Intraspecific Trait Variation and Phenotypic Plasticity Mediate Alpine Plant Species Response to Climate Change

In a rapidly changing climate, alpine plants may persist by adapting to new conditions. However, the rate at which the climate is changing might exceed the rate of adaptation through evolutionary processes in long-lived plants. Persistence may depend on phenotypic plasticity in morphology and physiology. Here we investigated patterns of leaf trait variation including leaf area, leaf thickness, specific leaf area, leaf dry matter content, leaf nutrients (C, N, P) and isotopes (δ13C and δ15N) across an elevation gradient on Gongga Mountain, Sichuan Province, China. We quantified inter- and intra-specific trait variation and the plasticity in leaf traits of selected species to experimental warming and cooling by using a reciprocal transplantation approach. We found substantial phenotypic plasticity in most functional traits where δ15N, leaf area, and leaf P showed greatest plasticity. These traits did not correspond with traits with the largest amount of intraspecific variation. Plasticity in leaf functional traits tended to enable plant populations to shift their trait values toward the mean values of a transplanted plants’ destination community, but only if that population started with very different trait values. These results suggest that leaf trait plasticity is an important mechanism for enabling plants to persist within communities and to better tolerate changing environmental conditions under climate change

The matrix metalloproteinase 9 (mmp-9) hemopexin domain is a novel gelatin binding domain and acts as an antagonist

Matrix metalloproteinases (MMPs) are involved in the remodeling processes of the extracellular matrix and the basement membrane. Most MMPs are composed of a regulatory, a catalytic, and a hemopexin subunit. In many tumors the expression of MMP-9 correlates with local tumor growth, invasion, and metastasis. To analyze the role of the hemopexin domain in these processes, the MMP-9 hemopexin domain (MMP-9-PEX) was expressed as a glutathione S-transferase fusion protein in Escherichia coli. After proteolytic cleavage, the isolated PEX domain was purified by size exclusion chromatography. In a zymography assay, MMP-9-PEX was able to inhibit MMP-9 activity. The association and dissociation rates for the interaction of MMP-9-PEX with gelatin were determined by plasmon resonance. From the measured rate constants, the dissociation constant was calculated to be K(d) = 2,4 x 10(-8) m, demonstrating a high affinity between MMP-9-PEX and gelatin. In Boyden chamber experiments the recombinant MMP-9-PEX was able to inhibit the invasion of melanoma cells secreting high amounts of MMP-9 in a dose-dependent manner. These data demonstrate for the first time that the hemopexin domain of MMP-9 has a high affinity binding site for gelatin, and the particular recombinant domain is able to block MMP-9 activity and tumor cell invasion. Because MMP-9 plays an important role in metastasis, this antagonistic effect may be utilized to design MMP inhibition-based cancer therapy

Combined chemotherapy and pembrolizumab salvages multi-chemotherapy agent and avelumab resistant choriocarcinoma: A case report

Introduction: Gestational trophoblastic neoplasia (GTN) including choriocarcinoma (CC) frequently requires multi-agent chemotherapy to achieve cure. In chemotherapy-resistant GTN, immunotherapy with the checkpoint inhibitors pembrolizumab, avelumab and camrelizumab are potential new treatment options previously described in small case series, phase 2 trials and case reports. Case description: A 32-year-old woman was diagnosed with gestational choriocarcinoma (FIGO score 5). Prior administered therapy regimes included methotrexate, actinomycin-D followed by open hysterectomy with bilateral salpingectomy (histology without GTN) as well as multi-agent chemotherapy and avelumab single-agent. After detection of a suspicious pulmonary mass video- assisted thoracoscopic left lung segmentectomy was performed confirming CC. The patient experienced an intracerebral haemorrhage and was treated with an emergency decompressive craniotomy. The cerebrospinal fluid showed an increased ratio of hCG compared to serum. Therapy with combined escalated etoposide and cisplatin with pembrolizumab was commenced followed by maintenance pembrolizumab achieving a complete hCG response and negative PET CT. Discussion: In the management of multi drug- resistant GTN, application of checkpoint inhibitor pembrolizumab is a new therapeutic strategy. In this heavily pre-treated patient incorporation of pembrolizumab resulted in complete long-term response in a patient who had also failed avelumab therapy

Electronic structure of neutral tryptophan radicals in ribonucleotide reductase studied by epr and endor spectroscopy

New transient protein-linked radicals have been analyzed by EPR and ENDOR spectroscopy in the radical enzyme ribonucteotide reductase of E coK, particularly in the mutant Y122F of the protein R2, during the reconstitution of the diiron center. Two different tryptophan radicals (Wa° and W0°) with life-times of several minutes are formed at room temperature. Wa° is freeze-trapped and investigated by EPR and ENDOR in normal and selectively deuterated proteins at 20K Two hyperfine couplings from the βmethylene protons, hyperfine tensors of two a-protons and the complete nitrogen hyperfine tensor are determined. Based on the absence of a large hyperfine coupling from the N-H proton, which could be expected for a cation radical, and on comparison of the experimental data with theoretical spin densities from density functional calculations, WV is assigned to an oxidized neutral tryptophan radical. A small anisotropic hyperfine coupling detected in selectively deuterated W." is tentatively assigned to a proton which is hydrogen bonded to the nitrogen of VW. A similar spin density distribution was obtained also for the second tryptophan radical. WV observed at room temperature by stopped-flow EPR is also assigned to an oxidized neutral radical. The site of Wa° and WtT in protein R2 has been determined from the comparison of the conformation of the βprotons (from EPR data) with X-ray structure data to W111 and W107, respectively, in close neighborhood to the iron center. For the first time, detailed hyperfine parameters are determined for protein-linked oxidized neutral tryptophan radicals. Using the same technique of iron reconstitution, in the mutant R2-Y122H, where the site of the catalytic essential stable tyrosyl radical has been replaced by a histidine, a new stable radical exhibiting a strong magnetic metal interaction is observed by EPR and ENDOR

MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia

Background: Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia. Methods: Young male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg−1, 3 mg kg−1 MT-102, or placebo by gavage. Results: Three mg kg−1d−1 MT-102 not only prevented progressive loss of fat mass (−6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. −37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. −60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg−1d−1 MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg-1d-1 MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16–0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively. Conclusions: The present study shows that 3 mg kg−1 MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival