Machine learning, a collection of data-analytical techniques aimed at building predictive models from multi-dimensional datasets, is becoming integral to modern biological research. By enabling one ...to generate models that learn from large datasets and make predictions on likely outcomes, machine learning can be used to study complex cellular systems such as biological networks. Here, we provide a primer on machine learning for life scientists, including an introduction to deep learning. We discuss opportunities and challenges at the intersection of machine learning and network biology, which could impact disease biology, drug discovery, microbiome research, and synthetic biology.
Machine-learning approaches are essential for pulling information out of the vast datasets that are being collected across biology and biomedicine. This Review considers the opportunities and challenges at the intersection of network biology and data science.
While synthetic biology has revolutionized our approaches to medicine, agriculture, and energy, the design of completely novel biological circuit components beyond naturally-derived templates remains ...challenging due to poorly understood design rules. Toehold switches, which are programmable nucleic acid sensors, face an analogous design bottleneck; our limited understanding of how sequence impacts functionality often necessitates expensive, time-consuming screens to identify effective switches. Here, we introduce Sequence-based Toehold Optimization and Redesign Model (STORM) and Nucleic-Acid Speech (NuSpeak), two orthogonal and synergistic deep learning architectures to characterize and optimize toeholds. Applying techniques from computer vision and natural language processing, we 'un-box' our models using convolutional filters, attention maps, and in silico mutagenesis. Through transfer-learning, we redesign sub-optimal toehold sensors, even with sparse training data, experimentally validating their improved performance. This work provides sequence-to-function deep learning frameworks for toehold selection and design, augmenting our ability to construct potent biological circuit components and precision diagnostics.
Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with ...obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Recent progress in DNA synthesis and sequencing technology has enabled systematic studies of protein function at a massive scale. We explore a deep mutational scanning study that measured the ...transcriptional repression function of 43,669 variants of the
LacI protein. We analyze structural and evolutionary aspects that relate to how the function of this protein is maintained, including an in-depth look at the C-terminal domain. We develop a deep neural network to predict transcriptional repression mediated by the lac repressor of
using experimental measurements of variant function. When measured across 10 separate training and validation splits using 5,009 single mutations of the lac repressor, our best-performing model achieved a median Pearson correlation of 0.79, exceeding any previous model. We demonstrate that deep representation learning approaches, first trained in an unsupervised manner across millions of diverse proteins, can be fine-tuned in a supervised fashion using lac repressor experimental datasets to more effectively predict a variant's effect on repression. These findings suggest a deep representation learning model may improve the prediction of other important properties of proteins.
Abstract Exoskeletons have the potential to assist and augment human performance. Understanding how users adapt their movement and neuromuscular control in response to external assistance is ...important to inform the design of these devices. The aim of this research was to evaluate changes in muscle recruitment and coordination for ten unimpaired individuals walking with an ankle exoskeleton. We evaluated changes in the activity of individual muscles, cocontraction levels, and synergistic patterns of muscle coordination with increasing exoskeleton work and torque. Participants were able to selectively reduce activity of the ankle plantarflexors with increasing exoskeleton assistance. Increasing exoskeleton net work resulted in greater reductions in muscle activity than increasing exoskeleton torque. Patterns of muscle coordination were not restricted or constrained to synergistic patterns observed during unassisted walking. While three synergies could describe nearly 95% of the variance in electromyography data during unassisted walking, these same synergies could describe only 85-90% of the variance in muscle activity while walking with the exoskeleton. Synergies calculated with the exoskeleton demonstrated greater changes in synergy weights with increasing exoskeleton work versus greater changes in synergy activations with increasing exoskeleton torque. These results support the theory that unimpaired individuals do not exclusively use central pattern generators or other low-level building blocks to coordinate muscle activity, especially when learning a new task or adapting to external assistance, and demonstrate the potential for using exoskeletons to modulate muscle recruitment and coordination patterns for rehabilitation or performance.
Intimate partner violence (IPV) and sexual violence (SV) are significant public health issues for women, particularly for college women. IPV and SV have been associated with numerous adverse health ...consequences and involvement in unhealthy behaviors. Given the health risks and high rates of IPV/SV among college women, it is important to understand and promote screening in this population. The purpose of this study was to examine college women’s experiences with IPV/SV screening at college health centers and identify individual and institutional characteristics associated with screening. Random samples of female undergraduate college students from five colleges in the northeast United States were recruited to participate in an anonymous online survey in January 2015. Inclusion criteria included at least one visit to the college health center during the preceding fall semester. Participants were questioned regarding demographics and whether they were screened or asked about IPV/SV at the college health center. A total of 873 women met the inclusion criteria and completed surveys. Only 10.2% of the college women in the study reported that they were screened for IPV/SV at their most recent visit to the college health center. Participants from public colleges/universities were 3 times more likely than others to report screening, whereas participants from urban college/university campuses were more than twice as likely as others to report screening. College women who went to the college health center for a gynecological or sexual health reason were nearly 4 times as likely as other women to report being screened for IPV/SV. Low rates of IPV/SV screening at college health centers represent missed opportunities. Further research across more numerous and diverse college sites is needed to understand the factors that promote or inhibit IPV/SV screening in college health centers to develop interventions to facilitate routine screening practices.
The Institute for Healthcare Improvement's 4-Ms framework of care for older adults recommends a multidisciplinary assessment of a patient's Medications, Mentation, Mobility, and What Matters Most. ...Electronic health record (EHR) systems were developed prior to this emphasis on the 4-Ms. We sought to understand how healthcare providers across the healthcare system perceive their EHRs and to identify any current best practices and ideas for improvement regarding integration of the 4-Ms.
Anonymous survey of healthcare providers who care for older adults. The survey aimed to evaluate efficiency, error tolerance, and satisfaction (usefulness and likeability). The survey was distributed through organizational list serves that focus on the care of older adults and through social media.
Sixty-six respondents from all geographic segments of the U.S. (n = 62) and non-U.S. practices (n = 4) responded. Most (82%) were physicians. Respondents used a range of EHRs and 82% had >5 years of experience with their current EHR. Over half of respondents agreed that their EHR had easy to find contact information (56%) and advance directives. Finding a patient's prior cognitive status (26% agreement), goals of care (24%), functional status (14%), and multidisciplinary geriatric assessments (27%) was more difficult. Only 3% were satisfied with how their EHR handles geriatric syndromes. In free text responses, respondents (79%) described three areas that the EHR assists in the care of older adults: screening tied to actions or orders; advance care planning, and medication alerts or review. Common suggestions on how to improve the EHR included incorporating geriatric assessments in notes, establishing a unified place to review the 4-Ms, and creating age-specific best practice alerts.
The majority of healthcare providers were not satisfied with how their EHR handles multidisciplinary geriatric assessment and geriatric care. EHR modifications would aide in reporting, communicating, and tracking the 4-Ms in EHRs.
There is much excitement about the opportunity to harness the power of large language models (LLMs) when building problem-solving assistants. However, the standard methodology of evaluating LLMs ...relies on static pairs of inputs and outputs; this is insufficient for making an informed decision about which LLMs are best to use in an interactive setting, and how that varies by setting. Static assessment therefore limits how we understand language model capabilities. We introduce CheckMate, an adaptable prototype platform for humans to interact with and evaluate LLMs. We conduct a study with CheckMate to evaluate three language models (InstructGPT, ChatGPT, and GPT-4) as assistants in proving undergraduate-level mathematics, with a mixed cohort of participants from undergraduate students to professors of mathematics. We release the resulting interaction and rating dataset, MathConverse. By analyzing MathConverse, we derive a taxonomy of human query behaviors and uncover that despite a generally positive correlation, there are notable instances of divergence between correctness and perceived helpfulness in LLM generations, among other findings. Further, we garner a more granular understanding of GPT-4 mathematical problem-solving through a series of case studies, contributed by experienced mathematicians. We conclude with actionable takeaways for ML practitioners and mathematicians: models that communicate uncertainty, respond well to user corrections, and can provide a concise rationale for their recommendations, may constitute better assistants. Humans should inspect LLM output carefully given their current shortcomings and potential for surprising fallibility.
Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless ...fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.
Bacteria use an array of sigma factors to regulate gene expression during different stages of their life cycles. Full-length, atomic-level structures of sigma factors have been challenging to obtain ...experimentally as a result of their many regions of intrinsic disorder. AlphaFold has now supplied plausible full-length models for most sigma factors. Here we discuss the current understanding of the structures and functions of sigma factors in the model organism,
, and present an X-ray crystal structure of a region of
SigE, a sigma factor that plays a critical role in the developmental process of spore formation.
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