bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-World Adherence to Guideline-Recommended Treatment for Small Cell Lung Cancer
Authors: Elegbede Anifat A. , Gibson Amanda J. , Fu Hao , Dean Michelle L. , Ezeife Doreen A. , Lau Harold , Cheung Winson Y. , Bebb Dafydd G.
Published: December 2019

Objectives:

The authors sought to quantify the treatment patterns and outcomes for limited-stage (LS) and extensive-stage (ES) small cell lung cancer (SCLC) in a real-world setting.

Methods:

A review was conducted using the Glans-Look Research Database of patients with SCLC managed at a tertiary cancer center in Canada from 2010 to 2016. Adherence was defined as the commencement of planned SCLC treatment. Rate of compliance with the Alberta Health Services, American Society of Clinical Oncology, and National Comprehensive Cancer Network SCLC treatment guidelines was evaluated. Outcomes were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.

Results:

A total of 404 patients met our inclusion criteria, 31% were LS. The median age at first treatment receipt was 67 years. LS treatment consisted mostly of chemoradiation (62%). Chemoradiation and surgery±adjuvant predicted better survival (median, 32 and 40 mo, respectively) compared with no treatment. ES treatment consisted mostly of chemotherapy (90%). Chemotherapy and thoracic radiotherapy correlated with longer overall survival (13 vs. 9 mo, respectively) compared with chemotherapy alone. Prophylactic cranial irradiation receipt in LS (50%) and ES (20%) predicted favorable survivals than none (LS: hazard ratio, 0.48; 95% CI, 0.29-0.79; ES: hazard ratio, 0.48; 95% CI, 0.33-0.70). Approximately a quarter of relapsed LS and ES had second-line chemotherapy; improved survival with second line was observed only in ES (P<0.01).

Conclusions:

This study highlights high rates of guideline-recommended first treatment among the real-world LS and ES patients but it also revealed important outcome differences in relapsed LS and ES patients treated with second-line chemotherapy.
Evaluation of Skyshine from an Accelerator Facility: Dependence on Distance and Angle
Authors: Liang Taiee Ted , Liu James C. , Rokni Sayed H.
Published: December 2019

Neutron skyshine from Linac Coherent Light Source II 4 GeV electron beam operation at SLAC National Accelerator Laboratory can contribute to prompt radiation exposure to the public at distances far beyond the accelerator tunnel housing. One of the shielding design requirements at SLAC is that the annual dose to a member of the public is no more than 0.05 mSv y−1. This study uses Monte Carlo code FLUKA to simulate the generation of neutrons from 4 GeV electron beam losses on a thick copper target inside a generalized geometry of the Linac Coherent Light Source II Beam Transport Hall accelerator tunnel section. The effective dose from neutron skyshine was characterized as a function of both distance from the tunnel wall (up to 1 km away) and angle relative to the beam direction (between 0° and 180°). This new methodology for evaluating neutron skyshine dose is applicable to high-energy GeV-range electron accelerator facilities both at SLAC and elsewhere.
Long-Term Outcomes of Descemet Membrane Endothelial Keratoplasty in Postvitrectomized Eyes With the Use of Pars Plana Infusion
Authors: Mednick Zale , Sorkin Nir , Einan-Lifshitz Adi , Santaella Gisella , Trinh Tanya , Chan Clara C. , Rootman David S.
Published: December 2019

Purpose:

To evaluate the use of pars plana infusion as part of Descemet membrane endothelial keratoplasty (DMEK) in eyes of patients who underwent vitrectomy.

Methods:

A retrospective chart review was conducted of patients at Toronto Western Hospital (Toronto, Canada) who had undergone DMEK with pars plana infusion, with a minimum follow-up of at least 12 months. Collected data included postoperative best-corrected visual acuity (BCVA), intraoperative complications, and postoperative complications such as graft detachment, rejection and failure, and rate of endothelial cell loss.

Results:

Fifteen eyes of 14 patients were included in this study. The mean follow-up time was 23.9 ± 5.7 months. Four grafts required rebubbling within the first month of surgery, and one graft required repeat DMEK right away. Two grafts failed secondarily at 24 months, and there was one episode of graft rejection. Five eyes had retinal complications including retinal detachment, retinoschisis, and cystoid macular edema. BCVA improved significantly from 1.7 ± 0.77 logarthim of the minimum angle of resolution (LogMAR) (mean Snellen 20/1000) preoperatively when compared with postoperative BCVA at 6 months (0.95 ± 0.74 LogMar, mean Snellen 20/180, P = 0.02, n = 10), 12 months (0.93 ± 0.6,P = 0.01, mean Snellen 20/170, n = 11), and 24 months (1.01 ± 0.68, mean Snellen 20/200 P = 0.046, n = 7).

Conclusions:

Although pars plana infusion is a helpful technique for DMEK in vitrectomized eyes, such cases are still quite difficult to perform compared with standard DMEK and use of an infusion may increase the risk of retinal complications. Descemet Stripping Automated Endothelial Keratoplasty may be the preferred technique in these challenging vitrectomized eyes.
Postoperative Symptoms and Quality of Life in Pituitary Macroadenomas Patients
Authors: Jang Min Kyeong , Oh Eui Geum , Lee HyangKyu , Kim Eui Hyun , Kim Sanghee
Published: December 2019

BACKGROUND

Patients with pituitary macroadenoma commonly experience symptoms such as headache, visual disturbance, and olfactory dysfunction due to tumor effects. Even after undergoing surgery for tumor removal, patients continue to experience these symptoms and have difficulty resuming their general activities, decreasing their quality of life (QOL). Although some studies have focused on QOL in pituitary macroadenoma, few studies have examined the relationship between postoperative symptoms and patient QOL in the period after surgery. This study aimed to identify the relationships between postoperative symptoms and QOL among pituitary macroadenoma patients.

METHODS

This study used a descriptive cross-sectional design to identify relationships between postoperative symptoms and QOL in pituitary macroadenoma patients. Medical records of 62 patients with pituitary macroadenomas who had undergone surgery were retrieved and reviewed 3 months after surgery; at that time, all participants completed a self-report survey addressing their current symptoms and QOL. The researchers then evaluated patient QOL and 3 common symptoms—headache, objectively measured visual disturbance, and olfactory dysfunction—using correlation analysis and multiple linear regression.

RESULTS

Three months after surgery, patients still experienced headache and lack of olfactory function. Headache showed a strong negative correlation with physical (r = −0.501, P < .001, R
2 = 36%) and mental (r = −0.448, P < .001, R
2 = 26%) QOL. Headache was a significant factor influencing QOL.

CONCLUSION

Study findings show that continuous assessment and intervention for headache are essential for improving QOL in pituitary macroadenoma patients after surgery. Nurses should prioritize assessment and management of postoperative headache in long-term care for such patients. The study findings support development of a clinical guideline for managing headache in such patients and thus improving their QOL.
Using Esophageal Temperature Management to Treat Severe Heat Stroke: A Case Report
Authors: Martin Katherine Riley , Naiman Melissa , Espinoza Maurice
Published: December 2019

BACKGROUND: Exertional heat stroke (EHS) is defined by a core body temperature that exceeds 40°C with associated central nervous system dysfunction, skeletal muscle injury, and multiple organ damage. The most important initial focus of treatment involves reduction of patient temperature. First approaches to achieve temperature reduction often include ice packs, water blankets, and cold intravenous fluid administration. When these measures fail, more advanced temperature management methods may be deployed but often require surgical expertise. Esophageal temperature management (ETM) has recently emerged as a new temperature management modality in which an esophageal heat transfer device replaces the standard orogastric tube routinely placed after endotracheal intubation and adds a temperature modulation capability. The objective of this case study is to report the first known use of ETM driven by bedside nursing staff in the treatment of EHS. METHOD: An ETM device was placed after endotracheal intubation in a 28-year-old man experiencing EHS over a 5-day course of treatment. RESULTS: Because the ETM device was left in place, when the patient experienced episodes of increasing temperature as high as 39.1°C, which required active cooling, nursing staff were able to immediately adjust the external heat exchange unit settings to achieve aggressive cooling at bedside. CONCLUSION: This nurse-driven technology offers a new means to rapidly deploy cooling to critically ill patients without needing to implement advanced surgical approaches or obstruct access to the patient, freeing the provider to continue optimal care in high-morbidity conditions.
A Multimodality Approach to Learning
Authors: Mason Heidi , Burgermeister Diane , Harden Karen , Price Deborah , Roth Roxanne
Published: December 2019

Palliative care education at the undergraduate and graduate level is necessary to improve the competency and confidence of nurses and ultimately improve the care of patients with a chronic illness. Unfortunately, the curriculum in nursing education programs lacks palliative care content, resulting in a lack of preparation and confidence among nursing students. The purpose of this study is to examine the effect of educating nursing students utilizing an interactive, multimodality palliative care class that focuses on palliative and end-of-life care. The Palliative Care Quiz for Nurses and Frommelt Attitude Toward Care of the Dying survey were used to assess nursing students before and after a newly developed palliative care class. A Wilcoxon matched-pairs signed rank test was used to determine a difference in pre and post scores. Results revealed a significant improvement in knowledge, attitude, and comfort with palliative and end-of-life care.
Unilateral Condylar Hyperplasia: A Comparison With Two Open-Source Softwares
Authors: Vellone Valentino , Costantini Ambra Maria , Ramieri Valerio , Alunni Fegatelli Danilo , Galluccio Gabriella , Cascone Piero
Published: December 2019

Unilateral condylar hyperplasia (UCH) is a condyle disorder that arises due to osteoblastic hyperactivity, resulting in facial asymmetry, malocclusion and dysfunction. Authors, in this retrospective study, compared “gold standard” manual-segmentation with a “semi-manual one” using 2 kinds of open-source software (Horos and ITK-SNAP; Penn Image Computing and Science Laboratory) to calculate volume of 80 UCH condyles (40 patients). Moreover, volumetric differences between affected condyle and unaffected 1, between males and females, ages, and classification type were also analyzed. Fifteen patients (37.5%) were male and 25 (62.5%) were female. The gender ratio was 5:2, not far from the ratio 2:1 shown in literature. The mean age was 24 (SD 8.6) years; 22.9 (SD 6.6) for males and 24.6 (SD 9.6) for females according with the mean age derived from the Raijmakers et al meta-analysis and the Nitzan et al study. Right side (60%, 24 patients) was more often affected than the left side (40%, 16 patients). The 67.5% (27 patients) were classified as trasversal type, 25% (10 patients) as vertical types and 7.5% (3 patients) as combined. Despite Horos and ITK-SNAP values presenting some differences, the data follows the same tendency. The relationship is stronger for healthy condyles than affected condyles.
The Effect of Concentrated Growth Factor on Calvarial Bone in Diabetic Healing
Authors: Kizilaslan Sema , Karabuda Zihni Cüneyt , Olgac Vakur
Published: December 2019

The aim of this study was to evaluate the effect of Concentrated Growth Factor (CGF) on bone healing in diabetic rat model. Experimental diabetes was induced in 24 male Sprague–Dawley rats by streptozotocin. Twenty-four animals served as healthy controls. The animals were divided into 4 subgroups; empty bone defect, grafting with xenogenous graft (Geno-os, OsteoBiol, Turin-Italy), CGF administration, and combined application of the CGF with the xenogenous graft in critical-sized defects in the calvaria of the rats. The diabetic group was given 4 units of Neutral Protamin Hagedorn per day. After 6 weeks, all animals were sacrificed and bone healing was histologically and histomorphometrically analyzed, and the evaluation revealed that the new bone formation in diabetic animals was significantly lower than in healthy group (P: 0.001, P: 0.023). In both groups, the highest rate of ossification was observed in the combined use of xenogenous graft and CGF. When the new bone formation was examined in the graft and CGF group, no significant difference was found between control and diabetic group (P = 0.562; P > 0.05). In conclusion, in patients with diabetes mellitus, combination therapy of CGF with graft is expected to contribute positively to the healing of bone defect.
One-year Outcome of Everolimus With Standard-dose Tacrolimus Immunosuppression in De Novo ABO-incompatible Living Donor Kidney Transplantation: A Retrospective, Single-center, Propensity Score Matching Comparison With Mycophenolate in 42 Transplants
Authors: Noguchi Hiroshi , Tsuchimoto Akihiro , Ueki Kenji , Kaku Keizo , Okabe Yasuhiro , Nakamura Masafumi
Published: December 2019

Background.

Despite improvement in immunosuppressive therapy, long-term kidney allograft survival remains a major challenge. The outcomes of therapy with everolimus (EVR) and standard-dose tacrolimus (Tac) have not been compared with those of mycophenolate mofetil (MMF) and standard-dose Tac in recipients of de novo ABO-incompatible (ABOi) living donor kidney transplantation (LDKT).

Methods.

This retrospective, observational, single-center, propensity score matching (PSM) study compared the outcomes of EVR and standard-dose Tac with those of MMF and standard-dose Tac following de novo ABOi LDKT. In total, 153 recipients of ABOi LDKT between January 2008 and March 2018 were screened for inclusion in the study. The variables considered for PSM were: recipient age/sex, duration of dialysis, cytomegalovirus mismatch (seronegative recipient and seropositive donor), cause of kidney disease, donor age/sex, and numbers of mismatches (HLA-A, HLA-B, and HLA-DR). After PSM, there were 21 patients in each group (n = 42 overall).

Results.

Four patients in the EVR group and 1 patient in the MMF group were withdrawn because of adverse effects. There were no significant differences between the 2 groups in 1-year outcomes regarding patient death, graft loss, delayed graft function, biopsy-proven acute rejection, infection requiring hospital admission, or estimated glomerular filtration rate. The 1-year protocol biopsy showed that the severity of interstitial fibrosis/tubular atrophy was significantly milder in the EVR group than in the MMF group.

Conclusions.

The findings suggest that the renal efficacy and safety of EVR and standard-dose Tac in recipients of de novo ABOi LDKT are comparable with those of MMF and standard-dose Tac.
Neural basis of basic composition: what we have learned from the red–boat studies and their extensions
Authors: Pylkkänen Liina
Published: December 2019

Language is our mind's most powerful generative system for the expression of meaning and thought. What are the neural mechanisms of our ability to compose complex meanings from simpler representations? This question is impossible to answer unless we decompose the notion of ‘meaning composition’ in some theoretically guided way and then begin to assess the extent to which brain activity tracks the posited subroutines. Here, I summarize results from a body of MEG research that has begun to address this question from the ground up, first focusing on simple combinations of two words. The work sets off with a hypothesis space offered by theoretical linguistics, positing syntactic and logico-semantic composition as the main combinatory routines, but then reveals that the most consistent and prominent reflection of composition, localized in the left anterior temporal cortex at 200–250 ms, cannot be described with this toolkit. Instead, this activity tracks a much more conceptually driven process, robustly sensitive to the density of the conceptual feature space of the composing items. I will describe our functional understanding of this activity and how it may operate within a broader ‘combinatory network.’

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
The acquisition of compositional meaning
Authors: Hendriks Petra
Published: December 2019

How do people create meaning from a string of sounds or pattern of dots? Insights into this process can be obtained from the way children acquire sentence meanings. According to the well-known principle of compositionality, the meaning of an expression is a function of the meanings of its parts and the way they are syntactically combined. However, children frequently seem to ignore syntactic structure in their sentence interpretations, suggesting that syntax is merely one of the sources of information constraining meaning and does not have a special status. A fundamental assumption in the argument in favour of compositionality is that speakers and listeners generally agree upon the meanings of sentences. Remarkably, however, children as listeners do not always understand what they are able to produce as speakers, and vice versa. For example, children's production of word order appears to develop ahead of their comprehension of word order in the acquisition of languages like English and Dutch. Such production–comprehension asymmetries are not uncommon in child language and motivate a view of compositionality as a principle pertaining to the result of perspective taking, and of meaning composition as a process of speaker–listener coordination.

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
Altered cortical gyrification in adults who were born very preterm and its associations with cognition and mental health
Authors: Papini Chiara , Palaniyappan Lena , Kroll Jasmin , Froudist-Walsh Sean , Murray Robin M , Nosarti Chiara
Published: December 2019

Background

The last trimester of pregnancy is a critical period for the establishment of cortical gyrification and altered folding patterns have been reported following very preterm birth (< 33 weeks of gestation) in childhood and adolescence. However, research is scant on the persistence of such alterations in adulthood and their associations with cognitive and psychiatric outcomes.

Methods

We studied 79 very-preterm adults and 81 age-matched full-term controls. T1-weighted images were used to measure local gyrification index (LGI), indicating the degree of folding across multiple vertices of the reconstructed cortical surface. Group and group-sex LGI differences were assessed using per-vertex adjustment for cortical thickness and overall intracranial volume. Within-group correlations were also computed between LGI and functional outcomes, including general intelligence (IQ) and psychopathology.

Results

Very preterm adults had significantly reduced LGI in extensive cortical regions encompassing the frontal, anterior temporal and occipito-parietal lobes. Alterations in lateral fronto-temporal-parietal and medial occipito-parietal regions were present in both males and females, although males reported more extensive alterations. In both very preterm adults and controls, higher LGI was associated with higher IQ and lower psychopathology scores, with the spatial distribution of these associations substantially differing between the two groups.

Conclusions

Very preterm adults’ brains are characterized by significant and widespread local hypogyria and these abnormalities might be implicated in cognitive and psychiatric outcomes. Gyrification reflects an early developmental process and provides a fingerprint for very preterm birth.
Global drivers of diversification in a marine species complex
Authors: Silva Catarina N.S. , Murphy Nicholas P. , Bell James J. , Green Bridget S. , Duhamel Guy , Cockcroft Andrew C. , Hernández Cristián E. , Strugnell Jan M.
Published: December 2019

Investigating historical gene flow in species complexes can indicate how environmental and reproductive barriers shape genome divergence before speciation. The processes influencing species diversification under environmental change remain one of the central focal points of evolutionary biology, particularly for marine organisms with high dispersal potential. We investigated genome-wide divergence, introgression patterns and inferred demographic history between species pairs of all extant rock lobster species (Jasusspp.), a complex with long larval duration, that has populated continental shelf and seamount habitats around the globe at approximately 40°S. Genetic differentiation patterns revealed the effects of the environment and geographic isolation. Species associated with the same habitat structure (either continental shelf or seamount/island) shared a common ancestry, even though the habitats were not adjacent. Differences in benthic temperature explained a significant proportion (41.3%) of the genetic differentiation. The Eastern Pacific species pair ofJ. caveorumandJ. frontalisretained a signal of strict isolation following ancient migration, whereas species pairs from Australia and Africa and seamounts in the Indian and Atlantic oceans included events of introgression after secondary contact. Parameters estimated for time in isolation and gene flow were congruent with genetic differentiation metrics suggesting that the observed differentiation patterns are the product of migration and genetic drift. Our results reveal important effects of habitat and demographic processes on the divergence of species within the genusJasusproviding the first empirical study of genome-wide drivers of diversification that incorporates all extant species in a marine genus with long pelagic larval duration.
Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex
Authors: Watanabe Hidenori , Sano Hiromi , Chiken Satomi , Kobayashi Kenta , Fukata Yuko , Fukata Masaki , Mushiake Hajime , Nambu Atsushi
Published: December 2019

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generated an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and injected into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 was strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induced prominent cortical activity: Even single-pulse, short duration oICMS evoked long-lasting repetitive firings of cortical neurons. In addition, oICMS elicited distinct forelimb movements and muscle activity, which were comparable to those elicited by conventional electrical ICMS. The present study removed obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.
Two distinct mechanisms of small molecule inhibition of LpxA acyltransferase essential for lipopolysaccharide biosynthesis
Authors: Han Wooseok , Ma Xiaolei , Balibar Carl J , Baxter Rath Christopher M , Benton Bret , Bermingham Alun , Casey Fergal , Chi-Leon Barbara , Cho Min-Kyu , Frank Andreas O , Frommlet Alexandra , Ho Chi-Min , Lee Patrick S , Li Min , Lingel Andreas , Ma Sylvia , Merritt Hanne , Ornelas Elizabeth , de Pascale Gianfranco , Prathapam Ramadevi , Prosen Katherine R , Rasper Dita , Ruzin Alexey , Sawyer William , Shaul Jacob , Shen Xiaoyu , Shia Steven , Steffek Micah , Subramanian Sharadha , Vo Jason , Wang Feng , Wartchow Charles , Uehara Tsuyoshi
Published: December 2019

The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multidrug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA and compound 2 is an uncompetitive inhibitor targeting the LpxA-product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1, and was optimized using structural information to achieve improved antibacterial activity against wild type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme-product complexes in drug discovery.
Molecular layer interneurons in the cerebellum encode for valence in associative learning
Authors: Ma Ming , Futia Gregory L. , De Souza Fabio M. Simoes , Ozbay Baris N. , Llano Isabel , Gibson Emily A. , Restrepo Diego
Published: December 2019

We used two-photon microscopy to study the role of ensembles of cerebellar molecular layer interneurons (MLIs) in a go-no go task where mice obtain a sugar water reward if they lick a spout in the presence of the rewarded odorant and avoid a time out when they refrain from licking for the unrewarded odorant. In naïve animals the MLI responses did not differ between the odorants. With learning, the rewarded odorant elicited a large increase in MLI calcium responses, and the identity of the odorant could be decoded from the differential response. Importantly, MLIs switched odorant responses when the valence of the stimuli was reversed. Finally, mice took a longer time to refrain from licking in the presence of the unrewarded odorant and had difficulty becoming proficient when MLIs were inhibited by chemogenetic intervention. Our findings support a role for MLIs in learning valence in the cerebellum.
Growth rate alterations of human colorectal cancer cells by 157 gut bacteria
Authors: Taddese Rahwa , Garza Daniel R. , Ruiter Lilian N. , de Jonge Marien I. , Belzer Clara , Aalvink Steven , Nagtegaal Iris D. , Dutilh Bas E. , Boleij Annemarie
Published: December 2019

Several bacteria in the human gut microbiome have been associated with colorectal cancer (CRC) by high-throughput screens. In some cases, molecular mechanisms have been elucidated that drive tumorigenesis, including bacterial membrane proteins or secreted molecules that interact with the human cancer cells. For most gut bacteria, however, it remains unknown if they enhance or inhibit cancer cell growth. Here, we screened bacteria-free supernatants (secretomes) and inactivated cells of over 150 cultured bacterial strains for their effect on CRC cell growth. We observed family-level and strain-level effects that often differed between bacterial cells and secretomes, suggesting that different molecular mechanisms are at play. Secretomes ofBacteroidaceae,Enterobacteriaceae,andErysipelotrichaceaebacteria enhanced CRC cell growth, while mostFusobacteriaceaecells and secretomes inhibited growth, contrasting prior findings. In some bacteria, the presence of specific functional genes was associated with CRC cell growth rates, including the virulence genes TcdA inClostridialesand FadA inFusobacteriaceae, which both inhibited growth.Bacteroidaceaecells that enhanced growth were enriched for genes of the cobalamin synthesis pathway, whileFusobacteriaceaecells that inhibit growth were enriched for genes of the ethanolamine utilization pathway. Together, our results reveal how different gut bacteria have wide-ranging effects on cancer cells, contribute a better understanding of the effects of the gut microbiome on the human host, and provide a valuable resource for identifying candidate target genes for potential microbiome-based diagnostics and treatment strategies.
Distinct transcriptomic cell types and neural circuits of the subiculum and prosubiculum along the dorsal-ventral axis
Authors: Ding Song-Lin , Yao Zizhen , Hirokawa Karla E. , Nguyen Thuc Nghi , Graybuck Lucas T. , Fong Olivia , Bohn Phillip , Ngo Kiet , Smith Kimberly A. , Koch Christof , Phillips John W. , Lein Ed S. , Harris Julie A. , Tasic Bosiljka , Zeng Hongkui
Published: December 2019

Subicular region plays important roles in spatial processing and many cognitive functions and these were mainly attributed to subiculum (Sub) rather than prosubiculum (PS). Using single-cell RNA-sequencing (scRNA-seq) technique we have identified up to 27 distinct transcriptomic clusters/cell types, which were registered to anatomical sub-domains in Sub and PS. Based on reliable molecular markers derived from transcriptomic clustering and in situ hybridization data, the precise boundaries of Sub and PS have been consistently defined along the dorsoventral (DV) axis. Using these borders to evaluate Cre-line specificity and tracer injections, we have found bona fide Sub projections topographically to structures important for spatial processing and navigation. In contrast, PS along DV axis sends its outputs to widespread brain regions crucial for motivation, emotion, reward, stress, anxiety and fear. Brain-wide cell-type specific projections of Sub and PS have also been revealed using specific Cre-lines. These results reveal two molecularly and anatomically distinct circuits centered in Sub and PS, respectively, providing a consistent explanation to historical data and a clearer foundation for future functional studies.

Highlights

27 transcriptomic cell types identified in and spatially registered to “subicular” regions.

Anatomic borders of “subicular” regions reliably determined along dorsal-ventral axis.

Distinct cell types and circuits of full-length subiculum (Sub) and prosubiculum (PS).

Brain-wide cell-type specific projections of Sub and PS revealed with specific Cre-lines.

In Brief

Ding et al. show that mouse subiculum and prosubiculum are two distinct regions with differential transcriptomic cell types, subtypes, neural circuits and functional correlation. The former has obvious topographic projections to its main targets while the latter exhibits widespread projections to many subcortical regions associated with reward, emotion, stress and motivation.
Separating overlapping bat calls with a bi-directional long short-term memory network
Authors: Zhang Kangkang , Liu Tong , Song Shengjing , Zhao Xin , Sun Shijun , Metzner Walter , Feng Jiang , Liu Ying
Published: December 2019

Acquiring clear and usable audio recordings is critical for acoustic analysis of animal vocalizations. Bioacoustics studies commonly face the problem of overlapping signals, but the issue is often ignored, as there is currently no satisfactory solution. This study presents a bi-directional long short-term memory (BLSTM) network to separate overlapping bat calls and reconstruct waveform audio sounds. The separation quality was evaluated using seven temporal-spectrum parameters. The applicability of this method for bat calls was assessed using six different species. In addition, clustering analysis was conducted with separated echolocation calls from each population. Results showed that all syllables in the overlapping calls were separated with high robustness across species. A comparison between the seven temporal-spectrum parameters showed no significant difference and negligible deviation between the extracted and original calls, indicating high separation quality. Clustering analysis of the separated echolocation calls also produced an accuracy of 93.8%, suggesting the reconstructed waveform sounds could be reliably used. These results suggest the proposed technique is a convenient and automated approach for separating overlapping calls using a BLSTM network. This powerful deep neural network approach has the potential to solve complex problems in bioacoustics.

Author summary

In recent years, the development of recording techniques and devices in animal acoustic experiment and population monitoring has led to a sharp increase in the volume of sound data. However, the collected sound would be overlapped because of the existence of multiple individuals, which laid restrictions on taking full advantage of experiment data. Besides, more convenient and automatic methods are needed to cope with the large datasets in animal acoustics. The echolocation calls and communication calls of bats are variable and often overlapped with each other both in the recordings from field and laboratory, which provides an excellent template for research on animal sound separation. Here, we firstly solved the problem of overlapping calls in bats successfully based on deep neural network. We built a network to separate the overlapping calls of six bat species. All the syllables in overlapping calls were separated and we found no significant difference between the separated syllables with non-overlapping syllables. We also demonstrated an instance of applying our method on species classification. Our study provides a useful and efficient model for sound data processing in acoustic research and the proposed method has the potential to be generalized to other animal species.
The 9aaTAD activation domains in the four Yamanaka Oct4, Sox2, Myc, and Klf4 transcription factors essential during the stem cell development
Authors: Piskacek Martin , Jendruchova Kristina , Rezacova Martina , Havelka Marek , Gasparik Norbert , Hofrova Alena , Knight Andrea
Published: December 2019

Somatic cells can be reprogrammed by the Yamanaka factors Oct4, Sox2, Myc and Klf4 activators into induced pluripotent stem cells. Throughout their genome, the Oct4, Sox2 and Klf4 cooperate with mediators of transcription, where the DNA binding sites serve as scaffolds for the phase-separated transcriptional condensates at distinct genome loci. In this study, we identified the 9aaTAD activation domains as the common interaction interface of the Yamanaka factors for transcription machinery. All four activation domains were identified by our online 9aaTAD prediction service and experimentally confirmed as strong activators of transcription. We considered the mediator interactions granted by 9aaTADs as part of the Yamanaka factors ability to reprogram cell fate.

Graphical abstract
Optical activation of TrkB receptors
Authors: Huang Peiyuan , Liu Aofei , Song Yutong , Hope Jen M. , Cui Bianxiao , Duan Liting
Published: December 2019

Brain-derived neurotrophic factor (BDNF), via activation of tropomyosin receptor kinase B (TrkB), plays a critical role in neuronal proliferation, differentiation, survival, and death. Dysregulation of TrkB signaling is implicated in neurodegenerative disorders and cancers. Precise activation of TrkB receptors with spatial and temporal resolution is greatly desired to study the dynamic nature of TrkB signaling and its role in related diseases. Here we develop different optogenetic approaches that use light to activate TrkB receptors. Utilizing the photosensitive proteinArabidopsis thalianacryptochrome 2 (CRY2), the light-inducible homo-interaction of the intracellular domain of TrkB (iTrkB) in the cytosol or on the plasma membrane is able to induce the activation of downstream MAPK/ERK and PI3K/Akt signaling as well as the neurite outgrowth of PC12 cells. Moreover, we prove that such strategies are generalizable to other optical homo-dimerizers by demonstrating the optical TrkB activation based on the light-oxygen-voltage domain of aureochrome 1 fromVaucheria frigida. The results open up new possibilities of many other optical platforms to activate TrkB receptors to fulfill customized needs. By comparing all the different strategies, we find that the CRY2-integrated approach to achieve light-induced cell membrane recruitment and homo-interaction of iTrkB is most efficient in activating TrkB receptors. The optogenetic strategies presented are promising tools to investigate BDNF/TrkB signaling with tight spatial and temporal control.
Nonparametric Anomaly Detection on Time Series of Graphs
Authors: Ofori-Boateng Dorcas , Gel Yulia R. , Cribben Ivor
Published: December 2019

Identifying change points and/or anomalies in dynamic network structures has become increasingly popular across various domains, from neuroscience to telecommunication to finance. One of the particular objectives of the anomaly detection task from the neuroscience perspective is the reconstruction of the dynamic manner of brain region interactions. However, most statistical methods for detecting anomalies have the following unrealistic limitation for brain studies and beyond: that is, network snapshots at different time points are assumed to be independent. To circumvent this limitation, we propose a distribution-free framework for anomaly detection in dynamic networks. First, we present each network snapshot of the data as a linear object and find its respective univariate characterization via local and global network topological summaries. Second, we adopt a change point detection method for (weakly) dependent time series based on efficient scores, and enhance the finite sample properties of change point method by approximating the asymptotic distribution of the test statistic using the sieve bootstrap. We apply our method to simulated and to real data, particularly, two functional magnetic resonance imaging (fMRI) data sets and the Enron communication graph. We find that our new method delivers impressively accurate and realistic results in terms of identifying locations of true change points compared to the results reported by competing approaches. The new method promises to offer a deeper insight into the large-scale characterizations and functional dynamics of the brain and, more generally, into intrinsic structure of complex dynamic networks.
A Multi-Niche Microvascularized Human Bone-Marrow-on-a-Chip
Authors: Nelson Michael R. , Ghoshal Delta , Mejías Joscelyn C. , Frey Rubio David , Keith Emily , Roy Krishnendu
Published: December 2019

The human bone marrow (hBM) is a complex organ critical for hematopoietic and immune homeostasis, and where many cancers metastasize. Yet, understanding the fundamental biology of the hBM in health and diseases remain difficult due to complexity of studying or manipulating the BM in humans. Accuratein vitromodels of the hBM microenvironment are critical to further our understanding of the BM niche and advancing new clinical interventions. Although,in vitroculture models that recapitulate some key components of the BM niche have been reported, there are no examples of a fully human,in vitro, organoid platform that incorporates the various niches of the hBM - specifically the endosteal, central marrow, and perivascular niches – thus limiting their physiological relevance. Here we report an hBM-on-a-chip that incorporates these three niches in a single micro-physiological device. Osteogenic differentiation of hMSCs produced robust mineralization on the PDMS surface (“bone layer”) and subsequent seeding of endothelial cells and hMSCs in a hydrogel network (“central marrow”) created an interconnected vascular network (“perivascular niche”) on top. We show that this multi-niche hBM accurately mimics the ECM composition, allows hematopoietic progenitor cell proliferation and migration, and is affected by radiation. A key finding is that the endosteal niche significantly contributes to hBM physiology. Taken together, this multi-niche micro-physiological system opens up new opportunities in hBM research and therapeutics development, and can be used to better understand hBM physiology, normal and impaired hematopoiesis, and hBM pathologies, including cancer metastasis, multiple myelomas, and BM failures.
Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20
Authors: Gadalla Mohamed Rasheed , Abrami Laurence , van der Goot F Gisou , Veit Michael
Published: December 2019

Hemagglutinin (HA), a glycoprotein of Influenza A viruses and its proton-channel M2 are site-specifically modified with fatty acids. Whereas two cysteines in the short cytoplasmic tail of HA contain only palmitate, stearate is exclusively attached to one cysteine located at the cytoplasmic border of the transmembrane region (TMR). M2 is palmitoylated at a cysteine positioned in an amphiphilic helix near the TMR. The enzymes catalyzing acylation of HA and M2 have not been identified, but zinc finger DHHC domain containing (ZDHHC) palmitoyltransferases are candidates. We used a siRNA library to knockdown expression of each of the 23 human ZDHHCs in HA-expressing HeLa cells. siRNAs against ZDHHC2 and 8 had the strongest effect on acylation of HA as demonstrated by acyl-RAC and confirmed by 3H-palmitate labelling. CRISPR/Cas9 knockout of ZDHHC2 and 8 in HAP1 cells, but also of the phylogenetically related ZDHHCs 15 and 20 strongly reduced acylation of group 1 and group 2 HAs and of M2, but individual ZDHHCs exhibit slightly different substrate preferences. These ZDHHCs co- localize with HA at membranes of the exocytic pathway in a human lung cell line. ZDHHC2, 8, 15 and 20 are not required for acylation of the hemagglutinin-esterase-fusion protein of Influenza C virus that contains only stearate at one transmembrane cysteine. Knockout of these ZDHHCs also did not compromise acylation of HA of Influenza B virus that contains two palmitoylated cysteines in its cytoplasmic tail. Results are discussed with respect to the acyl preferences and possible substrate recognition features of the identified ZDHHCs.
EffectorK, a comprehensive resource to mine for pathogen effector targets in the Arabidopsis proteome
Authors: González-Fuente Manuel , Carrère Sébastien , Monachello Dario , Marsella Benjamin G , Cazalé Anne-Claire , Zischek Claudine , Mitra Raka M , Rezé Nathalie , Cottret Ludovic , Mukhtar M Shahid , Lurin Claire , Noel Laurent D , Peeters Nemo
Published: December 2019

Pathogens deploy effector proteins that interact with host proteins to manipulate the host physiology to the pathogen’s own benefit. However, effectors can also be recognized by host immune proteins leading to the activation of defense responses. Effectors are thus essential components in determining the outcome of plant-pathogen interactions. Despite major efforts to decipher effector functions, our current knowledge on effector biology is scattered and often limited. In this study, we conducted two systematic large-scale yeast two-hybrid screenings to detect interactions between  Arabidopsis thaliana  proteins and effectors from two vascular bacterial pathogens:  Ralstonia pseudosolanacearum  and  Xanthomonas campestris . We then constructed an interactomic network focused on Arabidopsis and effector proteins from a wide variety of bacterial, oomycete, fungal and animal pathogens. This network contains our experimental data and protein-protein interactions from 2,035 peer-reviewed publications (48,200 Arabidopsis-Arabidopsis and 1,300 Arabidopsis-effector protein interactions). Our results show that effectors from different species interact with both common and specific Arabidopsis targets suggesting dual roles as modulators of generic and adaptive host processes. Network analyses revealed that effector targets, particularly effector hubs and bacterial core effector targets, occupy important positions for network organization as shown by their larger number of protein interactions and centrality. These interactomic data were incorporated in EffectorK, a new graph-oriented knowledge database that allows users to navigate the network, search for homology or find possible paths between host and/or effector proteins. EffectorK is available at  www.effectork.org  and allows users to submit their own interactomic data.
Maturation of pyramidal cells in anterior piriform cortex may be sufficient to explain the end of early olfactory learning in rats
Authors: Oruro Enver Miguel , Pardo Grace V.E. , Lucion Aldo B. , Calcagnotto Maria Elisa , Idiart Marco A. P.
Published: December 2019

Studies have shown that neonate rodents exhibit high ability to learn a preference for novel odors associated with thermo-tactile stimuli that mimics maternal care. Artificial odors paired with vigorous strokes in rat pups younger than 10 postnatal days (P), but not older, rapidly induce an orientation-approximation behavior toward the conditioned odor in a two-choice preference test. The olfactory bulb (OB) and the anterior olfactory cortex (aPC), both modulated by norepinephrine (NE), have been identified as part of a neural circuit supporting this transitory olfactory learning. One possible explanation at the neuronal level for why the odor-stroke pairing induces consistent orientation-approximation behavior in P10, is the coincident activation of prior existent neurons in the aPC mediating this behavior. Specifically, odor-stroke conditioning in P10 pups, promoting orientation-approximation behavior in the former but not in the latter. In order to test this hypothesis, we performed in vitro patch-clamp recordings of the aPC pyramidal neurons from rat pups from two age groups (P5–P8 and P14–P17) and built computational models for the OB-aPC neural circuit based on this physiological data. We conditioned the P5–P8 OB-aPC artificial circuit to an odor associated with NE activation (representing the process of maternal odor learning during mother–infant interactions inside the nest) and then evaluated the response of the OB-aPC circuit to the presentation of the conditioned odor. The results show that the number of responsive aPC neurons to the presentation of the conditioned odor in the P14–P17 OB-aPC circuit was lower than in the P5–P8 circuit, suggesting that at P14–P17, the reduced number of responsive neurons to the conditioned (maternal) odor might not be coincident with the responsive neurons for a second conditioned odor.
Integrating the production and the erection processes of pre-fabricated steel frames in building projects using phased lean management
Authors: Heravi Gholamreza , Kebria Majid Fazeli , Rostami Milad
Published: December 2019

Purpose

The purpose of this paper is to investigate the effects of implementing value stream mapping (VSM), just in time (JIT), continuous flow and total productive maintenance (TPM) methods throughout production and erection processes of pre-fabricated steel frames (PSFs) of building projects.

Design/methodology/approach

As phased lean management, after implementing the VSM technique, the JIT technique is implemented as first lean phase and the TPM and the continuous flow techniques are implemented as second lean phase. To evaluate the expected improvement of project performance due to reduce wastes by implementing lean techniques, discrete event simulation (DES) is utilized. In this research, an eight-story residential building project in Tehran, Iran, is studied.

Findings

Simultaneous use of lean techniques to integrate production and erection processes of PSFs leads to the improvement of the performance of production and erection stages, significantly. The results indicate 43 and 17 percent reduction in PSFs production and erection processes time and cost, respectively.

Research limitations/implications

In the present study, only the effects of implementing lean techniques on the production and erection of PSFs have been evaluated. However, it is also possible to apply these lean approaches and the key strategies to the other modular or pre-fabricated construction methods.

Originality/value

The main contribution to knowledge is improving the construction project performance by integrating the production and erection processes, using phased lean management through implementing lean techniques. The results of the current study provide valuable insight into the possibility of integrating and improving construction processes of pre-fabricated construction.