Molecular grammars of intrinsically disordered regions that span the human proteome.

Intrinsically disordered regions (IDRs) of proteins are defined by functionally relevant molecular grammars. This refers to IDR-specific non-random amino acid compositions and non-random patterning of distinct pairs of amino acid types. Here, we introduce GIN (Grammars Inferred using NARDINI+) as a resource, which we have used to extract the molecular grammars of all human IDRs and classified them into thirty distinct clusters.

Immunomechanobiology: Engineering the Activation and Function of Immune Cells with the Mechanical Signal of Fluid Shear Stress.

Immunomechanobiology, the study of how physical forces influence the behavior and function of immune cells, is a rapidly growing area of research. It is becoming increasingly recognized that mechanical stimuli, such as fluid shear forces, are a critical determinant of immune cell regulation. In this review, we discuss the principles and significance of various mechanical forces present within the human body, with a focus on fluid shear flow and its impact on immune cell activation and function.

Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis.

Non-surgical and safe prostate cancer (PCa) therapies are in demand. Soluble tumor necrosis factor (TNF-α) related apoptosis inducing ligand (TRAIL), a cancer-specific drug, shows preclinical efficacy but has a short circulation half-life. This research has shown that physiological fluid shear stress activates mechanosensitive ion channels (MSCs), such as Piezo1, enhancing TRAIL-mediated apoptosis in cancer cells.

Synapsin Condensation is Governed by Sequence-Encoded Molecular Grammars.

Multiple biomolecular condensates coexist at the pre- and post- synapse to enable vesicle dynamics and controlled neurotransmitter release in the brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers of condensation that enable clustering of synaptic vesicles (SVs). Using computational analysis, we show that the IDRs of SV proteins feature evolutionarily conserved non-random compositional biases and sequence patterns.

Simulation of Somatic Evolution Through the Introduction of Random Mutation to the Rules of Conway's Game of Life.

Introduction: Conway's Game of Life (GOL), and related cellular automata (CA) models, have served as interesting simulations of complex behaviors resulting from simple rules of interactions between neighboring cells, that sometime resemble the growth and reproduction of living things. Thus, CA has been applied towards understanding the interaction and reproduction of single-cell organisms, and the growth of larger, disorganized tissues such as tumors. Surprisingly, however, there have been few attempts to adapt simple CA models to recreate the evolution of either new species, or subclones within a multicellular, tumor-like tissue.

Therapeutic Exercises for Rehabilitation of Muscle Injury.

Successful rehabilitation of muscle injury requires a comprehensive understanding of the injury process, healing phases, and resources to be employed. The initial phase is characterized by acute inflammatory signs, followed by the regenerative and remodeling phases. Therapeutic exercises can be utilized in all 3 phases, progressing from isometric exercises to aquatic therapies.

Muscle Rehabilitation Techniques and Prevention of Injury.

Rehabilitation following muscle injury is critical in restoring the equine athlete to full function. Rehabilitation protocols should be tailored to each patient's global functional assessment, taking into account sports-specific demands, goals for return-to-performance, and overall prognosis. Rehabilitation protocols are often designed to modulate pain, enhance repair, improve proprioception, increase flexibility, restore muscle strength, joint range-of-motion, and neuromotor control.

Superhydrophobic Array Devices for the Enhanced Formation of 3D Cancer Models.

During the metastatic cascade, cancer cells travel through the bloodstream as circulating tumor cells (CTCs) to a secondary site. Clustered CTCs have greater shear stress and treatment resistance, yet their biology remains poorly understood. We therefore engineered a tunable superhydrophobic array device (SHArD).

Biomolecular condensates can function as inherent catalysts.

We report the discovery that chemical reactions such as ATP hydrolysis can be catalyzed by condensates formed by intrinsically disordered proteins (IDPs), which themselves lack any intrinsic ability to function as enzymes. This inherent catalytic feature of condensates derives from the electrochemical environments and the electric fields at interfaces that are direct consequences of phase separation. The condensates we studied were capable of catalyzing diverse hydrolysis reactions, including hydrolysis and radical-dependent breakdown of ATP whereby ATP fully decomposes to adenine and multiple carbohydrates.

Enhanced and sustained T cell activation in response to fluid shear stress.

The efficacy of T cell therapies in treating solid tumors is limited by poor persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable activation. Herein, we present a 10-day kinetic profile of T cells subjected to fluid shear stress (FSS) , with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2).

Multiplex, high-throughput method to study cancer and immune cell mechanotransduction.

Studying cellular mechanoresponses during cancer metastasis is limited by sample variation or complex protocols that current techniques require. Metastasis is governed by mechanotransduction, whereby cells translate external stimuli, such as circulatory fluid shear stress (FSS), into biochemical cues. We present high-throughput, semi-automated methods to expose cells to FSS using the VIAFLO96 multichannel pipetting device custom-fitted with 22 G needles, increasing the maximum FSS 94-fold from the unmodified tips.

A High-Avidity, Thermostable, and Low-Cost Synthetic Capture for Ultrasensitive Detection and Quantification of Viral Antigens and Aerosols.

Lateral flow assays (LFAs) are currently the most popular point-of-care diagnostics, rapidly transforming disease diagnosis from expensive doctor checkups and laboratory-based tests to potential on-the-shelf commodities. Yet, their sensitive element, a monoclonal antibody, is expensive to formulate, and their long-term storage depends on refrigeration technology that cannot be met in resource-limited areas. In this work, LCB1 affibodies (antibody mimetic miniproteins) were conjugated to bovine serum albumin (BSA) to afford a high-avidity synthetic capture (LCB1-BSA) capable of detecting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and virus like particles (VLPs).

Spatial distribution of tumor-associated macrophages in an orthotopic prostate cancer mouse model.

Mounting evidence suggests that the immune landscape within prostate tumors influences progression, metastasis, treatment response, and patient outcomes. In this study, we investigated the spatial density of innate immune cell populations within NOD.SCID orthotopic prostate cancer xenografts following microinjection of human DU145 prostate cancer cells.

Blood flow restriction training does not negatively alter the mechanical strength or histomorphology of uninjured equine superficial digital flexor tendons.

Background: Low load exercise training with blood flow restriction (BFR) has become increasingly used by human physical therapists to prescribe controlled exercise following orthopaedic injury; its effects on the equine superficial digital flexor tendon (SDFT), however, are unknown.

Objective: To investigate outcomes of pressure specific BFR walking exercise on uninjured equine SDFT biomechanics and histomorphology.

Study Design: Controlled in vivo experiment.

Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient.

Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass.

Emergent microenvironments of nucleoli.

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules.

Incorporation of ChatGPT and Other Large Language Models into a Graduate Level Computational Bioengineering Course.

The remarkable capabilities of generative artificial intelligence and large language models (LLMs) such as ChatGPT have delighted users around the world. Educators have regarded these tools as either a cause for great concern, an opportunity to educate students on cutting-edge technology, or often some combination of the two. Throughout the Fall 2023 semester, we explored the use of ChatGPT (and Bard, among other LLMs) in a graduate level numerical and statistical methods course for PhD-level bioengineers.

Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease.

Tuning of TRAIL clustering on the surface of nanoscale liposomes by phase separation.

Phase-separated liposomes were used to formulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that selectively kills cancer cells while sparing most healthy ones. By controlling the average number of TRAIL molecules per liposome, we demonstrate the ability to tune the formation of TRAIL clusters and their resulting apoptotic activity.

Tumor nano-lysate activates dendritic cells to evoke a preventative immune response.

A tumor nano-lysate "TNL" vaccine comprised of sonicated 4T1 cells was developed, characterized and implemented for the prevention of triple-negative breast cancer. This study aimed to gain a better understanding of the immune response behind the success of the vaccine in vivo, through use of ex vivo and in vivo assays. Here, we analyze the activation of various immune cells isolated from healthy mouse spleens and find that antigen-presenting cells (APCs) such as dendritic cells (DCs) are being activated following 24 h incubation with 1:10 mg TNL/mg splenocytes.

Activation of Dendritic Cells Isolated from the Blood of Patients with Prostate Cancer by Ex Vivo Fluid Shear Stress Stimulation.

Prostate cancer is one of the most common cancers among men in the United States and a leading cause of cancer-related death in men. Treatment options for patients with advanced prostate cancer include hormone therapies, chemotherapies, radioligand therapies, and immunotherapies. Provenge (sipuleucel-T) is an autologous cancer-vaccine-based immunotherapy approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Dual Affinity Nanoparticles for the Transport of Therapeutics from Carrier Cells to Target Cells under Physiological Flow Conditions.

In this study, a novel two-stage nanoparticle delivery platform was developed based on the dual functionalization of a liposome with moieties that have fundamentally different strengths of adhesion and binding kinetics. The essential concept of this system is that the nanoparticles are designed to loosely bind to the carrier cell until they come into contact with the target cell, to which they bind with greater strength. This allows the nanoparticle to be transferred from one cell to another, circulating for longer periods of time in the blood and delivering the therapeutic agent to the target circulating tumor cell.