Mechanisms of kinetic trapping in self-assembly and phase transformation

In self-assembly processes, kinetic trapping effects often hinder the formation of thermodynamically stable ordered states. In a model of viral capsid assembly and in the phase transformation of a lattice gas, we show how simulations in a self-assembling steady state can be used to identify two distinct mechanisms of kinetic trapping. We argue that one of these mechanisms can be adequately captured by kinetic rate equations, while the other involves a breakdown of theories that rely on cluster size as a reaction coordinate. We discuss how these observations might be useful in designing and optimising self-assembly reactions

Self-limited self-assembly of chiral filaments

The assembly of filamentous bundles with controlled diameters is common in biological systems and desirable for the development of nanomaterials. We discuss dynamical simulations and free energy calculations on patchy spheres with chiral pair interactions that spontaneously assemble into filamentous bundles. The chirality frustrates long-range crystal order by introducing twist between interacting subunits. For some ranges of system parameters this constraint leads to bundles with a finite diameter as the equilibrium state, and in other cases frustration is relieved by the formation of defects. While some self-limited structures can be modeled as twisted filaments arranged with local hexagonal symmetry, other structures are surprising in their complexity.Comment: 5 pages, 5 figure

Regulation of the spindle checkpoint by Mad2 binding proteins

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005.Includes bibliographical references.The spindle checkpoint ensures the fidelity of chromosome segregation by delaying anaphase until all sister chromatids form proper bipolar attachments to the mitotic spindle. Spindle checkpoint proteins localize to unattached or maloriented kinetochores in mitosis and generate a signal that prevents dissolution of sister chromatid cohesion. Checkpoint signaling requires binding of Mad2 to the checkpoint protein Madl and Cdc20, a subunit of the Anaphase Promoting Complex. We have characterized the interactions of human Mad2 with Madl, Cdc20, and CMT2, a checkpoint inhibitor. Cdc20 and Madl form competitive high affinity complexes through contacts in the peptide binding cleft of Mad2, while CMT2 binds noncompetitively to the closed conformation of the Mad2 C-terminus. I propose a model by which conformation- specific binding of CMT2 silences Mad2 signal generation. The requirement for active checkpoint inhibition in mitosis is not known. We examined the role of CMT2 in mitosis by fixed- and live-cell microscopy. CMT2 localizes to kinetochores in a Mad2-dependent manner and forms ternary complexes with Madl-Mad2 and Cdc20-Mad2 in vivo. Surprisingly, CMT2 is required for completion of mitosis even in the absence of spindle damage.(cont.) I show that CMT2 opposes Mad2 function at kinetochores and in the cytosol and propose that active silencing of the Mad2- dependent checkpoint is required for completion of mammalian mitosis.by Robert S. Hagan.Ph.D

The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection

Severe influenza infection represents a leading cause of global morbidity and mortality. Although influenza is primarily considered a viral infection that results in pathology limited to the respiratory system, clinical reports suggest that influenza infection is frequently associated with a number of clinical syndromes that involve organ systems outside the respiratory tract. A comprehensive MEDLINE literature review of articles pertaining to extra-pulmonary complications of influenza infection, using organ-specific search terms, yielded 218 articles including case reports, epidemiologic investigations, and autopsy studies that were reviewed to determine the clinical involvement of other organs. The most frequently described clinical entities were viral myocarditis and viral encephalitis. Recognition of these extra-pulmonary complications is critical to determining the true burden of influenza infection and initiating organ-specific supportive care

Fluctuation-dissipation ratios in the dynamics of self-assembly

We consider two seemingly very different self-assembly processes: formation of viral capsids, and crystallization of sticky discs. At low temperatures, assembly is ineffective, since there are many metastable disordered states, which are a source of kinetic frustration. We use fluctuation-dissipation ratios to extract information about the degree of this frustration. We show that our analysis is a useful indicator of the long term fate of the system, based on the early stages of assembly.Comment: 8 pages, 6 figure

Overview: Systemic Inflammatory Response Derived From Lung Injury Caused by SARS-CoV-2 Infection Explains Severe Outcomes in COVID-19

Most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF and IL-1β increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine release syndrome (CRS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is herein called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge.Indiana University Health—Indiana University School of Medicine Strategic Research Initiativ

Book reviews

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43350/1/11084_2005_Article_BF01808246.pd

Economic Diversification Supported the Growth of Mongolia’s Nomadic Empires

Populations in Mongolia from the late second millennium B.C.E. through the Mongol Empire are traditionally assumed, by archaeologists and historians, to have maintained a highly specialized horse-facilitated form of mobile pastoralism. Until recently, a dearth of direct evidence for prehistoric human diet and subsistence economies in Mongolia has rendered systematic testing of this view impossible. Here, we present stable carbon and nitrogen isotope measurements of human bone collagen, and stable carbon isotope analysis of human enamel bioapatite, from 137 well-dated ancient Mongolian individuals spanning the period c. 4400 B.C.E. to 1300 C.E. Our results demonstrate an increase in consumption of C4 plants beginning at c. 800 B.C.E., almost certainly indicative of millet consumption, an interpretation supported by archaeological evidence. The escalating scale of millet consumption on the eastern Eurasian steppe over time, and an expansion of isotopic niche widths, indicate that historic Mongolian empires were supported by a diversification of economic strategies rather than uniform, specialized pastoralism

Lateral opening in the intact β-barrel assembly machinery captured by cryo-EM

The β-barrel assembly machinery (BAM) is a ~203 kDa complex of five proteins (BamA-E) which is essential for viability in E. coli. BAM promotes the folding and insertion of β-barrel proteins into the outer membrane via a poorly understood mechanism. Several current models suggest that BAM functions through a ‘lateral gating’ motion of the β-barrel of BamA. Here we present a cryo-EM structure of the BamABCDE complex, at 4.9 Å resolution. The structure is in a laterally open conformation showing that gating is independent of BamB binding. We describe conformational changes throughout the complex, and interactions between BamA, B, D, and E and the detergent micelle that suggest communication between BAM and the lipid bilayer. Finally, using an enhanced reconstitution protocol and functional assays, we show that for the outer membrane protein OmpT, efficient folding in vitro requires lateral gating in BAM

Exotic foods reveal contact between South Asia and the Near East during the second millennium BCE

Aunque el papel clave del comercio a larga distancia en la transformación de las cocinas en todo el mundo está bien documentado desde al menos la época romana, la prehistoria del comercio de alimentos euroasiático es menos visible. Con el fin de arrojar luz sobre la transformación de las cocinas del Mediterráneo oriental durante la Edad del Bronce y la Edad del Hierro Temprana, analizamos los microrestos y las proteínas conservadas en el cálculo dental de individuos que vivieron durante el segundo milenio a. Nuestros resultados proporcionan evidencia clara del consumo de alimentos básicos esperados, como cereales (Triticeae), sésamo ( Sesamum ) y dátiles ( Phoenix ). Además, informamos evidencia del consumo de soja ( glicina ), probable banano ( Musa ) y cúrcuma (Curcuma ), que hace retroceder la evidencia más antigua de estos alimentos en el Mediterráneo por siglos (cúrcuma) o incluso milenios (soja). Descubrimos que, desde principios del segundo milenio en adelante, al menos algunas personas en el Mediterráneo oriental tuvieron acceso a alimentos de lugares distantes, incluido el sur de Asia, y esos productos probablemente se consumieron en forma de aceites, frutos secos y especias. Estos conocimientos nos obligan a repensar la complejidad y la intensidad del comercio indo-mediterráneo durante la Edad del Bronce, así como el grado de globalización en la cocina del Mediterráneo oriental temprano. Although the key role of long-distance trade in the transformation of cuisines worldwide has been well-documented since at least the Roman era, the prehistory of the Eurasian food trade is less visible. In order to shed light on the transformation of Eastern Mediterranean cuisines during the Bronze Age and Early Iron Age, we analyzed microremains and proteins preserved in the dental calculus of individuals who lived during the second millennium BCE in the Southern Levant. Our results provide clear evidence for the consumption of expected staple foods, such as cereals (Triticeae), sesame (Sesamum), and dates (Phoenix). We additionally report evidence for the consumption of soybean (Glycine), probable banana (Musa), and turmeric (Curcuma), which pushes back the earliest evidence of these foods in the Mediterranean by centuries (turmeric) or even millennia (soybean). We find that, from the early second millennium onwards, at least some people in the Eastern Mediterranean had access to food from distant locations, including South Asia, and such goods were likely consumed as oils, dried fruits, and spices. These insights force us to rethink the complexity and intensity of Indo-Mediterranean trade during the Bronze Age as well as the degree of globalization in early Eastern Mediterranean cuisine