bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin‐induced apoptosis in neural cancer cells
Authors: Yu Zhenlong , Tian Xiangge , Peng Yuling , Sun Zheng , Wang Chao , Tang Ning , Li Bin , Jian Yuqing , Wang Wei , Huo Xiaokui , Ma Xiaochi 
Published: February 2018

AbstractMelatonin is an endogenous indoleamine with a wide range of biological functions in the various organisms from bacteria to mammals. Evidence indicates that melatonin facilitates apoptosis in cancer cells and enhances the antitumor activity of chemotherapy in animals and clinical studies. However, the melatonin metabolism and the key metabolic targets in cancer cells still remain unknown. In this study, U118 and SH‐SY5Y tumor cell lines were used to investigate the metabolic pathways of melatonin in cancer cells. Interestingly, the inhibitory effect of melatonin on proliferation in SH‐SY5Y cells is more potent than that in U118 cells. In contrast, this inhibitory effect on the normal cells is absent. The antitumor effects of melatonin are positively associated with its metabolite N‐acetylserotonin (NAS). Unexpectedly, CYP1B1 is, for first time, identified to localize in the mitochondria of tumor cells, and it metabolizes melatonin to form NAS in situ, which subsequently triggers mitochondria‐dependent apoptosis in cancer cells. In normal cells, NAS does not induce apoptosis. A remarkable individual variation on CYP1B1 expression was also detected in human tumor tissue. These findings provide the novel mechanisms regarding the antitumor effects of melatonin in the level of mitochondria. Thus, we hypothesize that CYP1B1 overexpression in mitochondria would significantly enhance the antitumor effects of melatonin. Mitochondrial CYP1B1 can potentially serve as a specific target to modify the therapeutic and biological effects of melatonin on cancer patients.
The role of climate, forest fires and human population size in Holocene vegetation dynamics in Fennoscandia
Authors: Kuosmanen Niina , Marquer Laurent , Tallavaara Miikka , Molinari Chiara , Zhang Yurui , Alenius Teija , Edinborough Kevan , Pesonen Petro , Reitalu Triin , Renssen Hans , Trondman Anna‐Kari , Seppä Heikki 
Published: February 2018

AbstractQuestionsWe investigated the changing role of climate, forest fires and human population size in the broad‐scale compositional changes in Holocene vegetation dynamics before and after the onset of farming in Sweden (at 6,000 cal yr BP) and in Finland (at 4,000 cal yr BP).LocationSouthern and central Sweden, SW and SE Finland.MethodsHolocene regional plant abundances were reconstructed using the REVEALS model on selected fossil pollen records from lakes. The relative importance of climate, fires and human population size on changes in vegetation composition was assessed using variation partitioning. Past climate variable was derived from the LOVECLIM climate model. Fire variable was reconstructed from sedimentary charcoal records. Estimated trend in human population size was based on the temporal distribution of archaeological radiocarbon dates.ResultsClimate explains the highest proportion of variation in vegetation composition during the whole study period in Sweden (10,000–4,000 cal yr BP) and in Finland (10,000–1,000 cal yr BP), and during the pre‐agricultural period. In general, fires explain a relatively low proportion of variation. Human population size has significant effect on vegetation dynamics after the onset of farming and explains the highest variation in vegetation in S Sweden and SW Finland.ConclusionsMesolithic hunter‐gatherer populations did not significantly affect vegetation composition in Fennoscandia, and climate was the main driver of changes at that time. Agricultural communities, however, had greater effect on vegetation dynamics, and the role of human population size became a more important factor during the late Holocene. Our results demonstrate that climate can be considered the main driver of long‐term vegetation dynamics in Fennoscandia. However, in some regions the influence of human population size on Holocene vegetation changes exceeded that of climate and has a longevity dating to the early Neolithic.
Dual transcriptomics reveals co‐evolutionary mechanisms of intestinal parasite infections in blue mussels Mytilus edulis
Authors: Feis Marieke E. , John Uwe , Lokmer Ana , Luttikhuizen Pieternella C. , Wegner K. Mathias 
Published: February 2018

AbstractOn theoretical grounds, antagonistic co‐evolution between hosts and their parasites should be a widespread phenomenon but only received little empirical support so far. Consequently, the underlying molecular mechanisms and evolutionary steps remain elusive, especially in nonmodel systems. Here, we utilized the natural history of invasive parasites to document the molecular underpinnings of co‐evolutionary trajectories. We applied a dual‐species transcriptomics approach to experimental cross‐infections of blue mussel Mytilus edulis hosts and their invasive parasitic copepods Mytilicola intestinalis from two invasion fronts in the Wadden Sea. We identified differentially regulated genes from an experimental infection contrast for hosts (infected vs. control) and a sympatry contrast (sympatric vs. allopatric combinations) for both hosts and parasites. The damage incurred by Mytilicola infection and the following immune response of the host were mainly reflected in cell division processes, wound healing, apoptosis and the production of reactive oxygen species (ROS). Furthermore, the functional coupling of host and parasite sympatry contrasts revealed the concerted regulation of chitin digestion by a Chitotriosidase 1 homolog in hosts with several cuticle proteins in the parasite. Together with the coupled regulation of ROS producers and antagonists, these genes represent candidates that mediate the different evolutionary trajectories within the parasite's invasion. The host–parasite combination‐specific coupling of these effector mechanisms suggests that underlying recognition mechanisms create specificity and local adaptation. In this way, our study demonstrates the use of invasive species’ natural history to elucidate molecular mechanisms of host–parasite co‐evolution in the wild.
Insights into transcriptional silencing and anti‐silencing in Shigella flexneri: a detailed molecular analysis of the icsP virulence locus
Authors: Weatherspoon‐Griffin Natasha , Picker Michael A. , Pew Krystle L. , Park Hiromichi S. , Ginete Daren R. , Karney Monika MA. , Usufzy Pashtana , Castellanos Maria I. , Duhart Juan Carlos , Harrison Dustin J. , Socea Jillian N. , Karabachev Alexander D. , Hensley Christopher T. , Howerton Amber J. , Ojeda‐Daulo Rosa , Immak Joy A. , Wing Helen J. 
Published: February 2018

SummaryTranscriptional silencing and anti‐silencing mechanisms modulate bacterial physiology and virulence in many human pathogens. In Shigella species, many virulence plasmid genes are silenced by the histone‐like nucleoid structuring protein H‐NS and anti‐silenced by the virulence gene regulator VirB. Despite the key role that these regulatory proteins play in Shigella virulence, their mechanisms of transcriptional control remain poorly understood. Here, we characterize the regulatory elements and their relative spacing requirements needed for the transcriptional silencing and anti‐silencing of icsP, a locus that requires remotely located regulatory elements for both types of transcriptional control. Our findings highlight the flexibility of the regulatory elements' positions with respect to each other, and yet, a molecular roadblock docked between the VirB binding site and the upstream H‐NS binding region abolishes transcriptional anti‐silencing by VirB, providing insight into transcriptional anti‐silencing. Our study also raises the need to re‐evaluate the currently proposed VirB binding site. Models of transcriptional silencing and anti‐silencing at this genetic locus are presented, and the implications for understanding these regulatory mechanisms in bacteria are discussed.
Methionine is required for cAMP‐PKA‐mediated morphogenesis and virulence of Candida albicans
Authors: Schrevens Sanne , Van Zeebroeck Griet , Riedelberger Michael , Tournu Hélène , Kuchler Karl , Van Dijck Patrick 
Published: February 2018

SummaryCandida albicans is a major human fungal pathogen, causing superficial, as well as life‐threatening invasive infections. Therefore, it has to adequately sense and respond to the host defense by expressing appropriate virulence attributes. The most important virulence factor of C. albicans is the yeast‐to‐hyphae morphogenetic switch, which can be induced by numerous environmental cues, including the amino acid methionine. Here, we show an essential role for methionine permease Mup1 in methionine‐induced morphogenesis, biofilm formation, survival inside macrophages and virulence. Furthermore, we demonstrate that this process requires conversion of methionine into S‐adenosyl methionine (SAM) and its decarboxylation by Spe2. The resulting amino‐propyl group is then used for biosynthesis of polyamines, which have been shown to activate adenylate cyclase. Inhibition of the SPE2 SAM decarboxylase gene strongly impairs methionine‐induced morphogenesis on specific media and significantly delays virulence in the mouse systemic infection model system. Further proof of the connection between methionine uptake and initial metabolism and the cAMP‐PKA pathway was obtained by showing that both Mup1 and Spe2 are required for cAMP production in response to methionine. Our results suggest that amino acid transport and further metabolism are interesting therapeutic targets as inhibitors of this may prevent the morphogenetic switch, thereby preventing virulence.
Role of bi‐weekly serum galactomannan screening for the diagnosis of invasive aspergillosis in haematological cancer patients
Authors: Couchepin Jade , Brunel Anne‐Sophie , Jaton Katia , Meylan Pascal , Bochud Pierre‐Yves , Lamoth Frédéric 
Published: February 2018

SummaryInvasive aspergillosis (IA) is a life‐threatening infection affecting haematological cancer patients with chemotherapy‐induced neutropenia. The diagnosis of IA often relies on the detection of galactomannan (GM) in serum or bronchoalveolar lavage fluid (BAL). Bi‐weekly serum GM screening has been proposed for a pre‐emptive therapeutic approach of IA in patients not receiving mold‐active prophylaxis. We have analysed all IA cases among patients with haematological malignancies and prolonged chemotherapy‐induced neutropenia (>14 days) in our institution over a 10‐year period (2007‐2017). Serum GM was measured twice weekly and mold‐active prophylaxis was not routinely administered. Thirty IA cases were observed and a positive serum GM was the first indicator of IA in 10 (33%) of them, which represents a need of approximately 500 GM tests for the detection of a single IA case. In the other 20 (67%) cases, suggestive chest CT lesion was the first sign of IA and bronchoscopy was required in 15 (50%) cases with negative serum GM for establishing the diagnosis of probable/proven IA. A positive serum GM was associated with a worse prognosis (57% 12‐week survival vs 100% among serum GM‐negative patients, P = .006), irrespective of the timing of GM positivity compared to CT. We concluded that bi‐weekly serum GM screening demonstrated limited benefit in this population.
A new method for the rapid characterization of root growth and distribution using digital image correlation
Authors: Bao Tan , Melenka Garrett W. , Ljubotina Megan K. , Carey Jason P. , Cahill James F. 
Published: February 2018

Summary

Rapidly determining root growth patterns is biologically important and technically challenging. Current methods focus on direct observation of roots and require destructive excavations or time‐consuming root tracing.

We developed a novel methodology based on analyzing soil particle displacement, rather than direct observation of roots. This inferred root growth method uses digital image correlation (DIC) analysis, an established and high‐throughput method used in many engineering and science disciplines.

By applying DIC analyses to repeated images of plants grown in clear window boxes, we produced visually intuitive and quantifiable strain maps, indicating the magnitude and direction of soil movement. From this, we could infer root growth and rapidly quantify root system metrics. Strain measures were closely associated with the spatial distribution of roots and correlated with root length measured using conventional approaches. The method also allowed for the detection of root proliferation in nutrient‐enriched soil patches, indicating its suitability for quantifying biological patterns.

This novel application of DIC in root biology is effective, scalable, low cost, flexible and complementary to existing technologies. This method offers a new tool for answering questions in plant biology and will be particularly useful in studies involving temporal dynamics of root processes.
Distinct domains of the AVRPM3A2/F2 avirulence protein from wheat powdery mildew are involved in immune receptor recognition and putative effector function
Authors: McNally Kaitlin Elyse , Menardo Fabrizio , Lüthi Linda , Praz Coraline Rosalie , Müller Marion Claudia , Kunz Lukas , Ben‐David Roi , Chandrasekhar Kottakota , Dinoor Amos , Cowger Christina , Meyers Emily , Xue Mingfeng , Zeng Fangsong , Gong Shuangjun , Yu Dazhao , Bourras Salim , Keller Beat 
Published: February 2018

Summary

Recognition of the AVRPM3A2/F2 avirulence protein from powdery mildew by the wheat PM3A/F immune receptor induces a hypersensitive response after co‐expression in Nicotiana benthamiana. The molecular determinants of this interaction and how they shape natural AvrPm3a2/f2 allelic diversity are unknown.

We sequenced the AvrPm3a2/f2 gene in a worldwide collection of 272 mildew isolates. Using the natural polymorphisms of AvrPm3a2/f2 as well as sequence information from related gene family members, we tested 85 single‐residue‐altered AVRPM3A2/F2 variants with PM3A, PM3F and PM3FL456P/Y458H (modified for improved signaling) in Nicotiana benthamiana for effects on recognition.

An intact AvrPm3a2/f2 gene was found in all analyzed isolates and the protein variant recognized by PM3A/F occurred globally at high frequencies. Single‐residue alterations in AVRPM3A2/F2 mostly disrupted, but occasionally enhanced, the recognition response by PM3A, PM3F and PM3FL456P/Y458H. Residues enhancing hypersensitive responses constituted a protein domain separate from both naturally occurring polymorphisms and positively selected residues of the gene family.

These results demonstrate the utility of using gene family sequence diversity to screen residues for their role in recognition. This approach identified a putative interaction surface in AVRPM3A2/F2 not polymorphic in natural alleles. We conclude that molecular mechanisms besides recognition drive AvrPm3a2/f2 diversification.
Barley stripe mosaic virus infection requires PKA‐mediated phosphorylation of γb for suppression of both RNA silencing and the host cell death response
Authors: Zhang Xuan , Dong Kai , Xu Kai , Zhang Kun , Jin Xuejiao , Yang Meng , Zhang Yongliang , Wang Xianbing , Han Chenggui , Yu Jialin , Li Dawei 
Published: February 2018

Summary

The Barley stripe mosaic virus (BSMV) γb protein is a viral suppressor of RNA silencing (VSR) and symptom determinant. However, it is unclear how post‐translational modification affects the different functions of γb.

Here, we demonstrate that γb is phosphorylated at Ser‐96 by a PKA‐like kinase in vivo and in vitro. Mutant viruses containing a nonphosphorylatable substitution (BSMVS96A or BSMVS96R) exhibited reduced viral accumulation in Nicotiana benthamiana due to transient induction of the cell death response that constrained the virus to necrotic areas. By contrast, a BSMVS96D mutant virus that mimics γb phosphorylation spread similarly to the wild‐type virus.

Furthermore, the S96A mutant had reduced local and systemic γb VSR activity due to having compromised its binding activity to 21‐bp dsRNA. However, overexpression of other VSRs in trans or in cis failed to rescue the necrosis induced by BSMVS96A, demonstrating that suppression of cell death by γb phosphorylation is functionally distinct from its RNA silencing suppressor activities.

These results provide new insights into the function of γb phosphorylation in regulating RNA silencing and the BSMV‐induced host cell death response, and contribute to our understanding of how the virus optimizes the balance between viral replication and virus survival in the host plants during virus infection.
A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma
Authors: Mehnert Janice M. , Silk Ann W. , Lee J. H. , Dudek Liesel , Jeong Byeong‐Seon , Li Jiadong , Schenkel Jason M. , Sadimin Evita , Kane Michael , Lin Hongxia , Shih Weichung J. , Zloza Andrew , Chen Suzie , Goydos James S. 
Published: February 2018

SummaryStudies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1‐positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis‐generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.
Unusual spontaneous porto‐systemic shunt: The importance of diagnosing non‐anatomical porto‐systemic shunts to improve portal flow in pediatric living–related liver transplantation. Case report
Authors: Rubio Juan S. , Rumbo Carolina , Farinelli Pablo A. , Aguirre Nicolás , Ramisch Diego A. , Paladini Hugo , D´Angelo Pablo , Barros Schelotto Pablo , Gondolesi Gabriel E. 
Published: February 2018

AbstractCollateral circulation secondary to liver cirrhosis may cause the development of large PSSs that may steal flow from the main portal circulation. It is important to identify these shunts prior to, or during the transplant surgery because they might cause an insufficient portal flow to the implanted graft. There are few reports of “steal flow syndrome” cases in pediatrics, even in biliary atresia patients that may have portal hypoplasia as an associated malformation. We present a 12‐month‐old female who received an uneventful LDLT from her mother, and the GRWR was 4.8. During the early post‐operative period, she became hemodynamically unstable, developed ascites, and altered LFT. The post‐operative ultrasound identified reversed portal flow, finding a non‐anatomical PSS. A 3D CT scan confirmed the presence of a mesocaval shunt through the territory of the right gonadal vein, draining into the right iliac vein, with no portal inflow into the liver. The patient was re‐operated, and the shunt was ligated. An intraoperative Doppler ultrasound showed adequate portal inflow after the procedure; the patient evolved satisfactorily and was discharged home on day number 49. The aim was to report a case of post‐operative steal syndrome in a pediatric recipient due to a mesocaval shunt not diagnosed during the pretransplant evaluation.
Living‐donor liver transplantation for mild Zellweger spectrum disorder: Up to 17 years follow‐up
Authors: Demaret Tanguy , Varma Sharat , Stephenne Xavier , Smets Françoise , Scheers Isabelle , Wanders Ronald , Van Maldergem Lionel , Reding Raymond , Sokal Etienne 
Published: February 2018

AbstractMild Zellweger spectrum disorder, also described as Infantile Refsum disease, is attributable to mutations in PEX genes. Its clinical course is characterized by progressive hearing and vision loss, and neurodevelopmental regression. Supportive management is currently considered the standard of care, as no treatment has shown clinical benefits. LT was shown to correct levels of circulating toxic metabolites, partly responsible for chronic neurological impairment. Of three patients having undergone LT for mild ZSD, one died after LT, while the other two displayed significant neurodevelopmental improvement on both the long‐term (17 years post‐LT) and short‐term (9 months post‐LT) follow‐up. We documented a sustained improvement of biochemical functions, with a complete normalization of plasma phytanic, pristanic, and pipecolic acid levels. This was associated with stabilization of hearing and visual functions, and improved neurodevelopmental status, which has enabled the older patient to lead a relatively autonomous lifestyle on the long term. The psychomotor acquisitions have been markedly improved as compared to their affected siblings, who did not undergo LT and exhibited a poor neurological outcome with severe disabilities. We speculate that LT performed before the onset of severe sensorineural defects in mild ZSD enables partial metabolic remission and improved long‐term clinical outcomes.
Multimodal treatment including tandem high‐dose chemotherapy and autologous stem cell transplantation in children with anaplastic ependymomas
Authors: Lee Ji Won , Lim Do Hoon , Sung Ki Woong , Lee Hyeong Jin , Yi Eun Sang , Yoo Keon Hee , Koo Hong Hoe , Suh Yeon‐Lim , Shin Hyung Jin 
Published: February 2018

AbstractIn this study, we evaluated the results of multimodal treatment that included tandem HDCT/auto‐SCT in children with anaplastic ependymomas. Fourteen patients with anaplastic ependymomas were enrolled from 2006 to 2014. Six cycles of induction chemotherapy were administered to all patients before they underwent tandem HDCT/auto‐SCT. Patients who were older than 3 years of age were administered RT after two cycles of induction chemotherapy. In patients under 3 years of age, RT was either omitted or delayed until they reached 3 years of age, if the patients experienced CR after tandem HDCT/auto‐SCT. All patients, including two who experienced disease progression during induction treatment, underwent the first HDCT/auto‐SCT, and 13 subsequently underwent the second HDCT/auto‐SCT. One patient died from hepatic VOD during the second HDCT/auto‐SCT; other toxicities occurring during tandem HDCT/auto‐SCT were manageable. Relapses or progression occurred in seven patients, and five of seven of them remain alive till date after salvage treatment, including surgery and RT. The 5‐year overall and event‐free survival rates were 85.1% ± 9.7% and 50.0% ± 13.4%, respectively. These findings suggest that multimodal treatment including tandem HDCT/auto‐SCT could be a feasible option for improving survival in children with anaplastic ependymomas.