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"McDermott, Joseph Peter"
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A social history of the Chinese book：books and literati culture in late imperial China
In this learned, yet readable, book, Joseph McDermott introduces the history of the book in China in the late imperial period from 1000 to 1800. He assumes little knowledge of Chinese history or culture and compares the Chinese experience with books with
eBook
The Making of a New Rural Order in South China
Among the large caches of private documents discovered and collected in China, few rival the Huizhou sources for the insight they provide into Chinese local society and economy over the past millennium. Having spent decades researching these exceptionally rich sources, Joseph P. McDermott presents in two volumes his findings about the major social and economic changes in this important prefecture of south China from around 900 to 1700. In this first volume, we learn about village settlement, competition among village religious institutions, premodern agricultural production, the management of land and lineage, the rise of the lineage as the dominant institution, and its members' application of commercial practices to local forestry operations. This landmark study of religious life and economic activity, of lineage and land, and of rural residents and urban commercial practices provides a compelling new framework for understanding a distinctive path of economic and social development for premodern China and beyond.
eBook
The Making of a New Rural Order in South China
Utilising the exceptionally rich sources that survive from Huizhou in southeast China, McDermott traces how the major institutions of village life changed in this region from around 900 to 1600, providing a detailed analysis of pre-modern Chinese agricultural production, lineage and land management, village religious institutions, and the evolution of economic networks.
eBook
A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite
The identification of antibodies targeting a conserved site of vulnerability in the
Plasmodium falciparum
circumsporozoite protein reveals opportunities for passive prevention of malaria in vulnerable individuals and provides insights for rational vaccine design.
Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the
Plasmodium falciparum
(Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.
Journal Article
Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET
The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic
1
–
8
. Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3)
8
–
10
. It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP.664 trimers)
5
,
11
–
18
. Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1
JR-FL
strain in complex with the antibody PGT151
19
. Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pre-triggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies—and thus of interest for the design of immunogens—remains unknown.
Single-molecule fluorescence resonance energy transfer imaging of conformational states of HIV-1 envelope glycoprotein trimers on intact virus and of trimers used in previous structural studies reveal the latter as downstream—rather than pre-triggered—conformations.
Journal Article
Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
Background
Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses.
Methods
We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry.
Results
We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g.,
HOXA9
DNA methylation) and tumor progression (e.g.,
TBC1D16
DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated
PON3
DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration.
Conclusions
Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.
Journal Article
Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529
Crystal structures of the HIV-1 Env trimer with cell-entry inhibitor antiviral drug leads BMS-378806 and BMS-626529 along with biophysical data define allosteric and competitive mechanisms to inhibit CD4-induced structural changes in Env.
The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20–21 hairpin. In both structures, the β20–21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.
Journal Article