bluuebunny/crossref_metadata_2025 huggingface dataset:
Preinjury and Postinjury Factors That Predict Sports-Related Concussion and Clinical Recovery Time
Authors: Putukian Margot , Riegler Kaitlin , Amalfe Stephanie , Bruce Jared , Echemendia Ruben
Published: December 2018

Objectives:

To evaluate the relationship between preinjury risk factors (RFs) and subsequent occurrence of concussion and examine whether preinjury RFs or postinjury assessments predict clinical recovery in collegiate athletes.

Methods:

Risk factors (sex, sport, and self-report history of concussion, migraine, attention-deficit disorder, learning disability, depression, and anxiety) and Sport Concussion Assessment Tool (SCAT), depression/anxiety screenings, and neuropsychological testing were obtained before the season. For athletes who sustained concussion, RFs, postinjury SCAT, neuropsychological assessment, and clinical recovery were assessed.

Results:

We assessed 1152 athletes (69% male) at baseline and 145 (75% male) after subsequent concussion diagnosis. Only sport type (Wald = 40.29, P = 0.007) and concussion history (Wald = 9.91, P = 0.007) accounted for unique variance in subsequent concussion. Of athletes followed until full recovery, mean days until symptom-free (DUSF) was 9.84 ± 11.11 days (n = 138, median = 5 days, range = 1-86) and mean days until full return to play (DUFRTP) was 20.21 ± 19.17 (n = 98, median = 20.21, range = 4-150). None of the RFs or baseline testing measures were associated with DUSF or DUFRTP (P's > 0.05). After injury, athletes who reported more total symptoms (r

s
= 0.31, P < 0.001) and higher symptom severity (r

s
= 0.33, P < 0.001) exhibited longer DUSF. Days until symptom-free correlated with DUFRTP (r

s
= 0.75, P < 0.001). Among athletes assessed within 2 days after injury, DUSF was associated with Immediate Postconcussion Assessment and Cognitive Test visual motor (r

s
= −0.31, P = 0.004), reaction time (r

s
= 0.40, P < 0.001), and symptom score (r

s
= 0.54, P < 0.001).

Conclusions:

Only sport type and concussion history predicted subsequent occurrence of concussion, and none of the RFs or baseline measures predicted clinical recovery. Immediate postinjury assessments, including symptom number and severity, and select clinical measures predicted longer clinical recovery.
Systematic review addressing nurse practitioner reimbursement policy: Part one of a four-part series on critical topics identified by the 2015 nurse practitioner research agenda
Authors: Harkless Gene , Vece Loretta
Published: December 2018

Background and purpose:

The growth and sustainability of nurse practitioners (NPs) requires transparent, fair and equitable reimbursement policies. Complicating this issue is variation in reimbursement policy within and across federal, state, and other payers. Even with explicit regulations, there remain questions on how reimbursement policies are covertly operationalized in practice. This systematic review aims to identify knowledge gaps related to reimbursement policy issues and outlines recommendations for further research.

Methods:

Eight major databases were searched using terms including “nurse practitioner,” “reimbursement,” “policy,” and “research,” limited to the United States and inclusive of December 2006–September 2017. Articles meeting the inclusion criteria were analyzed for themes and gaps.

Conclusion:

The final review includes 17 articles identifying themes including state-determined Medicaid reimbursement and scope of practice legislation shapes NP clinical practice; NPs as identified primary care providers: credentialing and contracting; reimbursement parity; and “incident to” billing. Moreover, there is evidence of discriminatory policies that disadvantage NPs and limit their access to patients, direct billing, and direct reimbursement.

Implications for practice:

Future research needs to focus on outcomes of discriminatory, as well as supportive, reimbursement policies in organizations, and their influence on patient access and quality care.
Naunton's Masking Dilemma Revisited
Authors: Seneviratne Sheran , McNeill Celene , Greenberg Simon L. , Kong Jonathan
Published: December 2018

Background:

Pure-tone audiometry is essential in diagnosing clinical hearing loss. Masking of the nontest ear is mandatory for determining accurate hearing thresholds in the presence of asymmetrical levels between the two ears and for ascertaining the presence of a conductive hearing loss. Paradoxically, over masking occurs when the intensity of the required masking noise to the contralateral ear is such that it exceeds interaural cranial attenuation by an amount sufficient to mask the test ear. Ralph F Naunton was the first to describe this phenomenon, which has since been known as “Naunton's masking dilemma.”

Methods:

A formula was derived mathematically to predict when Naunton's masking dilemma might occur in air and bone conduction. Review of Ralph F Naunton's primary works and related publications was performed.

Results:

Our derived mathematical formulae predict when “Naunton's masking dilemma” may occur. During air conduction testing, a masking dilemma may occur when the sum of the air/bone gaps is greater than or equal to twice the interaural attenuation minus 15 dB (Σ ABG

NTE+TE

≥ 2 × IA – 15 dB). During bone conduction testing, a masking dilemma may occur when the air-bone gap of the nontest ear is greater than or equal to the interaural attenuation minus 15 dB (ABG

NTE

≥ IA

AIR

− 15 dB).

Conclusion:

Naunton's masking dilemma imposes a significant limitation to conventional audiometric testing. To the best of our knowledge, we think this is the first time that Naunton's masking dilemma has been represented in a simplified mathematical equation.
Perioperative Recording of Cochlear Implant Evoked Brain Stem Responses After Removal of the Intralabyrinthine Portion of a Vestibular Schwannoma in a Patient with NF2
Authors: Rahne Torsten , Hocke Thomas , Strauß Christian , Kösling Sabrina , Fröhlich Laura , Plontke Stefan K.
Published: December 2018

Objective:

To predict and optimize hearing outcomes with a cochlear implant (CI) in patients with intracochlear schwannoma and neurofibromatosis type 2 (NF2).

Patient:

A patient with NF2 and bilateral deafness.

Interventions:

The intracochlear portion of a vestibular schwannoma was removed with a partial cochleoectomy. During the procedure, a CI was implanted.

Main Outcome Measures:

Perioperatively, electrically evoked auditory brainstem responses (eABRs) were recorded with a novel intracochlear, CI-evoked, broad band stimulus to support the decision to implant a CI.

Results:

We found positive eABR responses, with thresholds at around the 200 current level. The eV wave was discernible at all stimulated electrodes, with a prolonged latency of about 6.5 ms. The eIII wave was detected at electrodes 9 and 13, with a latency of 4.5 ms. The acoustic reflex was detectable at all stimulated electrodes. Subjective auditory perception could be achieved by stimulating 3 days after surgery. In open-set word recognition, the patient achieved 60% recognition of monosyllables after the first audio processor fitting and 100% 1 month later.

Conclusions:

After a partial cochleoectomy, this method may serve as a peri-operative, objective assessment of cochlear nerve integrity that could potentially impact the prediction of CI performance. Potential future applications might be assessments of cochlear nerve integrity in patients with inner ear malformations, radiologically suspected cochlear nerve deficiencies, and resected or irradiated spontaneous vestibular schwannomas or NF2.
Evaluation of Coupling Efficiency in Round Window Vibroplasty With a New Handheld Probe
Authors: Schwarz David , Pazen David , Gostian Antoniu-Oreste , Lüers Jan-Christoffer , Hüttenbrink Karl Bernd
Published: December 2018

Hypothesis:

A handheld measuring probe was developed that analyzes the vibration characteristics of the stapes footplate after backward stimulation of the cochlea in round window vibroplasty. In temporal bone experiments, the measuring accuracy of the probe was tested.

Background:

In round window vibroplasty, the effectiveness of the transmitted vibrations into the inner ear is provided with limited visual and tactile information. Currently, there is no objective measuring tool available.

Methods:

In five unfixed temporal bones, a floating mass transducer was coupled to the round window membrane. During the excitation with different voltage levels (0, 5, 25, 100, 300 mV root mean square) corresponding to 0, 80, 94, 106, and 116 dB equivalent ear canal sound pressure respectively, the deflections of the footplate were recorded in parallel by laser Doppler vibrometry and the measuring probe.

Results:

The probe allowed for differentiation of the coupling efficiency. The measured footplate vibrations from the excitation levels of 106 dB (and 116 dB) were statistically significant compared with the testing without excitation. The footplate deflections determined in parallel by laser Doppler vibrometry showed comparable results.

Conclusion:

In principal, the newly developed measuring probe allows for measuring the quality of retrograde cochlear excitation in a round window vibroplasty by detecting footplate vibrations. Further developments are directed for its application in clinical, intraoperative procedures.
Decreased Fecal Bacterial Diversity and Altered Microbiome in Children Colonized With Clostridium difficile
Authors: Chen Lea Ann , Hourigan Suchitra K. , Grigoryan Zoya , Gao Zhan , Clemente Jose C. , Rideout Jai Ram , Chirumamilla Sankar , Rabidazeh Shervin , Saeed Shehzad , Elson Charles O. , Oliva‐Hemker Maria , Blaser Martin J. , Sears Cynthia L.
Published: December 2018

Objectives:

The gut microbiome is believed to play a role in the susceptibility to and treatment of Clostridium difficile infections (CDIs). It is, however, unknown whether the gut microbiome is also affected by asymptomatic C difficile colonization. Our study aimed to evaluate the fecal microbiome of children based on C difficile colonization, and CDI risk factors, including antibiotic use and comorbid inflammatory bowel disease (IBD).

Methods:

Subjects with IBD and non‐IBD controls were prospectively enrolled from pediatric clinics for a biobanking project (n = 113). A fecal sample was collected from each subject for research purposes only and was evaluated for asymptomatic toxigenic C difficile colonization. Fecal microbiome composition was determined by 16S rRNA sequencing.

Results:

We found reduced bacterial diversity and altered microbiome composition in subjects with C difficile colonization, concurrent antibiotic use, and/or concomitant IBD (all P < 0.05). Accounting for antibiotic use and IBD status, children colonized with C difficile had significant enrichment in taxa from the genera Ruminococcus, Eggerthella, and Clostridium. Children without C difficile had increased relative abundances of Faecalibacterium and Rikenellaceae. Imputed metagenomic functions of those colonized were enriched for genes in oxidative phosphorylation and beta‐lactam resistance, whereas in the subjects without C difficile, several functions in translation and metabolism were over‐represented.

Conclusions:

In children, C difficile colonization, or factors that predispose to colonization such as antibiotic use and IBD status were associated with decreased gut bacterial diversity and altered microbiome composition. Averting such microbiome alterations may be a method to prevent or treat CDI.
Relationship between body image and physical functioning following rehabilitation for lower-limb amputation
Authors: Desrochers Jessica , Frengopoulos Courtney , Payne Michael W.C. , Viana Ricardo , Hunter Susan W.
Published: December 2018

The aim of the present study was to evaluate change in body image and the association between body image at discharge and mobility 4 months after rehabilitation. A prospective cohort comprising adults older than or equal to 50 years of age undergoing rehabilitation for first major lower-limb amputation at an inpatient prosthetic rehabilitation program were assessed at discharge and 4 months after rehabilitation. Paired t-tests compared total Amputee Body Image Scale (ABIS), gait velocity, and L-test scores between discharge (T1) and 4 months (T2). Multivariable linear regression assessed relationship between ABIS scores and mobility. Nineteen participants completed assessments (mean±SD age=60.86±6.85 years; 63.20% male patients). Body image changed from T1 (43.58±7.83) to T2 (48.26±12.21), but was not statistically significant (P=0.063). Mobility significantly improved at T2. ABIS scores at T1 were not associated with mobility at T2. Mobility improved after discharge but was not related to body image at T1. Additional research on the impact of body image perception on patient outcomes after rehabilitation is needed.
Application of Caring Theory to Nursing Care of Women Experiencing Stillbirth
Authors: Nurse-Clarke Natasha , DiCicco-Bloom Barbara , Limbo Rana
Published: December 2018

Purpose:

The purpose of this study was to determine the extent to which labor and delivery nurses used the tenets of Swanson's middle-range theory to care for women whose babies were stillborn.

Study Design and Methods:

A secondary analysis of qualitative in-depth interview data from 20 labor and delivery nurses obtained during a recent grounded theory study was conducted using the directed content analysis method. The five caring processes as described in Swanson's theory were used as a priori codes to conduct the analysis.

Results:

Nursing care of a woman experiencing a stillbirth included finding a way to connect with her and to understand what she was experiencing (knowing), spending extra time with her (being with), protecting her and preserving her dignity (doing for), providing information and explanations in a clear and methodical manner (enabling), and ensuring that she did not blame herself to facilitate the grieving/healing process (maintaining belief).

Clinical Implications:

The caring processes outlined in Swanson's theory of caring provide a valuable guide that can be used when caring for women experiencing stillbirth.
Bleeding Meckel Diverticulum: A Retrospective Analysis of Computed Tomography Enterography Findings
Authors: Chen Ying , Tang Yonghua , Hu Chunhong , Chen Shuangqing
Published: December 2018

Objective

The aim of this study was to evaluate the computed tomography enterography (CTE) characteristics of bleeding Meckel diverticulum.

Methods

The CTE images of 35 patients with Meckel diverticulum and gastrointestinal bleeding were retrospectively evaluated.

Results

Meckel diverticulum was visualized in 33 of 35 patients and located in the right lower abdomen (20/33), midline lower abdomen (8/33), left lower abdomen (3/33), or paramedially near the umbilicus (2/33). The Meckel diverticulum was visualized on the antimesenteric side of the ileum in 16 patients (48.5%) and pointed toward the umbilicus in 10 (30.3%). The diverticulum appeared as a blind-ended tubular (22/33 [66.7%]) or saccular (11/33 [33.3%]) bowel segment. Separated supplying vessel was identified in 15 patients (45.5%) and associated with diverticulum (P = 0.037). The ectopic tissue was pathologically confirmed in 11 (33.3%) of 33 patients and was associated with diverticular nodules (P = 0.002).

Conclusions

Awareness of CTE features could aid in the preoperative assessment of bleeding Meckel diverticulum.
Maxillary Sinus Mass as First Presentation of Silent Metastatic Renal Cell Carcinoma
Authors: Moffa Antonio , Casale Manuele , Moffa Angelo Pio , Grilli Gianluigi , Grilli Gianpaolo , Macarini Luca , Cassano Michele
Published: December 2018

Renal cell carcinoma accounts for more than 3% of all malignant diseases. Metastatic disease to the head and neck ranges from 15% to 30%. The 5-year survival rate after nephrectomy is 60% to 75%, but with multiorgan metastases the 5-year survival rate is significantly lower, 0% to 7%. The authors present the case of a patient with a progressive, painless right facial swelling over the maxillary area of 3-month's duration associated with a considerable decrease of right visual acuity. Cranial computed tomography scan and magnetic resonance imaging showed a maxillary sinus mass extending to the orbital cavity and 2 choroidal and retinal thickenings. The mass biopsy was performed by Caldwell–Luc procedure and pathology report suggested metastatic renal cell carcinoma. Following histological findings, a total body computed tomography scan showed a heterogeneous mass at the middle-lower portion of the right kidney measuring approximately 8 × 12 × 4 cm with associated ipsilateral renal vein thrombosis. The patient was referred to the Oncology Department for further treatment. Unfortunately, 3 months after the mass biopsy, the patient died due to complications of multiorgan failure. Although metastases of renal cell carcinoma to the head and neck are very rare, it should be first suspected when investigating a metastatic tumor in this region.
The Management of Mesh Infection After Laparoscopic Inguinal Hernia Repair
Authors: Yang Huiqi , Liu Yiting , Chen Jie , Shen Yingmo
Published: December 2018

We present our experience in managing mesh infection after laparoscopic inguinal hernia repair. We analyzed 19 patients with extensive mesh infection treated between 2012 and 2017 via laparoscopic mesh excision after preoperative workup. After mesh removal and insertion of a drain into the preperitoneal space, the peritoneal flap was closed with 3/0 absorbable consecutive suture. The operative course in all patients was uneventful. Sigmoidectomy for a fistula was required in 1 patient. Two patients required a second laparoscopic surgery for infection on the contralateral side and residual mesh around the pubic bone. In total, 3 cases of recurrence were identified during follow-up. Laparoscopic mesh excision is an effective and minimally invasive method for the management of infection that also avoids unnecessary disruption of healthy layers of the abdominal wall.
Immune potentiator for increased safety and improved protection of vaccines by NF-kB modulation
Authors: Moser Brittany A. , Steinhardt Rachel C. , Escalante-Buendia Yoseline , Boltz David A. , Barker Kaylynn M. , Yoo Stan , McGonnigal Bethany G. , Esser-Kahn Aaron P.
Published: December 2018

Many modern vaccines include adjuvants that activate the immune system and provide an enhanced humoral or cellular response. Current approved adjuvants are unable to provide desired responses against some pathogens (e.g. HIV or dengue). Many new adjuvants have been developed and demonstrate promising results, but side effects from the inflammatory response induced by these adjuvants have resulted in limited FDA approvals. No adjuvants yet possess the capability to independently modulate inflammation and protection. Here we demonstrate a method to limit inflammation and side effects associated with vaccination while retaining the protective responses using a variety of promising adjuvants. To accomplish this, we combined a selective NF-kB inhibitor with the immune adjuvant. The resulting vaccines reduce systemic inflammation and boost antibody responses. In an influenza challenge model, we demonstrate that this approach enhances protection. This method is generalizable across a broad range of adjuvants and antigens. We anticipate these studies will lead to a novel approach to vaccine formulation design that may prove general across a wide range of adjuvants, enabling their greater use in the public realm.
Structure-specific regulation of nutrient absorption, metabolism and transfer in arbuscular mycorrhizal fungi
Authors: Kameoka Hiromu , Maeda Taro , Okuma Nao , Kawaguchi Masayoshi
Published: December 2018

Arbuscular mycorrhizal fungi (AMF) establish symbiotic relationships with most land plants, mainly for the purpose of nutrient exchange. Many studies have revealed the regulation of absorption, metabolism, and transfer of nutrients in AMF and the genes involved in these processes. However, the spatial regulation of the genes among the structures comprising each developmental stage are not well understood. Here, we demonstrate the structure-specific transcriptome of the model AMF species, Rhizophagus irregularis. We performed an ultra-low input RNA-seq analysis, SMART-seq2, comparing five extraradical structures, germ tubes, runner hyphae, branched absorbing structures, immature spores, and mature spores. In addition, we reanalyzed the recently reported RNA-seq data comparing intraradical hyphae and arbuscules. Our analyses captured the distinct features of each structure and revealed the structure-specific expression patterns of genes related to absorption, metabolism, and transfer of nutrients. Of note, the transcriptional profiles suggest the distinct functions of branched absorbing structures in nutrient absorption. These findings provide a comprehensive dataset to advance our understanding of the transcriptional dynamics of fungal nutrition in this symbiotic system.
Nerves innervating copulatory organs show common FMRFamide, FVRIamide, MIP and serotonin immunoreactivity patterns across Dinophilidae (Annelida) indicating their conserved role in copulatory behaviour
Authors: Kerbl Alexandra , Tolstrup Emilie Winther , Worsaae Katrine
Published: December 2018

Background: Males of the microscopic annelid family Dinophilidae use their prominent glandomuscular copulatory organ (penis) to enzymatically dissolve the female's epidermis and thereafter inject sperm. In order to test for putative conserved copulatory structures and neural orchestration across three dinophilid species, we reconstructed the reproductive myo- and neuroanatomy and mapped neurotransmitter immunoreactivity patterns of two specific markers with reported roles in invertebrate male mating behaviour (FVRIamide, MIP) and three general neural markers (acetylated α-tubulin, serotonin, FMRFamide).
Results: Seminal vesicles (one or two pairs), surrounded by a thin layer of longitudinal and circular muscles and innervated by nerve fibres, are found between testes and copulatory organ in the larger males of Dinophilus vorticoides and Trilobodrilus axi, but are missing in the only 0.05 mm long D. gyrociliatus dwarf males. The midventral copulatory organ is in all species composed of an outer muscular penis sheath and an inner penis cone. Nerves encircle the organ equatorially, either as a ring-shaped circumpenial fibre mass or as dorsal and ventral commissures, which are connected to the ventrolateral nerve cords. All three examined dinophilids show similar serotonin-, FMRFamide-, and FVRIamide-like immunoreactivity patterns in the nerves surrounding the penis, supporting the general involvement of these neurotransmitters in copulatory behaviour in meiofaunal annelids. MIP-like immunoreactivity is restricted to the circumpenial fibre mass in D. gyrociliatus and commissures around the penis in T. axi (but not found in D. vorticoides), indicating its role in controlling the copulatory organ.
Conclusions: The overall myo- and neuroanatomy of the reproductive organs is rather similar in the three studied species, suggesting a common ancestry of the unpaired glandomuscular copulatory organ and its innervation in Dinophilidae. This is furthermore supported by the similar immunoreactivity patterns of the tested neurotransmitters around the penis. Smaller differences in the immunoreactivity patterns around the seminal vesicles and spermioducts might account for additional, individual traits. We thus show morphological support for the putatively conserved role of FMRFamide, FVRIamide, MIP and serotonin in dinophilid copulatory behaviour.
Collateral development and arteriogenesis in hindlimbs of domestic swine after ligation of arterial inflow
Authors: Patel NS , Gao Y , Aravind S , Fuglestad M , Casale GP , Pipinos II , Carlson MA
Published: December 2018

Introduction

The development of collateral vasculature is a key mechanism compensating for arterial occlusions in patients with peripheral artery disease (PAD). We aimed to examine the development of collateral pathways after ligation of native vessels in a porcine model of PAD.

Methods

Right hindlimb Ischemia was induced in domestic swine (N=11, male, kg) using two different versions of arterial ligation. Version 1 (N=6) consisted of ligation/division of the right external iliac, profunda femoral (RPFA) and superficial femoral arteries (RSFA). Version 2 (N=5) consisted of the ligation of Version 1 with additional ligation/division of the right internal iliac artery (RIIA). Development of collateral pathways was evaluated with standard angiography at baseline (prior to arterial ligation) and at termination (4-8 weeks later). Relative luminal diameter of the arteries supplying the ischemic right hindlimb were determined by 2D angiography, as percent of the size of the distal aortic diameter.

Results

The dominant collateral pathway that developed after version 1 ligation connected the RIIA to the RPFA and RSFA/popliteal artery. Mean luminal diameter (± standard error) of the RIIA at termination increased by 38% (P<0.05) compared to baseline. Two co-dominant collateral pathways developed in version: (i) from the common internal iliac trunk and left internal iliac artery to the reconstituted RIIA, which then supplied the RPFA and RSFA/popliteal arteries; and (ii) from left profunda artery to the reconstituted RPFA. Mean diameter of the common internal iliac trunk and left profunda artery both increased at termination in the range of 20% (p < 0.05).

Conclusion

Two versions of hindlimb ischemia induction (right ilio-femoral artery ligation with and without right internal iliac artery ligation in swine produced differing collateral pathways, along with changes to the diameter of the inflow vessels (i.e., arteriogenesis). Radiographic and anatomical data of the collateral formation in this porcine model should have value in investigation of the pathophysiology of hindlimb ischemia, and assessment of angiogenic therapies as potential treatments for PAD.
Consequences of measurement error in qPCR telomere data: A simulation study
Authors: Nettle Daniel , Seeker Luise , Nussey Dan , Froy Hannah , Bateson Melissa
Published: December 2018

The qPCR method provides an inexpensive, rapid method for estimating relative average telomere length across a set of biological samples. Like all laboratory methods, it involves some degree of measurement error. The estimation of relative telomere length is done subjecting the actual measurements made (the Cq values for telomere and a control gene) to non-linear transformations and combining them into a ratio. Here, we use computer simulations, supported by mathematical analysis, to explore how errors in measurement affect qPCR estimates of relative telomere length, both in cross-sectional and longitudinal data. We show that errors introduced at the level of Cq values are magnified when the TS ratio is calculated. If the errors at the Cq level are normally distributed and independent of telomere length, those in the TS ratio are positively skewed and proportional to telomere length. The repeatability of the TS ratio declines abruptly with increasing error in measurement of the telomere sequence and/or the control gene. In simulated longitudinal data, measurement error alone can produce a pattern of low correlation between successive measures of telomere length, coupled with a strong dependency of the rate of change on initial telomere length. Our results illustrate the importance of control of measurement error: a small increase in error in Cq values can have large consequences for the power and interpretability of qPCR estimates of relative telomere length. They also illustrate the importance of characterising the measurement error that exists in each dataset—coefficients of variation are generally unhelpful, and researchers should report standard deviations of Cq values and/or repeatabilities of TS ratios—and allowing for the known effects of measurement error when interpreting patterns of TS ratio change over time.
Maternal brain gain: enlarged representation of the peripersonal space in pregnancy
Authors: Cardini Flavia , Fatemi-Ghomi Natalie , Gajewska-Knapik Katarzyna , Gooch Victoria , Aspell Jane Elizabeth
Published: December 2018

Our ability to maintain a coherent bodily self despite continuous changes within and outside our body relies on the highly flexible multisensory representation of the body, and of the space surrounding it: the peripersonal space (PPS). The aim of our study was to investigate whether during pregnancy - when extremely rapid changes in body size and shape occur - a likewise rapid plastic reorganization of the neural representation of the PPS occurs. We used an audio-tactile integration task to measure the PPS boundary at different stages of pregnancy. We found that in the second trimester of pregnancy and postpartum women did not show differences in their PPS size as compared to the control group (non-pregnant women). However, in the third trimester the PPS was larger than the controls' PPS and the shift between representation of near and far space was more gradual. We therefore conclude that during pregnancy the brain adapts to the sudden bodily changes, by expanding the representation of the space around the body. This may represent a mechanism to protect the vulnerable abdomen from injury from surrounding objects.
Sustained oscillations of epithelial cell sheets
Authors: Peyret Grégoire , Mueller Romain , d’Alessandro Joseph , Begnaud Simon , Marcq Philippe , Mège René-Marc , Yeomans Julia M , Doostmohammadi Amin , Ladoux Benoît
Published: December 2018

Morphological changes during development, tissue repair, and disease largely rely on coordinated cell movements and are controlled by the tissue environment. Epithelial cell sheets are often subjected to large scale deformation during tissue formation. The active mechanical environment in which epithelial cells operate have the ability to promote collective oscillations, but how these cellular movements are generated and relate to collective migration remains unclear. Here, combining in vitro experiments and computational modelling we describe a novel mode of collective oscillations in confined epithelial tissues where the oscillatory motion is the dominant contribution to the cellular movements. We show that epithelial cells exhibit large-scale coherent oscillations when constrained within micro-patterns of varying shapes and sizes, and that their period and amplitude are set by the smallest confinement dimension. Using molecular perturbations, we then demonstrate that force transmission at cell-cell junctions and its coupling to cell polarity are pivotal for the generation of these collective movements. We find that the resulting tissue deformations are sufficient to trigger mechanotransduction within cells, potentially affecting a wide range of cellular processes.
Single cell DNA sequencing reveals distinct molecular types of basal cell carcinoma with unique transcriptome features
Authors: Bakker Bjorn , Terra Jorrit , Zhou Lin , Racz Emoke , Paljic Sonja , Garcia-Martinez Jorge , Oliveira Vera , Bakker Petra L , Spierings Diana C.J. , Jonkman Marcel F. , Foijer Floris
Published: December 2018

Background: Aneuploidy, a hallmark of cancer, is the result of chromosomal instability (CIN) during mitosis. While some aneuploid cancers display stable karyotypes, other tumours display cell-to-cell karyotype variability indicative of CIN. CIN cancers are typically associated with poor clinical outcome, as they are endowed with the potential to adjust their genomes to changing conditions including therapy. To further explore this, we assessed the degree of aneuploidy and CIN in basal cell carcinoma (BCC) and investigated whether the karyotypic makeup of tumours was associated with distinct transcriptional responses.
Patients and Methods: Samples from 11 BCC patients were processed for single-cell whole genome sequencing (scWGS) to measure aneuploidy and karyotype heterogeneity. In parallel, samples were processed for transcriptome analysis.
Results: scWGS revealed different grades of aneuploidy between BCCs, ranging from euploidy to tumours with up to 7 aneusomic chromosomes. Importantly, a subset of BCCs displayed intratumour karyotype heterogeneity, indicating that CIN can play a role in BCC. Samples were clustered into three groups based on the level of aneuploidy and intratumour karyotype heterogeneity. Karyotype-driven group classification was also reflected by the tumour transcriptomes and revealed distinct gene expression signatures related to metabolism for aneuploid BCCs and a DNA damage signature for CIN BCCs.
Conclusions: While BCCs are typically classified based on histopathological features, we find that BCCs can be stratified based on karyotypic landscape. Importantly, this classification is linked to distinct molecular features and could thus be the starting point of a molecular classification system for BCC including a readout for CIN. Importantly, the approach that we have developed is broadly applicable and could therefore also improve the diagnosis and treatment of other cancer types.
A non-Lamarckian model for the inheritance of the epigenetically-coded phenotypic characteristics: a new paradigm for Genetics, Genomics and, above all, Ageing studies
Authors: Marsellach Xavi
Published: December 2018

In this paper I would like to introduce some theoretical considerations, which, if proven right by the experimental frameworks designed to test them, might stand for a paradigmatic change on genetics, genomics and ageing studies. This paper further develops a theoretical framework previously proposed by this author (Marsellach, 2017). Despite this, this paper is written as a standalone paper, which describe in more detail the previously hinted model (Marsellach, 2017), and adds emphasis in the putative implications that, the proposed theoretical framework, might have in describing the way in which the epigenetic information is transmitted from one generation to the following ones, and in the implications that this might have for genetics, genomics and ageing studies.
Identifying conserved molecular mechanisms of thermo-acclimation in symbiotic organisms
Authors: Alves Monteiro Homere J. , Brahmi Chloe , Mayfield Anderson Blair , Vidal-Dupiol Jeremie , Lapeyre Bruno , Le Luyer Jeremy
Published: December 2018

Seawater temperature rise in French Polynesia has repeatedly resulted in symbiosis breakdown between giant clam (Tridacna maxima) and dinoflagellates (Symbiodinium spp.), particularly in small individuals. Herein, we explored the physiological and gene expression responses of the clam hosts and their photosynthetically active symbionts over a 65-day experiment in which clams were exposed to either normal or environmentally relevant elevated seawater temperatures. These data were combined with publicly available data for both free-living Symbiodinium (clades C1 and F) and Symbiodinium spp. in hospite with the coral Pocillopora damicornis. Gene module preservation analysis revealed that the function of the symbionts' photosystem II was impaired at high temperatures, and this response was conserved across all holobionts and Symbiodinium clades examined. Similarly, activation of the phytohormone abscisic acid signaling and epigenetics modulation appeared to be a key response mechanisms for symbionts in hospite with giant clams exposed to high temperatures and also distinguish thermo-tolerant from thermo-sensitive Symbiodinium C1 phenotypes.
Real-time capture of horizontal gene transfers from gut microbiota by engineered CRISPR-Cas acquisition
Authors: Munck Christian , Sheth Ravi U. , Freedberg Daniel E. , Wang Harris H.
Published: December 2018

Horizontal gene transfer (HGT) is central to the adaptation and evolution of bacteria. However, our knowledge about the flow of genetic material within complex microbiomes is lacking; most studies of HGT rely on bioinformatic analyses of genetic elements maintained on evolutionary timescales or experimental measurements of phenotypically trackable markers (e.g. antibiotic resistance). Consequently, our knowledge of the capacity and dynamics of HGT in complex communities is limited. Here, we utilize the CRISPR-Cas spacer acquisition process to detect HGT events from complex microbiota in real-time and at nucleotide resolution. In this system, a recording strain is exposed to a microbial sample, spacers are acquired from foreign transferred elements and permanently stored in genomic CRISPR arrays. Subsequently, sequencing and analysis of these spacers enables identification of the transferred elements. This approach allowed us to quantify transfer frequencies of individual mobile elements without the need for phenotypic markers or post-transfer replication. We show that HGT in human clinical fecal samples can be extensive and rapid, often involving multiple different plasmid types, with the IncX type being the most actively transferred. Importantly, the vast majority of transferred elements did not carry readily selectable phenotypic markers, highlighting the utility of our approach to reveal previously hidden real-time dynamics of mobile gene pools within complex microbiomes.
Netrin/UNC-6 triggers actin assembly and non-muscle myosin activity to drive dendrite retraction in the self-avoidance response
Authors: Sundararajan Lakshmi , Smith Cody J. , Watson Joseph D. , Millis Bryan A. , Tyska Matthew J. , Miller David M.
Published: December 2018

Dendrite growth is constrained by the self-avoidance response but the downstream pathways that balance these opposing mechanisms are unknown. We have proposed that the diffusible cue UNC-6(Netrin) is captured by UNC-40 (DCC) for a short-range interaction with UNC-5 to trigger self-avoidance in theC. elegansPVD neuron. Here we report that the actin-polymerizing proteins UNC-34(Ena/VASP), WSP-1(WASP), UNC-73(Trio), MIG-10(Lamellipodin) and the Arp2/3 complex effect dendrite retraction in the self-avoidance response mediated by UNC-6(Netrin). The paradoxical idea that actin polymerization results in shorter rather than longer dendrites is explained by our finding that NMY-1 (non-muscle myosin II) is necessary for retraction and could therefore mediate this effect in a contractile mechanism. Our results also show that dendrite length is determined by the antagonistic effects on the actin cytoskeleton of separate sets of effectors for retraction mediated by UNC-6(Netrin) versus outgrowth promoted by the DMA-1 receptor. Thus, our findings suggest that the dendrite length depends on an intrinsic mechanism that balances distinct modes of actin assembly for growth versus retraction.
Cyclosporine A inhibits MRTF-SRF signalling through Na+/K+ ATPase inhibition & Actin remodelling
Authors: Burat Bastien , Faucher Quentin , Čechová Petra , Arnion Hélène , Meo Florent Di , Sauvage François-Ludovic , Marquet Pierre , Essig Marie
Published: December 2018

Calcineurin Inhibitors (CNI) are the pillars of immunosuppression in transplantation. However, they display a potent nephrotoxicity whose mechanisms remained widely unsolved. We used an untargeted quantitative proteomic approach (iTRAQ technology) to highlight new targets of CNI in renal proximal tubular cells (RPTCs). CNI-treated RPTCs proteome displayed an over-representation of Actin-binding proteins with a CNI-specific expression profile. Cyclosporine A (CsA) induced F-Actin remodelling and depolymerisation, decreased F-Actin-stabilizing, polymerization-promoting Cofilin (CFL) oligomers and inhibited the G-Actin-regulated serum responsive factor (SRF) pathway. Inhibition of CFL canonical phosphorylation pathway reproduced CsA effects; however, Ser3, an analogue of the phosphorylation site of CFL prevented the effects of CsA which suggests that CsA acted independently from the canonical CFL regulation. CFL is known to be regulated by the Na+/K+-ATPase. Molecular docking calculations evidenced 2 inhibiting sites of CsA on Na+/K+-ATPase and a 23% decrease in Na+/K+-ATPase activity of RPTCs was observed with CsA. Ouabain, a specific inhibitor of Na+/K+-ATPase also reproduced CsA effects on Actin organization and SRF activity. Altogether, these results described a new original pathway explaining CsA nephrotoxicity.
An Unsupervised Learning Method for Disease Classification Based on DNA Methylation Signatures
Authors: Firouzi Mohammad , Turinsky Andrei , Choufani Sanaa , Siu Michelle T. , Weksberg Rosanna , Brudno Michael
Published: December 2018

Recent work has shown that genome-wide DNA methylation (DNAm) profiles can be used to discern signatures that can identify specific genetic disorders. These methods are especially effective at identifying single gene (Mendelian) disease, and methods to identify such signatures have been built by comparing methylation profiles of known disease versus control samples. These methods, however, have to-date been supervised, precluding the application of these methods to diseases with as-yet-unknown genetic cause. In this work, we tackle the problem of unsupervised disease classification based on DNAm signatures. Our method combines pre-filtration of the data to identify most promising methylation sites, clustering to identify co-varying sites, and an iterative method to further refine the signatures to build an effective clustering framework. We validate the proposed method on four diseases with known DNAm signatures (CHARGE, Kabuki, Sotos, and Weaver syndromes) and show high accuracy at determining the correct disease using unsupervised analysis. We also experiment with our approach on a novel dataset of patients with a clinical diagnosis of Autism, and illustrate the de novo identification of a specific subtype.
The Dot/Icm-translocated effector LegC4 potentiates cytokine-mediated restriction of Legionella within accidental hosts.
Authors: Ngwaga Tshegofatso , Hydock Alex J , Ganesan Sandhya , Shames Stephanie Rochelle
Published: December 2018

Legionella pneumophila is ubiquitous in freshwater environments where it replicates within unicellular protozoa. However, L. pneumophila is also an accidental human pathogen that can cause Legionnaires’ Disease in immunocompromised individuals by uncontrolled replication within alveolar macrophages. To replicate within eukaryotic phagocytes, L. pneumophila utilizes a Dot/Icm type IV secretion system to translocate a large arsenal of over 300 effector proteins directly into host cells. In mammals, translocated effectors contribute to innate immune restriction of L. pneumophila. We found previously that the effector LegC4 is important for L. pneumophila replication within a natural host protist but is deleterious to replication in a mouse model of Legionnaires’ Disease. In the present study, we used cultured mouse primary macrophages to investigate how LegC4 attenuates L. pneumophila replication. We found that LegC4 enhanced restriction of L. pneumophila replication within macrophages activated with tumor necrosis factor (TNF) or interferon (IFN)-γ. Specifically, TNF-mediated signaling was required for LegC4-mediated attenuation of L. pneumophila replication within macrophages. In addition, expression of legC4 was sufficient to restrict L. longbeachae replication within TNF- or IFN-γ-activated macrophages. Thus, this study demonstrates that LegC4 contributes to L. pneumophila clearance from healthy hosts by potentiating cytokine-mediated host defense mechanisms.
Mechanistic insights into the evolution of DUF26-containing proteins in land plants
Authors: Vaattovaara Aleksia , Brandt Benjamin , Rajaraman Sitaram , Safronov Omid , Veidenberg Andres , Luklová Markéta , Kangasjärvi Jaakko , Löytynoja Ari , Hothorn Michael , Salojärvi Jarkko , Wrzaczek Michael
Published: December 2018

Large protein families are a prominent feature of plant genomes and their size variation is a key element for adaptation in plants. Here we infer the evolutionary history of a representative protein family, the DOMAIN OF UNKNOWN FUNCTION (DUF) 26-containing proteins. The DUF26 first appeared in secreted proteins. Domain duplications and rearrangements led to the emergence of CYSTEINE-RICH RECEPTOR-LIKE PROTEIN KINASES (CRKs) and PLASMODESMATA-LOCALIZED PROTEINS (PDLPs). While the DUF26 itself is specific to land plants, structural analyses of Arabidopsis PDLP5 and PDLP8 ectodomains revealed strong similarity to fungal lectins. Therefore, we propose that DUF26-containing proteins constitute a novel group of plant carbohydrate-binding proteins. Following their appearance, CRKs expanded both through tandem duplications and preferential retention of duplicates in whole genome duplication events, whereas PDLPs evolved according to the dosage balance hypothesis. Based on our findings, we suggest that the main mechanism of expansion in new gene families is small-scale duplication, whereas genome fractionation and genetic drift after whole genome multiplications drive families towards dosage balance.
The Notch and EGFR signaling regulate caspase inhibitor Diap1 to match supply with intestinal demand
Authors: Reiff Tobias , Antonello Zeus A , Ballesta-Illan Esther , Mira Laura , Sala Salvador , Navarro Maria , Martinez Luis M , Dominguez Maria
Published: December 2018

The regenerative activity of adult stem cells carries a high risk of cancer, particularly in highly renewable tissues. To guarantee that the correct organ size is attained and to cope with the continual risk of cancer, developing tissues often use programmed cell death (PCD) as an adaptive mechanism to cull excess and abnormal cells. Members of the family of Inhibitor of Apoptosis Proteins (IAPs) inhibit caspases and cell death and are often overexpressed in cancer. Here, we show that Diap1 is expressed in committed progenitor (enteroblast) cells in the adult Drosophila intestine. Blocking endogenous caspases uncovered that more than half of enteroblasts produced by intestinal stem cells (ISCs) are actively eliminated by apoptosis in the physiological intestine and also led to tumorigenesis. We find that antagonistic interplay between the Notch and EGFR signaling on Diap1 regulation governs the enteroblast cell death or survival decision via the conserved Klumpfuss/WT1-Lozenge/RUNX axis, which also regulates of differentiation plasticity of enteroblasts. These data provide new insights into how apoptosis drives adult tissue renewal and protection against tumors.
Physical activity in children and adolescents with Charcot-Marie-Tooth disease: A cross-sectional case-controlled study
Authors: Kennedy Rachel , Carroll Kate , Paterson Kade L. , Ryan Monique M. , Burns Joshua , Rose Kristy , McGinley Jennifer L.
Published: December 2018

Background

Disability related to the progressive and degenerative neuropathies known as Charcot-Marie-Tooth disease (CMT) affects gait and function, increasing with age and influencing physical activity in adults with CMT. The relationship between disease, ambulatory function and physical activity in children and adolescents with CMT is unknown.

Method

A cross-sectional case-controlled study of 50 children with CMT and age- and gender-matched typically developing (TD) controls [mean age 12.5 (SD 3.9) years]. A 7-day recall questionnaire assessed physical activity; disease severity and gait-related function were measured to explore factors associated with physical activity.

Results

Children with CMT were less active than TD controls (estimated weekly moderate to vigorous physical activity CMT 283.6 (SD 211.6) mins, TD 318.0 (SD 202.5) mins; p < 0.001). The children with CMT had moderate disability [CMT Pediatric Scale mean score 20 (SD 8) /44] and reduced ambulatory capacity in a six-minute walk test [CMT 485.1 (SD 160.9) metres, TD 639.8 (83.1) metres; p < 0.001]. Physical activity correlated with greater disease severity (ρ = -0.52, p < 0.001) and six-minute walk distance (ρ = 0.71, p < 0.001).

Conclusions

Disease-related disability affects physical activity and gait-related function in children and adolescents with CMT compared to TD peers. Reduced physical activity adversely affects function across the timespan of childhood and adolescence into adulthood.