bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncological and Survival Outcomes in Watch and Wait Patients With a Clinical Complete Response After Neoadjuvant Chemoradiotherapy for Rectal Cancer
Authors: Dattani Mit , Heald Richard J. , Goussous Ghaleb , Broadhurst Jack , São Julião Guilherme P. , Habr-Gama Angelita , Perez Rodrigo Oliva , Moran Brendan J. 
Published: May 2018

Objective:
The aim of this study was to evaluate the oncological and survival outcomes of a Watch and Wait policy in rectal cancer after a clinical complete response (cCR) following neoadjuvant chemoradiotherapy.

Background:
The detection of a cCR after neoadjuvant treatment may facilitate a nonoperative approach in selected patients. However, the long-term safety of this strategy remains to be validated.

Method:
This is a systematic review of the literature to determine the oncological outcomes in Watch and Wait patients. The primary outcome was the cumulative rate of local regrowth, success of salvage surgery, and incidence of metastases. We also evaluated survival outcomes. A pooled analysis of manually extracted summary statistics from individual studies was carried out using inverse variance weighting.

Results:
Seventeen studies comprising 692 patients were identified; incidence of cCR was 22.4% [95% confidence interval (CI),14.3–31.8]. There were 153 (22.1%) local regrowths, of which 96% (n = 147/153) manifested in the first 3 years of surveillance. The 3-year cumulative risk of local regrowth was 21.6% (95% CI, 16.0–27.8). Salvage surgery was performed in 88% of patients, of which 121 (93%) had a complete (R0) resection. Fifty-seven metastases (8.2%) were detected, and 35 (60%) were isolated without evidence of synchronous regrowths; 3-year incidence was 6.8% (95% CI, 4.1–10.2). The 3-year overall survival was 93.5% (95% CI, 90.2–96.2).

Conclusion:
In rectal cancer patients with a cCR following neoadjuvant chemoradiotherapy, a Watch and Wait policy appears feasible and safe. Robust surveillance with early detection of regrowths allows a high rate of successful salvage surgery, without an increase in the risk of systemic disease, or adverse survival outcomes.
MRI of non-Alzheimer's dementia: current and emerging knowledge
Authors: Filippi Massimo , Agosta Federica 
Published: May 2018

Purpose of review
The correct classification of non-Alzheimer's dementia is crucial to study disease mechanisms, predict disease progression and test disease-specific treatments. Brain atrophy assessment with morphometric MRI is currently the gold standard for in-vivo localization of neurodegeneration. Structural and functional connectivity biomarkers are becoming increasingly available. This review emphasizes the potential applications of MRI in the main non-Alzheimer's dementia such as dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).

Recent findings
MRI can predict co-occurrence of Alzheimer's disease pathology in DLB patients and pathological subtypes in patients with FTD. Innovative applications of brain connectivity are providing neural substrates explaining the network-dependent spread of pathology in non-Alzheimer's dementia. Advanced MRI can be relevant in characterizing the temporal sequence of the earliest functional and structural brain changes in individuals at risk for neurodegenerative non-Alzheimer's diseases.

Summary
Morphometric MRI is clinically applied at an individual level for the differentiation between Alzheimer's and non-Alzheimer's dementia and may help in predicting underlying pathology, which will be critical for the success of disease-modifying therapies. Longitudinal, multimodal MRI studies are required to demonstrate whether advanced magnetic resonance techniques can be reliable outcome measures to monitor disease progression in clinical trials, starting from the presymptomatic stage.
Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation
Authors: Guerrero-Gómez David , Mora-Lorca José Antonio , Sáenz-Narciso Beatriz , Naranjo-Galindo Francisco José , Muñoz-Lobato Fernando , Parrado-Fernández Cristina , Cedazo-Minguez Ángel , Link Christopher D. , Neri Christian , Sequedo María Dolores , Vázquez-Manrique Rafael P. , Fernández-Suárez Elena , Goder Veit , Pané Roser , Cabiscol Elisa , Askjaer Peter , Cabello Juan , Miranda-Vizuete Antonio 
Published: May 2018

ABSTRACTIn the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans mutants lacking glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.
Rapid sex-specific evolution of age at maturity is shaped by genetic architecture in Atlantic salmon
Authors: Czorlich Y. , Aykanat T. , Erkinaro J. , Orell P. , Primmer CR. 
Published: May 2018

AbstractUnderstanding the mechanisms by which populations adapt to their environments is a fundamental aim in biology. However, it remains challenging to identify the genetic basis of traits, provide evidence of genetic changes and quantify phenotypic responses. Age at maturity in Atlantic salmon represents an ideal trait to study contemporary adaptive evolution as it has been associated with a single locus in thevgll3region, and has also strongly changed in recent decades. Here, we provide an empirical example of contemporary adaptive evolution of a large effect locus driving contrasting sex-specific evolutionary responses at the phenotypic level. We identified an 18% decrease in thevgll3allele associated with late maturity (L) in a large and diverse salmon population over 36 years, induced by sex-specific selection during the sea migration. Those genetic changes resulted in a significant evolutionary response in males only, due to sex-specific dominance patterns andvgll3allelic effects. Thevgll3allelic and dominance effects differed greatly in a second population and were likely to generate different selection and evolutionary patterns. Our study highlights the importance of knowledge of genetic architecture to better understand fitness trait evolution and phenotypic diversity. It also emphasizes the potential role of adaptive evolution in the trend toward earlier maturation observed in numerous Atlantic salmon populations worldwide.
Effects of Parkinson’s disease and dopamine on digit span measures of working memory
Authors: Grogan John Patrick , Knight Lisa Emily , Smith Laura , Irigoras Izagirre Nerea , Howat Alexandra , Knight Brogan Elizabeth , Bickerton Anastasia , Isotalus Hanna Kristiina , Coulthard Elizabeth Jane 
Published: May 2018

ABSTRACTRationaleParkinson’s disease (PD) impairs working memory (WM) - the ability to maintain items in memory for short periods of time and manipulate them. There is conflicting evidence on the nature of the deficits caused by the disease, and the potential beneficial and detrimental effects of dopaminergic medication on different WM processes.ObjectivesWe hypothesised that PD impairs both maintenance and manipulation of items in WM and dopaminergic medications improve this in PD patients but impair it in healthy older adults.MethodsWe tested 68 PD patients ON and OFF their dopaminergic medication, 83 healthy age-matched controls, and 30 healthy older adults after placebo and levodopa administration. We used the digit span, a WM test with three components (forwards, backwards and sequence recall) that differ in the amount of manipulation required. We analysed the maximum spans and the percentage of lists correctly recalled, which probe capacity of WM and the accuracy of the memory processes within this capacity, respectively.ResultsPD patients had lower WM capacity across all three digit span components, but only showed reduced percentage accuracy on the components requiring manipulation (backwards and sequence spans). Dopaminergic medication did not affect performance in PD patients. In healthy older adults, levodopa did not affect capacity, but did impair accuracy on one of the manipulation components (sequence), without affecting the other (backwards).ConclusionsThis suggests a non-dopaminergic deficit of maintenance capacity and manipulation accuracy in PD patients, and a potential “overdosing” of intact manipulation mechanisms in healthy older adults by levodopa.
Inhibitory and excitatory mechanisms in the human cingulate-cortex support reinforcement learning
Authors: Bezalel Vered , Paz Rony , Tal Assaf 
Published: May 2018

AbstractThe dorsal anterior cingulate cortex (dACC) is crucial for motivation, reward- and error-guided decision-making, yet its excitatory and inhibitory mechanisms remain poorly explored in humans. In particular, the balance between excitation and inhibition (E/I), demonstrated to play a role in animal studies, is difficult to measure in behaving humans. Here, we used magnetic-resonance-spectroscopy (1H-MRS) to examine these mechanisms during reinforcement learning with three different conditions: high cognitive load (uncertainty); probabilistic discrimination learning; and a control null-condition. Subjects learned to prefer the gain option in the discrimination phase and had no preference in the other conditions. We found increased GABA levels during the uncertainty condition, suggesting recruitment of inhibitory systems during high cognitive load when trying to learn. Further, higher GABA levels during the null (baseline) condition correlated with improved discrimination learning. Finally, excitatory and inhibitory levels were correlated during high cognitive load. The result suggests that availability of dACC inhibitory resources enables successful learning. Our approach establishes a novel way to examine the contribution of the balance between excitation and inhibition to learning and motivation in behaving humans.
Testing Darwin’s hypothesis about the most wonderful plant in the world: The Venus flytrap’s marginal spikes are a ‘horrid prison’ for moderate-sized insect prey
Authors: Davis Alexander L. , Babb Matthew H. , Lee Brandon T. , Martin Christopher H. 
Published: May 2018

AbstractBotanical carnivory is a novel feeding strategy associated with numerous physiological and morphological adaptations. However, the benefits of these novel carnivorous traits are rarely tested. Here, we used field observations and lab experiments to test the prey capture function of the marginal spikes on snap traps of the Venus flytrap (Dionaea muscipula). Our field and laboratory results suggested surprisingly inefficient capture success: fewer than 1 in 4 prey encounters led to prey capture. Removing the marginal spikes decreased the rate of prey capture success for moderate-sized cricket prey by 90%, but this effect disappeared for larger prey. The nonlinear benefit of spikes suggests that they provide a better cage for capturing more abundant insects of moderate and small sizes, but may also provide a foothold for rare large prey to escape. Our observations support Darwin’s hypothesis that the marginal spikes form a ‘horrid prison’ that increases prey capture success for moderate-sized prey, but the decreasing benefit for larger prey is unexpected and previously undocumented. Thus, we find surprising complexity in the adaptive landscape for one of the most wonderful evolutionary innovations among all plants. These findings further enrich our understanding of the evolution and diversification of novel trap morphology in carnivorous plants.
Neural plasticity following surgical correction of strabismus in monkeys
Authors: Pullela Mythri , Ağaoğlu Mehmet N. , Joshi Anand C. , Ağaoğlu Sevda , Coats David K. , Das Vallabh E. 
Published: May 2018

AbstractThe preferred treatment for correcting strabismus in humans involves the surgical manipulation of extraocular muscles (EOM). Although widely practiced, this treatment has varying levels of success and permanence, possibly due to adaptive responses within the brain or at the muscle. We investigated neural plasticity following strabismus surgery by recording responses from cells in the oculomotor and abducens nuclei before and after two monkeys with exotropia (divergent strabismus) underwent a strabismus correction surgery that involved weakening of the lateral rectus (LR) and strengthening of the medial rectus (MR) muscle of one eye. Eye movement and neuronal data were collected for a period of 6-10 months after surgery during a monocular viewing smooth-pursuit task. These data were fit with a first-order equation and resulting coefficients were used to estimate the population neuronal drive (ND) to each EOM of the viewing and deviated eyes. Surgery resulted in an~70% reduction in strabismus angle in both animals that reverted towards pre-surgical misalignment by about 6 months after treatment. In the first month after surgery, the ND to the treated MR reduced in one animal and ND to the LR increased in the other animal, both indicating active neural plasticity that reduced the effectiveness of the treatment. Although these neuronal drive changes resolved by 6 months, we also found evidence for an inappropriate peripheral muscle adaptation that limited the effectiveness of surgery over the long term. Outcome of strabismus correction surgery could be improved by identifying ways to enhance ‘positive’ adaptation and limit ‘negative’ adaptation.Significance statementThis is the first study of its kind to longitudinally follow behavioral and neural responses before and after a typical strabismus correction surgery in a monkey model for strabismus. We show the nature of muscle and neuronal plasticity that follows strabismus correction surgery.
MiR-29b-1-5p is altered in BRCA1 mutant tumours and is a biomarker in basal-like breast cancer
Authors: Milevskiy Michael J.G. , Sandhu Gurveen K. , Wronski Anna , Korbie Darren , Brewster Brooke L. , Shewan Annette , Edwards Stacey L. , French Juliet D. , Brown Melissa A. 
Published: May 2018

AbstractDepletion of BRCA1 protein in mouse mammary glands results in defects in lactational development and increased susceptibility to mammary cancer. Extensive work has focussed on the role of BRCA1 in the normal breast and in the development of breast cancer, the cell of origin for BRCA1 tumours and the protein-coding genes altered in BRCA1 deficient cells. However, the role of non-coding RNAs in BRCA1-deficient cells is poorly understood. To evaluate miRNA expression in BRCA1 deficient mammary cells, RNA sequencing was performed on the mammary glands of Brca1 knockout mice. We identified 140 differentially expressed miRNAs, 9 of which were also differentially expressed in human BRCA1 breast tumours or familial non-BRCA1 patients and during normal gland development. We show that BRCA1 binds to putativecis-elements in promoter regions of the miRNAs and regulates their expression, and that four miRNAs (miR-29b-1-5p, miR-664, miR-16-2 and miR-744) significantly stratified the overall survival of basal-like tumours. Importantly the prognostic value of miR-29b-1-5p was higher in significance than several commonly used clinical biomarkers. These results emphasize the role of Brca1 in modulating expression of miRNAs and highlights the potential for BRCA1 regulated miRNAs to be informative biomarkers associated with BRCA1 loss and survival in breast cancer.
Low-bias RNA sequencing of the HIV-2 genome from blood plamsa
Authors: James Katherine L. , de Silva Thushan , Brown Katherine , Whittle Hilton , Taylor Stephen , McVean Gilean , Esbjörnsson Joakim , Rowland-Jones Sarah L. 
Published: May 2018

ABSTRACTAccurate determination of the genetic diversity present in the HIV quasi-species is critical for the development of a preventative vaccine: in particular, little is known about viral genetic diversity for the second strain of HIV, HIV-2. A better understanding of HIV-2 biology is relevant to the HIV vaccine field because a substantial proportion of infected people experience long-term viral control, and prior HIV-2 infection is associated with slower HIV-1 disease progression in co-infected subjects. The majority of traditional and next generation sequencing methods have relied on target amplification prior to sequencing, introducing biases that may obscure the true signals of diversity in the viral population. Additionally, target-enrichment through PCR requiresa priorisequence knowledge, which is lacking for HIV-2. Therefore, a target enrichment free method of library preparation would be valuable for the field. We applied an RNA shotgun sequencing (RNA-Seq) method without PCR amplification to cultured viral stocks and patient plasma samples from HIV-2 infected individuals. Libraries generated from total plasma RNA were analysed with a two-step pipeline: (1)de novogenome assembly, followed by (2) read re-mapping. By this approach, whole genome sequences were generated with a 28x-67x mean depth of coverage. Assembled reads showed a low level of GC-bias and comparison of the genome diversity on the intra-host level showed low diversity in the accessory genevpxin all patients. Our study demonstrates that RNA-Seq is a feasible full-genomede novosequencing method for blood plasma samples collected from HIV-2 infected individuals.IMPORTANCEAn accurate picture of viral genetic diversity is critical for the development of a globally effective HIV vaccine. However, sequencing strategies are often complicated by target enrichment prior to sequencing, introducing biases that can distort variant frequencies, which are not easily corrected for in downstream analyses. Additionally, detaileda priorisequence knowledge is needed to inform robust primer design when employing PCR amplification, a factor that is often lacking when working with tropical diseases localised in developing countries. Previous work has demonstrated that direct RNA shotgun sequencing (RNA-Seq) can be used to circumvent these issues for HCV and Norovirus. We applied shotgun RNA sequencing (RNA-Seq) to total RNA extracted from HIV-2 blood plasma samples, demonstrating the applicability of this technique to HIV-2 and allowing us to generate a dynamic picture of genetic diversity over the whole genome of HIV-2 in the context of low-bias sequencing.
Developing NMR methods for macromolecular machines: Measurement of residual dipolar couplings to probe dynamic regions of the ribosome
Authors: Wang Xiaolin , Kirkpatrick John P. , Launay Hélène M. M. , de Simone Alfonso , Häussinger Daniel , Dobson Christopher M. , Vendruscolo Michele , Cabrita Lisa D. , Waudby Christopher A. , Christodoulou John 
Published: May 2018

ABSTRACTWe describe an NMR approach based on the measurement of residual dipolar couplings (RDCs) to probe the structural and motional properties of the dynamic regions of the ribosome. Alignment of intact 70S ribosomes in filamentous bacteriophage enabled measurement of RDCs in the stalk protein bL12, and this information was used to refine a 3D structure of its C-terminal domain (CTD). Orientational constraints on the CTD alignment arising from the semiflexible linker sequence were further probed by a paramagnetic alignment strategy, and provided direct experimental validation of a structural ensemble previously derived from SAXS and NMR relaxation measurements. Our results demonstrate the prospect of better characterising dynamical and functional regions of more challenging macromolecular machines and systems, for example ribosome–nascent chain complexes.
Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knock-Out Mice
Authors: Das Sharma Sohani , Metz Jordan B. , Li Hongyu , Hobson Benjamin D. , Hornstein Nicholas , Sulzer David , Tang Guomei , Sims Peter A. 
Published: May 2018

SummaryFMRP is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in Fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene-specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we used ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24 day-old Fmr1 knock-out mice. We found a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP, and an increase for terminal oligo-pyrimidine (TOP) motif-containing genes canonically controlled by mTOR-4EBP-eIF4E signaling. Amino acid motif- and gene-level analyses both showed a widespread reduction of translational pausing in Fmr1 knock-out mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in Fragile X syndrome.
Production of spliced long noncoding RNAs specifies regions with increased enhancer activity
Authors: Gil Noa , Ulitsky Igor 
Published: May 2018

AbstractActive enhancers in mammals produce enhancer RNAs (eRNAs), that are bidirectionally transcribed, unspliced, and unstable noncoding RNAs. Enhancer regions are also enriched with long noncoding RNA (lncRNA) genes, which are typically spliced and are longer and substantially more stable than eRNAs. In order to explore the relationship between these two classes of RNAs and the implications of lncRNA transcription on enhancer functionality, we analyzed DNAse hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA producing centers (EPCs). A subset of EPCs, which are found very close to the transcription start site of lncRNA genes, exhibit attributes of both enhancers and promoters, including distinctive DNA motifs and a characteristic landscape of bound proteins. These EPCs are associated with a subset of relatively highly active enhancers. This stronger enhancer activity is driven, at least in part, by the presence of evolutionary conserved, directional splicing signals that promote lncRNA production, pointing at a causal role of lncRNA processing in enhancer activity. Together, our results suggest a model whereby the ability of some enhancers to produce lncRNAs, which is conserved in evolution, enhances their activity in a manner likely mediated through maturation of the associated lncRNA.