bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of 1116 Consecutive Patients Diagnosed With Anterior Cutaneous Nerve Entrapment Syndrome (ACNES)
Authors: Mol Frédérique M. U. , Maatman Robbert C. , De Joode Luuke E. G. H. , Van Eerten Percy , Scheltinga Marc R. , Roumen Rudi
Published: March 2019

Objective:

The aim of this study was to discuss patient history and subjective findings at physical examination in a large case series to validate a proposed comprehensive set of major and minor diagnostic criteria.

Summary Background Data:

Chronic abdominal pain in some patients is caused by the anterior cutaneous nerve entrapment syndrome (ACNES). ACNES is a clinical diagnosis as no functional testing or imaging modalities are available up to date.

Methods:

This study retrospectively analyzed prospectively obtained data from consecutive patients who received the diagnosis ACNES during evaluation at the SolviMáx Center of Excellence for Abdominal Wall and Groin Pain, Eindhoven, The Netherlands, between June 1, 2011 and September 1, 2016. Questionnaires, standard case forms, and digital case files containing characteristics of individuals were used for analysis.

Results:

Data of 1116 patients suspected and treated for ACNES consistently showed the presence of the following 4 characteristics: sensory disturbances at the painful abdominal area (78%), a positive pinch sign (78%), a positive Carnett's sign (87%), and a positive response to a modified rectus sheath block (>50% pain reduction, 81%). The majority of patients are female of young or middle age with a normal BMI reporting complaints that occurred spontaneously in either a sudden or gradual timeframe, developing a severe (NRS 6-8) chronic abdominal pain that was only diagnosed after a substantial doctor's delay.

Conclusion:

A combination of typical findings in history and physical examination, combined with a positive modified rectus sheath block, may allow for diagnosing ACNES in patients with chronic abdominal pain.
Lymphocyte-C-reactive Protein Ratio as Promising New Marker for Predicting Surgical and Oncological Outcomes in Colorectal Cancer
Authors: Okugawa Yoshinaga , Toiyama Yuji , Yamamoto Akira , Shigemori Tsunehiko , Ide Shozo , Kitajima Takahito , Fujikawa Hiroyuki , Yasuda Hiromi , Hiro Junichiro , Yoshiyama Shigeyuki , Yokoe Takeshi , Saigusa Susumu , Tanaka Koji , Shirai Yumiko , Kobayashi Minako , Ohi Masaki , Araki Toshimitsu , McMillan Donald C. , Miki Chikao , Goel Ajay , Kusunoki Masato
Published: March 2019

Background:

Systemic inflammation via host-tumor interactions is currently recognized as a hallmark of cancer. The aim of this study was to evaluate the prognostic value of various combinations of inflammatory factors using preoperative blood, and to assess the clinical significance of our newly developed inflammatory score in colorectal cancer (CRC) patients.

Method:

In total 477 CRC patients from the discovery and validation cohorts were enrolled in this study. We assessed the predictive impact for recurrence using a combination of nine inflammatory markers in the discovery set, and focused on lymphocyte-C-reactive protein ratio (LCR) to elucidate its prognostic and predictive value for peri-operative risk in both cohorts.

Results:

A combination of lymphocytic count along with C-reactive protein levels demonstrated the highest correlation with recurrence compared with other parameters in CRC patients. Lower levels of preoperative LCR significantly correlated with undifferentiated histology, advanced T stage, presence of lymph node metastasis, distant metastasis, and advanced stage classification. Decreased preoperative LCR (using an optimal cut-off threshold of 6000) was an independent prognostic factor for both disease-free survival and overall survival, and emerged as an independent risk factor for postoperative complications and surgical-site infections in CRC patients. Finally, we assessed the clinical feasibility of LCR in an independent validation cohort, and confirmed that decreased preoperative LCR was an independent prognostic factor for both disease-free survival and overall survival, and was an independent predictor for postoperative complications and surgical-site infections in CRC patients.

Conclusion:

Preoperative LCR is a useful marker for perioperative and postoperative management of CRC patients.
The Unconventional Role for Gastric Volume in the Response to Bariatric Surgery for Both Weight Loss and Glucose Lowering
Authors: Evers Simon S. , Lewis Alfor G. , Tong Cindy , Shao Yikai , Alvarez Rafael , Ridelman Elika , Grant Bethany , Seeley Randy J.
Published: March 2019

Objective:

To study the relationship between the amount of surgery-induced gastric volume reduction and long-term weight loss and glucose tolerance.

Background Data:

Vertical sleeve gastrectomy (VSG) has recently surpassed gastric bypass to become the most popular surgical intervention to induce sustained weight loss. Besides inducing significant weight loss, VSG also improves glucose tolerance. Although no clear correlation has been observed between the size of the residual stomach and sustained weight loss, this begs the question whether less aggressive gastric volume reduction may provide sufficient efficacy when weight loss is not the major goal of the surgical intervention.

Methods:

A series of strategies to reduce gastric volume were developed and tested in Long Evans male rats, namely: VSG, Fundal (F)-Resection, Gastric Sleeve Plication (GSP), Fundal-Plication, and Fundal-Constrained.

Results:

All surgical interventions resulted in a reduction of gastric volume relative to sham, but none of the interventions were as effective as the VSG. Gastric volume was linearly correlated to increased gastric emptying rate as well as increased GLP-1 response. Overall, cumulative food intake was the strongest correlate to weight loss and was logarithmically related to gastric volume. Regression modeling revealed a nonlinear inverse relation between body weight reduction and gastric volume, confirming that VSG is the only effective long-term weight loss strategy among the experimental operations tested.

Conclusions:

The data suggest a minimum threshold volume of the residual stomach that is necessary to induce sustained weight loss. Although all gastric volume interventions increased the GLP-1 response, none of the interventions, except VSG, significantly improved glucose tolerance. In conclusion, if weight loss is the primary goal of surgical intervention, significant volume reduction is required, and this most likely requires excising gastric tissue.
Association of Adjuvant Radiotherapy With Survival After Margin-negative Resection of Pancreatic Ductal Adenocarcinoma
Authors: Kamarajah Sivesh K. , Sonnenday Christopher J. , Cho Clifford S. , Frankel Timothy L. , Bednar Filip , Lawrence Theodore S. , Nathan Hari
Published: March 2019

Introduction:

There is conflicting evidence for the benefit of adjuvant radiotherapy (RT) after resection of pancreatic ductal adenocarcinoma (PDAC), especially for margin-negative (R0) resections. We aimed to evaluate the association of adjuvant RT with survival after R0 resection of PDAC.

Methods:

Using National Cancer Database (NCDB) data from 2004 to 2013, we identified patients with R0 resection of nonmetastatic PDAC. Patients with neoadjuvant radiotherapy and chemotherapy and survival <6 months were excluded. Propensity score matching was used to account for treatment selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of RT with survival.

Results:

Of 4547 (36%) RT and 7925 (64%) non-RT patients, 3860 RT and 3860 non-RT patients remained in the cohort after matching. Clinicopathologic and demographic variables were well balanced after matching. Lymph node metastases were present in 68% (44% N1, 24% N2). After matching, RT was associated with higher survival (median 25.8 vs 23.9 mo, 5-yr 27% vs 24%, P < 0.001). After multivariable adjustment, RT remained associated with a survival benefit (HR 0.89, 95% CI 0.84–0.94, P < 0.001). Stratified and multivariable interaction analyses showed that this benefit was restricted to patients with node-positive disease: N1 (HR: 0.68, CI95%: 0.62–0.76, P = 0.007) and N2 (HR: 0.59, CI95%: 0.54–0.64, P = 0.04).

Conclusions:

In this large retrospective cohort study, adjuvant RT after R0 PDAC resection was associated with a survival benefit in patients with node-positive disease. Adjuvant RT should be considered after R0 resection of PDAC with node-positive disease.
Concordance Between Registry and Administrative Data in the Determination of Comorbidity
Authors: Etzioni David A. , Lessow Cynthia , Bordeianou Liliana G. , Kunitake Hiroko , Deery Sarah E. , Carchman Evie , Papageorge Christina M. , Fuhrman George , Seiler Rachel L. , Ogilvie James , Habermann Elizabeth B. , Chang Yu-Hui H. , Money Samuel R.
Published: March 2019

Objective:

To characterize agreement between administrative and registry data in the determination of patient-level comorbidities.

Background:

Previous research finds poor agreement between these 2 types of data in the determination of outcomes. We hypothesized that concordance between administrative and registry data would also be poor.

Methods:

A cohort of inpatient operations (length of stay 1 day or greater) was obtained from a consortium of 8 hospitals. Within each hospital, National Surgical Quality Improvement Program (NSQIP) data were merged with intra-institutional inpatient administrative data. Twelve different comorbidities (diabetes, hypertension, congestive heart failure, hemodialysis-dependence, cancer diagnosis, chronic obstructive pulmonary disease, ascites, sepsis, smoking, steroid, congestive heart failure, acute renal failure, and dyspnea) were analyzed in terms of agreement between administrative and NSQIP data.

Results:

Forty-one thousand four hundred thirty-two inpatient surgical hospitalizations were analyzed in this study. Concordance (Cohen Kappa value) between the 2 data sources varied from 0.79 (diabetes) to 0.02 (dyspnea). Hospital variation in concordance (intersite variation) was quantified using a test of homogeneity. This test found significant intersite variation at a level of P < 0.001 for each of the comorbidities except for dialysis (P = 0.07) and acute renal failure (P = 0.19). These findings imply significant differences between hospitals in their generation of comorbidity data.

Conclusion:

This study finds significant differences in how administrative versus registry data assess patient-level comorbidity. These differences are of concern to patients, payers, and providers, each of which had a stake in the integrity of these data. Standardized definitions of comorbidity and periodic audits are necessary to ensure data accuracy and minimize bias.
Adjuvant Hepatic Artery Infusion Chemotherapy is Associated With Improved Survival Regardless of KRAS Mutation Status in Patients With Resected Colorectal Liver Metastases
Authors: Gholami Sepideh , Kemeny Nancy E. , Boucher Taryn M. , Gönen Mithat , Cercek Andrea , Kingham T. Peter , Balachandran Vinod , Allen Peter , DeMatteo Ronald , Drebin Jeffrey , Jarnagin William , D’Angelica Michael
Published: March 2019

Objective:

To investigate the impact of adjuvant hepatic artery infusion (HAI) in relation to KRAS mutational status in patients with resected colorectal cancer liver metastases (CRLM).

Background:

Patients with KRAS-mutated CRLM have worse outcomes after resection. Adjuvant HAI chemotherapy improves overall survival after liver resection.

Methods:

Patients with resected CRLM treated at MSKCC with and without adjuvant HAI who had available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospectively maintained institutional database. Correlations between KRAS status, adjuvant HAI, clinical factors, and outcomes were analyzed. Cox proportional hazard model was used to adjust for confounders.

Results:

Between 1993 and 2012, 674 patients (418 KRAS-WT, 256 MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAI. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAI group; however, there were more patients with resected extrahepatic metastases in the no-HAI group. In KRAS-WT tumors, 5-year survival was 78% for patients treated with HAI versus 57% for patients without HAI [hazard ratio (HR) 0.51, P < 0.001]. In KRAS-MUT tumors, 5-year survival was 59% for patients treated with HAI versus 40% for patients without HAI (HR 0.56, P < 0.001). On multivariate analysis, HAI remained associated with improved OS (HR 0.53, P < 0.002) independent of KRAS status and other clinicopathologic factors.

Conclusion:

Adjuvant HAI after resection of CRLM is independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant HAI may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM.
Nontechnical Skill Assessment of the Collective Surgical Team Using the Non-Technical Skills for Surgeons (NOTSS) System
Authors: Jung James J. , Yule Steven , Boet Sylvain , Szasz Peter , Schulthess Pansy , Grantcharov Teodor
Published: March 2019

Objective:

To validate the Non-Technical Skills for Surgeons (NOTSS) system for assessment of the collective surgical teams’ nontechnical skills after observing recordings of actual OR environment.

Background:

The NOTSS system is a widely accepted tool to measure nontechnical skills of individual surgeons, and has mostly been used in the simulated setting. Surgical procedures are rarely performed by a single surgeon, but by a surgical team of attending surgeons, surgical assistants, and surgical trainees. Therefore, assessment of nontechnical skills may benefit from holistic assessment of the collective surgical teams.

Methods:

Five trained participants assessed surgical team and attending surgeon using the NOTSS system after watching ten 20-minute long videos obtained from live OR. A set of reference ratings was provided by a multidisciplinary expert committee. We performed analyses to assess system sensitivity; examine inter-rater reliability of ratings; investigate concurrent construct validity; and assess feasibility and acceptability of using the NOTSS system to measure surgical team performance.

Results:

There was adequate system sensitivity when comparing participants’ and reference ratings. Inter-rater reliability among the participants’ ratings was good except for decision-making category. The level of inter-rater reliability was similar when rating teams and attending surgeons. There was strong positive correlation between teams’ and attending surgeons’ NOTSS ratings at category [Pearson coefficient 0.86, 95% confidence interval (CI) 0.82–0.89] and element levels (0.83, 95% CI 0.80–0.85), demonstrating evidence of concurrent construct validity. The participants felt that the use of NOTSS system to measure teams’ nontechnical skills was acceptable and feasible to a fair extent.

Conclusion:

The NOTSS system, although developed for assessment of individual surgeons, is a useful tool for observing and rating surgical teams.
Long-term Survival in Esophageal Cancer After Minimally Invasive Compared to Open Esophagectomy
Authors: Gottlieb-Vedi Eivind , Kauppila Joonas H. , Malietzis George , Nilsson Magnus , Markar Sheraz R. , Lagergren Jesper
Published: March 2019

Objective:

Evaluate the existing literature comparing long-term survival after minimally invasive esophagectomy (MIE) and open esophagectomy (OE), and conduct a meta-analysis based on relevant studies.

Background:

It is unknown whether the choice between MIE and OE influences the long-term survival in esophageal cancer.

Methods:

A systematic electronic search for articles was performed in Medline, Embase, Web of Science, and Cochrane Library for studies comparing long-term survival after MIE and OE. Additionally, an extensive hand-search was conducted. The I
2 test and χ2 test were used to test for statistical heterogeneity. Publication bias and small-study effects were assessed using Egger test. A random-effects meta-analysis was performed for all-cause 5-year (main outcome) and 3-year mortality, and disease-specific 5-year and 3-year mortality. Meta-regression was performed for the 5-year mortality outcomes with adjustment for the covariates age, physical status, tumor stage, and neoadjuvant or adjuvant therapy. The results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs).

Results:

The review identified 55 relevant studies. Among all 14,592 patients, 7358 (50.4%) underwent MIE and 7234 (49.6%) underwent OE. The statistical heterogeneity was limited [I
2 = 12%, 95% confidence interval (CI) 0%–41%, and χ2 = 0.26] and the funnel plot was symmetrical both according to visual and statistical testing (Egger test = 0.32). Pooled analysis revealed 18% lower 5-year all-cause mortality after MIE compared with OE (HR 0.82, 95% CI 0.76–0.88). The meta-regression indicated no confounding.

Conclusions:

The long-term survival after MIE compares well with OE and may even be better. Thus, MIE can be recommended as a standard surgical approach for esophageal cancer.
The Impact of Preoperative Immune Modulating Nutrition on Outcomes in Patients Undergoing Surgery for Gastrointestinal Cancer
Authors: Adiamah Alfred , Skořepa Pavel , Weimann Arved , Lobo Dileep N.
Published: March 2019

Objective:

To define the influence of preoperative immune modulating nutrition (IMN) on postoperative outcomes in patients undergoing surgery for gastrointestinal cancer.

Background:

Although studies have shown that perioperative IMN may reduce postoperative infectious complications, many of these have included patients with benign and malignant disease, and the optimal timing of such an intervention is not clear.

Methods:

The Embase, Medline, and Cochrane databases were searched from 2000 to 2018, for prospective randomized controlled trials evaluating preoperative oral or enteral IMN in patients undergoing surgery for gastrointestinal cancer. The primary endpoint was the development of postoperative infectious complications. Secondary endpoints included postoperative noninfectious complications, length of stay, and up to 30-day mortality. The analysis was performed using RevMan v5.3 software.

Results:

Sixteen studies reporting on 1387 patients (715 IMN group, 672 control group) were included. Six of the included studies reported on a mixed population of patients undergoing all gastrointestinal cancer surgery. Of the remaining, 4 investigated IMN in colorectal cancer surgery, 2 in pancreatic surgery, and another 2 in patients undergoing surgery for gastric cancer. There was 1 study each on liver and esophageal cancer. The formulation of nutrition used in all studies in the treated patients was Impact (Novartis/Nestlé), which contains ω-3 fatty acids, arginine, and nucleotides. Preoperative IMN in patients undergoing surgery for gastrointestinal cancer reduced infectious complications [odds ratio (OR) 0.52, 95% confidence interval (CI) 0.38–0.71, P < 0.0001, I
2 = 16%, n = 1387] and length of hospital stay (weighted mean difference −1.57 days, 95% CI −2.48 to −0.66, P = 0.0007, I
2 = 34%, n = 995) when compared with control (isocaloric isonitrogeneous feed or normal diet). It, however, did not affect noninfectious complications (OR 0.98, 95% CI 0.73–1.33, P = 0.91, I
2 = 0%, n = 1303) or mortality (OR 0.55, 95% CI 0.18–1.68, P = 0.29, I
2 = 0%, n = 955).

Conclusion:

Given the significant impact on infectious complications and a tendency to shorten length of stay, preoperative IMN should be encouraged in routine practice in patients undergoing surgery for gastrointestinal cancer.
Clinical Significance of Alloantibodies in Hand Transplantation: A Multicenter Study
Authors: Berglund Erik , Andersen Ljungdahl Mette , Bogdanović Darko , Berglund David , Wadström Jonas , Kowalski Jan , Brandacher Gerald , Kamińska Dorota , Kaufman Christina L. , Talbot Simon G. , Azari Kodi , Landin Luis , Höhnke Christoph , Dwyer Karen M. , Cavadas Pedro C. , Thione Alessandro , Clarke Brendan , Kay Simon , Wilks Dan , Iyer Subramania , Iglesias Martin , Özkan Ömer , Özkan Özlenen , Krapf Johanna , Weissenbacher Annemarie , Petruzzo Palmina , Schneeberger Stefan
Published: March 2019

Background.

Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact.

Methods.

We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome.

Results.

Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge.

Conclusions.

While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.
Immune Cell Trafficking to the Liver
Authors: Chaudhry Sulemon , Emond Jean , Griesemer Adam
Published: March 2019

The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body’s immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
Chordoid Glioma Infiltrating Optic Structures
Authors: Sanda Nicolae , Mircea Claudiu-Nicolae , Bernier Michèle , Safran Avinoam B. , Aldea Sorin
Published: March 2019

Chordoid glioma of the third ventricle (CGTV) is a rare, slow-growing, World Health Organization Grade II glial tumor, with stereotyped localization in the anterior third ventricle. Despite being considered a noninvasive tumor, CGTV is usually associated with a poor clinical outcome due to its close proximity to important cerebral structures, such as the hypothalamus and visual pathways. Our patient with CGTV experienced visual involvement, but after subtotal surgical resection showed no evidence of progression at 5-year follow-up.
Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: Insights from accelerated molecular dynamics simulations
Authors: Bueren-Calabuig Juan A. , Bage Marcus , Cowling Victoria H. , Pisliakov Andrei V.
Published: March 2019

The RNA guanine-7 methyltransferase (RNMT) in complex with RNMT-Activating Miniprotein (RAM) catalyses the formation of a N7-methylated guanosine cap structure on the 5’ end of nascent RNA polymerase II transcripts. The mRNA cap protects the transcript from exonucleases and recruits cap-binding complexes that mediate RNA processing, export and translation. By using microsecond standard and accelerated molecular dynamics simulations, we provide for the first time a detailed molecular mechanism of allosteric regulation of RNMT by RAM. We show that RAM selects the RNMT active site conformations that are optimal for binding of substrates (AdoMet and the cap), thus enhancing their affinity. Furthermore, our results strongly suggest the likely scenario in which the cap binding promotes the subsequent AdoMet binding, consistent with the previously suggested cooperative binding model. By employing the dynamic network and community analyses, we revealed the underlying long-range allosteric networks and paths that are crucial for allosteric regulation by RAM. Our findings complement and explain previous experimental data on RNMT activity. Moreover, this study provides the most complete description of the cap and AdoMet binding poses and interactions within the enzyme’s active site. This information is critical for the drug discovery efforts that consider RNMT as a promising anti-cancer target.
Network resonance during slow-wave sleep facilitates memory consolidation through phase-coding
Authors: Skilling Quinton M. , Clawson Brittany C. , Eniwaye Bolaji , Shaver James , Ognjanovski Nicolette , Aton Sara J. , Zochowski Michal
Published: March 2019

Sleep plays a critical role in memory consolidation, however, the exact role that sleep and its effects on neural network dynamics play in this process is still unclear. Here, we combine computational and experimental approaches to study the dynamical, network-wide underpinnings of hippocampal memory consolidation during sleep. We provide data to support a novel hypothesis on the role of cellular resonance with sleep-associated theta band (4-12 Hz) hippocampal oscillations in this process. We show that increases in the stability of hippocampal memory representations after learning (which predicts successful memory consolidation) are mediated through emergent network-wide resonance and locking of neuronal activity to network oscillations. These changes arise in the network as a function of changes to network structure during learning, and mirror experimental findings in the hippocampus. Finally, we show that input-dependent pattern formation (e.g. “replay”) in the hippocampus during sleep states, together with spike timing dependent plasticity (STDP)-based memory consolidation, leads to universal network activity reorganization. This reorganization generates heterogeneous changes in neuronal spiking frequency, similar to what has been observed in a variety of brain circuits across periods of sleep. Our results support the hypothesis that sleep plays an active role in memory consolidation by switching the hippocampal network from rate-based to phase-based information representation. The mechanisms through which this occurs supports the integration of heterogeneous cell populations into memory traces.

Significance Statement

In this study, we provide a mechanistic explanation of how sleep selectively facilitates memory consolidation, through recruitment of heterogeneous neuronal populations and structural reorganization of the network into an engram. Specifically, we show that emergent theta band oscillations during sleep facilitate stabilization of memory representations via spike timing dependent reinforcement. This stabilization, together with STDP, allows for systematic reorganization of synaptic connections within these populations, universally redistributing firing rates of participating neurons. Simultaneously, network oscillations facilitate a switch from rate-to phase-coding of information among neuronal populations with highly heterogenous firing frequencies, incorporating more neurons into the engram. Our results reconcile discrepant findings on network reorganization during sleep, and demonstrate a clear mechanism for both strengthening and weakening of synaptic efficacy during sleep.
Temporal Metrics of Multisensory Processing Change in the Elderly
Authors: Basharat Aysha , Mahoney Jeannette R. , Michael-Barnett-Cowan
Published: March 2019

Older adults exhibit greater multisensory response time (RT) facilitation by violating the race model more than younger adults; this is commonly interpreted as an enhancement in perception. Older adults typically exhibit wider temporal binding windows (TBWs) and points of subjective simultaneity (PSS) that are farther from true simultaneity as compared to younger adults when simultaneity judgment (SJ) and temporal order judgment (TOJ) tasks are utilized; this is commonly interpreted as an impairment in perception. Here we explore the relation between the three tasks in younger and older adults in order to better understand the underlying mechanisms that subserve audiovisual multisensory temporal processing. Our results confirm previous reports showing that audiovisual RT, TBWs and PSSs change with age, and we show for the first time a significant positive relation between the magnitude of race model violation in younger adults as a function of the PSS obtained from the audiovisual TOJ task with (r: 0.49,p: 0.007), that is absent among the elderly (r: 0.13,p: 0.58). Furthermore, we find no evidence for the relation between race model violation as a function of the PSS obtained from the audiovisual SJ task in both younger (r: −0.01,p: 0.94) and older adults (r: 0.1,p: 0.66). Our results confirm previous reports that i) audiovisual temporal processing changes with age; ii) there is evidence for distinct neural networks involved in simultaneity and temporal order perception; and iii) common processing between race model violation and temporal order judgment is impaired in the elderly.
A lineage-resolved molecular atlas of C. elegans embryogenesis at single cell resolution
Authors: Packer Jonathan S. , Zhu Qin , Huynh Chau , Sivaramakrishnan Priya , Preston Elicia , Dueck Hannah , Stefanik Derek , Tan Kai , Trapnell Cole , Kim Junhyong , Waterston Robert H. , Murray John I.
Published: March 2019

C. elegans is an animal with few cells, but a striking diversity of cell types. Here, we characterize the molecular basis for their specification by profiling the transcriptomes of 84,625 single embryonic cells. We identify 284 terminal and pre-terminal cell types, mapping most single cell transcriptomes to their exact position in C. elegans’ invariant lineage. We use these annotations to perform the first quantitative analysis of the relationship between lineage and the transcriptome for a whole organism. We find that a strong lineage-transcriptome correlation in the early embryo breaks down in the final two cell divisions as cells adopt their terminal fates and that most distinct lineages that produce the same anatomical cell type converge to a homogenous transcriptomic state. Users can explore our data with a graphical application “VisCello”.
Machine learning-guided channelrhodopsin engineering enables minimally-invasive optogenetics
Authors: Bedbrook Claire N. , Yang Kevin K. , Robinson J. Elliott , Gradinaru Viviana , Arnold Frances H.
Published: March 2019

We have engineered light-gated channelrhodopsins (ChRs) whose current strength and light sensitivity enable minimally-invasive neuronal circuit interrogation. Current ChR tools applied to the mammalian brain require intracranial surgery for transgene delivery and implantation of invasive fiber-optic cables to produce light-dependent activation of a small volume of brain tissue [~1 mm3]. To enable optogenetics for large brain volumes and without the need for invasive implants, our ChR engineering approach leverages the significant literature of ChR variants to train statistical models for the design of new, high-performance ChRs. With Gaussian Process models trained on a limited experimental set of 102 functionally characterized ChR variants, we designed high-photocurrent ChRs with unprecedented light sensitivity; three of these, ChRger1, ChRger2, and ChRger3, enable optogenetic activation of the nervous system via minimally-invasive systemic transgene delivery with rAAV-PHP.eB, which was not possible previously due to low per-cell transgene copy produced by systemic delivery. These engineered ChRs enable light-induced neuronal excitation without invasive intracranial surgery for virus delivery or fiber optic implantation, i.e. they enable minimally-invasive optogenetics.
C-type lectins CTL4 and CTLMA2: conserved heterodimeric structure and glycan specificity in Anopheles mosquitoes
Authors: Bishnoi Ritika , Contet Alicia , Day Christopher J , Hou David Chun-Feng , Profitt Lauren A. , Singla Deepak , Sousa Gregory L. , Jennings Michael P , Povelones Michael , Valentine Ann M. , Baxter Richard H. G.
Published: March 2019

Abstract

The C-type lectins CTL4 and CTLMA2 cooperatively influence Plasmodium infection in the malaria vector Anopheles. Here we report the purification and biochemical characterization of CTL4 and CTLMA2 from An. gambiae and An. albimanus. CTL4 and CTLMA2 are known to form a disulfide-bridged heterodimer via an N-terminal tri-cysteine CXCPC motif. We demonstrate in vitro that CTL4 and CTLMA2 intermolecular disulfide formation is promiscuous within this motif. Furthermore, CTL4 and CTLMA2 exhibit charge complementarity that promotes the formation of higher oligomeric states at physiological pH. Both lectins bind specific sugars, with an apparent preference for glycosaminoglycan motifs comprising β1-3/β1-4 linkages between glucose (Glc), galactose (Gal) and their respective hexosamines. Small-angle x-ray scattering data supports a compact heterodimer between the CTL domains. Recombinant CTL4/CTLMA2 is functional in vivo, reversing the enhancement of phenoloxidase activity in dsCTL4-treated mosquitoes. We propose these molecular features underline a common function for CTL4/CTLMA2 in mosquitoes, with species and strain-specific variation in degrees of activity in response to Plasmodium infection.

Author Summary

Mosquitoes of the genus Anopheles are vectors for the single-celled parasite Plasmodium, the causative agent of malaria. Mosquitoes, like all insects, utilize the process of melanization for both wound healing and defense against pathogens. CTL4 and CTLMA2 are two proteins found in Anopheles mosquitoes that act as inhibitors of melanization, so understanding their molecular function is important to understanding the immune response of Anopheles mosquitoes to Plasmodium infection. We have purified CTL4 and CTLMA2 from two species of Anopheles and studied their molecular properties with a variety of biochemical and biophysical techniques. We also verified that our purified protein is functional by injecting it into mosquitoes. We learned that CTL4 and CTLMA2 are joined together by a disulfide bond between any one of three cysteine residues near the N-terminus of each protein. The CTL4/CTLMA2 complex is compact, but can associate into larger structures in solution, probably because of a loop in each protein that carries an opposite charge. The proteins cooperatively bind calcium and sugars, specifically glycosaminoglycan sugars, which are typically present in the connective tissues of insects. This information will aid in further investigations of the function of CTL4 and CTLMA2.
Influenza A matrix protein M1 is sufficient to induce lipid membrane deformation
Authors: Dahmani Ismail , Ludwig Kai , Chiantia Salvatore
Published: March 2019

The matrix protein M1 of the Influenza A virus is considered to mediate viral assembly and budding at the plasma membrane (PM) of infected cells. In order for a new viral particle to form, the PM lipid bilayer has to bend into a vesicle towards the extracellular side. Studies in cellular models have proposed that different viral proteins might be responsible for inducing membrane curvature in this context (including M1), but a clear consensus has not been reached. In this study, we use a combination of fluorescence microscopy, cryogenic transmission electron microscopy (cryo-TEM), cryo-electron tomography (cryo-ET) and scanning fluorescence correlation spectroscopy (sFCS) to investigate M1-induced membrane deformation in biophysical models of the PM. Our results indicate that M1 is indeed capable to cause membrane curvature in lipid bilayers containing negatively-charged lipids, in the absence of other viral components. Furthermore, we prove that simple protein binding is not sufficient to induce membrane restructuring. Rather, it appears that stable M1-M1 interactions and multimer formation are required in order to alter the bilayer three-dimensional structure, through the formation of a protein scaffold. Finally, our results suggest that, in a physiological context, M1-induced membrane deformation might be modulated by the initial bilayer curvature and the lateral organization of membrane components (i.e. the presence of lipid domains).
Social status in mouse social hierarchies is associated with variation in oxytocin and vasopressin 1a receptor densities
Authors: Lee Won , Hiura Lisa C , Yang Eilene , Broekman Katherine A , Ophir Alexander G , Curley James P
Published: March 2019

The neuropeptides oxytocin and vasopressin and their receptors have established roles in the regulation of mammalian social behavior including parental care, sex, affiliation and pair-bonding, but less is known regarding their relationship to social dominance and subordination within social hierarchies. We have previously demonstrated that male mice can form stable linear dominance hierarchies with individuals occupying one of three classes of social status: alpha, subdominant, subordinate. Alpha males exhibit high levels of aggression and rarely receive aggression. Subdominant males exhibit aggression towards subordinate males but also receive aggression from more dominant individuals. Subordinate males rarely exhibit aggression and receive aggression from more dominant males. Here, we examined whether variation in social status was associated with levels of oxytocin (OTR) and vasopressin 1a (V1aR) receptor binding in socially relevant brain regions. We found that socially dominant males had significantly higher OTR binding in the nucleus accumbens core than subordinate animals. Alpha males also had higher OTR binding in the anterior olfactory nucleus, posterior part of the cortical amygdala and rostral lateral septum compared to more subordinate individuals. Conversely, alpha males had lower V1aR binding in the rostral lateral septum and lateral preoptic area compared to subordinates. These observed relationships have two potential explanations. Preexisting individual differences in the patterns of OTR and V1aR binding may underlie behavioral differences that promote or inhibit the acquisition of social status. More likely, the differential social environments experienced by dominant and subordinate animals may shift receptor expression, potentially facilitating the expression of adaptive social behaviors.

Highlights

Mice living in social hierarchies express different levels of oxytocin receptor (OTR) and vasopressin 1a receptor (V1aR) binding in various brain regions according to their social status.

Alphas and subdominants have higher OTR binding in the nucleus accumbens compared to subordinates.

Alphas have higher OTR binding in the anterior olfactory nucleus compared to subdominants and subordinates.

Alphas have higher OTR and lower V1aR binding in the rostral lateral septum compared to subordinates.

Alphas have lower V1aR binding in the lateral preoptic area compared to subordinates.
Sensitive determination of proteolytic proteoforms in limited microscale proteome samples
Authors: Weng Samuel S.H. , Demir Fatih , Ergin Enes K. , Dirnberger Sabrina , Uzozie Anuli , Tuscher Domenic , Nierves Lorenz , Tsui Janice , Huesgen Pitter F. , Lange Philipp F.
Published: March 2019

Protein N-termini reveal fundamental regulatory mechanisms and their perturbation in disease. Current terminome identification approaches are limited to whole organs or expandable cultured cells. We present a robust, sensitive, scalable and automatable method for system-wide identification of thousands of N-termini from minute samples. Identification of distinct N- terminal profiles in sorted immune cells, subcellular compartments, clinical biopsies, plasma from pediatric cancer patients, and protease substrates in Arabidopsis seedlings demonstrate broad applicability.
A Framework for Collective Behavior in Plant Inspired Growth-Driven Systems, Based on Kinematics of Allotropism
Authors: Bastien Renaud , Porat Amir , Meroz Yasmine
Published: March 2019

A variety of biological systems are not motile, but sessile in nature, relying on growth as the main driver of their movement. Groups of such growing organisms can form complex structures, such as the functional architecture of growing axons, or the adaptive structure of plant root systems. These processes are not yet understood, however the decentralized growth dynamics bear similarities to the collective behavior observed in groups of motile organisms, such as flocks of birds or schools of fish. Equivalent growth mechanisms make these systems amenable to a theoretical framework inspired by tropic responses of plants, where growth is considered implicitly as the driver of the observed bending towards a stimulus. We introduce two new concepts related to plant tropisms: point tropism, the response of a plant to a nearby point signal source, and allotropism, the growth-driven response of plant organs to neighboring plants. We first analytically and numerically investigate the 2D dynamics of single organs responding to point signals fixed in space. Building on this we study pairs of organs interacting via allotropism, i.e.each organ senses signals emitted at the tip of their neighbor and responds accordingly. In the case of local sensing we find a rich phase space. We describe the different phases, as well as the sharp transitions between them. We also find that the form of the phase space depends on initial conditions. This work sets the stage towards a theoretical framework for the investigation and understanding of systems of interacting growth-driven individuals.
The expanding toolkit for structural biology: synchrotrons, X-ray lasers and cryoEM
Authors: Muench Stephen P. , Antonyuk Svetlana V. , Hasnain S. Samar
Published: March 2019

Structural biology continues to benefit from an expanding toolkit, which is helping to gain unprecedented insight into the assembly and organization of multi-protein machineries, enzyme mechanisms and ligand/inhibitor binding. The combination of results from X-ray free-electron lasers (XFELs), modern synchrotron crystallographic beamlines and cryo-electron microscopy (cryoEM) is proving to be particularly powerful. The highly brilliant undulator beamlines at modern synchrotron facilities have empowered the crystallographic revolution of high-throughput structure determination at high resolution. The brilliance of the X-rays at these crystallographic beamlines has enabled this to be achieved using microcrystals, but at the expense of an increased absorbed X-ray dose and a consequent vulnerability to radiation-induced changes. The advent of serial femtosecond crystallography (SFX) with X-ray free-electron lasers provides a new opportunity in which damage-free structures can be obtained from much smaller crystals (2 µm) and more complex macromolecules, including membrane proteins and multi-protein complexes. For redox enzymes, SFX provides a unique opportunity by providing damage-free structures at both cryogenic and ambient temperatures. The promise of being able to visualize macromolecular structures and complexes at high resolution without the need for crystals using X-rays has remained a dream, but recent technological advancements in cryoEM have made this come true and hardly a month goes by when the structure of a new/novel macromolecular assembly is not revealed. The uniqueness of cryoEM in providing structural information for multi-protein complexes, particularly membrane proteins, has been demonstrated by examples such as respirasomes. The synergistic use of cryoEM and crystallography in lead-compound optimization is highlighted by the example of the visualization of antimalarial compounds in cytochromebc1. In this short review, using some recent examples including our own work, we share the excitement of these powerful structural biology methods.
Older age is associated with a reduced likelihood of ambulance transport to a trauma centre after major trauma in Perth
Authors: Brown Elizabeth , Tohira Hideo , Bailey Paul , Fatovich Daniel , Pereira Gavin , Finn Judith
Published: March 2019

Objective

To describe the characteristics and outcomes of older adult (≥65 years) major trauma patients in comparison with younger adults (16–64 years). To determine whether older age is associated with a reduced likelihood of transport (directly or indirectly) to a major trauma centre and whether this is associated with in‐hospital mortality.

Methods

A retrospective cohort study of major trauma patients transported to hospital by St John Ambulance paramedics in Perth, Western Australia, between 1 January 2013 and 31 December 2016. Multivariate logistic regression was used to test the relationship between age and major trauma centre transport. Multivariate logistic regression analysis using inverse probability of treatment weighting was used to determine if major trauma centre transport was associated with in‐hospital mortality in older adults.

Results

One thousand six hundred and twenty‐five patients were included; of these 576 (35%) were ≥65 years. In comparison with younger adults, older adults had more falls as their mechanism of injury (n = 358 [62%] versus n = 102 [10%], P ≤ 0.001) and more major head injuries (n = 472 [82%] versus n = 609 [58%], P ≤ 0.001). Older adults had lower odds (adjusted odds ratio 0.52, 95% confidence interval [CI] 0.35–0.78) of major trauma centre transport and this was associated with 1.7 times the likelihood of in‐hospital mortality (95% CI 1.04–2.7).

Conclusions

Older adults who were not transported to the trauma centre had an increased odds of in‐hospital mortality. However, older age was associated with a significantly reduced likelihood of trauma centre transport. With the aging population, the development of specific prehospital triage criteria to enable the complexities of this higher‐risk population to be identified is important.