Exploration of the polymorphic solid-state landscape of an amide-linked organic cage using computation and automation.

Organic cages can possess complex, functionalised cavities that make them promising candidates for synthetic enzyme mimics. Conformationally flexible, chemically robust structures are needed for adaptable guest binding and catalysis, but rapidly exchanging systems are difficult to resolve in solution. Here, we use low-cost calculations and high-throughput crystallisation to identify accessible conformers of a recently reported organic cage by 'locking' them in the solid state. The conformers exhibit varying distances between the internal carboxylic acid groups, suggesting adaptability for binding a wide array of target guest molecules.

Identifying teeth and tooth fragments from digital 3D models.

Dental anatomy is an essential skill for human identification in forensic odontology. With the advent of technology enabling virtual autopsies, there is scope for virtual consultation by forensic odontologists especially when the expertise is unavailable but needed in zones of conflict or disasters. This study aimed to investigate potential benefits and challenges of identifying intact and damaged teeth from 3D scanned digital models. Ten 3D tooth models - nine permanent and deciduous human teeth and one animal tooth were uploaded on a hosting platform. A 3-part survey was circulated among 60 forensic odontologists with questions about demography (P1), tooth identification of the scanned 3D models (P2) and the perceived usefulness of 3D models for tooth identification (P3). This was the first time that a survey required the identification of individual human teeth (intact or not) and animal tooth combined. The response rate for study participation was 58%. Substantial agreement among participants was seen in the determination of tooth classification (i.e., molars, premolars) or non-human and tooth within the same tooth class (i.e., lateral incisors, second molar) (both k=0.61). The least agreement (k=0.21) was seen in identification of tooth according to the FDI notation with a mean accuracy of 0.34. While most responders correctly identified the animal tooth, most incorrect responses were seen in the identification of the intact third molar. While 3D-scanned teeth have the potential to be identified virtually, forensic odontologists should continuously test their skills in tooth morphology and dental anatomy of humans (damaged or not) and animals.

Magnetically locked Janus particle clusters with orientation-dependent motion in AC electric fields.

Active particles, or micromotors, locally dissipate energy to drive locomotion at small length scales. The type of trajectory is generally fixed and dictated by the geometry and composition of the particle, which can be challenging to tune using conventional fabrication procedures. Here, we report a simple, bottom-up method to magnetically assemble gold-coated polystyrene Janus particles into "locked" clusters that display diverse trajectories when stimulated by AC electric fields. The orientation of particles within each cluster gives rise to distinct modes of locomotion, including translational, rotational, trochoidal, helical, and orbital. We model this system using a simplified rigid beads model and demonstrate qualitative agreement between the predicted and experimentally observed cluster trajectories. Overall, this system provides a facile means to scalably create micromotors with a range of well-defined motions from discrete building blocks.

Dissolved gases from pressure changes in the lungs elicit an immune response in human peripheral blood.

Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung-on-a-chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen-reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 hour and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS.

Microrobots for Biomedicine: Unsolved Challenges and Opportunities for Translation.

Microrobots are being explored for biomedical applications, such as drug delivery, biological cargo transport, and minimally invasive surgery. However, current efforts largely focus on proof-of-concept studies with nontranslatable materials through a "design-and-apply" approach, limiting the potential for clinical adaptation. While these proof-of-concept studies have been key to advancing microrobot technologies, we believe that the distinguishing capabilities of microrobots will be most readily brought to patient bedsides through a "design-by-problem" approach, which involves focusing on unsolved problems to inform the design of microrobots with practical capabilities. As outlined below, we propose that the clinical translation of microrobots will be accelerated by a judicious choice of target applications, improved delivery considerations, and the rational selection of translation-ready biomaterials, ultimately reducing patient burden and enhancing the efficacy of therapeutic drugs for difficult-to-treat diseases.

Bubble-Based Microrobots with Rapid Circular Motions for Epithelial Pinning and Drug Delivery.

Remotely powered microrobots are proposed as next-generation vehicles for drug delivery. However, most microrobots swim with linear trajectories and lack the capacity to robustly adhere to soft tissues. This limits their ability to navigate complex biological environments and sustainably release drugs at target sites. In this work, bubble-based microrobots with complex geometries are shown to efficiently swim with non-linear trajectories in a mouse bladder, robustly pin to the epithelium, and slowly release therapeutic drugs. The asymmetric fins on the exterior bodies of the microrobots induce a rapid rotational component to their swimming motions of up to ≈150 body lengths per second. Due to their fast speeds and sharp fins, the microrobots can mechanically pin themselves to the bladder epithelium and endure shear stresses commensurate with urination. Dexamethasone, a small molecule drug used for inflammatory diseases, is encapsulated within the polymeric bodies of the microrobots. The sustained release of the drug is shown to temper inflammation in a manner that surpasses the performance of free drug controls. This system provides a potential strategy to use microrobots to efficiently navigate large volumes, pin at soft tissue boundaries, and release drugs over several days for a range of diseases.

Systemic Tumor Suppression via Macrophage-Driven Automated Homing of Metal-Phenolic-Gated Nanosponges for Metastatic Melanoma.

Cell-based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug-loading with high accumulations in solid tumors. Herein, a tumor-targeting cellular drug delivery system (MAGN) by surface engineering of tumor-homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron-tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the "ON-OFF" gating effect of the polyphenol-based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor-targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs.

Electrokinetic Active Particles for Motion-Based Biomolecule Detection.

Detection of biomolecules is essential for patient diagnosis, disease management, and numerous other applications. Recently, nano- and microparticle-based detection has been explored for improving traditional assays by reducing required sample volumes and assay times as well as enhancing tunability. Among these approaches, active particle-based assays that couple particle motion to biomolecule concentration expand assay accessibility through simplified signal outputs. However, most of these approaches require secondary labeling, which complicates workflows and introduces additional points of error. Here, we show a proof-of-concept for a label-free, motion-based biomolecule detection system using electrokinetic active particles. We prepare induced-charge electrophoretic microsensors (ICEMs) for the capture of two model biomolecules, streptavidin and ovalbumin, and show that the specific capture of the biomolecules leads to direct signal transduction through ICEM speed suppression at concentrations as low as 0.1 nM. This work lays the foundation for a new paradigm of rapid, simple, and label-free biomolecule detection using active particles.

Patient Reported Outcomes Using Medical Cannabis for Managing Pain in Charcot-Marie-Tooth Disease.

Objective: Chronic pain is a major problem for patients with Charcot-Marie-Tooth (CMT) disease. This exploratory study examined patient reported efficacy of medical cannabis for pain management in this population. Methods: Participants (N = 56; 71.4% female; Age = 48.9, SD = 14.6; 48.5% CMT1) were recruited though the Hereditary Neuropathy Foundation. The online survey contained 52 multiple choice questions about demographics, medical cannabis use, symptomology, efficacy, and adverse effects. Results: Nearly all (90.9%) of respondents reported experiencing pain, including all (100%) females and 72.7% of males (chi-square P < .05) with 91.7% of respondents indicating cannabis provided at least 50% pain relief. The most frequent response was an 80% reduction in pain. Moreover, 80.0% of respondents reported using less opiates, 69% noted using less sleep medication, and 50.0% reported using less anxiety/antidepressant medications. Negative side effects were noted by 23.5% of respondents. However, almost all (91.7%) of that subgroup did not have plans to stop consuming cannabis. One-third (33.9%) possessed a medical cannabis certificate. Patient perceptions of their physicians' attitudes regarding patient medical cannabis use greatly impacted whether respondents informed their providers of their usage. Conclusion: The vast majority of patients with CMT reported that cannabis was effective to manage pain symptoms. These data support the need for prospective, randomized, controlled trials using standardized dosing protocols to further delineate and optimize the potential use of cannabis to treat pain related to CMT.

Two-dimensional diffusiophoretic colloidal banding: optimizing the spatial and temporal design of solute sinks and sources.

Diffusiophoresis refers to the phenomenon where colloidal particles move in response to solute concentration gradients. Existing studies on diffusiophoresis, both experimental and theoretical, primarily focus on the movement of colloidal particles in response to one-dimensional solute gradients. In this work, we numerically investigate the impact of two-dimensional solute gradients on the distribution of colloidal particles, i.e., colloidal banding, induced via diffusiophoresis. The solute gradients are generated by spatially arranged sources and sinks that emit/absorb a time-dependent solute molar rate. First we study a dipole system, i.e., one source and one sink, and discover that interdipole diffusion and molar rate decay timescales dictate colloidal banding. At timescales shorter than the interdipole diffusion timescale, we observe a rapid enhancement in particle enrichment around the source due to repulsion from the sink. However, at timescales longer than the interdipole diffusion timescale, the source and sink screen each other, leading to a slower enhancement. If the solute molar rate decays at the timescale of interdipole diffusion, an optimal separation distance is obtained such that particle enrichment is maximized. We find that the partition coefficient of solute at the interface between the source and bulk strongly impacts the optimal separation distance. Surprisingly, the diffusivity ratio of solute in the source and bulk has a much weaker impact on the optimal dipole separation distance. We also examine an octupole configuration, i.e., four sinks and four sources, arranged in a circle, and demonstrate that the geometric arrangement that maximizes enrichment depends on the radius of the circle. If the radius of the circle is small, it is preferred to have sources and sinks arranged in an alternating fashion. However, if the radius of the circle is large, a consecutive arrangement of sources and sinks is optimal. Our numerical framework introduces a novel method for spatially and temporally designing the banded structure of colloidal particles in two dimensions using diffusiophoresis and opens up new avenues in a field that has primarily focused on one-dimensional solute gradients.

Fallibility of tattooing colonic neoplasia ahead of laparoscopic resection: a retrospective cohort study.

INTRODUCTION: Precise geographical localisation of colonic neoplasia is a prerequisite for proper laparoscopic oncological resection. Preoperative endoscopic peri-tumoural tattoo practice is routinely recommended but seldom scrutinised. METHODS: A retrospective review of recent consecutive patients with preoperative endoscopic lesional tattoo who underwent laparoscopic colonic resection as identified from our prospectively maintained cancer database with supplementary clinical chart and radiological, histological, endoscopic and theatre database/logbook interrogation. RESULTS: Some 210 patients with 'tattooed' colonic neoplasia were identified, of whom 169 underwent laparoscopic surgery (mean age 68 years, median BMI 27.8kg/m2, male-to-female ratio 95:74). The majority of tumours were malignant (149; 88%), symptomatic (133; 79%) and proximal to the splenic flexure (92; 54%). Inaccurate colonoscopist localisation judgement occurred in 12% of cases, 60% of which were corrected by preoperative staging computed tomography scan. A useful lesional tattoo was absent in 11/169 cases (6.5%) being specifically stated as present in 104 operation notes (61%) and absent in 10 (5.9%). Tumours missing overt peritumoral tattoos intraoperatively were more likely to be smaller, earlier stage and injected longer preoperatively (p=0.006), although half had histological ink staining. Eight lesions missing tattoos were radiologically occult. Four (44%) of these patients had on-table colonoscopy, and five (55%) needed laparotomy (conversion rate 55% vs 23% overall, p<0.005) with one needing a second operation to resect the initially missed target lesion. Mean (range) operative duration and postoperative length of stay of those missing tattoos compared with those with tattoos was 200 (78-300) versus 188 (50-597) min and 15.5 (4-22) versus 12(4-70) days (p>0.05). CONCLUSIONS: Tattoo in advance of attempting laparoscopic resection is vital for precision cancer surgery especially for radiologically unseen tumours to avoid adverse clinical consequence.

Increases in Future AR Count and Size: Overview of the ARTMIP Tier 2 CMIP5/6 Experiment.

The Atmospheric River (AR) Tracking Method Intercomparison Project (ARTMIP) is a community effort to systematically assess how the uncertainties from AR detectors (ARDTs) impact our scientific understanding of ARs. This study describes the ARTMIP Tier 2 experimental design and initial results using the Coupled Model Intercomparison Project (CMIP) Phases 5 and 6 multi-model ensembles. We show that AR statistics from a given ARDT in CMIP5/6 historical simulations compare remarkably well with the MERRA-2 reanalysis. In CMIP5/6 future simulations, most ARDTs project a global increase in AR frequency, counts, and sizes, especially along the western coastlines of the Pacific and Atlantic oceans. We find that the choice of ARDT is the dominant contributor to the uncertainty in projected AR frequency when compared with model choice. These results imply that new projects investigating future changes in ARs should explicitly consider ARDT uncertainty as a core part of the experimental design.

Magnetic systems for cancer immunotherapy.

Immunotherapy is a rapidly developing area of cancer treatment due to its higher specificity and potential for greater efficacy than traditional therapies. Immune cell modulation through the administration of drugs, proteins, and cells can enhance antitumoral responses through pathways that may be otherwise inhibited in the presence of immunosuppressive tumors. Magnetic systems offer several advantages for improving the performance of immunotherapies, including increased spatiotemporal control over transport, release, and dosing of immunomodulatory drugs within the body, resulting in reduced off-target effects and improved efficacy. Compared to alternative methods for stimulating drug release such as light and pH, magnetic systems enable several distinct methods for programming immune responses. First, we discuss how magnetic hyperthermia can stimulate immune cells and trigger thermoresponsive drug release. Second, we summarize how magnetically targeted delivery of drug carriers can increase the accumulation of drugs in target sites. Third, we review how biomaterials can undergo magnetically driven structural changes to enable remote release of encapsulated drugs. Fourth, we describe the use of magnetic particles for targeted interactions with cellular receptors for promoting antitumor activity. Finally, we discuss translational considerations of these systems, such as toxicity, clinical compatibility, and future opportunities for improving cancer treatment.