Unearthing real-time 3D ant tunneling mechanics.

Granular excavation is the removal of solid, discrete particles from a structure composed of these objects. Efficiently predicting the stability of an excavation during particle removal is an unsolved and highly nonlinear problem, as the movement of each grain is coupled to its neighbors. Despite this, insects such as ants have evolved to be astonishingly proficient excavators, successfully removing grains such that their tunnels are stable. Currently, it is unclear how ants use their limited information about the environment to construct lasting tunnels. We attempt to unearth the ants' tunneling algorithm by taking three-dimensional (3D) X-ray computed tomographic imaging (XRCT), in real time, of Pogonomyrmex ant tunnel construction. By capturing the location and shape of each grain in the domain, we characterize the relationship between particle properties and ant decision-making within an accurate, virtual recreation of the experiment. We discover that intergranular forces decrease significantly around ant tunnels due to arches forming within the soil. Due to this force relaxation, any grain the ants pick from the tunnel surface will likely be under low stress. Thus, ants avoid removing grains compressed under high forces without needing to be aware of the force network in the surrounding material. Even more, such arches shield tunnels from high forces, providing tunnel robustness. Finally, we observe that ants tend to dig piecewise linearly downward. These results are a step toward understanding granular tunnel stability in heterogeneous 3D systems. We expect that such findings may be leveraged for robotic excavation.

Citizen science frontiers: Efficiency, engagement, and serendipitous discovery with human-machine systems.

Citizen science has proved to be a unique and effective tool in helping science and society cope with the ever-growing data rates and volumes that characterize the modern research landscape. It also serves a critical role in engaging the public with research in a direct, authentic fashion and by doing so promotes a better understanding of the processes of science. To take full advantage of the onslaught of data being experienced across the disciplines, it is essential that citizen science platforms leverage the complementary strengths of humans and machines. This Perspectives piece explores the issues encountered in designing human-machine systems optimized for both efficiency and volunteer engagement, while striving to safeguard and encourage opportunities for serendipitous discovery. We discuss case studies from Zooniverse, a large online citizen science platform, and show that combining human and machine classifications can efficiently produce results superior to those of either one alone and how smart task allocation can lead to further efficiencies in the system. While these examples make clear the promise of human-machine integration within an online citizen science system, we then explore in detail how system design choices can inadvertently lower volunteer engagement, create exclusionary practices, and reduce opportunity for serendipitous discovery. Throughout we investigate the tensions that arise when designing a human-machine system serving the dual goals of carrying out research in the most efficient manner possible while empowering a broad community to authentically engage in this research.

The National Cancer Institute Investment in Biomechanics in Oncology Research.

The qualitative description of tumors feeling stiffer than surrounding normal tissue has been long appreciated in the clinical setting. These empirical observations have been corroborated by the precise measurement and characterization of mechanical properties of cancerous tissues. Much of the advancement in our understanding of mechanics in oncology has been enabled by the development of innovative technologies designed to probe cells and tissues as well as integrative software analysis tools that facilitate biological interpretation and generation of testable hypotheses. While some mechanics in oncology research has been investigator-initiated and supported by the National Cancer Institute (NCI), several NCI programs described herein have helped to foster the growth of the burgeoning field. Programs highlighted in this chapter include Innovative Molecular Analysis Technologies (IMAT), Physical Sciences-Oncology Network (PS-ON), Tumor Microenvironment Network (TMEN), Integrative Cancer Biology Program (ICBP), and the Cancer Systems Biology Consortium (CSBC). This chapter showcases the scientific contributions of these programs to the field of biomechanics in oncology.

Driving forces for condensation of synapsin are governed by sequence-encoded molecular grammars.

Brain functioning relies on orchestrated synaptic vesicle dynamics and controlled neurotransmitter release. Multiple biomolecular condensates coexist at the pre- and post-synapse and they are driven by condensation that combines binding, phase separation, and percolation. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers of condensation that enable clustering of synaptic vesicles (SVs). Although sequences of IDRs are poorly conserved across evolution, our computational analysis reveals the existence of non-random compositional biases and sequence patterns (molecular grammars) in IDRs of pre-synaptic proteins. For example, synapsin-1, which is essential for condensation of SVs, contains a conserved valence of arginine residues and blocks of polar and proline residues that are segregated from one another along the linear sequence. We show that these conserved features are crucial for driving synapsin-1 condensation in vitro and in cells. Our results highlight how conserved molecular grammars drive the condensation of key proteins at the pre-synapse.

Activity-driven chromatin organization during interphase: compaction, segregation, and entanglement suppression.

In mammalian cells, the cohesin protein complex is believed to translocate along chromatin during interphase to form dynamic loops through a process called active loop extrusion. Chromosome conformation capture and imaging experiments have suggested that chromatin adopts a compact structure with limited interpenetration between chromosomes and between chromosomal sections. We developed a theory demonstrating that active loop extrusion causes the apparent fractal dimension of chromatin to cross over between two and four at contour lengths on the order of 30 kilo-base pairs (kbp). The anomalously high fractal dimension D=4 is due to the inability of extruded loops to fully relax during active extrusion. Compaction on longer contour length scales extends within topologically associated domains (TADs), facilitating gene regulation by distal elements. Extrusion-induced compaction segregates TADs such that overlaps between TADs are reduced to less than 35% and increases the entanglement strand of chromatin by up to a factor of 50 to several Mega-base pairs. Furthermore, active loop extrusion couples cohesin motion to chromatin conformations formed by previously extruding cohesins and causes the mean square displacement of chromatin loci during lag times (Δt) longer than tens of minutes to be proportional to Δt1/3. We validate our results with hybrid molecular dynamics - Monte Carlo simulations and show that our theory is consistent with experimental data. This work provides a theoretical basis for the compact organization of interphase chromatin, explaining the physical reason for TAD segregation and suppression of chromatin entanglements which contribute to efficient gene regulation.

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds.

Despite recent experimental progress in characterizing cell migration mechanics, our understanding of the mechanisms governing rapid cell movement remains limited. To effectively limit tumor growth, antitumoral T cells need to rapidly migrate to find and kill cancer cells. To investigate the upper limits of cell speed, we developed a new hybrid stochastic-mean field model of bleb-based cell motility. We first examined the potential for adhesion-free bleb-based migration and show that cells migrate inefficiently in the absence of adhesion-based forces, i.e., cell swimming. While no cortical contractility oscillations are needed for cells to swim in viscoelastic media, high-to-low cortical contractility oscillations are necessary for cell swimming in viscous media. This involves a high cortical contractility phase with multiple bleb nucleation events, followed by an intracellular pressure buildup recovery phase at low cortical tensions, resulting in modest net cell motion. However, our model suggests that cells can employ a hybrid bleb- and adhesion-based migration mechanism for rapid cell motility and identifies conditions for optimality. The model provides a momentum-conserving mechanism underlying rapid single-cell migration and identifies factors as design criteria for engineering T cell therapies to improve movement in mechanically complex environments.

Excess Mortality in the United States, 2020-21: County-level Estimates for Population Groups and Associations with Social Vulnerability.

To assess the excess mortality burden of Covid-19 in the United States, we estimated sex, age and race stratified all-cause excess deaths in each county of the US during 2020 and 2021. Using spatial Bayesian models trained on all recorded deaths between 2003-2019, we estimated 463,187 (95% uncertainty interval (UI): 426,139 - 497,526) excess deaths during 2020, and 544,105 (95% UI: 492,202 - 592,959) excess deaths during 2021 nationally, with considerable geographical heterogeneity. Excess mortality rate (EMR) nearly doubled for each 10-year increase in age and was consistently higher among men than women. EMR in the Black population was 1.5 times that of the White population nationally and as high as 3.8 times in some states. Among the 25-54 year population excess mortality was highest in the American Indian/Alaskan Native (AI/AN) population among the four racial groups studied, and in a few states was as high as 6 times that of the White population. Strong association of EMR with county-level social vulnerability was estimated, including positive associations with prevalence of disability (standardized effect: 40.6 excess deaths per 100,000), older population (37.6), poverty (23.6), and unemployment (18.5), whereas population density (-50), higher education (-38.6), and income (-35.4) were protective. Together, these estimates provide a more reliable and comprehensive understanding of the mortality burden of the pandemic in the US thus far. They suggest that Covid-19 amplified social and racial disparities. Short-term measures to protect more vulnerable groups in future Covid-19 waves and systemic corrective steps to address long-term societal inequities are necessary.

Best billiard ball in the 19th century: Composite materials made of celluloid and bone as substitutes for ivory.

The demystification of how 19th-century novelly designed materials became significant elements of modern technological, economic, and cultural life requires a complete understanding of the material dimensions of historical artifacts. The objects frequently described as the earliest manufactured plastic products-the billiard balls made by John Wesley Hyatt and his associates from the late 1860s-are examined closely for the first time and are found to be more complex and functionally more successful than has been described. Modern analytical techniques such as optical microscopy, scanning electron microscope-energy dispersive X-ray spectroscopy, X-ray fluorescence, micro-Fourier transformed infrared, and handheld/micro-Raman spectroscopies were used to reveal the complex composition of the Smithsonian Institution's "original" 1868 celluloid billiard ball. Comparisons with billiard and pool balls commercialized from the 1880s to the 1960s showed an unexpected consistency in material formulations. All specimens were made of an unprecedented composite material prepared with a mixture of cellulose nitrate, camphor, and ground bone; the source of the bone was identified as cattle by peptide mass fingerprint (ZooMS). Patent specifications and contemporary journal descriptions explained how and when these formulations emerged. Combining the technical analyses of compositions with a careful reading of the historical record and contemporary descriptions reveals the key elements of the first successful efforts to substitute materials to assist the survival of endangered animals.

Challenges in the application of the Tshivenda scientific register in the teaching and learning of state of matter and the kinetic molecular theory in grade 10 physical sciences classrooms.

Background: This paper investigated some of the challenges in the application of Tshivenda scientific register (TSR) during classroom practices of some physical sciences teachers in some of the public secondary schools in the Vhembe West District, South Africa. Methods: It was an interpretative qualitative case study wherein three physical sciences teachers and 40 learners took part in the study. The study conducted at schools of Vhuronga 2 circuit in Vhembe West District between January 2022 to November 2022. Semi-structured interviews and classroom observations were used for data collections. Researchers analyzed their data through Data Analysis Scheme (DAS) which comprised of themes, categories, and characteristics in this qualitative study. Texts that belong to a particular theme were highlighted using same colour and track changes was also used to codify categories and characteristics of a theme. Results: The research findings had shown numerous challenges in the teaching and learning of physical sciences including teachers and learners not used to physical sciences being taught and learnt through TSR, not familiar with some scientific words in TSR, difficulties in understanding scientific term in TSR as well as absence of Tshivenda physical sciences resources beside TSR. Consequently, this has impacts on teacher and learner's ability to implement TSR in the teaching and learning of Physical Sciences. Moreover, the findings also show that teachers and learners participated in the study sometimes switch from Tshivenda Scientific words to English Scientific words during Physical Sciences lessons. Conclusions: Therefore, it is suggested that the above-mentioned challenges in the development and application of TSR for Physical Sciences teaching need to be addressed so that teachers can teach learners Physical Sciences through language they know best. Hence, physical sciences teachers must be developed, trained, and furnished with essential language skills for them to develop Tshivenda scientific language registers on other sciences topics.

Dereplication of polar extracts from Croton antisyphiliticus Mart. roots and its anti-inflammatory and antinociceptive potential.

Croton antisyphiliticus Mart. is a plant popularly used in folk medicine by traditional communities from Brazilian savannah to treat general inflammation. According to ethnopharmacological data, this specie can be considered a source of biologically active molecules for the development of new drugs. Thereby, this study reports the results of the dereplication approach of C. antisyphiliticus roots extracts and the in vivo evaluation of its potential antinociceptive and anti-inflammatory in albino Swiss mice. Based on HPLC coupled to Q-Exactive Orbitrap Mass Spectrometer and using GNPS, a total of thirteen polyphenolic compounds were noticed, including four compounds that have been reported for the first time in the genus Croton. Ethanolic and aqueous roots extracts demonstrated a dose-dependent inhibition for the number of writes, reduced pain induced by formalin and hyperalgesia induced by carrageenan. These extracts also reduced paw edema, cell migration, and myeloperoxidase activity, with effects similar to indomethacin and dexamethasone drugs.

Small Molecule in situ Resin Capture - A Compound First Approach to Natural Product Discovery.

Microbial natural products remain an important resource for drug discovery. Yet, commonly employed discovery techniques are plagued by the rediscovery of known compounds, the relatively few microbes that can be cultured, and laboratory growth conditions that do not elicit biosynthetic gene expression among myriad other challenges. Here we introduce a culture independent approach to natural product discovery that we call the Small Molecule In situ Resin Capture (SMIRC) technique. SMIRC exploits in situ environmental conditions to elicit compound production and represents a new approach to access poorly explored chemical space by capturing natural products directly from the environments in which they are produced. In contrast to traditional methods, this compound-first approach can capture structurally complex small molecules across all domains of life in a single deployment while relying on Nature to provide the complex and poorly understood environmental cues needed to elicit biosynthetic gene expression. We illustrate the effectiveness of SMIRC in marine habitats with the discovery of numerous new compounds and demonstrate that sufficient compound yields can be obtained for NMR-based structure assignment. Two new compound classes are reported including one novel carbon skeleton that possesses a functional group not previously observed among natural products and a second that possesses potent biological activity. We introduce expanded deployments, in situ cultivation, and metagenomics as methods to facilitate compound discovery, enhance yields, and link compounds to producing organisms. This compound first approach can provide unprecedented access to new natural product chemotypes with broad implications for drug discovery.

An injectable PEG-like conjugate forms a subcutaneous depot and enables sustained delivery of a peptide drug.

Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. However, the improvement in the plasma half-life of PEGylated drugs' is at an asymptote because the development of branched PEG has only had a modest impact on pharmacokinetics and pharmacodynamics. Here, we developed an injectable PEG-like conjugate that forms a subcutaneous depot for the sustained delivery of biologics. The PEG-like conjugate consists of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) conjugated to exendin, a peptide drug used in the clinic to treat type 2 diabetes. The depot-forming exendin-POEGMA conjugate showed greater efficacy than a PEG conjugate of exendin as well as Bydureon, a clinically approved sustained-release formulation of exendin. The injectable depot-forming exendin-POEGMA conjugate did not elicit an immune response against the polymer, so that it remained effective and safe for long-term management of type 2 diabetes upon chronic administration. In contrast, the PEG conjugate induced an anti-PEG immune response, leading to early clearance and loss of efficacy upon repeat dosing. The exendin-POEGMA depot also showed superior long-term efficacy compared to Bydureon. Collectively, these results suggest that an injectable POEGMA conjugate of biologic drugs that forms a drug depot under the skin, providing favorable pharmacokinetic properties and sustained efficacy while remaining non-immunogenic, offers significant advantages over other commonly used drug delivery technologies.

To have value, comparisons of high-throughput phenotyping methods need statistical tests of bias and variance.

The gap between genomics and phenomics is narrowing. The rate at which it is narrowing, however, is being slowed by improper statistical comparison of methods. Quantification using Pearson's correlation coefficient (r) is commonly used to assess method quality, but it is an often misleading statistic for this purpose as it is unable to provide information about the relative quality of two methods. Using r can both erroneously discount methods that are inherently more precise and validate methods that are less accurate. These errors occur because of logical flaws inherent in the use of r when comparing methods, not as a problem of limited sample size or the unavoidable possibility of a type I error. A popular alternative to using r is to measure the limits of agreement (LOA). However both r and LOA fail to identify which instrument is more or less variable than the other and can lead to incorrect conclusions about method quality. An alternative approach, comparing variances of methods, requires repeated measurements of the same subject, but avoids incorrect conclusions. Variance comparison is arguably the most important component of method validation and, thus, when repeated measurements are possible, variance comparison provides considerable value to these studies. Statistical tests to compare variances presented here are well established, easy to interpret and ubiquitously available. The widespread use of r has potentially led to numerous incorrect conclusions about method quality, hampering development, and the approach described here would be useful to advance high throughput phenotyping methods but can also extend into any branch of science. The adoption of the statistical techniques outlined in this paper will help speed the adoption of new high throughput phenotyping techniques by indicating when one should reject a new method, outright replace an old method or conditionally use a new method.

The structure of a C. neoformans polysaccharide motif recognized by protective antibodies: A combined NMR and MD study.

Cryptococcus neoformans is a fungal pathogen responsible for cryptococcosis and cryptococcal meningitis. The C. neoformans capsular polysaccharide and shed exopolysaccharide functions both as a key virulence factor and to protect the fungal cell from phagocytosis. Currently, a glycoconjugate of these polysaccharides is being explored as a vaccine to protect against C. neoformans infection. In this combined NMR and MD study, experimentally determined NOEs and J-couplings support a structure of the synthetic decasaccharide, GXM10-Ac3, obtained by MD. GXM10-Ac3 was designed as an extension of glucuronoxylomannan (GXM) polysaccharide motif (M2) which is common in the clinically predominant serotype A strains and is recognized by protective forms of GXM-specific monoclonal antibodies. The M2 motif is characterized by a 6-residue α-mannan backbone repeating unit, consisting of a triad of α-(1→3)-mannoses, modified by ß-(1→2)-xyloses on the first two mannoses and a ß-(1→2)-glucuronic acid on the third mannose. The combined NMR and MD analyses reveal that GXM10-Ac3 adopts an extended structure, with xylose/glucuronic acid branches alternating sides along the α-mannan backbone. O-acetyl esters also alternate sides and are grouped in pairs. MD analysis of a twelve M2-repeating unit polymer supports the notion that the GXM10-Ac3 structure is uniformly represented throughout the polysaccharide. This experimentally consistent GXM model displays high flexibility while maintaining a structural identity, yielding new insights to further explore intermolecular interactions between polysaccharides, interactions with anti-GXM mAbs, and the cryptococcal polysaccharide architecture.

A MULTISCALE VISION-ILLUSTRATIVE APPLICATIONS FROM BIOLOGY TO ENGINEERING.

Modeling and simulation have quickly become equivalent pillars of research along with traditional theory and experimentation. The growing realization that most complex phenomena of interest span many orders of spatial and temporal scales has led to an exponential rise in the development and application of multiscale modeling and simulation over the past two decades. In this perspective, the associate editors of the International Journal for Multiscale Computational Engineering and their co-workers illustrate current applications in their respective fields spanning biomolecular structure and dynamics, civil engineering and materials science, computational mechanics, aerospace and mechanical engineering, and more. Such applications are highly tailored, exploit the latest and ever-evolving advances in both computer hardware and software, and contribute significantly to science, technology, and medical challenges in the 21st century.

Mechanical Communication Acts as a Noise Filter.

Cells can communicate mechanically by responding to mechanical deformations generated by their neighbors. Here, we describe a new role for mechanical communication by demonstrating that mechanical coupling between cells acts as a signaling cue that reduces intrinsic noise in the interacting cells. We measure mechanical interaction between beating cardiac cells cultured on a patterned flexible substrate and find that beat-to-beat variability decays exponentially with coupling strength. To demonstrate that such noise reduction is indeed a direct consequence of mechanical coupling, we reproduce the exponential decay in an assay where a beating cell interacts mechanically with an artificial stochastic 'mechanical cell'. The mechanical cell consists of a probe that mimics the deformations generated by a stochastically beating neighboring cardiac cell. We show that noise reduction through mechanical coupling persists long after stimulation stops and identify microtubule integrity, NOX2, and CaMKII as mediators of noise reduction.

Phase Equilibria in the Nb-Rich Region of Al-Nb-Sn at 900 and 1200 °C.

The Al-Nb-Sn phase diagram was studied experimentally in the Nb-rich region to provide important phase equilibria information for alloy design of Nb-silicide based materials for aero engine applications. Three alloys were produced: Nb-17Al-17Sn, Nb-33Al-13Sn and Nb-16Al-20Sn (at.%). As-cast and heat-treated alloys (900 and 1200 °C) were analysed using XRD (X-ray diffraction) and SEM/EDS (scanning electron microscopy/ electron dispersive x-ray spectroscopy). Tin showed a high solubility in Nb2Al, reaching up to 21 at.% in the Sn-rich areas, substituting for Al atoms. Tin and Al also substituted for each other in the A15 phases (Nb3Al and Nb3Sn). Tin showed limited solubility in NbAl3, not exceeding 3.6 at.% as it substituted Al atoms. The solubility of Al in NbSn2 varied from 4.8 to 6.8 at.%. A ternary phase, Nb5Sn2Al with the tI32 W5Si3 crystal structure, was found to be stable. This phase was observed in the 900 °C heat-treated samples, but not in the 1200 °C heated samples.

New Horizons in Advocacy Engaged Physical Sciences and Oncology Research.

To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplinary connectivity between cancer biologists, physical scientists, mathematicians, chemists, biomedical engineers, computer scientists, clinicians, and advocates is fueling the emergence of new scientific frontiers, principles, and opportunities within physical sciences and oncology. In parallel to highlighting the advances, challenges, and acceptance of advocates as credible contributors, we offer recommendations for addressing real world hurdles in advancing equitable partnerships among advocacy stakeholders.

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary 'VoxTox' research programme.

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

Towards clinically translatable in vivo nanodiagnostics.

Nanodiagnostics as a field makes use of fundamental advances in nanobiotechnology to diagnose, characterize and manage disease at the molecular scale. As these strategies move closer to routine clinical use, a proper understanding of different imaging modalities, relevant biological systems and physical properties governing nanoscale interactions is necessary to rationally engineer next-generation bionanomaterials. In this Review, we analyse the background physics of several clinically relevant imaging modalities and their associated sensitivity and specificity, provide an overview of the materials currently used for in vivo nanodiagnostics, and assess the progress made towards clinical translation. This work provides a framework for understanding both the impressive progress made thus far in the nanodiagnostics field as well as presenting challenges that must be overcome to obtain widespread clinical adoption.