Molecular Determinants of Fetal Tolerance and the Transition to Adult Immunity

The perinatal immune system is highly tolerogenic and is phenotypically and functionally distinct from the adult immune system. This tolerogenic nature is a double-edged sword for newborns. While it is beneficial to prevent excessive inflammation against the vast array of foreign antigens encountered after birth, it also causes a lack of immune responses to life-threatening infections. My dissertation research aims to investigate the mechanisms by which perinatal T cells contribute to immune tolerance in infants. A deeper understanding of the nature of the perinatal immune system will provide pivotal knowledge to develop safe and effective strategies to protect infants from infection and to establish immune homeostasis with commensal microbes. Using umbilical cord blood (UCB) T cells as a model to study perinatal immunity, we found that antigen receptor stimulation of T cells in UCB leads to the development of Foxp3+ T cells in both CD4+ and CD8+ T cell subsets. These UCB-derived Foxp3+ T cells are phenotypically and epigenetically distinct from canonical thymus-derived Tregs (tTregs) in adults, but they carry immune regulatory functions in vitro and in vivo. The development of Foxp3+ T cells requires CD36hi monocytes. Adult blood contains a group of lymphocytes that inhibits monocyte-induced Foxp3+ T cell development, showing how perinatal blood differs from adult blood. Foxp3+ T cell development also requires IL-2. Alcohol, which is known to cause immunological defects, reduces the expression of CD25, a component of the high affinity IL-2 receptor, and blocks Foxp3+ T cell development. The result suggests that immunological dysfunctions found among infants born from alcoholic mothers may be in part due to the impaired development of these Foxp3+ T cells during their fetal life. To further elucidate the mechanisms that contribute to perinatal immunological tolerance, we investigated the expression of Helios, another transcription factor known to be expressed by tTregs along with Foxp3. We found that Helios is expressed significantly more frequently by UCB and neonatal peripheral blood T cells than adult T cells. Similar results were observed in mice. The expression frequency decreased rapidly after birth. The data suggested that T cells from fetal/perinatal origin express Helios. Indeed, we found that most gut-associated T cells, which are known to originate from the fetal thymus, express Helios in the fetus and maintained Helios expression throughout adulthood. Additionally, human T cells that matured in mice that received UCB hematopoietic stem cells also express Helios. Gene knockout of Helios in UCB T cells showed a significant increase in expression of multiple effector cytokines, suggesting that one of Helios\u27 functions is to suppress effector cytokine production by activated T cells. Together, these data demonstrated multiple mechanisms by which T cells can contribute to immune tolerance in neonates. First, the perinatal peripheral environment promotes T cells to differentiate into a unique group of Foxp3+ T cells that carry suppressive functions. Second, perinatal T cells express high levels of Helios, which suppress activated T cells to produce effector cytokines. Together, both intrinsic (Helios) and extrinsic (CD36hi monocytes) mechanisms promote the tolerogenic nature of the perinatal immune system

pH affects growth, physiology and agar properties of agarophyte Gracilaria changii (Rhodophyta) under low light intensity from Morib, Malaysia

Changes in coastal water pH alter inorganic carbon chemistry and impose abiotic stress on photosynthetic marine organisms. The red algal cell wall contains sulfated agar which protects them against environmental stresses. In this study, we investigated the effects of three different pHs (6.61, 8.04 and 9.30) on Gracilaria changii cultured in artificial seawater for 3 and 6 days, respectively. The growth rate of G. changii was the highest and the lowest at pH 6.61 and pH 9.30, respectively. Partial thallus degradation was observed in seaweeds treated at pH 9.30. Upon a 3-day treatment, the levels of allophycocyanin, total phycobilins in G. changii cultured at pH 6.61, and all photosynthetic pigments in G. changii cultured at pH 9.30, were significantly lower than those cultured at pH 8.04. G. changii exposed to pH 9.30 for 6 days also had significantly lower levels of chlorophyll a and allophycocyanin than those treated at pH 8.04. A six-day treatment at pH 6.61 caused a decline in the content of chlorophyll a and carotenoids, but an increase in the levels of phycoerythrin, phycocyanin, and total phycobilins, compared to those treated at pH 8.04. G. changii samples treated at pH 6.61 and pH 9.30 have a higher agar content compared to those cultured at 8.04. Gel strength was significantly lower in seaweed cultured at pH 9.30, compared to those cultured at pH 8.04. Gelling temperature and 3,6-anhydrogalactose content of agar were significantly affected by different pHs, but no significant changes were found in the melting temperature, gel syneresis and sulfate content of agar upon treatments. These information enhance our knowledge on physiological response and agar production in G. changii at different pHs, and useful for optimization of seaweed cultivation system in future

Unveiling the practices and challenges of professional learning community in a Malaysia Chinese School

Professional learning community (PLC) studies in the Asian Chinese nations remain scarce despite the emerging interest in the practice of PLC beyond the Western context. This study attempts to provide an understanding of the practices of PLC and challenges in implementing PLC in a Malaysian Chinese culture–dominated secondary school. This qualitative study used a phenomenological constructivist approach as a strategy of inquiry. Semi-structured interview data were collected from six middle leaders and ordinary teachers in a national-type Chinese secondary school in the northern region. Findings informed three existing PLC practices at the school level, namely, (a) peer coaching, (b) sharing of personal practices, and (c) professional development courses. However, the practice of PLC encounters various challenges, including excessive workload, teachers’ passive attitudes, unsupportive conditions in the school, poor execution of PLC by the school community, and a vague understanding of PLC. Interestingly, this study identified two uncovered challenges hindering the development of PLC: misconception about PLC and lack of supervision from the authority. Implications and future studies are presented

Unveiling the practices and challenges of professional learning community in a Malaysian Chinese Secondary School

Professional learning community (PLC) studies in the Asian Chinese nations remain scarce despite the emerging interest in the practice of PLC beyond the Western context. This study attempts to provide an understanding of the practices of PLC and challenges in implementing PLC in a Malaysian Chinese culture–dominated secondary school. This qualitative study used a phenomenological constructivist approach as a strategy of inquiry. Semi-structured interview data were collected from six middle leaders and ordinary teachers in a national-type Chinese secondary school in the northern region. Findings informed three existing PLC practices at the school level, namely, (a) peer coaching, (b) sharing of personal practices, and (c) professional development courses. However, the practice of PLC encounters various challenges, including excessive workload, teachers’ passive attitudes, unsupportive conditions in the school, poor execution of PLC by the school community, and a vague understanding of PLC. Interestingly, this study identified two uncovered challenges hindering the development of PLC: misconception about PLC and lack of supervision from the authority. Implications and future studies are presented

Unveiling the Practices and Challenges of Professional Learning Community in a Malaysian Chinese Secondary School

Professional learning community (PLC) studies in the Asian Chinese nations remain scarce despite the emerging interest in the practice of PLC beyond the Western context. This study attempts to provide an understanding of the practices of PLC and challenges in implementing PLC in a Malaysian Chinese culture– dominated secondary school. This qualitative study used a phenomenological constructivist approach as a strategy of inquiry. Semi-structured interview data were collected from six middle leaders and ordinary teachers in a national-type Chinese secondary school in the northern region. Findings informed three existing PLC practices at the school level, namely, (a) peer coaching, (b) sharing of personal practices, and (c) professional development courses. However, the practice of PLC encounters various challenges, including excessive workload, teachers’ passive attitudes, unsupportive conditions in the school, poor execution of PLC by the school community, and a vague understanding of PLC. Interestingly, this study identified two uncovered challenges hindering the development of PLC: misconception about PLC and lack of supervision from the authority. Implications and future studies are presented

Full-sky ray-tracing simulation of weak lensing using ELUCID simulations: exploring galaxy intrinsic alignment and cosmic shear correlations

The intrinsic alignment of galaxies is an important systematic effect in weak-lensing surveys, which can affect the derived cosmological parameters. One direct way to distinguish different alignment models and quantify their effects on the measurement is to produce mocked weak-lensing surveys. In this work, we use full-sky ray-tracing technique to produce mock images of galaxies from the ELUCID $N$-body simulation run with the WMAP9 cosmology. In our model we assume that the shape of central elliptical galaxy follows that of the dark matter halo, and spiral galaxy follows the halo spin. Using the mocked galaxy images, a combination of galaxy intrinsic shape and the gravitational shear, we compare the predicted tomographic shear correlations to the results of KiDS and DLS. It is found that our predictions stay between the KiDS and DLS results. We rule out a model in which the satellite galaxies are radially aligned with the center galaxy, otherwise the shear-correlations on small scales are too high. Most important, we find that although the intrinsic alignment of spiral galaxies is very weak, they induce a positive correlation between the gravitational shear signal and the intrinsic galaxy orientation (GI). This is because the spiral galaxy is tangentially aligned with the nearby large-scale overdensity, contrary to the radial alignment of elliptical galaxy. Our results explain the origin of detected positive GI term from the weak-lensing surveys. We conclude that in future analysis, the GI model must include the dependence on galaxy types in more detail.Comment: 23 pages, 13 figures, published in ApJ. Our mock galaxy catalog is available upon request by email to the author ([email protected], [email protected]

An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma.

Lessons learnedTKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.BackgroundPolo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.MethodsA 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.ResultsThe study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.ConclusionTKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted

ELUCID IV: Galaxy Quenching and its Relation to Halo Mass, Environment, and Assembly Bias

We examine the quenched fraction of central and satellite galaxies as a function of galaxy stellar mass, halo mass, and the matter density of their large scale environment. Matter densities are inferred from our ELUCID simulation, a constrained simulation of local Universe sampled by SDSS, while halo masses and central/satellite classification are taken from the galaxy group catalog of Yang et al. The quenched fraction for the total population increases systematically with the three quantities. We find that the `environmental quenching efficiency', which quantifies the quenched fraction as function of halo mass, is independent of stellar mass. And this independence is the origin of the stellar mass-independence of density-based quenching efficiency, found in previous studies. Considering centrals and satellites separately, we find that the two populations follow similar correlations of quenching efficiency with halo mass and stellar mass, suggesting that they have experienced similar quenching processes in their host halo. We demonstrate that satellite quenching alone cannot account for the environmental quenching efficiency of the total galaxy population and the difference between the two populations found previously mainly arises from the fact that centrals and satellites of the same stellar mass reside, on average, in halos of different mass. After removing these halo-mass and stellar-mass effects, there remains a weak, but significant, residual dependence on environmental density, which is eliminated when halo assembly bias is taken into account. Our results therefore indicate that halo mass is the prime environmental parameter that regulates the quenching of both centrals and satellites.Comment: 21 pages, 16 figures, submitted to Ap