bluuebunny/crossref_metadata_2025 huggingface dataset:
PS02.226: PREDICTIVE FACTORS FOR EARLY RECOVERY OF ORAL INTAKE IN PATIENTS WHO UNDERWENT CURATIVE ESOPHAGECTOMY FOR ESOPHAGEAL CANCER
Authors: Isobe Yujiro , Kawakubo Hirofumi , Amada En , Mayanagi Shuhei , Fukuda Kazumasa , Nakamura Rieko , Wada Norihito , Suda Koichi , Ando Makiko , Ishikawa Aiko , Muraoka Kaori , Kitagawa Yuko
Published: September 2018

Background

Evaluating swallowing function by Videoendoscopic evaluation of swallowing (VE) and Videofluorography (VF) is vital in reintroducing oral diet to patients who underwent esophagectomy. However, performing VE and VF requires specific facility and experts. So, the aim of this study is to evaluate predictive factors for early recovery of oral intake.

Methods

One-hundred and thirty-six patients who underwent minimally invasive esophagectomy for thoracic esophageal cancer with three-field-lymph node dissection were enrolled. Patients’ characteristics, surgical and pathological factors, postoperative complications, duration from surgery to reintroducing oral intake, results of repetitive saliva swallowing test (RSST) and maximum phonation time (MPT) on seventh postoperative day (7POD) were analyzed. We classified patients that duration of reintroducing oral intake is shorter than 10 days into Normal-intake (N) group and patients that duration of oral intake is longer than 11 days into Delayed-intake (D) group.

Results

The average age of all patients was 64 ± 9 years old and average hospital stay of them was 30 ± 15 days. Three-field-lymph node dissection was performed in 96% of the cases and all patients have been performed cervical esophagogastrostomy. N group had significantly many patients who completed neoadjuvant chemo(radio)therapy (neo-C(R)Tx)) compared to D group (74% vs. 51%, P = 0.01). Also, patients in N group had significantly low level of preoperative indocyanine green test (ICG test; determined by colorimetric method at 15 minutes after injection of indocyanine green solution) and maximum postoperative serum C-reactive protein level until 7POD (max-CRP) compared to D group (P = 0.047, P = 0.001, respectively). Moreover, average time of MPT on 7POD was long in N group compared to D group (P = 0.05). In multivariate analysis, completion of neo-C(R)Tx, ICG ≤ 9, max-CRP ≤ 14.5 mg/dL was independent predictive factor of early recovery of oral intake (OR: 2.6 P = 0.023, OR: 4.6 P = 0.003, OR: 1.7 P = 0.008, respectively).

Conclusion

Preoperative good liver function, completion of neoadjuvant treatment and relatively low postoperative inflammation were considered to be predictive factors for early recovery of oral intake in patients who underwent curative esophagectomy for esophageal cancer.

Disclosure

All authors have declared no conflicts of interest.
PS02.237: IDENTIFICATION OF THREE DISTINCT BIOLOGICAL SUBTYPES IN ESOPHAGEAL AND JUNCTIONAL ADENOCARCINOMA BY RNA SEQUENCING
Authors: Krishnadath Kausilia , Hoefnagel Sanne , Calpe Silvia , Sancho-Del Serra Carmen , Van Berge Henegouwen M I , Hulshof Maarten , Van Laarhoven Hanneke , Gisbertz Suzanne , Bergman Jacques , Koster Jan
Published: September 2018

Background

Advances in therapy have achieved incremental improvements in overall outcome in patients with Esophageal Adenocarcinoma (EAC), but over- and undertreatment of undefined subgroups of patients might undermine these benefits. The biological diversity of EAC complicates patient selection and treatment stratification and impedes the development of new targeted agents. Further insight into the heterogeneous molecular pathology of EAC to select patients for standard chemo-radiotherapy and/or novel targeted strategies is urgent.

Methods

In our analysis, we included 110 patients with EAC and junctional adenocarcinomas diagnosed between 2012 and 2017. Patients either received neoadjuvant chemo-radiotherapy (nCRT) with carboplatin and paclitaxel, followed by surgical resection or chemotherapy only. Pre-treatment tissue samples of the tumor were collected during upper gastrointestinal endoscopy. RNA was extracted from these samples and RNA sequencing profiles were obtained. We performed unsupervised hierarchical clustering on the tumor RNA profiles to identify distinct subtypes. We used a machine learning approach to train a model with our AMC dataset. This model was applied to the a public TCGA dataset.

Results

We could identify three distinct biological subtypes. We found that that subgroup 2 and 3 had slightly poorer overall survival, although the difference was not significant. The TCGA dataset resulted in the identification of similar groups with similar signatures. One of the pathways that we discovered proved to be highly upregulated in group 2, was NOTCH signaling. Genes within the NOTCH signaling pathway can be targeted by specific antibodies that are currently in research phase for several types of cancer.

Conclusion

Our studies support the existence of three distinct EAC/junctional subtypes. Clinical use of an EAC subtype classifier might lead to identification of new therapeutic targets and improve stratification of patients for (targeted) therapies and subsequently improve outcomes. However, our results need to be further validated in independent cohorts.

Disclosure

All authors have declared no conflicts of interest.
PS02.239: SPECIFIC INHIBITION OF BONE MORPHOGENIC PROTEIN (BMP4) AS A POTENTIAL THERAPEUTIC STRATEGY FOR ESOPHAGEAL ADENOCARCINOMA
Authors: Krishnadath Kausilia , Hoefnagel Sanne , Calpe Silvia , Read Matthew , Straub Danielle , Correia Ana , Sancho-Del Serra Carmen
Published: September 2018

Background

In Western countries, the highly malignant Esophageal adenocarcinoma (EAC) have the most dramatically rising incidence of all malignancies. BMP4 is a growth factor important for carcinogenesis. We found that BMP4 is aberrantly expressed in Barret's esophagus, the pecursor lesion of EAC, and that together with CDX2 drives the intestinalization of epithelial metaplasia. However, its role in esophageal adenocarcinoma (EAC) remains uncertain.

Methods

Method: To elucidate whether BMP4 is involved in malignancy in EAC we used an RNA sequencing database of 56 EAC treatment naive endoscopic biopsies to investigate if there is a subgroup of cancers with high BMP signaling. We validated results by qPCR and immunohistochemistry in matching tumor samples. Next we used our recently developed effective and highly specific anti-BMP4 antibodies(1,2) to study the effect of inhibition of BMP4 on both in vitro as well as in vivo models of EAC.

Results

Using a gene set that was recently published for BMP signaling, we were able to distinguish a subgroup of EAC patients with increased BMP signaling. By IHC we confirmed that 70% of EAC tumors express BMP4 at the protein level. We found that patients with high levels of BMP4 expression tend to have a poorer recurrence-free survival compared to patients with low BMP4 expression, which suggests a more aggressive tumor behavior in BMP4 expressing EAC tumors. Most importantly, inhibition of BMP4 function in EAC cells by our recently developed anti-BMP4 antibodies lead to an increase in chemo-sensitivity and a decreased in invasive and migratory capabilities in vitro. Preclinical in vivo studies with a patient-derived tumor xenograft mouse model of an EAC tumor confirmed that anti-BMP4 antibodies can effectively reduce tumor growth and synergistically act with chemotherapy agents.

Conclusion

We identified a subgroup of EAC with increased BMP signaling. Our studies support a role of BMP4 in chemo-resistance and invasiveness in EAC, and indicate that inhibition of BMP4 with highly our specific llama-derived antibodies is an attractive therapy for improving outcomes of EAC.

Disclosure

All authors have declared no conflicts of interest.
RA03.07: LEARNING CURVE FOR ROBOTIC AND VIDEO-ASSISTED THORACOSCOPIC ESOPHAGECTOMY: A MULTIDIMENSIONAL ANALYSIS
Authors: Chao Yin-Kai
Published: September 2018

Background

Lymph node dissection (LND) along the left recurrent laryngeal nerve (RLN) is a technically challenging part of esophageal cancer surgery, especially after chemoradiotherapy (CRT). Robotic surgery holds promise to increase its safety and feasibility.

Methods

Patients who underwent minimally invasive esophagectomy and RLN dissection following CRT were dichotomized according to the use of robotic surgery (robotic esophagectomy [RE] versus video-assisted thoracoscopic esophagectomy [VATE]). Comparisons were made in terms of 1) number of dissected nodes, 2) rates of RLN palsy, 3) rates of perioperative complications, and 4) learning curves. Analysis of learning curves was performed with the cumulative sum (CUSUM) method (target failure rate for left RLN palsy: 15%).

Results

The RE and VATE groups consisted of 39 and 67 patients, respectively. The intraoperative identification of the left RLN was more common in the RE group (97.4%) than in the VATE group (68.7%, P < 0.001). Postoperative left RLN palsy was significantly more frequent in the VATE group (26.9%) than in the RE group (10.3%, P = 0.042), with a higher rate of pneumonia in the former (16.4% versus 2.6%, P = 0.03). CUSUM analysis revealed a longer learning curve when left RLN LND was performed through VATE. Left RLN palsy rates did not decrease below the target rate with the use of VATE, whereas RE allowed achieving the predefined target rate after 12 operations.

Conclusion

In the current study, we compared for the first time the learning curves of traditional and robotic surgery for RLN LND (which can be considered as one of the most technically challenging parts of esophageal cancer surgery). Our goal was to determine the minimum number of treated cases required to achieve an acceptable technical competency. Our data indicate that RE significantly facilitated a complex procedure like left RLN LND, resulting in a shorter learning curve compared with VATE. Notably, the left RLN was more easily identifiable with the use of RE, which in turn resulted in lower post-procedural left nerve palsy rates. Although MA analysis revealed that robotic surgery was initially more time-consuming than VATE, RE procedural times improved rapidly and became shorter than those of VATE after treatment of 26 cases.

Disclosure

All authors have declared no conflicts of interest.
RA10.04: POSTOPERATIVE PNEUMONIA IS ASSOCIATED WITH SHORT-TERM AND LONG-TERM MORTALITY OF DEFINITIVE CHEMORADIOTHERAPY FOLLOWED BY SALVAGE ESOPHAGECTOMY FOR ESOPHAGEAL CANCER
Authors: Takeuchi Masashi , Kawakubo Hirofumi , Mayanagi Shuhei , Fukuda Kazumasa , Nakamura Rieko , Suda Koichi , Wada Norihito , Kitagawa Yuko
Published: September 2018

Background

Although definitive chemoradiotherapy (CRT) with salvage esophagectomy has improved overall survival (OS) for esophageal cancer, it is a more invasive approach than neoadjuvant CRT followed by surgery or surgery alone, and causes high mortality after surgery. The purpose of this study was to investigate the short and long-term outcomes of salvage esophagectomy, to determine their prognostic factors, and to create a prediction model for OS using a classification and regression tree (CART).

Methods

Ninety patients who had undergone CRT followed by esophagectomy for thoracic esophageal cancer at Keio University Hospital, Tokyo, Japan, between June 1994 and August 2014 were identified for this study. We divided the 90 patients into two groups—the salvage group and the neoadjuvant group—according to the dose of irradiation of CRT. Forty-four patients who underwent CRT with radiation dose less than 50 Gy, followed by planned esophagectomy, were allocated to the neoadjuvant group. Forty-six patients with salvage esophagectomy for locally recurrent or residual cancer after definitive CRT (greater than 50 Gy) were allocated to the salvage group.

Results

Patients from the salvage group tended to have a lower OS (median survival: Salvage, 25 months vs neoadjuvant, 50 months, P = 0.149). In the salvage group, pneumonia and age were identified as factors predictive of in-hospital mortality. OS was significantly lower in patients with postoperative pneumonia and female gender. We set the prediction model for OS in the salvage group using survival CART. The group of R1/2 resection aged ≥ 56.5 years and the group suffering from postoperative pneumonia were the groups at highest risk; the area under the curve was 0.72.

Conclusion

The present study demonstrates the short-term and long-term prognostic factors of salvage esophagectomy after definitive CRT for esophageal cancer. Achieving improvement in OS after salvage surgery requires increased R0 resection rates and decreased pulmonary complications. Both informed decision making in the adoption of salvage surgery and specific plans to reduce pneumonia through means such as pulmonary rehabilitation are required.

Disclosure

All authors have declared no conflicts of interest.
Impact of Aging and HIV Infection on the Function of the C-Type Lectin Receptor MINCLE in Monocytes
Authors: Zapata Heidi J , Van Ness Peter H , Avey Stefan , Siconolfi Barbara , Allore Heather G , Tsang Sui , Wilson Jean , Barakat Lydia , Mohanty Subhasis , Shaw Albert C
Published: September 2018

Both aging and HIV infection are associated with an enhanced pro-inflammatory environment that contributes to impaired immune responses and is mediated in part by innate immune pattern-recognition receptors. MINCLE is a C-type lectin receptor that recognizes trehalose-6,6ʹ-dimycolate or “cord factor,” the most abundant glycolipid in Mycobacterium tuberculosis. Here, we evaluated MINCLE function in monocytes in a cohort of HIV-infected and uninfected young (21–35 years) and older adults (≥60 years) via stimulation of peripheral blood mononuclear cells with trehalose-6,6-dibehenate, a synthetic analog of trehalose-6,6ʹ-dimycolate and measurement of cytokine production (interleukin [IL]-10, IL-12, IL-6, tumor necrosis factor-α) by multicolor flow cytometry. Our studies show an age- and HIV-associated increase in cytokine multifunctionality of monocytes both at the population and single cell level that was dominated by IL-12, IL-10, and IL-6. These findings provide insight into the host response to M. tuberculosis and possible sources for the pro-inflammatory environment seen in aging and HIV infection.
C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
Authors: Inoue Shin-ichi , Morozumi Naomi , Yoshikiyo Kazunori , Maeda Hiroaki , Aoki Yoko
Published: September 2018

Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.
The contribution of ice algae to the winter energy budget of juvenile Antarctic krill in years with contrasting sea ice conditions
Authors: Bernard Kim S , Gunther Lacey A , Mahaffey Sean H , Qualls Katelyn M , Sugla Monisha , Saenz Benjamin T , Cossio Anthony M , Walsh Jennifer , Reiss Christian S
Published: September 2018

Krill overwintering strategies vary with ontogeny and year; understanding this variability is essential to predicting how the species will respond to climate change in the future. Overwintering studies have focused on larval and adult krill, but we know little about how juvenile krill overwinter. The late winter diet of juvenile krill is important because it will determine their growth and development rates and consequently their reproductive potential the following spring. A diet rich in ice algae would promote growth and reproductive development. The Bransfield Strait (northern Antarctic Peninsula, AP) is an important overwintering ground for krill; it has been proposed this region offers a food-rich winter environment. We examined the contribution of ice algae to the energy budget of overwintering juvenile krill during 2 years with contrasting sea ice conditions. Grazing on ice algae contributed ∼146% to their winter energy budget in 2015, even though ice concentrations were ≤50% and consisted of newly formed pancake ice. However, when sea ice advanced late in the Bransfield Strait (2016), ice algae contributed significantly less (∼16%) to the winter energy budget of juvenile krill. Delayed sea ice advance may negatively affect growth and reproductive development of overwintering juvenile krill.
Should a fistula first policy be revisited in elderly haemodialysis patients?
Authors: Lomonte Carlo , Basile Carlo , Mitra Sandip , Combe Christian , Covic Adrian , Davenport Andrew , Kirmizis Dimitrios , Schneditz Daniel , van der Sande Frank
Published: September 2018

Life-sustaining haemodialysis requires a durable vascular access (VA) to the circulatory system. The ideal permanent VA must provide longevity for use with minimal complication rate and supply sufficient blood flow to deliver the prescribed dialysis dosage. Arteriovenous fistulas (AVFs) have been endorsed by many professional societies as the VA of choice. However, the high prevalence of comorbidities, particularly diabetes mellitus, peripheral vascular disease and arterial hypertension in elderly people, usually make VA creation more difficult in the elderly. Many of these patients may have an insufficient vasculature for AVF maturation. Furthermore, many AVFs created prior to the initiation of haemodialysis may never be used due to the competing risk of death before dialysis is required. As such, an arteriovenous graft and, in some cases, a central venous catheter, become a valid alternative form of VA. Consequently, there are multiple decision points that require careful reflection before an AVF is placed in the elderly. The traditional metrics of access patency, failure and infection are now being seen in a broader context that includes procedure burden, quality of life, patient preferences, morbidity, mortality and cost. This article of the European Dialysis (EUDIAL) Working Group of ERA-EDTA critically reviews the current evidence on VA in elderly haemodialysis patients and concludes that a pragmatic patient-centred approach is mandatory, thus considering the possibility that the AVF first approach should not be an absolute.
Parenting Desires Among Individuals Living With Human Immunodeficiency Virus in the United States
Authors: Cohn Susan E , Haddad Lisa B , Sheth Anandi N , Hayford Christina , Chmiel Joan S , Janulis Patrick F , Schmandt Justin
Published: September 2018

Background

In 1988, 1 of 3 women (W) and heterosexual men living with human immunodeficiency virus (HIV) reported wanting children, but little is known about parenting desires of men who have sex with men (MSM) living with HIV. We examined parenting desires among persons initiating antiretroviral therapy (ART).

Methods

Of 1809 participants in the AIDS Clinical Trials Group (ACTG) Study 5257, 1425 W aged ≤45 years or men completed questionnaires about parenting desires at baseline and 96 weeks after initiating ART. Self-reported desires for children in the future (yes/unsure vs no) and associations between baseline sociodemographics and parenting desires at 96 weeks were examined using multivariable logistic regression, overall and within subgroups.

Results

The 1425 participants were as follows: 36% white, 39% black, 22% Hispanic; median age 36 (interquartile range, 28–44); 70% MSM, 13% men reported sex only with W (MSW), 17% W. At baseline, 42% may want children in the future (42% MSM, 37% MSW, 43% W); at 96 weeks, 41% may want children (41% MSM, 37% MSW, 43% W). At follow-up, approximately 10% of responses changed in each direction. In multivariable analyses, education greater than high school, <30 years, and having no children were significantly associated with future parenting desires among all subgroups. Among MSM, being black was associated with desiring children.

Conclusions

Approximately 40% of MSM, W, and MSW with HIV may want children, both at baseline and 96 weeks after ART initiation. These results highlight the need to regularly assess parenting goals, provide access to comprehensive reproductive services, and address prevention of vertical and heterosexual HIV transmission.
Validation of an Antimicrobial Stewardship-Driven Verigene Blood-Culture Gram-Negative Treatment Algorithm to Improve Appropriateness of Antibiotics
Authors: Claeys Kimberly C , Schlaffer K E , Heil E L , Leekha S , Johnson J K
Published: September 2018

Rapid diagnostic testing (RDT) allows for early adjustment of antibiotic therapy. This study examined the potential impact of a stewardship-driven antibiotic treatment algorithm, incorporating RDT into the management of Gram-negative bacteremia. The proposed algorithm would have resulted in 88.4% of cases receiving appropriate antibiotic therapy versus 78.1% by standard of care (P = .014).
Human Thelaziasis: Emerging Ocular Pathogen in Nepal
Authors: Sah Ranjit , Khadka Shusila , Adhikari Mahesh , Niraula Reema , Shah Apoorva , Khatri Anadi , Donovan Suzanne
Published: September 2018

Thelaziasis is an ocular arthropod-borne, zoonotic disease of the eye infecting the conjunctival sac, lacrimal duct, and lacrimal gland caused by a nematode of the genus Thelazia. We report the first case of human ocular thelaziasis in Nepal in a 6-month-old child from a Rukum district, Nepal. The infant presented with conjunctivitis, and his visual acuity and dilated fundal examination were normal. A total of 6 worms were removed for identification. Collected nematodes were identified based on morphological keys as Thelazia callipaeda. The patient’s symptoms improved after removal of the nematodes.
Middle Cerebral Artery Aneurysm “Neck Overhang”: Decreased Postclipping Residual Using the Intersecting Clipping Technique
Authors: Dimitriadis Stavros , Qeadan Fares , Taylor Christopher L , Yonas Howard , Carlson Andrew P
Published: September 2018

BACKGROUND

Middle cerebral artery (MCA) aneurysms continue to be viewed by many as primarily surgical entities.

OBJECTIVE

To introduce a new, easily measurable dimension termed “neck overhang,” defined as the amount of the aneurysm that extends proximal to the 2 dimensionally defined “neck” and to evaluate the utility of the intersecting clipping technique (use of straight clip and intersecting fenestrated clip) to adapt to this overhanging segment's specific dimensions and achieve better obliteration of the MCA aneurysms.

METHODS

We reviewed retrospectively 100 MCA aneurysms treated surgically over the last 10 yr at our institution. We identified the clipping technique that was performed (intersecting vs “standard” technique) and we evaluated the presence of a postoperative remnant. We then correlated these with the aneurysm's overhanging neck length.

RESULTS

Forty-three aneurysms were treated with the intersecting clipping technique. The overall rate of remnant was 16%. In the standard group, the rate of remnant was 23%, whereas with intersecting clipping that was 7% (P = .029). Within the standard clipping group, we found that the optimum threshold for length of the neck overhang was ≥1.9 mm in order to predict the occurrence of residual. Applying this threshold to the intersecting clipping technique group resulted in a reduction in remnant from 35% in the standard group to 9%.

CONCLUSION

Neck overhang >1.9 mm is associated with a higher chance of postclipping residual aneurysm in MCA aneurysms. The intersecting clipping technique is a versatile technique that can conform to various aneurysms’ geometry and can reduce the rate of post clipping residual for aneurysms with high neck overhang.
Spectral Contrast Optical Coherence Tomography Angiography Enables Single-Scan Vessel Imaging
Authors: Winkelmann James A. , Eid Aya , Spicer Graham , Almassalha Luay M. , Nguyen The-Quyen , Backman Vadim
Published: September 2018

Optical coherence tomography angiography relies on motion for contrast and requires at least two data acquisitions per pointwise scanning location. We present a method termed spectral contrast optical coherence tomography angiography using visible light that relies on the spectral signatures of blood for angiography from a single scan using endogenous contrast. We demonstrate the molecular sensitivity of this method, which enables lymphatic vessel, blood, and tissue discrimination.
Generalization via superposition: Combined effects of mixed reference frame representations for explicit and implicit learning in a visuomotor adaptation task
Authors: Poh Eugene , Taylor Jordan A.
Published: September 2018

Studies on generalization of learned visuomotor perturbations has generally focused on whether learning is coded in extrinsic or intrinsic reference frames. This dichotomy, however, is challenged by recent findings showing that learning is represented in a mixed reference frame. Overlooked in this framework is how learning is the result of multiple processes, such as explicit re-aiming and implicit motor adaptation. Therefore the proposed mixed representation may simply reflect the superposition of explicit and implicit generalization functions, each represented in different reference frames. Here, we characterized the individual generalization functions of explicit and implicit learning in relative isolation to determine if their combination could predict the overall generalization function when both processes are in operation. We modified the form of feedback in a visuomotor rotation task to isolate explicit and implicit learning, and tested generalization across different limb postures to dissociate the extrinsic and intrinsic representations. We found that explicit generalization occurred predominantly in an extrinsic reference frame but the amplitude was reduced with postural changes, whereas implicit generalization was phase-shifted according to a mixed reference frame representation and amplitude was maintained. A linear combination of individual explicit and implicit generalization functions accounted for nearly 85% of the variance associated with the generalization function in a typical visuomotor rotation task, where both processes are in operation. This suggests that each form of learning results from a mixed representation with distinct extrinsic and intrinsic contributions, and the combination of these features shape the generalization pattern observed at novel limb postures.

New and noteworthy

Generalization following learning in visuomotor adaptation tasks can reflect how the brain represents what it learns. In this study, we isolated explicit and implicit forms of learning, and showed that they are derived from a mixed reference frame representation with distinct extrinsic and intrinsic contributions. Furthermore, we showed that the overall generalization pattern at novel workspaces is due to the superposition of independent generalization effects developed by explicit and implicit learning processes.
Fast temporal dynamics and causal relevance of face processing in the human temporal cortex
Authors: Schrouff Jessica , Raccah Omri , Baek Sori , Rangarajan Vinitha , Salehi Sina , Mourão-Miranda Janaina , Helili Zeinab , Daitch Amy L. , Parvizi Josef
Published: September 2018

Recordings with a large number of intracranial electrodes in eight neurosurgical subjects offered a unique opportunity to examine the fast temporal dynamics of face processing simultaneously across a relatively large extent of the human temporal cortex (TC). Measuring the power of slow oscillatory bands of activity (θ, α, β, and γ) as well as High-Frequency Broadband (HFB, 70-177 Hz) signal, we found that the HFB showed the strongest univariate and multivariate changes in response to face compared to non-face stimuli. Using the HFB signal as a surrogate marker for local cortical engagement, we identified recording sites with selective responses to faces that were anatomically consistent across subjects and responded with graded strength to human, mammal, bird, and marine animal faces. Importantly, the most face selective sites were located more posteriorly and responded earlier than those with less selective responses to faces. Using machine learning based methods, we demonstrated that a sparse model focusing on information from the human face selective sites performed as well as, or better than, anatomically distributed models of face processing when discriminating faces from non-faces stimuli. Lastly, we identified the posterior fusiform (pFUS) site as causally the most relevant node for inducing distortion of face perception by direct electrical stimulation. Our findings support the notion of face information being processed first in the most selective sites - that are anatomically discrete and localizable within individual brains and anatomically consistent across subjects – which is then distributed in time to less selective anterior temporal sites within a time window that is too fast to be detected by current neuroimaging methods. The new information about the fast spatio-temporal dynamics of face processing across multiple sites of the human brain provides a new common ground for unifying the seemingly contradictory modular and distributed models of face processing in the human brain.
NetWheels: A web application to create high quality peptide helical wheel and net projections
Authors: Mól A.R. , Castro M.S. , Fontes W.
Published: September 2018

Helices are one of the most common secondary structures found in peptides and proteins. The wheel and net projections have been proposed to represent in two dimensions the tridimensional helical structures and facilitate the observation of their properties, especially in terms of residues polarity and intramolecular bonding. Nevertheless, there are few software options to create these projections. We have developed a web-based application that has several futures to create, customize and export these projections and is freely available athttp://lbqp.unb.br/NetWheels.
Timing mechanism of sexually dimorphic nervous system differentiation
Authors: Pereira Laura , Aeschimann Florian , Wang Chen , Lawson Hannah , Serrano-Saiz Esther , Portman Douglas S. , Großhans Helge , Hobert Oliver
Published: September 2018

In all animals, sexual differentiation of somatic tissue is precisely timed, yet the molecular mechanisms that control the timing of sexual differentiation, particularly in the brain, are poorly understood. We have used sexually dimorphic molecular, anatomical and behavioral features of theC. elegansnervous system to decipher a regulatory pathway that controls the precise timing of sexual differentiation. We find that the sexually dimorphic differentiation of postmitotic neurons in the male nervous system is abrogated in animals that carry a mutation in the miRNAlet-7and prematurely executed in animals either lacking thelet-7inhibitorlin-28, or the directlet-7targetlin-41, an RNA-binding, posttranscriptional regulator. We show that an isoform of a phylogenetically conserved transcription factor,lin-29a, is a critical target of LIN-41 in controlling sexual maturation of sex-shared neurons.lin-29ais expressed in a male-specific manner in a subset of sex-shared neurons at the onset of sexual maturation.lin-29aacts cell-autonomously in these neurons to control the expression of sexually dimorphic neurotransmitter switches, sensory receptor expression, neurite anatomy and connectivity, and locomotor behavior.lin-29ais not only required but also sufficient to impose male-specific features at earlier stages of development and in the opposite sex. The temporal, sexual and spatial specificity oflin-29aexpression is controlled intersectionally through thelin-28/let-7/lin-41heterochronic pathway, sex chromosome configuration and neuron type-specific terminal selector transcription factors. Two Doublesex-like transcription factors represent additional neuron-type specific targets of LIN-41 and are regulated in a similar intersectional manner, indicating the existence of modular outputs downstream of the heterochronic pathway. In conclusion, we have provided insights into the molecular logic of the timing of sexual differentiation in theC. elegansnervous system. Remarkably, thelin28/let7axis also controls the timing of sexual differentiation in mice and humans thereby hinting toward a striking universality of the control mechanisms of sexual differentiation.
High throughput gene expression profiling of yeast colonies with microgel-culture Drop-seq
Authors: Liu Leqian , Dalal Chiraj , Heineike Ben , Abate Adam
Published: September 2018

Yeasts can be engineered into “living foundries” for non-natural chemical production by reprogramming their genome using a synthetic biology “design-build-test” cycle. While methods for “design” and “build” are scalable and efficient, “test” remains a labor-intensive bottleneck, limiting the effectiveness of the genetic reprogramming results. Here we describe Isogenic Colony Sequencing (ICO-seq), a massively-parallel strategy to assess the gene expression, and thus engineered pathway efficacy, of large numbers of genetically distinct yeast colonies. We use the approach to characterize opaque-white switching in 658 C. albicans colonies. By profiling transcriptomes of 1642 engineered S. cerevisiae strains, we use it to assess gene expression heterogeneity in a protein mutagenesis library. Our approach will accelerate synthetic biology by allowing facile and cost-effective transcriptional profiling of large numbers of genetically distinct yeast strains.
Gut Microbiota in male patients with chronic traumatic complete spinal cord injury
Authors: Zhang Chao , Zhang Wenhao , Zhang Jie , Jing Yingli , Yang Mingliang , Du Liangjie , Gao Feng , Gong Huiming , Chen Liang , Li Jun , Liu Hongwei , Qin Chuan , Jia Yanmei , Qiao Jiali , Wei Bo , Yu Yan , Zhou Hongjun , Liu Zhizhong , Yang Degang , Li Jianjun
Published: September 2018

This study examined the diversity and structure of gut microbiota in healthy adults and chronic traumatic complete spinal cord injury (SCI) patients, documented neurogenic bowel management of SCI patients. The V3-V4 region of 16S rRNA gene from DNA of 91 fecal samples of 48 healthy and 43 diseased subjects was amplified and sequenced. There was difference in gut microbiota between healthy adult males and females. Neurogenic bowel dysfunction (NBD) was common in patients with chronic traumatic complete SCI, patients with quadriplegia have longer time to defecate than paraplegic patients, with higher NBD scores and heavier neurogenic bowel symptoms. Gut microbiota dysbiosis existed in SCI patients. The abundance of Veillonellaceae and Prevotellaceae increased while Bacteroidaceae and Bacteroides decreased in SCI group. The abundance of Bacteroidaceae, Bacteroides in quadriplegia group and Acidaminococcaceae, Blautia in paraplegia group were significant high than the health male group. Serum biomarkers GLU, HDL, CR and NBD symptoms defecation time, COURSE had significant correlation with microbial community structure. This study presents a comprehensive landscape of gut microbiota in adult male patients with chronic traumatic complete SCI and documents their neurogenic bowel management. The gut microbiota dysbiosis of SCI patients was correlation with serum biomarkers and NBD symptoms.

IMPORTANCE

Neurogenic bowel dysfunction is a major physical and psychological problem in patients with spinal cord injury, which can seriously affect the quality life of them. Gut dysbiosis are highly likely to occur in spinal cord injury patients There are few studies on intestinal microecology after spinal cord injury, and the clinical studies are fewer. It is importance to document their neurogenic bowel management and present a landscape of gut microbiota in them. We found the gut microbiota dysbiosis of spinal cord injury patients was correlation with serum biomarkers and neurogenic bowel dysfunction symptoms. These results may have implications in the next study about metagenomics and precision treatment of neurogenic bowel dysfunction in spinal cord injury patients.
Synthetic Metabolic Pathway for the Production of 1-Alkenes from Lignin-derived Molecules
Authors: Luo Jin , Lehtinen Tapio , Efimova Elena , Santala Ville , Santala Suvi
Published: September 2018

Integration of synthetic metabolic pathways to catabolically diverse chassis provides new opportunities for sustainable production. One attractive scenario is the use of abundant waste material to produce readily collectable product, minimizing production costs. Towards that end, we established the production of semivolatile medium-chain α-olefins from lignin-derived monomers: we constructed 1-undecene synthesis pathway inAcinetobacter baylyiADP1 using ferulate as the sole carbon source. In order to overcome the toxicity of ferulate, we first applied adaptive laboratory evolution, resulting in a highly ferulate-tolerant strain. Next, we demonstrated the 1-undecene production from glucose by heterologously expressing a fatty acid decarboxylase UndA and a thioesterase ‘TesA in the wild type strain. Finally, we constructed the alkene synthesis pathway in the ferulate-tolerant strain. We were able to produce 1-undecene from ferulate and collect the product from the culture headspace without downstream processing. This study demonstrates the potential of bacterial lignin upgradation into value-added products.
Modeling the Electro-chemical Properties of Microbial Opsin ChrimsonR for Application to Optogenetics-based Vision Restoration
Authors: Sabatier Quentin , Joffrois Corentin , Gauvain Grégory , Chavas Joël , Pruneau Didier , Picaud Serge , Benosman Ryad
Published: September 2018

Optogenetic activation of neurons [1] have greatly contributed to our understanding of how neural circuits operate, and holds huge promise in the field of neural prosthetics, particularly in sensory restoration. The discovery of new channelrhodopsins, Chrimson — which is 45 nm more red-shifted than any previously discovered or engineered channelrhodopsin — and its mutant ChrimsonR with faster kinetics [2] made this technology available for medical applications. However, a detailed model that would be able to accurately reproduce the membrane potential dynamics in cells transfected with ChrimsonR under light stimulation is missing. We address this issue by developing the first model for the electrochemical behavior of ChrimsonR that predicts its conductance in response to arbitrary light stimulation. Our model captures ON and OFF dynamics of the protein for stimuli with frequencies up to 100 Hz and their relationship with the brightness, as well as its activation curve, the steady-state amplitude of the response as a function of light intensity. Additionally, we capture a slow adaptation mechanism at a timescale at the order of minutes. Our model holds for light intensities covering the whole dynamic range of the channel (from response onset to saturation) and for timescales in the order of up to several minutes. This model is a new step towards modeling the spiking activity of ChrimsonR-expressing neurons, required for the precise control of information transmission in optogenetics-based Brain-Computer Interfaces, and will inform future applications of ChrimsonR based optogenetics.
Multi-laminate Annulus Fibrosus Repair Scaffold with an Interlamellar Matrix Enhances Impact Resistance, Prevents Herniation and Assists in Restoring Spinal Kinematics
Authors: Borem Ryan , Madeline Allison , Vela Ricardo , Gill Sanjitpal , Mercuri Jeremy
Published: September 2018

Focal defects in the annulus fibrosus (AF) of the intervertebral disc (IVD) from herniation or surgical injury have detrimental impacts on IVD mechanical function. Thus, biomaterial-based repair strategies, which can restore the mechanical integrity of the AF and support long-term tissue regeneration are needed. Accordingly, a collagen-based multi-laminate scaffold with an underlying “angle-ply” architecture has been previously reported demonstrating similar mechanical properties to native AF tissue. The objectives of this work were to: 1) enhance the biomaterials impact strength, 2) define its contribution to spinal kinematics, and 3) assess its ability to prevent IVD herniation. First, AFRP’s were enriched with a glycosaminoglycan-based (GAG) interlamellar matrix (ILM), and then tested for its radially-directed impact resistance under physiological stresses. Subsequent kinematic testing was conducted using a characterized GAG-enriched AFRP as an AF focal defect closure device. In summary, AFRPs demonstrated 1) incorporation of a GAG-based ILM significantly increased radial impact strength, 2) restoration of axial FSU kinematics and 3) ability to prevent herniation of native IVD tissues. Together, these results suggest that the AFRP demonstrates the mechanical robustness and material properties to restore an IVD’s physiological mechanical function through the adequate closure of an AF focal defect.
Intrahost speciations and host switches shaped the evolution of herpesviruses
Authors: Brito Anderson F. , Pinney John W.
Published: September 2018

Cospeciation has been suggested to be the main force driving the evolution of herpesviruses, with viral species co-diverging with their hosts along more than 400 million years of evolutionary history. Recent studies, however, have been challenging this assumption, showing that other co-phylogenetic events, such as intrahost speciations and host switches play a central role on their evolution. Most of these studies, however, were performed with undated phylogenies, which may underestimate or overestimate the frequency of certain events. In this study we performed co-phylogenetic analyses using time-calibrated trees of herpesviruses and their hosts. This approach allowed us to (i) infer co-phylogenetic events over time, and (ii) integrate crucial information about continental drift and host biogeography to better understand virus-host evolution. We observed that cospeciations were in fact relatively rare events, taking place mostly after the Late Cretaceous (~100 Millions of years ago). Host switches were particularly common among alphaherpesviruses, where at least 10 transfers were detected. Among beta- and gammaherpesviruses, transfers were less frequent, with intrahost speciations followed by losses playing more prominent roles, especially from the Early Jurassic to the Early Cretaceous, when those viral lineages underwent several intrahost speciations. Our study reinforces the understanding that cospeciations are uncommon events in herpesvirus evolution. More than topological incongruences, mismatches in divergence times were the main disagreements between host and viral phylogenies. In most cases, host switches could not explain such disparities, highlighting the important role of losses and intrahost speciations in the evolution of herpesviruses.
A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity
Authors: Xie Yubin , Kazmierczyk Marcel , Graham Bruce P. , Dutia Mayank B. , Stefan Melanie I. , Dutia Mayank B.
Published: September 2018

Neurons in the medial vestibular nucleus (MVN) display hyperpolarisation-gated synaptic plasticity, where inhibition believed to come from cerebellar cortical Purkinje cells can induce long-term potentiation (LTP) or long-term depression (LTD) of vestibular nerve afferent synapses. This phenomenon is thought to underlie the plasticity of the vestibulo-ocular reflex (VOR). The molecular and cellular mechanisms involved are largely unknown. Here we present a novel multi-scale computational model, which captures both electrophysiological and biochemical signalling at vestibular nerve synapses on proximal dendrites of the MVN neuron. We show that AMPA receptor phosphorylation at the vestibular synapse depends in complex ways on dendritic calcium influx, which is in turn shaped by patterns of post-synaptic hyperpolarisation and vestibular nerve stimulation. Hyperpolarisation-gated synaptic plasticity critically depends on the activation of LVA calcium channels and on the interplay between CaMKII and PP2B in dendrites of the post-synaptic MVN cell. The extent and direction of synaptic plasticity depend on the strength and duration of hyperpolarisation, and on the relative timing of hyperpolarisation and vestibular nerve stimulation. The multi-scale model thus enables us to explore in detail the interactions between electrophysiological activation and post-synaptic biochemical reaction systems. More generally, this model has the potential to address a wide range of questions about neural signal integration, post-synaptic biochemical reaction systems and plasticity.
Alcohol consumption and mate choice in UK Biobank: comparing observational and Mendelian randomization estimates
Authors: Howe Laurence J , Lawson Daniel J , Davies Neil M , Pourcain Beate St. , Lewis Sarah J , Smith George Davey , Hemani Gibran
Published: September 2018

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle the effects of alcohol consumption on mate-selection from social factors or cohabitation leading to spouses becoming more similar over time. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection.

Therefore, in a sample of over 47,000 spouse-pairs in the UK Biobank we utilised a well-characterised alcohol related variant, rs1229984 in ADH1B, as a genetic proxy for alcohol use. We compared the phenotypic concordance between spouses for self-reported alcohol use with the association between an individual’s self-reported alcohol use and their partner’s rs1229984 genotype using Mendelian randomization. This was followed up by an exploration of the spousal genotypic concordance for the variant and an analysis determining if relationship length may be related to spousal alcohol behaviour similarities.

We found strong evidence that both an individual’s self-reported alcohol consumption and rs1229984 genotype are associated with their partner’s self-reported alcohol use. The Mendelian randomization analysis found that each unit increase in an individual’s weekly alcohol consumption increased their partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P=1.10×10-5). Furthermore, the rs1229984 genotype was concordant within spouse-pairs, suggesting that some spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest that this concordance is unlikely to be explained by population stratification. Overall, our findings suggest that alcohol behaviour directly influences mate selection.