionary information learned from a natural sequence variants and (iii) physics-grounded modeling. Using a Restricted Boltzmann Machine (RBM), we learn a sequence model of a protein family. We use semi-supervision to leverage available functional information during the RBM training.

Infer global, predict local: Quantity-relevance trade-off in protein fitness predictions from sequence data.

Predicting the effects of mutations on protein function is an important issue in evolutionary biology and biomedical applications. Computational approaches, ranging from graphical models to deep-learning architectures, can capture the statistical properties of sequence data and predict the outcome of high-throughput mutagenesis experiments probing the fitness landscape around some wild-type protein. However, how the complexity of the models and the characteristics of the data combine to determine the predictive performance remains unclear.

Comparisons among barley-pea mixed crop combinations in a replacement design as related to N fertilization and soil variation.

Two field trials (2017 and 2018) evaluated the performance of barley-pea mixed cropping by comparing different sowing densities (replacement design) and tailoring N fertilization on barley sowing density (split-plot design). High and Low N inputs were applied to whole plots whereas barley and pea, as pure and in mixed crops, were applied to subplots. The 2017 trial suggested the occurrence of an interaction between soil physical properties and N fertilization.

Short term effects of digestate and composted digestate on soil health and crop yield: Implications for sustainable biowaste management in the bioenergy sector.

Composting mitigates environmental risks associated with using solid digestate as fertilizer. However, evidence is lacking on benefits of using composted digestate as fertilizer in enhancing soil health and increasing agronomic yield compared to non-composted digestate (hereafter, digestate). A field study was conducted consisting of digestate, composted digestate, co-composted digestate with biogas feedstocks (corn [Zea mays L.

Transition paths in Potts-like energy landscapes: General properties and application to protein sequence models.

We study transition paths in energy landscapes over multicategorical Potts configurations using the mean-field approach introduced by Mauri et al. [Phys. Rev.

A transfer-learning approach to predict antigen immunogenicity and T-cell receptor specificity.

Antigen immunogenicity and the specificity of binding of T-cell receptors to antigens are key properties underlying effective immune responses. Here we propose diffRBM, an approach based on transfer learning and Restricted Boltzmann Machines, to build sequence-based predictive models of these properties. DiffRBM is designed to learn the distinctive patterns in amino-acid composition that, on the one hand, underlie the antigen's probability of triggering a response, and on the other hand the T-cell receptor's ability to bind to a given antigen.

Interleukin 1β triggers synaptic and memory deficits in Herpes simplex virus type-1-infected mice by downregulating the expression of synaptic plasticity-related genes via the epigenetic MeCP2/HDAC4 complex.

Extensive research provides evidence that neuroinflammation underlies numerous brain disorders. However, the molecular mechanisms by which inflammatory mediators determine synaptic and cognitive dysfunction occurring in neurodegenerative diseases (e.g.

Mutational Paths with Sequence-Based Models of Proteins: From Sampling to Mean-Field Characterization.

Identifying and characterizing mutational paths is an important issue in evolutionary biology, with potential applications to bioengineering. We here propose an algorithm to sample mutational paths, which we benchmark on exactly solvable models of proteins in silico, and apply to data-driven models of natural proteins learned from sequence data with restricted Boltzmann machines. We then use mean-field theory to characterize paths for different mutational dynamics of interest, and to extend Kimura's estimate of evolutionary distances to sequence-based epistatic models of selection.

Machine learning for evolutionary-based and physics-inspired protein design: Current and future synergies.

Computational protein design facilitates the discovery of novel proteins with prescribed structure and functionality. Exciting designs were recently reported using novel data-driven methodologies that can be roughly divided into two categories: evolutionary-based and physics-inspired approaches. The former infer characteristic sequence features shared by sets of evolutionary-related proteins, such as conserved or coevolving positions, and recombine them to generate candidates with similar structure and function.

Emergence of time persistence in a data-driven neural network model.

Establishing accurate as well as interpretable models of network activity is an open challenge in systems neuroscience. Here, we infer an energy-based model of the anterior rhombencephalic turning region (ARTR), a circuit that controls zebrafish swimming statistics, using functional recordings of the spontaneous activity of hundreds of neurons. Although our model is trained to reproduce the low-order statistics of the network activity at short time scales, its simulated dynamics quantitatively captures the slowly alternating activity of the ARTR.

Noise-induced auditory damage affects hippocampus causing memory deficits in a model of early age-related hearing loss.

Several studies identified noise-induced hearing loss (NIHL) as a risk factor for sensory aging and cognitive decline processes, including neurodegenerative diseases, such as dementia and age-related hearing loss (ARHL). Although the association between noise- and age-induced hearing impairment has been widely documented by epidemiological and experimental studies, the molecular mechanisms underlying this association are not fully understood as it is not known how these risk factors (aging and noise) can interact, affecting memory processes. We recently found that early noise exposure in an established animal model of ARHL (C57BL/6 mice) accelerates the onset of age-related cochlear dysfunctions.

Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aβ Metabolism.

Maternal overnutrition has been reported to affect brain plasticity of the offspring by altering gene expression, regulating both synaptic plasticity and adult neurogenesis. However, whether perinatal metabolic stress may influence the accumulation of misfolded proteins and the development of neurodegeneration remains to be clarified. We investigated the impact of maternal high fat diet (HFD) in an experimental model of Alzheimer's disease (AD).

Holm oak (Quercus ilex L.) cover: A key soil-forming force in controlling C and nutrient stocks in long-time coppice-managed forests.

In forest ecosystems, soil-plant interactions drive the physical, chemical, and biological soil properties and, through soil organic matter cycling, control the dynamics of nutrient cycles. Parent material also plays a fundamental role in determining soil's chemical properties and nutrient availability. In this study, eight long-time coppice-managed Holm oak forests under conversion to high forest, located under similar climatic conditions in Tuscany and Sardinia Regions (Italy), and grown on soils developed from three different lithologies (limestone, biotite granite, and granite with quartz veins) were evaluated.

Displacement and dissociation of oligonucleotides during DNA hairpin closure under strain.

The hybridization kinetic of an oligonucleotide to its template is a fundamental step in many biological processes such as replication arrest, CRISPR recognition, DNA sequencing, DNA origami, etc. Although single kinetic descriptions exist for special cases of this problem, there are no simple general prediction schemes. In this work, we have measured experimentally, with no fluorescent labelling, the displacement of an oligonucleotide from its substrate in two situations: one corresponding to oligonucleotide binding/unbinding on ssDNA and one in which the oligonucleotide is displaced by the refolding of a dsDNA fork.

Generative and interpretable machine learning for aptamer design and analysis of in vitro sequence selection.

Selection protocols such as SELEX, where molecules are selected over multiple rounds for their ability to bind to a target of interest, are popular methods for obtaining binders for diagnostic and therapeutic purposes. We show that Restricted Boltzmann Machines (RBMs), an unsupervised two-layer neural network architecture, can successfully be trained on sequence ensembles from single rounds of SELEX experiments for thrombin aptamers. RBMs assign scores to sequences that can be directly related to their fitnesses estimated through experimental enrichment ratios.

Soil fertility in slash and burn agricultural systems in central Mozambique.

Slash and burn is a land use practice widespread all over the world, and nowadays it is formally recognized as the principal livelihood system in rural areas of South America, Asia, and Africa. The practice consists of a land rotation where users cut native or secondary forest to establish a new crop field and, in some cases, build charcoal kilns with the cut wood to produce charcoal. Due to several socio-economic changes in developing countries, some scientists and international organizations have questioned the sustainability of slash and burn since in some cases, crop yield does not justify the soil degradation caused.

Association of Trainee Participation in Colonoscopy Procedures With Quality Metrics.

Importance: Trainees routinely participate in colonoscopy procedures, yet whether their involvement is positively or negatively associated with procedural quality is unknown because prior studies involved small number of trainees and/or supervisors, lacked generalizability, and/or failed to adjust for potential confounders.

Objective: To assess the association between trainee participation and colonoscopy quality metrics.

Design, Setting, And Participants: This multicenter population-based cohort study was conducted at 21 academic and community hospitals between April 1, 2017, and October 31, 2018, among consecutive adult patients undergoing colonoscopy.

A synaptic signal for novelty processing in the hippocampus.

Episodic memory formation and recall are complementary processes that rely on opposing neuronal computations in the hippocampus. How this conflict is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments.

Inhibition of autophagy by chloroquine prevents resistance to PI3K/AKT inhibitors and potentiates their antitumor effect in combination with paclitaxel in triple negative breast cancer models.

Background: Triple negative breast cancer (TNBC) is an aggressive disease characterized by high risk of relapse and development of resistance to different chemotherapy agents. Several targeted therapies have been investigated in TNBC with modest results in clinical trials. Among these, PI3K/AKT inhibitors have been evaluated in addition to standard therapies, yielding conflicting results and making attempts on elucidating inherent mechanisms of resistance of great interest.

Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.

Cancer immunoediting is a hallmark of cancer that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years.

Effect of coppice conversion into high forest on soil organic C and nutrients stock in a Turkey oak (Quercus cerris L.) forest in Italy.

In forest ecosystems, a variety of abiotic and biotic soil forming factors drives soil organic matter (SOM) and nutrients cycling with a profitable outcome on climate change mitigation. As a consequence, type and intensity of forest management, through its impact on carbon (C) and nutrient soil stocks, can be considered as an additional soil forming force. In this study, we investigated the influence of the coppice conversion into high forest on pedogenesis and on soil C and nutrient (N, P, Ca, Mg, and K) stocks, fifty years later the beginning of the conversion-cycle.