Immune responses against bovine tropical theileriosis: with particular reference to reimmunisation with Theileria annulata infected cell lines

This study describes the effect of allogeneic immune responses on immunisation against Theileria annulata with a parasite infected cell line. The dynamics of lymphocyte populations during development of the immune response against the parasite after cell line immunisation and sporozoite challenge were investigated in peripheral blood, and lymph efferent from the lymph node draining the site of infection.ph node draining the site of infection. T. annulata infected cell lines have been used as vaccines against tropical theileriosis in several countries. Inoculated animals produce a strong response against the allogeneic MHC antigens of the immunising cell line followed by an and parasite response. There is evidence that immunity to the parasite wanes in the absence of challenge and reimmunisation is often recommended. However, the effect of pre-existing allogeneic responses generated after first immunisation with T. annulata infected cell lines upon development of immunity against the parasite at the time of reimmunisation, is not known. To investigate this, an allogeneic response was first generated in the animals followed by immunisation with a T. annulata infected cell line of the same BoLA type. A mild allogeneic response generated by inoculation of uninfected leucocytes did not affect the development of immunity during cell line immunisation. However, a strong anti MHC response generated by skin grafting interfered with the development of a parasite specific immune response when the animals were immunised with lxlO6 cells. The effect of the allogeneic response was more marked when vaccination was carried out with a lower cell dose of 1 xlO4 cells, where the development of immunity against T. annulata was completely blocked. These observations are of immediate importance in endemic areas where T. annulata infected cell lines are being used as vaccines to control the disease.The kinetics of various leucocyte subpopulations in the peripheral blood of animals revealed that leucopenia in response to T. annulata infection was caused by decline in the number of circulating neutrophils and lymphocytes. Lymphocytopaenia was caused mainly by reduction in the levels of circulating CD4+ cells and B cells, and to a lesser degree of CD8+ cells and 7<5 T cells. Cells of the monocyte/macrophage lineage were least affected. The severity of leucopenia was related to the ensuing parasitological reactions after immunisation with cell line or challenge with sporozoites. The recovery and development of immunity in animals after cell line immunisation and sporozoite challenge was associated with an increase in CD25+ cells in the peripheral blood. A transient increase in the levels of CD8+ cells initially followed by a sustained increase in monocytes was associated with recovery indicating that immunity to T. annulata is mainly mediated by mechanisms involving cells of these two types. These cellular changes were not observed in animals undergoing cell line immunisation where the pre-existing allogeneic responses blocked development of parasite specific immune responses.trated on parasite dissemination and T cell activation in the draining efferent lymphatics following sporozoite infection or allogeneic cell line immunisation. During lethal sporozoite infection in the naive animals, the parasite induced strong lymphoproliferation. There was a massive increase in the output of blasting cells in efferent lymph from day 6 with a 5-10 fold increase in the flow rate and cell output. Efferent lymph contained very high levels of interferon-7 between day 5 to 9 after acute sporozoite infection. Parasite infected cells were seen from day 6 onwards. An initial increase in the percentage of CD2+ cells corresponding with an increase in CD4+ cells was observed from day 5. Many CD4+ cells expressed CD25 transiently and became MHC class II+. This was followed by increased output of blasting CD8+ cells with high MHC class II expression. Blasting CD4+ and CD8+ cells gradually lost CD2 expression with the progression of infection. These cells were MHC class II+ but had lost CD25 expression suggesting an inappropriate activation of T cells in response to the parasite. Efferent lymph cells were less responsive to Con. A or exogenous IL-2 stimulation in vitro during the later stages of infection. The cells did not proliferate in vitro in response to autologous parasite infected cells and did not kill autologous parasite infected cells suggesting lymphocyte unresponsiveness.Animals immunised with lxlO6 T. annulata infected cells exhibited a 2-4 fold increase in the flow rate and cell output in efferent lymph. Parasite infected cells of the recipient origin were isolated from day 11 onwards, but cells of donor origin were never isolated. Two peaks of blasting cells were observed. The first corresponded to an allogeneic response against MHC antigens of the immunising cell line and the second was associated with the parasite specific response. However, a few CD4+ and CD8+ cells not expressing CD2 were also observed during the second parasite specific phase of the response. At this stage, CD25 and MHC class II expression on T cells increased. The inhibition of parasite development after cell line immunisation as a result of the pre-existing allogeneic response was not associated with any of these changes.The results indicate that infection with T. annulata sporozoites leading to acute theileriosis induces an inappropriate proliferation and nonspecific activation of T cells in the efferent lymph. T cells initially express normal activation markers but lose CD2, a very important adhesion molecule with the progression of the disease. Both specific and some non-specific T cell activation is initiated after immunisation with T. annulata infected allogeneic cell lines which induce immunity to sporozoite challenge

Metastable Mixing of Markov Chains: Efficiently Sampling Low Temperature Exponential Random Graphs

In this paper we consider the problem of sampling from the low-temperature exponential random graph model (ERGM). The usual approach is via Markov chain Monte Carlo, but Bhamidi et al. showed that any local Markov chain suffers from an exponentially large mixing time due to metastable states. We instead consider metastable mixing, a notion of approximate mixing relative to the stationary distribution, for which it turns out to suffice to mix only within a collection of metastable states. We show that the Glauber dynamics for the ERGM at any temperature -- except at a lower-dimensional critical set of parameters -- when initialized at $G(n,p)$ for the right choice of $p$ has a metastable mixing time of $O(n^2\log n)$ to within total variation distance $\exp(-\Omega(n))$.Comment: No figures. We don't do that around her

Self-Stabilization: The Implicit Bias of Gradient Descent at the Edge of Stability

Traditional analyses of gradient descent show that when the largest eigenvalue of the Hessian, also known as the sharpness $S(\theta)$, is bounded by $2/\eta$, training is "stable" and the training loss decreases monotonically. Recent works, however, have observed that this assumption does not hold when training modern neural networks with full batch or large batch gradient descent. Most recently, Cohen et al. (2021) observed two important phenomena. The first, dubbed progressive sharpening, is that the sharpness steadily increases throughout training until it reaches the instability cutoff $2/\eta$. The second, dubbed edge of stability, is that the sharpness hovers at $2/\eta$ for the remainder of training while the loss continues decreasing, albeit non-monotonically. We demonstrate that, far from being chaotic, the dynamics of gradient descent at the edge of stability can be captured by a cubic Taylor expansion: as the iterates diverge in direction of the top eigenvector of the Hessian due to instability, the cubic term in the local Taylor expansion of the loss function causes the curvature to decrease until stability is restored. This property, which we call self-stabilization, is a general property of gradient descent and explains its behavior at the edge of stability. A key consequence of self-stabilization is that gradient descent at the edge of stability implicitly follows projected gradient descent (PGD) under the constraint $S(\theta) \le 2/\eta$. Our analysis provides precise predictions for the loss, sharpness, and deviation from the PGD trajectory throughout training, which we verify both empirically in a number of standard settings and theoretically under mild conditions. Our analysis uncovers the mechanism for gradient descent's implicit bias towards stability.Comment: First two authors contributed equall

“Making a list and checking it twice”

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83758/1/876_ftp.pd

Identifying good directions to escape the NTK regime and efficiently learn low-degree plus sparse polynomials

A recent goal in the theory of deep learning is to identify how neural networks can escape the "lazy training," or Neural Tangent Kernel (NTK) regime, where the network is coupled with its first order Taylor expansion at initialization. While the NTK is minimax optimal for learning dense polynomials (Ghorbani et al, 2021), it cannot learn features, and hence has poor sample complexity for learning many classes of functions including sparse polynomials. Recent works have thus aimed to identify settings where gradient based algorithms provably generalize better than the NTK. One such example is the "QuadNTK" approach of Bai and Lee (2020), which analyzes the second-order term in the Taylor expansion. Bai and Lee (2020) show that the second-order term can learn sparse polynomials efficiently; however, it sacrifices the ability to learn general dense polynomials. In this paper, we analyze how gradient descent on a two-layer neural network can escape the NTK regime by utilizing a spectral characterization of the NTK (Montanari and Zhong, 2020) and building on the QuadNTK approach. We first expand upon the spectral analysis to identify "good" directions in parameter space in which we can move without harming generalization. Next, we show that a wide two-layer neural network can jointly use the NTK and QuadNTK to fit target functions consisting of a dense low-degree term and a sparse high-degree term -- something neither the NTK nor the QuadNTK can do on their own. Finally, we construct a regularizer which encourages our parameter vector to move in the "good" directions, and show that gradient descent on the regularized loss will converge to a global minimizer, which also has low test error. This yields an end to end convergence and generalization guarantee with provable sample complexity improvement over both the NTK and QuadNTK on their own.Comment: v2: NeurIPS 2022 camera ready versio

The optimization of the Osborne Extraction Method for the fractionation and characterization of oat proteins

The growing number of wheat-related allergies worldwide has resulted in a new trend towards gluten-free alternatives. In this context, alternative cereals such as sorghum and oats are attracting new interest. Given the limited data available, the question of whether these cereals are completely safe and gluten-free for allergy sufferers remains open. One of the key steps in protein research is their efficient extraction. In this work, the Osborne sequential extraction method was developed and optimized using the response surface methodology in order to fractionate oat proteins. An optimized desirability of 0.986 was achieved with an extraction time of 4.7 min, a speed of 6, and a sample/solvent ratio of 5. The corresponding optimized responses were 8.7, 4.0, and 5.1% for the extraction yields of the avenin, avenalin, and albumin/globulin fractions, respectively. Further characterization of the extracts was carried out on 24 homogeneous and commercial oat samples via LC-MS/MS, targeting six potentially allergenic proteins. The avenin-E protein featured prominently, with relative contents of 60.7, 32.2, 58.0, and 59.8% in the total extract, avenin, avenalin, and albumin/globulin fractions, respectively, while the Avenin-3, ATI-2, avenin, SSG2, and SSG1 proteins in the total extract showed levels of 16.4, 9.3, 6.6, 4.8, and 2.2%, respectively. The preliminary results of an ELISA performed on the different fractions revealed low levels of gluten (from 1.24 ± 0.14 to 3.61 ± 0.16 mg/kg), which were well below the threshold limit of 20 mg/kg. These results support the hypothesis that oats can be a safe food for people suffering from cereal-related allergies. These results open the door to further studies into the comprehensive characterization of oat proteins