A Forward Genetic Screen for Molecules Involved in Pheromone-Induced Dauer Formation in Caenorhabditis elegans

Animals must constantly assess their surroundings and integrate sensory cues to make appropriate behavioral and developmental decisions. Pheromones produced by conspecific individuals provide critical information regarding environmental conditions. Ascaroside pheromone concentration and composition are instructive in the decision of Caenorhabditis elegans to either develop into a reproductive adult or enter into the stress-resistant alternate dauer developmental stage. Pheromones are sensed by a small set of sensory neurons, and integrated with additional environmental cues, to regulate neuroendocrine signaling and dauer formation. To identify molecules required for pheromone-induced dauer formation, we performed an unbiased forward genetic screen and identified phd (pheromone response-defective dauer) mutants. Here, we describe new roles in dauer formation for previously identified neuronal molecules such as the WD40 domain protein QUI-1 and MACO-1 Macoilin, report new roles for nociceptive neurons in modulating pheromone-induced dauer formation, and identify tau tubulin kinases as new genes involved in dauer formation. Thus, phd mutants define loci required for the detection, transmission, or integration of pheromone signals in the regulation of dauer formation. © 2016 Neal et al.1

Impact of Left Atrial Appendage Morphology on Recurrence in Embolic Stroke of Undetermined Source and Atrial Cardiopathy

Background: The left atrial appendage (LAA) is a major source of thrombus and non-chicken wing (CW). LAA morphology is a risk factor for embolic events in atrial fibrillation. However, the association of non-CW morphology with embolic stroke recurrence is unknown in patients with embolic stroke of undetermined source (ESUS) and atrial cardiopathy.Methods: We conducted retrospective analyses using a prospective institutional stroke registry (2013–2017). Patients with ESUS and atrial cardiopathy were enrolled. Atrial cardiopathy was diagnosed if an increased left atrial diameter (>40 mm, men; >38 mm, women), supraventricular tachycardia, or LAA filling defect on computed tomography (CT) were present. Patients admitted >24 h after onset were excluded. LAA morphology was evaluated using CT and categorized into CW vs. non-CW types. The primary outcome was embolic stroke recurrence. Multivariable Cox proportional hazards models were used to examine the independent association between LAA morphology and outcome.Results: Of 157 patients, 81 (51.6%) had CW LAA morphology. The median follow-up was 41.5 (interquartile range 12.3–58.5) months corresponding to 509.8 patient years. In total, 18 participants experienced embolic stroke recurrences (3.80 per 100 patient-years). Non-CW morphology was more associated with embolic stroke recurrence than CW morphology (hazard ratio (HR), 3.17; 95% confidence interval (CI), 1.13–8.91; p = 0.029). After adjusting for CHA2DS2-VASc score and number of potential embolic sources, non-CW morphology showed an independent association with outcome (adjusted HR, 2.90; 95% CI, 1.02–8.23; p = 0.045).Conclusions: The LAA morphology types may help identify high risk of embolic stroke recurrence in ESUS with atrial cardiopathy. LAA morphology in atrial cardiopathy may provide clues for developing therapies tailored to specific mechanisms

Predictive biomarkers for 5-fluorouracil and oxaliplatin-based chemotherapy in gastric cancers via profiling of patient-derived xenografts.

Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies

예쁜꼬마선충의 G 단백질 연결 수용기를 통한 농도 의존적 후각 행동의 전환에 관한 기작 연구

G-단백질 연결 수용기, Chemotaxis, 회피행동, Dimethyl trisulfide, 예쁜꼬마선충Animals detect and discriminate countless environmental chemicals for their wellbeing and survival. Although a single chemical can trigger opposing behavioral responses depending on its concentration, the mechanisms underlying such a concentration-dependent switching remain poorly understood. Here, we show that C. elegans exhibits either attraction or avoidance of the bacteria-derived volatile chemical dimethyl trisulfide (DMTS), depending on its concentration. This behavioral switching is mediated by two different types of chemosensory neurons, both of which express the DMTS-sensitive seven-transmembrane G protein-coupled receptor (GPCR) SRI-14. These two sensory neurons share downstream interneurons that process and translate DMTS signals via distinct glutamate receptors to generate the appropriate behavioral outcome. Thus, our results present one mechanism by which an animal connects two distinct types of chemosensory neurons detecting a common ligand to alternate downstream circuitry, thus efficiently switching between specific behavioral programs based on ligand concentration.|동물들은 그들의 생존과 번식 보존을 위해서 주변환경에서 발생하는 수많은 화학물질들을 감지하고 구별해낸다. 그 중에서 재미있는 현상 중 하나는, 여러 종의 동물들이 동일한 후각물질에 대해 농도를 다르게 감지해 내고 그 농도에 따라 정반대의 행동을 보인다는 점이다. 하지만 이러한 농도 의존적 후각 행동 전환의 분자적 기작에 대해서는 아직 잘 알려지지 않았었다. 이 연구를 통하여 본 연구자는 예쁜꼬마선충이 그들의 먹이와 감염원의 세균 종 들에서 공통으로 분비되는 DMTS라는 황화합물에 대해 그 농도에 따라 좋아하기도 하고 싫어하기도 하는 농도 의존적 후각 행동을 보임을 확인하였다. 또한 이러한 행동의 전환은 SRI-14 G 단백질 연결 수용기를 발현하고 있는 다른 두종류의 AWC 와 ASH 감각뉴런들에 의해서 매게 된다는 것을 확인하였다. 본 연구자의 돌연변이 실험에 의하면 두 감각뉴런 중 AWC 후각 뉴런이 없는 선충의 경우 낮은 농도의 DMTS에 대한 선호반응이 사라졌으며, ASH 통각 뉴런이 없는 선충의 경우 높은 농도의 DMTS에 대한 회피반응을 보이지 않는 것을 확인하였다. AWC와 ASH뉴런은 공통적으로 SRI-14 G 단백질 연결 수용기를 발현하고 있기 때문에 이 SRI-14 단백질이 DMTS를 감지한다는 가설을 세우게 되었고 SRI-14의 돌연변이에서 DMTS에 대한 선호반응과 회피반응이 모두 사라지는 것을 확인하였다. SRI-14 돌연변이들에게 SRI-14유전자를 AWC뉴런에 특정하게 재 발현시켜 주었을 경우 저농도의 DMTS에 대한 선호반응이 회복되었으나 고농도에 대한 회피반응은 회복되지 않았다. 반대로 ASH 통각 뉴런에 SRI-14 유전자를 재 발현시켜 주었을 경우 고농도 DMTS에 대한 회피반응은 돌아왔으나 저농도에 대한 선호반응은 돌아오지 않았다. 따라서 본 연구자는 AWC 후각 뉴런에 발현하는 SRI-14 수용기가 낮은 농도에 대한 DMTS 선호반응을 매개하고 ASH 통각 뉴런에 발현하는 SRI-14 수용기는 DMTS에 대한 회피반응을 매개한다는 것을 확인하였다. 다음으로 1) SRI-14가 본래는 발현하지 않는 ADL 감각뉴런에 SRI-14를 발현시킨 형질전환 동물들은 ADL 뉴런의 칼슘이미징에서 DMTS에 대한 비정상적인 Ca2+ 반응이 생성된다는 점에서, 2) 또한 인간세포에 SRI-14 수용기를 발현시켰을 때 이 세포는 DMTS 노출에 따라 반응을 나타냄을 확인함으로써, SRI-14가 실제로 DMTS에 결합하는 수용기임을 증명했다. 다음으로, 본 연구자는 선충이 이러한 농도 의존적 행동 전환을 보이기 위해 ASH 와 AWC 하위의 인터뉴런이 DMTS 신호를 어떻게 번역하고 처리하는지를 조사했다. 본 연구자는 AWC와 ASH 뉴런에서 신호를 수신하는 AIB interneuron이 DMTS의 농도에 따라 뚜렷한 Ca2+ 반응을 보인다는 것을 발견했다. 또한, AIB interneuron을 없앴을 경우 DMTS에 대한 선호와 회피반응이 약해짐을 확인하였다. 선행 연구에 의하여 AWC와 ASH뉴런은 글루타메이트를 통하여 하위 뉴런에 신호를 보낸다는 것이 알려져 있었다. 따라서 DMTS에 대한 신호들도 글루타메이트를 통해 전달될 것이라 가설을 세웠고 글루타메이트의 수송 단백질의 돌연변이 동물들의 경우 DMTS에 대한 선호반응과 회피반응이 약해지는 것을 확인하였다. 다음으로 AIB 인터뉴런이 어떠한 수용기를 통해서 AWC와 ASH로부터 오는 DMTS 정보를 받아들이는지 알아보았다.YI. INTRODUCTION 1 1.1 Chemosensory systems in C. elegans 1 1.2 AWC olfactory neurons 2 1.3 ASH nociceptive neurons 3 1.4 Concentration dependent odor preferences in animals 4 1.5 Concentration dependent odor preferences in C. elegans 4 1.6 The across-fiber pattern Theories 5 1.7 The labeled-line theory 6 1.8 Overall introduction 14 II. MATERIALS AND METHODS 17 III. RESULTS 27 3.1 C. elegans is attracted to bacteria-derived sulfur odors 27 3.2 C. elegans avoids high concentration DMTS 34 3.3 The chemosensory GPCR SRI-14 is required for concentration-dependent DMTS response 40 3.4 The AWC and ASH neurons respond differently to DMTS via SRI-14 50 3.5 The AIB interneurons process DMTS signals from AWC and ASH 60 3.6 Distinct glutamate receptors mediate concentration-dependent behavioral switching upon DMTS exposure 67 3.7 SRI-14 GPCR is a chemosensory receptor for DMTS 71 IV. DISCUSSIONS 79 V. REFERENCES 84 VI. SUMMARY IN Koreans 97DoctordCollectio

The complete chloroplast genome of Scapania ampliata Steph., 1897 (Scapaniaceae, Jungermanniales)

We completed chloroplast genome of Scapania ampliata Steph., presenting distinct morphological features including yellowish brown, one-celled gemmae, and decurrent dorsal lobe. It is 118,026 bp long and has four subregions: 80,850 bp of large single copy (LSC) and 19,436 bp of small single copy (SSC) regions are separated by 8,870 bp of inverted repeat (IR) regions including 130 genes (86 protein-coding genes, 8 ribosomal RNAs, and 36 transfer RNAs). The overall guanine cytosine (GC) content is 34.0% and those in the LSC, SSC, and IR regions are 31.9%, 31.0%, and 46.3%, respectively. Phylogenetic trees show S. ampliata is clustered with Scapania ciliata

The complete chloroplast genome of Wiesnerella denudata (Mitt.) Steph. (Wiesnerellaceae, Marchantiophyta)

We completed chloroplast genome of Wiesnerella denudata (Mitt.) Steph, only one species of the monotypic Wiesnerella genus and family Wiesnerellaceae Inoue. It is 122,500 bp and has four subregions: 82,143 bp of large single copy (LSC) and 20,009 bp of small single copy (SSC) regions are separated by 10,174 bp of inverted repeat (IR) regions including 132 genes (88 protein-coding genes, eight rRNAs, and 36 tRNAs). The overall GC content is 28.8% and those in the LSC, SSC, and IR regions are 26.4, 24.6, and 42.8%, respectively. Phylogenetic trees show incongruencies of phylogenetic relationship of W. denudata, requiring additional research

Long-Term Outcomes of Local Tirofiban Infusion for Intracranial Atherosclerosis-Related Occlusion

Local tirofiban infusion has been reported as a rescue strategy for intracranial atherosclerotic stenosis (ICAS)-related stroke. However, the long-term outcomes of local tirofiban infusion during endovascular reperfusion therapy (ERT) for ICAS-related stroke are still uncertain. This study aimed to investigate the long-term outcomes of local tirofiban infusion during ERT. We retrospectively analyzed acute patients with ICAS-related stroke who were treated with local tirofiban as a rescue strategy during ERT. The primary outcomes were ischemic stroke, transient ischemic stroke (TIA), and stroke-related death within 30 days. Secondary outcomes included ischemic stroke and TIA beyond 30 days and up to 2 years after ERT in the corresponding treated vessel, symptomatic brain hemorrhage, any stroke, and non-stroke-related death. During a median follow-up of 24.0 months, 12 patients developed an ischemic stroke and TIA (4 within 30 days and 8 afterward). The 1-year risk of stroke and TIA was 9.2% (95% confidence interval, 8.0–18.6%). This study demonstrates that 1-year outcomes of local tirofiban infusion were comparable to the results of intracranial stenting in patients with symptomatic ICAS. Local tirofiban infusion for ICAS-related stroke may be a feasible rescue strategy that can have a bridging role until the maximum effect of antiplatelet agents is achieved

The complete mitochondrial genome of Wiesnerella denudata (Mitt.) Steph. (Wiesnerellaceae, Marchantiophyta): large number of intraspecific variations on mitochondrial genomes of W. denudata

Wiesnerella denudata (Mitt.) Steph. is a thallose liverwort distributed in Asian subtropical to tropical regions. It is the only one species in genus Wiesnerella and family Wiesnerellaceae. To investigate intraspecific variations on mitochondrial genomes of W. denudata, we completed mitochondrial genome of W. denudata. Its length is 185,640 bp, longer than that of the previously sequenced mitochondrial genome by 71 bp and contains 73 genes (41 protein-coding genes, 3 rRNAs, 28 tRNAs, and 1 pseudogene). A total of 149 single nucleotide polymorphisms (SNPs) and 3,033 insertions and deletions are identified, much higher than those of Marchantia polymorpha subsp. ruderalis and Riccia fluitans. Phylogenetic trees show that W. denudata is clustered with Monosolenium tenerum belonging to Monosoleniaceae

The complete mitochondrial genome of Scapania ampliata Steph., 1897 (Scapaniaceae, Jungermanniales)

Scapania ampliata Steph. is the endemic species in East Asia. To investigate intraspecific variations on mitochondrial genomes of S. ampliata, we completed mitochondrial genome of S. ampliata isolated in Korea. It is 143,664 bp long and contains 73 genes (41 protein-coding genes, three rRNAs, 28 tRNAs, and one pseudogene). 823 single nucleotide polymorphisms (SNPs; 0.057%) and 2,242 insertions and deletions were identified between two S. ampliata mitochondrial genomes, which is large number of intraspecific variations in comparison to the other cases of Bryophyte mitochondrial genomes. Phylogenetic trees show that S. ampliata is clustered with those of two Scapania species with high supportive values