下颌骨升支骨结核一例

颌骨结核作为肺外结核的少见病近年呈增多趋势,其发病形式、临床表现也有了较大的变化,容易被误诊为炎症或良恶性肿瘤。本文就近期收治的1例发生于下颌升支骨结核的临床表征、病理表现及相关实验室特点作一阐述,并通过文献复习,分析颌骨结核的临床特征,以期引起重视,提高对疾病的认识。     

非综合征性唇腭裂候选基因和位点研究进展

先天性唇腭裂是一种常见的出生缺陷,其病因复杂,目前认为是遗传因素和环境因素共同作用的结果。最常见的是非综合征型唇腭裂（NSCL/P）,其发病机制尚无定论。近来,研究人员采用流行病学分析、详细分型、全基因组关联研究和动物模型的分析相结合,一些新的候选基因和位点已经确定与NSCL/P有关。这些发现推进了发育生物的理解,也为临床转化研究创造了新的机遇。     

下牙槽神经相关神经肽及其非神经传导功能

下牙槽神经作为一种混合神经,不仅可以通过外感受器发挥神经传导功能,而且还可通过释放神经肽发挥其非神经传导功能。神经肽是一类由神经细胞合成并释放,通过细胞外的受体对目标细胞发挥调节作用的生物活性多肽,与下牙槽神经相关的神经肽主要有P物质、降钙素基因相关肽、神经肽Y和神经激肽A等。下牙槽神经可以通过释放这些神经肽调节牙体发育及神经源性炎症,维持体内免疫稳态、促进骨折愈合,在组织的修复再生中起重要作用。通过对下牙槽神经非传导作用的研究,进一步从分子、细胞及组织多层面探讨神经与组织再生间的关系,揭示神经因素在促进组织再生并提高其再生质量等方面的作用,将成为未来重要的研究方向。本文将就下牙槽神经及其非神经传导作用作一综述。     

Exact solution for a metapopulation version of Schelling’s model

In 1971, Schelling introduced a model in which families move if they have too many neighbors of the opposite type. In this paper, we will consider a metapopulation version of the model in which a city is divided into N neighborhoods, each of which has L houses. There are ρNL red families and ρNL blue families for some ρ < 1/2. Families are happy if there are ≤ρ_cL families of the opposite type in their neighborhood and unhappy otherwise. Each family moves to each vacant house at rates that depend on their happiness at their current location and that of their destination. Our main result is that if neighborhoods are large, then there are critical values ρ_b < ρ_d < ρ_c, so that for ρ < ρ_b, the two types are distributed randomly in equilibrium. When ρ > ρ_b, a new segregated equilibrium appears; for ρ_b < ρ < ρ_d, there is bistability, but when ρ increases past ρ_d the random state is no longer stable. When ρ_c is small enough, the random state will again be the stationary distribution when ρ is close to 1/2. If so, this is preceded by a region of bistability.In 1971, Schelling (1) introduced one of the first agent-based models in the social sciences. Families of two types inhabit cells in a finite square, with 25–30% of the squares vacant. Each family has a neighborhood that consists of a 5 × 5 square centered at their location. Schelling used a number of different rules for picking the next family to move, but the most sensible seems to be that we pick a family at random on each step. If the fraction of neighbors of the opposite type is too large, then they move to the closest location that satisfies their constraints. Schelling simulated this and many other variants of this model (using dice and checkers) to argue that if people have a preference for living with those of their own color, the movements of individual families invariably led to complete segregation (2).As Clark and Fossett (3) explain “The Schelling model was mostly of theoretical interest and was rarely cited until a significant debate about the extent and explanations of residential segregation in US urban areas was engaged in the 1980s and 1990s. To that point, most social scientists offered an explanation that invoked housing discrimination, principally by whites.” At this point Schelling’s article has been cited more than 800 times. For a sampling of results from the social sciences literature, see Fossett’s lengthy survey (4) or other more recent treatments (5–7). About 10 y ago, physicists discovered this model and analyzed a number of variants of it using techniques of statistical mechanics (8–14). However, to our knowledge, the only rigorous work is ref. 15, which studies the 1D model in which the threshold for happiness is ρ_c = 0.5 and two unhappy families within distance w swap places at rate 1.Here, we will consider a metapopulation version of Schelling’s model in which there are N neighborhoods that have L houses, but we ignore spatial structure within the neighborhoods and their physical locations. We do this to make the model analytically tractable, but these assumptions are reasonable from a modeling point of view. Many cities in the United States are divided into neighborhoods that have their own identities. In Durham, these neighborhoods have names like Duke Park, Trinity Park, Watts-Hillendale, Duke Forest, Hope Valley, Colony Park, etc. They are often separated by busy roads and have identities that are reinforced by e-mail newsgroups that allow people to easily communicate with everyone in their neighborhood. Because of this, it is the overall composition of the neighborhood that is important not just the people who live next door. In addition, when a family decides to move they can easily relocate anywhere in the city.Families, which we suppose are indivisible units, come in two types that we call red and blue. There are ρNL of each type, leaving (1 − 2ρ)NL empty houses. This formulation was inspired by Grauwin et al. (16), who studied segregation in a model with one type of individual whose happiness is given by a piecewise linear unimodal function of the density of occupied sites in their neighborhood. To define the rules of movement, we introduce the threshold level ρ_c such that a neighborhood is happy for a certain type of agent if the fraction of agents of the opposite type is ≤ρ_c. For each family and empty house, movements occur at rates that depend on the state of the source and destination houses:where q, r < 1, and ϵ are small, e.g., 0.1 or smaller. Because there are O(NL) vacant houses, dividing the rates by NL makes each family moves at a rate O(1). Because ϵ is small, happy families are very reluctant to move to a neighborhood in which they would be unhappy, whereas unhappy families move at rate 1 to neighborhoods that will make them happy. As we will see later, the equilibrium distribution does not depend on the values of the rates q and r for transitions that do not change a family’s happiness. We do not have an intuitive explanation for this result.     

Thermotropic liquid crystals from biomacromolecules

Complexation of biomacromolecules (e.g., nucleic acids, proteins, or viruses) with surfactants containing flexible alkyl tails, followed by dehydration, is shown to be a simple generic method for the production of thermotropic liquid crystals. The anhydrous smectic phases that result exhibit biomacromolecular sublayers intercalated between aliphatic hydrocarbon sublayers at or near room temperature. Both this and low transition temperatures to other phases enable the study and application of thermotropic liquid crystal phase behavior without thermal degradation of the biomolecular components.Liquid crystals (LCs) play an important role in biology because their essential characteristic, the combination of order and mobility, is a basic requirement for self-organization and structure formation in living systems (1–3). Thus, it is not surprising that the study of LCs emerged as a scientific discipline in part from biology and from the study of myelin figures, lipids, and cell membranes (4). These and the LC phases formed from many other biomolecules, including nucleic acids (5, 6), proteins (7, 8), and viruses (9, 10), are classified as lyotropic, the general term applied to LC structures formed in water and stabilized by the distinctly biological theme of amphiphilic partitioning of hydrophilic and hydrophobic molecular components into separate domains. However, the principal thrust and achievement of the study of LCs has been in the science and application of thermotropic materials, structures, and phases in which molecules that are only weakly amphiphilic exhibit LC ordering by virtue of their steric molecular shape, flexibility, and/or weak intermolecular interactions [e.g., van der Waals and dipolar forces (11)]. These characteristics enable thermotropic LCs (TLCs) to adopt a wide variety of exotic phases and to exhibit dramatic and useful responses to external forces, including, for example, the electro-optic effects that have led to LC displays and the portable computing revolution. This general distinction between lyotropic LCs and TLCs suggests there may be interesting possibilities in the development of biomolecular or bioinspired LC systems in which the importance of amphiphilicity is reduced and the LC phases obtained are more thermotropic in nature. Such biological TLC materials are very appealing for several reasons. Most biomacromolecules were extensively characterized in aqueous environments, but in TLC phases, their solvent-free properties and functions could be investigated in a state in which no or only traces of water are present. Water exhibits a high dielectric constant and has the ability to form hydrogen bonds, greatly influencing the structure and functions of biomacromolecules or compromising electronic properties such as charge transport (12–15). Indeed, anhydrous TLC systems containing glycolipids (16–19), ferritin (20), and polylysine have been reported (21–23). However, a general approach to fabricating TLCs based on nucleic acids, polypeptides, proteins, and protein assemblies of large molecular weights such as virus particles remains elusive.Here we propose that the combination of biomaterials with suitably chosen surfactants, followed by dehydration, can be effectively applied as a simple generic scheme for producing biomacromolecular-based TLCs. We demonstrate that biological TLCs can be made from a remarkable range of biomolecules and bio-inspired molecules, including nucleic acids, polypeptides, fusion proteins, and viruses. TLC materials typically combine rigid or semirigid anisometric units, which introduce orientational anisotropy, with flexible alkyl chains, which suppress crystallization (24). In the present experiments, negatively charged biomolecules and bio-inspired molecules act as rigid parts, and cationic surfactants make up the flexible units to produce TLC phases with remarkably low LC-isotropic clearing temperatures, which is another TLC signature. Electrostatic interactions couple these rigid and flexible components into hybrid assemblies, which then order into lamellar phases of alternating rigid and flexible layers (Fig. 1) stabilized by the tendency in TLCs for rigid and flexible to spatially segregate (25).Open in a separate windowFig. 1.Proposed structures of TLCs formed by the biological building blocks complexed with surfactants, showing sketches of various lamellar phases and the corresponding phase transition temperatures (°C). The lamellar bilayer structures are made of, alternately, a sublayer of the biomacromolecules and an interdigitated sublayer of the surfactants, where the negatively charged parts of the biomolecules (e.g., phosphate groups of ssDNA and ssRNA, glutamate residues of supercharged ELPs, and N-terminal glutamate and aspartate residues of pVIII protein in phages) electrostatically interact with the cationic head groups of the surfactants. For the ssDNA–DOAB and ssRNA–DOAB smectic TLCs, the oligonucleotides are randomly orientated in the DNA (RNA) sublayers. For the ELP–DDAB complexes, in addition to the bilayer smectic phase, a modulated smectic (Sm_mod) phase is observed at lower temperature. For the phage–DOAB–DDAB lamellar structures, rodlike virus particles are embedded in a sublayer between interdigitated surfactants with additional in-plane orientational order.     

Nonlinear conduction via solitons in a topological mechanical insulator

Networks of rigid bars connected by joints, termed linkages, provide a minimal framework to design robotic arms and mechanical metamaterials built of folding components. Here, we investigate a chain-like linkage that, according to linear elasticity, behaves like a topological mechanical insulator whose zero-energy modes are localized at the edge. Simple experiments we performed using prototypes of the chain vividly illustrate how the soft motion, initially localized at the edge, can in fact propagate unobstructed all of the way to the opposite end. Using real prototypes, simulations, and analytical models, we demonstrate that the chain is a mechanical conductor, whose carriers are nonlinear solitary waves, not captured within linear elasticity. Indeed, the linkage prototype can be regarded as the simplest example of a topological metamaterial whose protected mechanical excitations are solitons, moving domain walls between distinct topological mechanical phases. More practically, we have built a topologically protected mechanism that can perform basic tasks such as transporting a mechanical state from one location to another. Our work paves the way toward adopting the principle of topological robustness in the design of robots assembled from activated linkages as well as in the fabrication of complex molecular nanostructures.Mechanical structures composed of folding components, such as bars or plates rotating around pivots or hinges, are ubiquitous in engineering, materials science, and biology (1). For example, complex origami-like structures can be created by folding a paper sheet along suitably chosen creases around which two nearby faces can freely rotate (2–4). Similarly, linkages can be viewed as 1D versions of origami where rigid bars (links) are joined at their ends by joints (vertices) that permit full rotation of the bars (Fig. 1 A–C). Some of the joints can be pinned to the plane while the remaining ones rotate relative to each other under the constraints imposed by the network structure of the linkage (5). Familiar examples include the windshield wiper, robotic arms, biological linkages in the jaw and knee, and toys like the Jacob’s ladder (6) and the Hoberman sphere. Moreover, linkages and origami can be used in the design of microscopic and structural metamaterials whose peculiar properties are controlled by the geometry of the unit cell (7, 8).Open in a separate windowFig. 1.The chain of rotors in the flipper phase. (A) The translation symmetric system with θ=θ¯ constant. We show a linkage made from plastic and metal screws. (B) A computer sketch of the elastic chain (11): The masses are blue, rigid rotors are black, and springs are dashed red lines. The green arrows depict the amplitude of displacement of each mass of the edge-localized zero mode of the system. (C) A configuration of the linkage showing a soliton as a domain wall between right-leaning and left-leaning states. (D) A computer-simulated static configuration. The arrows beneath show the x projections of each rotor.Many of these examples are instances of what mechanical engineers call mechanisms: structures where the degrees of freedom are nearly balanced by carefully chosen constraints so that the allowed free motions encode a desired mechanical function. However, as the number of components increases, more can go wrong: lack of precision machining or undesired perturbations. Robustness in this sense is a concern relevant to the design of complex mechanical structures from the microscopic to the architectural scale, typically addressed at the cost of higher manufacturing tolerances or active feedback.Here, we take an alternative approach inspired by recent developments in the design of fault tolerant quantum devices (9). Consider, as an example, the quantized Hall conductivity of a 2D electron gas that is topologically protected in the sense that it cannot change when the Hamiltonian is smoothly varied (10). In this article, we present a topologically protected classical mechanism that can transport a mechanical state across a chain-like linkage without being affected by changes in material parameters or smooth deformations of the underlying structure, very much like its quantum counterparts.Kane and Lubensky (11) recently took an important step toward establishing a dictionary between the quantum and classical problems. Their starting point, which seems at first disconnected from the linkages we study here, was to analyze the phonons in elastic systems composed of stretchable springs. In particular they derived a mathematical mapping between electronic states in topological insulators and superconductors (10) and the mechanical zero modes in certain elastic lattices (12). The simplest is the 1D elastic chain, shown in Fig. 1B, inspired by the Su–Schrieffer–Heeger (SSH) model for polyacetylene (13), a linear polymer chain with topologically protected electronic states at its free boundaries. In the mechanical chain, the electronic modes map onto zero-energy vibrational modes with a nontrivial topological index, whose eigenvectors represented as green arrows in Fig. 1B are localized at one of the edges (11). An intriguing question then arises: Could these zero-energy edge modes propagate through the system in the form of finite deformations?We address this question by building and analyzing a linkage of rigid bars as an extreme limit of the 1D lattice of springs. This linkage allows no stretching deformations, yet it still displays the distinctive zero-energy mode localized at the edges (Fig. 1 and Movie S1). By nudging the rotors along the direction of the zero-energy mode (Fig. 1B and Movie S2), we provide a vivid demonstration of how the initially localized edge mode can indeed propagate and be moved around the chain at an arbitrarily small energy cost. We then show analytically and numerically that the mechanism underlying the mechanical conduction is in fact an evolution of the edge mode into a nonlinear topological soliton, which is the only mode of propagation in the chain of linkages that costs zero potential energy. The soliton or domain wall interpolates between two distinct topological mechanical phases of the chain and derives its robustness from the presence of a band gap within linear elasticity and the boundary conditions imposed at the edges of the chain. Although the topological protection ensures the existence of a domain wall, the dynamical nature of the soliton falls into two distinct classes that can ultimately be traced to the geometry of the unit cell. The prototypes we built therefore provide simple examples of structures that we dub topological metamaterials whose excitations are topologically protected zero-energy solitons (9).     

Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice

Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1–derived PGE₂ in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals. En face aortic lesion analysis revealed markedly reduced atherogenesis in Mac-mPGES-1-KOs, which was concomitant with a reduction in oxidative stress, reflective of reduced macrophage infiltration, less lesional expression of inducible nitric oxide synthase (iNOS), and lower aortic expression of NADPH oxidases and proinflammatory cytokines. Reduced oxidative stress was reflected systemically by a decline in urinary 8,12-iso-iPF_2α-VI. In contrast to exaggeration of the response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or both had no detectable phenotypic impact on atherogenesis. Macrophage foam cell formation and cholesterol efflux, together with plasma cholesterol and triglycerides, were unchanged as a function of genotype. In conclusion, myeloid cell mPGES-1 promotes atherogenesis in hyperlipidemic mice, coincident with iNOS-mediated oxidative stress. By contrast, mPGES-1 in vascular cells does not detectably influence atherogenesis in mice. This strengthens the therapeutic rationale for targeting macrophage mPGES-1 in inflammatory cardiovascular diseases.Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by suppressing the formation of proinflammatory prostaglandins (PGs), particularly prostaglandin E₂ (PGE₂) formed by cyclooxygenase-2 (COX-2) (1). However, the development of NSAIDs specific for inhibition of COX-2 revealed a cardiovascular hazard attributable to suppression of cardioprotective PGs, especially prostacyclin (PGI₂) (2). This risk appears to extend to some of the older NSAIDs, like diclofenac, that also inhibit specifically COX-2 (3, 4). These developments prompted interest in microsomal PGE synthase (mPGES)-1 as a downstream alternative drug target to COX-2 (5): it is the dominant source among PGES enzymes in the biosynthesis of PGE₂ (6). Unlike NSAIDs, inhibitors of mPGES-1 would spare PGI₂ from suppression. Indeed, blockade or deletion of mPGES-1 results in accumulation of its PGH₂ substrate, rendering it available for metabolism by other PG synthases, including PGI₂ synthase (PGIS) (7).Consistent with these observations, we have found that whereas deletion of COX-2 in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) renders mice susceptible to thrombosis and hypertension (2), deletion of mPGES-1 in vascular cells has no such effect (8). Indeed, global deficiency of mPGES-1 restrains atherogenesis (9), the proliferative response to vascular injury (10) and angiotensin-induced aortic aneurysm formation (11) in mice.Despite this attractive cardiovascular profile, mPGES-1 is a complex drug target. The dominant prostanoid products of substrate rediversion differ among cell types. For example, whereas PGI₂ might be augmented in vascular cells, the consequence of mPGES-1 blockade in other cells might be an increase in thromboxane (Tx)A₂, a PG that promotes platelet activation, vasoconstriction, and atherogenesis (9). Even if an increase in PGI₂ afforded a desirable cardiovascular profile, it might undermine the analgesic efficacy of mPGES-1 inhibitors. Although the impacts of global deletion of mPGES-1 and COX-2 in many mouse models of analgesia are indistinguishable (12, 13), in some, PGI₂ rather than PGE₂ predominates (14) and thus may be the dominant mediator in certain subtypes of human pain. Finally, the consequences of PGE₂ suppression might differ between cell types. PGE₂ activates four E prostanoid (EP) receptors with contrasting intracellular signaling and consequent biology (15, 16). Indeed, the contrasting effect of mPGES-1 deletion in myeloid vs. vascular cells on the proliferative response to vascular injury reflects the differential consequences of EP activation rather than substrate rediversion (8).A potentially discriminating feature among inhibitors of COX-2 and mPGES-1 is their effect on atherosclerosis. Global postnatal deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice (17), an observation that accords with a similar effect of deleting the PGI₂ receptor (the IP) (18, 19) and with the delayed detection of a cardiovascular hazard in randomized trials of COX-2 inhibitors in patients initially selected for being at low cardiovascular risk (20). By contrast, global deletion of mPGES-1 restrains atherogenesis in mice; in this case suppression of PGE₂ coincides with an increase in biosynthesis of PGI₂ (9). Here, we wished to segregate the effects on atherosclerosis of mPGES-1 depletion in myeloid from vascular cells. Our results strengthen the rationale for targeting macrophage mPGES-1 in the treatment of inflammatory cardiovascular disease.