Multicritical Point on the de Almeida-Thouless Line in Spin Glasses in d>6 Dimensions.

The de Almeida-Thouless (AT) line in Ising spin glasses is the phase boundary in the temperature T and magnetic field h plane below which replica symmetry is broken. Using perturbative renormalization group (RG) methods, we show that, when the dimension d of space is just above six, there is a multicritical point (MCP) on the AT line, which separates a low-field regime, in which the critical exponents have mean-field values, from a high-field regime, where the RG flows run away to infinite coupling strength; as d approaches six from above, the MCP approaches the zero-field critical point exponentially in 1/(d-6). Thus, on the AT line, perturbation theory for the critical properties breaks down at a sufficiently large magnetic field even above 6 dimensions, as well as for all nonzero fields when d≤6, as was known previously. We calculate the exponents at the MCP to first order in ϵ=d-6>0. The fate of the MCP as d increases from just above six to infinity is not known.

Absence of Hyperuniformity in Amorphous Hard-Sphere Packings of Nonvanishing Complexity.

We relate the structure factor S(k→0) in a system of jammed hard spheres of number density ρ to its complexity per particle Σ(ρ) by the formula S(k→0)=-1/[ρ^{2}Σ^{″}(ρ)+2ρΣ^{'}(ρ)]. We have verified this formula for the case of jammed disks in a narrow channel, for which it is possible to find Σ(ρ) and S(k) analytically. Hyperuniformity, which is the vanishing of S(k→0), will therefore not occur if the complexity is nonzero. An example is given of a jammed state of hard disks in a narrow channel which is hyperuniform when generated by dynamical rules that produce a nonextensive complexity.

Gardner Transition in Physical Dimensions.

The Gardner transition is the transition that at mean-field level separates a stable glass phase from a marginally stable phase. This transition has similarities with the de Almeida-Thouless transition of spin glasses. We have studied a well-understood problem, that of disks moving in a narrow channel, which shows many features usually associated with the Gardner transition. We show that some of these features are artifacts that arise when a disk escapes its local cage during the quench to higher densities. There is evidence that the Gardner transition becomes an avoided transition, in that the correlation length becomes quite large, of order 15 particle diameters, even in our quasi-one-dimensional system.

Fractal Dimension of Interfaces in Edwards-Anderson and Long-range Ising Spin Glasses: Determining the Applicability of Different Theoretical Descriptions.

The fractal dimension of excitations in glassy systems gives information on the critical dimension at which the droplet picture of spin glasses changes to a description based on replica symmetry breaking where the interfaces are space filling. Here, the fractal dimension of domain-wall interfaces is studied using the strong-disorder renormalization group method pioneered by Monthus [Fractals 23, 1550042 (2015)FRACEG0218-348X10.1142/S0218348X15500425] both for the Edwards-Anderson spin-glass model in up to 8 space dimensions, as well as for the one-dimensional long-ranged Ising spin-glass with power-law interactions. Analyzing the fractal dimension of domain walls, we find that replica symmetry is broken in high-enough space dimensions. Because our results for high-dimensional hypercubic lattices are limited by their small size, we have also studied the behavior of the one-dimensional long-range Ising spin-glass with power-law interactions. For the regime where the power of the decay of the spin-spin interactions with their separation distance corresponds to 6 and higher effective space dimensions, we find again the broken replica symmetry result of space filling excitations. This is not the case for smaller effective space dimensions. These results show that the dimensionality of the spin glass determines which theoretical description is appropriate. Our results will also be of relevance to the Gardner transition of structural glasses.

Replica symmetry broken states of some glass models.

We have studied in detail the M-p balanced spin-glass model, especially the case p=4. These types of model have relevance to structural glasses. The models possess two kinds of broken replica states; those with one-step replica symmetry breaking (1RSB) and those with full replica symmetry breaking (FRSB). To determine which arises requires studying the Landau expansion to quintic order. There are nine quintic-order coefficients, and five quartic-order coefficients, whose values we determine for this model. We show that it is only for 2≤M<2.4714⋯ that the transition at mean-field level is to a state with FRSB, while for larger M values there is either a continuous transition to a state with 1RSB (when M≤3) or a discontinuous transition for M>3. The Gardner transition from a 1RSB state at low temperatures to a state with FRSB also requires the Landau expansion to be taken to quintic order. Our result for the form of FRSB in the Gardner phase is similar to that found when 2≤M<2.4714⋯, but differs from that given in the early paper of Gross et al. [Phys. Rev. Lett. 55, 304 (1985)0031-900710.1103/PhysRevLett.55.304]. Finally we discuss the effects of fluctuations on our mean-field solutions using the scheme of Höller and Read [Phys. Rev. E 101, 042114 (2020)2470-004510.1103/PhysRevE.101.042114] and argue that such fluctuations will remove both the continuous 1RSB transition and discontinuous 1RSB transitions when 8>d≥6 leaving just the FRSB continuous transition. We suggest values for M and p which might be used in simulations to confirm whether fluctuation corrections do indeed remove the 1RSB transitions.

Study of the de Almeida-Thouless line in the one-dimensional diluted power-law XY spin glass.

We study the de Almeida-Thouless (AT) line in the one-dimensional power-law diluted XY spin-glass model, in which the probability that two spins separated by a distance r interact with each other, decays as 1/r^{2σ}. Tuning the exponent σ is equivalent to changing the space dimension of a short-range model. We develop a heat bath algorithm to equilibrate XY spins; using this in conjunction with the standard parallel tempering and overrelaxation sweeps, we carry out large-scale Monte Carlo simulations. For σ=0.6, which is in the mean-field regime above six dimensions-it is similar to being in 10 dimensions-we find clear evidence for an AT line. For σ=0.75 and σ=0.85, which are in the non-mean-field regime and similar to four and three dimensions, respectively, our data is like that found in previous studies of the Ising and Heisenberg spin glasses when reducing the temperature at fixed field. For σ=0.75, there is evidence from finite-size-scaling studies for an AT transition but for σ=0.85, the evidence for a transition is nonexistent. We have also studied these systems at fixed temperature varying the field and discovered that at both σ=0.75 and at σ=0.85 there is evidence of an AT transition! Confusingly, the correlation length and spin-glass susceptibility as a function of the field are both entirely consistent with the predictions of the droplet picture and hence the nonexistence of an AT line. In the usual finite-size critical point scaling studies used to provide evidence for an AT transition, there is seemingly good evidence for an AT line at σ=0.75 for small values of the system size N, which is strengthening as N is increased, but for N>2048 the trend changes and the evidence then weakens as N is further increased. We have also studied with fewer bond realizations the system at σ=0.70, which is the analog of a system with short-range interactions just below six dimensions, and found that it is similar in its behavior to the system at σ=0.75 but with larger finite-size corrections. The evidence from our simulations points to the complete absence of the AT line in dimensions outside the mean-field region and to the correctness of the droplet picture. Previous simulations which suggested there was an AT line can be attributed to the consequences of studying systems which are just too small. The collapse of our data to the droplet scaling form is poor for σ=0.75 and to some extent also for σ=0.85, when the correlation length becomes of the order of the length of the system, due to the existence of excitations which only cost a free energy of O(1), just as envisaged in the TNT picture of the ordered state of spin glasses. However, for the case of σ=0.85 we can provide evidence that for larger system sizes, droplet scaling will prevail even when the correlation length is comparable to the system size.

Free-energy barriers in the Sherrington-Kirkpatrick model.

The free-energy landscape of the Sherrington-Kirkpatrick (SK) Ising spin glass is simple in the framework of the Thouless-Anderson-Palmer (TAP) equations as each solution (which are minima of the free energy) has associated with it a nearby index-one saddle point. The free-energy barrier to escape the minimum is just the difference between the saddle point free energy and that at its associated minimum. This difference is calculated for the states with free energies f>f_{c}. It is very small for these states, decreasing as 1/N^{2}, where N is the number of spins in the system. These states are not marginally stable. We argue that such small barriers are why numerical studies never find these states when N is large. Instead, the states that are found are those that have marginal stability. For them the barriers are at least of O(1). f_{c} is the free energy per spin below which the states develop broken replica-symmetry-like overlaps with each other. In the regime f

Dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can initiate antigen-specific humoral immunity independent of CD4+ T cells.

We have investigated whether dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can trigger B cells to produce antigen-specific antibodies without CD4+ T-cell help. Dendritic cells modified with a recombinant adenovirus vector to express CD40 ligand and pulsed with heat-killed Pseudomonas induced naive B cells to produce antibodies against Pseudomonas in the absence of CD4+ T cells in vitro, initiated Pseudomonas-specific humoral immune responses in vivo in wild-type and CD4-/- mice, and protected immunized wild-type and CD4-/-, but not B-cell -/- mice, from lethal intrapulmonary challenge with Pseudomonas. Thus, genetic modification of dendritic cells with CD40 ligand enables them to present a complex mixture of microbial antigens and establish CD4+ T cell-independent, B cell-mediated protective immunity against a specific microbe.

Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.

The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.

Droplet-scaling versus replica symmetry breaking debate in spin glasses revisited.

Simulational studies of spin glasses since the early 2010s have focused on the so-called replicon exponent α as a means of determining whether the low-temperature phase of spin glasses is described by the replica symmetry breaking picture of Parisi or by the droplet-scaling picture. On the latter picture, it should be zero, but we shall argue that it will only be zero for systems of linear dimension L>L^{*}. The crossover length L^{*} may be of the order of hundreds of lattice spacings in three dimensions and approach infinity in six dimensions. We use the droplet-scaling picture to show that the apparent nonzero value of α when L

Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha.

Several cytokines, especially granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha), have been identified that foster the development of dendritic cells from blood and bone marrow precursors in suspension cultures. These precursors are reported to be infrequent or to yield small numbers of dendritic cells in colony-forming assays. Here we readily identify dendritic cell colony-forming units (CFU-DC) that give rise to pure dendritic cell colonies. Human CD34+ bone marrow progenitors were expanded in semi-solid cultures with serum-replete medium containing c-kit-ligand, GM-CSF, and TNF-alpha. The addition of TNF-alpha to GM-CSF did not alter the number of typical GM colonies but did generate pure dendritic cell colonies that accounted for approximately 40% of the total colony growth. When the two distinct types of colonies were plucked from methylcellulose and tested for T cell-stimulatory activity in the mixed leukocyte reaction, the potency of colony-derived dendritic cells exceeded that of CFU-GM progeny from the same cultures by at least 1.5-2 logs. Immunophenotyping and cytochemical staining of the CFU-DC-derived progeny was also characteristic of dendritic cells. Other myeloid cells were not identified in these colonies. The addition of c-kit-ligand to GM-CSF- and TNF-alpha-supplemented suspensions of CD34+ bone marrow cells expanded CFU-DCs almost 100-fold by 14 d. We conclude that normal human CD34+ bone marrow cells include substantial numbers of clonogenic progenitors, distinct from CFU-GMs, that can give rise to pure dendritic cell colonies. These CFU-DCs can be expanded for several weeks by in vitro culture with c-kit-ligand, and their differentiation requires exogenous TNF-alpha in addition to GM-CSF. We speculate that this dendritic cell-committed pathway may in the steady state contribute cells to the epidermis and afferent lymph, where dendritic cells are the principal myeloid cell type, and may increase the numbers of these specialized antigen-presenting cells during T cell-mediated immune responses.

Experimental studies on the development of the thymus.

Experiments utilizing chromosome marker and histological techniques in combination with parabiosis and transplanatation procedures have demonstrated an inflow of blood-home stem cells into the chick embryo thymic rudiment. There is close similarity between the histological picture in the chick and in the mouse thymic rudiment, and it is proposed that a similar developmental process takes place in both. It may be concluded that the epithelial component of the thymic rudiment, rather than producing lymphoid cells itself, furnishes an inductive environment for the proliferation and differentiation of stem cells derived extrinsically.

Growth of B-lymphocytes clones in semisolid culture is mitogen dependent.

A substance which was mitogenic for murine B lymphocytes in the presence of 2-mercaptoethanol was isolated from agar. Stimulating activity of this material was stable to proteolysis or protein denaturants but was destroyed by periodate treatment. Agar-derived mitogen stimulation was distinct from that obtained with dextran sulfate or lipopolysaccharide and may define different populations of B lymphocytes.

Lysozyme synthesis by established human and murine histiocytic lymphoma cell lines.

A human cell line established in culture from a histiocytic lymphoma patient synthesizes and secretes the monocyte-granulocyte specific enzyme lysozyme. 18 other human cell lines with characteristics of T-lymphocyte, B-lymphocyte, Burkitt's lymphoma, non-Burkitt's lymphoma, myeloma, and bone marrow epithelial cells were not associated with lysozyme. Among murine cell lines, lysozyme was produced by (a) three histiocytic lymphoma or macrophage lines, which mediate antibody-dependent phagocytosis and cytolysis; (b) myelomonocytic leukemia line which also secretes myeloid colony-stimulating factor; and (c) a spontaneous lymphoma and an Abelson leukemia virus-induced lymphoma. Lysozyme-negative lines include another Abelson lymphoma, myelomas, T lymphomas, and mastocytoma.

Defects in hematopoietic differentiation in NZB and NZC mice.

Hematopoietic stem cell activity in inbred NZB and NZC mice has been determined by transplantation and endogenous spleen colony assays. Whereas NZB mice show normal colony-forming unit (CFU) activity in the transplantation assay, they show markedly elevated endogenous CFU. NZC mice also show this markedly elevated endogenous CFU activity, but in the transplantation assay show only about 5-10% of normal CFU counts. When NZC stem cells are tested for CFU activity in irradiated recipients of the H-2(d) type, almost normal colony numbers occur. NZB stem cells however also cannot form colonies in NZC mice. These results suggest that NZC mice have a defect in the micro-environment of the spleen which renders them incapable of allowing transplanted CFU to form colonies. Genetic analysis of both the NZC defect as a CFU recipient, and the elevated endogenous count in NZB and NZC, shows that both are controlled by single recessive genes which are not linked to either coat color, agouti, H-2 or Ig loci. Of even more relevance is the finding that these hematopoietic abnormalities are not linked to the genes involved in controlling autoantibody formation to red cells in the NZB mice. These mice therefore appear to show two distinct hematopoietic abnormalities, the analysis of which may be of considerable value in understanding the detailed events of hematopoietic stem cell differentiation.

A macrophage tumor cell line and plasminogen activator. A potential model system for macrophage regulation of enzyme production.

The macrophage cell line, RAW264.10, synthesizes and secretes plasminogen activator. Production of this enzyme is inhibited by low concentrations of glucocorticoids and increased by phorbol myristate acetate. It is proposed that this line could be a suitable model for the regulation of enzyme synthesis by mouse peritoneal macrophages.

Synthesis and release of erythroid colony- and burst-potentiating activities by purified populations of murine peritoneal macrophages.

We investigated the effects of murine resident peritoneal macrophages on the in vitro proliferation of erythropoietin (Ep)-sensitive committed precursors colony-forming unit-erythroid (CFU-E) and burst-forming unit-erythroid (BFU-E) with a two-layer cloning system of methylcellulose and semisolid agar. The addition of increasing numbers of macrophages to the agar underlayer resulted in a progressive increase in the numbers of both CFU-E and BFU-E that proliferated in the presence of Ep. CFU-E, but not BFU-E, proliferated to form colonies in the absence Qf exogenously added Ep, and this proliferation was enhanced in a dose-dependent fashion by the presence of macrophages in the underlayer. The enhancing effects of a given number of macrophages and a given concentration of Ep were greater than the sum of the individual effects of macrophages and Ep alone. This erythropoietic syngerism was more evident with BFU-E because burst formation was not seen in the absence of exogenously added Ep. Macrophage underlayers stimulated three to five times the number of erythroid bursts seen with Ep alone. Cell-free agar underlayers or agar underlayers prepared with nonadherent peritoneal cells or unseparated cells from thymus, lymph node, or spleen failed to augment Ep- dependent erythroid colony formation. No enhancement of CFU-E or BFU-E was demonstrable after depletion ofadherent cells from peritoneal cell suspensions by passage over columns of Sephadex G-10. Analysis by sedimentation velocity of peritoneal cells confirmed that the cells responsible for elaborating the erythroid-enhancing activity were macrophages on the basis of morphologic, histochemical, and functional criteria. Serum- free media conditioned by macrophages in the absence of Ep contained the erythroid-enhancing activities, which indicated that Ep was not required for the elaboration of these diffusible substances. These studies indicate that although macrophages are not obligate for the growth of erythroid precursors, they serve as an important source of diffusible factors that reduce the in vitro requirement for Ep.

Maintenance of hemopoietic stem cells and production of differentiated progeny in allogeneic and semiallogeneic bone marrow chimeras in vitro.

A culture system is described in which bone marrow-derived adherent cells can support prolonged proliferation and differentiation of genetically incompatible stem cells and precursor cells. The results suggest that the reactive cells responsible in vivo for host transplantation resistance and for graft-versus-host disease are selectively lost or inhibited in such cultures, which may provide a vehicle for studying some of the cellular mechanisms involved in transplantation resistance.

Regulation of B-lymphocyte clonal proliferation by stimulatory and inhibitory macrophage-derived factors.

A functional subpopulation of murine B lymphocytes proliferate in semisolid agar culture in the presence of 2-mercaptoethanol to form colonies. The effects of diffusible macrophage-derived factors on this focal proliferation was investigated using a two-layer culture system which prevented macrophage-lymphocyte contact and permitted B-cell activation to be critically assessed under conditions of extremely low cell densities. Adherent peritoneal macrophages incorporated within underlayers of spleen or lymph node cell cultures potentiated both the number and size of developing B-cell colonies. These effects were most striking when low numbers of spleen or lymph node cells, or macrophage- depleted lymphoid cell suspensions were used. Thus, macrophage-depleted lymph node ceils gave rise to virtually no colonies, but colony-forming ability was restored by the presence of an optimal number of macrophages. When the number of macrophages exceeded that required for optimal stimulation, colony formation was suppressed; an effect which was largely prevented by indomethacin, an inhibitor of prostaglandin synthesis. Under these conditions, stimulation and inhibition of B-cell activation by macrophages could be dissociated, indicating that each signal is selectively controlled by individual molecules elaborated by the macrophage. With an appropriate number of macrophages required for B-cell activation, and sufficient indomethacin to inhibit the accumulation of macrophage-derived prostaglandin, B-lymphocyte clonal proliferation was a linear function of the number of B cells placed in culture. In the absence of macrophages, B-cell colony formation was potentiated by both lipopolysaccharide and intact sheep erythrocytes through a mechanism different from that of the macrophage-derived stimulatory factor. In addition to their direct stimulatory effect on B-cell proliferation, lipopolysaccharide and sheep erythrocytes were each capable of modulating the production and/or release of B-cell stimulatory and inhibitory factors by the macrophage. Parallel studies of conventional mitogen- stimulated lymphocyte cultures did not show a requirement for macrophages and confirm that the semisolid assay is uniquely suited to studies on the regulatory role of the macrophage in B-cell activation.

The fate of fetal and adult B-cell progenitors grafted into immunodeficient CBA/N mice.

The relative ability of various precursors to generate functional B cells in vivo was assessed by transferring normal, chromosomally-marked CBA/H-T6T6 cells to irradiated or unirradiated immunodeficient CBA/N mice. Emergence of donor-derived B cells was monitored by means of a B-cell cloning assay (in which CBA/N cells are inactive), and by karyotpic analysis of lymphoid, myeloid, and stem cell metaphases. Grafts of lymph node, spleen, anti-mu surface immunoglobin suppressed bone marrow, sIg+ cell-depleted marrow, normal marrow, fetal liver, and yolk sac suggest: (a) there is little self-renewal of sIg+ B cells in these models; (b) pre-committed cells have extensive proliferative/differentiative potential and at least initially contribute most of the newly-formed B cells; (c) populations or pre-B cells obtained from various sources differ in their regenerative ability; (d) CBA/N mice are deficient in a category of pre-B cells which are found in fetal liver; and (e) selective B-cell chimerism results from grafting of unirradiated CBA/N mice.