bluuebunny/crossref_metadata_2025 huggingface dataset:
PRDM10-rearranged Soft Tissue Tumor
Authors: Puls Florian , Pillay Nischalan , Fagman Henrik , Palin-Masreliez Anne , Amary Fernanda , Hansson Magnus , Kindblom Lars-Gunnar , McCulloch Tom A. , Meligonis George , Muc Ronald , Rissler Pehr , Sumathi Vaiyapuri P. , Tirabosco Roberto , Hofvander Jakob , Magnusson Linda , Nilsson Jenny , Flanagan Adrienne M. , Mertens Fredrik
Published: December 2018

Gene fusion transcripts containing PRDM10 were recently identified in low-grade undifferentiated pleomorphic sarcomas (UPS). Here, we describe the morphologic and clinical features of 9 such tumors from 5 men and 4 women (age: 20 to 61 y). Three cases had previously been diagnosed as UPS, 3 as superficial CD34-positive fibroblastic tumor (SCD34FT), 2 as pleomorphic liposarcoma, and 1 as pleomorphic hyalinizing angiectatic tumor. The tumors were located in the superficial and deep soft tissues of the thigh/knee region (4 cases), shoulder (2 cases), foot, trunk, and perineum (1 case each) ranging in size from 1 to 6 cm. All showed poorly defined cellular fascicles of pleomorphic cells within a fibrous stroma with frequent myxoid change and a prominent inflammatory infiltrate. All displayed highly pleomorphic nuclear features, but a low mitotic count. Most tumors were well circumscribed. One of 9 tumors recurred locally, but none metastasized. Immunohistochemically, all were CD34+ and showed nuclear positivity for PRDM10; focal positivity for cytokeratins was seen in 5/6 cases. PRDM10 immunoreactivity was evaluated in 50 soft tissue tumors that could mimic PRDM10-rearranged tumors, including 4 cases exhibiting histologic features within the spectrum of SCD34FT. Except for 2/6 pleomorphic liposarcomas and 1/4 myxofibrosarcomas, other tumors did not show nuclear positivity but displayed weak to moderate cytoplasmic immunoreactivity. In conclusion, PRDM10-rearranged soft tissue tumor is characterized by pleomorphic morphology and a low mitotic count. Its morphologic spectrum overlaps with SCD34FT. Clinical features of this small series suggest an indolent behavior, justifying its distinction from UPS and other sarcomas.
The Functional Anatomy of the Deep Facial Fat Compartments: A Detailed Imaging-Based Investigation
Authors: Cotofana Sebastian , Gotkin Robert H. , Frank Konstantin , Koban Konstantin C. , Targosinski Stefan , Sykes Jonathan M. , Schlager Markus , Schlattau Alexander , Schenck Thilo L.
Published: December 2018

Background:

Injection of soft-tissue fillers into the facial fat compartments is frequently performed to ameliorate the signs of facial aging. This study was designed to investigate the functional anatomy of the deep facial fat compartments and to provide information on the effects of injected material in relation to age and gender differences.

Methods:

Forty fresh frozen cephalic specimens of 17 male and 23 female Caucasian body donors (mean age, 76.9 ± 13.1 years; mean body mass index, 23.6 ± 5.3 kg/m2) were investigated. Computed tomographic and magnetic resonance imaging procedures were carried out using colored contrast-enhanced materials with rheologic properties similar to commercially available soft-tissue fillers. Anatomical dissections were performed to guide conclusions.

Results:

No statistically significant influences of age or gender were detected in the investigated sample. Increased amounts of injected contrast agent did not correlate with inferior displacement of the material in any of the investigated compartments: deep pyriform, deep medial cheek, deep lateral cheek, deep nasolabial (located within the premaxillary space), and the medial and lateral sub–orbicularis oculi fat.

Conclusions:

Increasing volume in the deep midfacial fat compartments did not cause inferior displacement of the injected material. This underscores the role of deep soft-tissue filler injections (i.e., in contact with the bone) in providing support for overlying structures and resulting in anterior projection.
Persistent Opioid Use and High-Risk Prescribing in Body Contouring Patients
Authors: Bennett Katelyn G. , Kelley Brian P. , Vick Alexis D. , Lee Jay S. , Gunaseelan Vidhya , Brummett Chad M. , Waljee Jennifer F.
Published: December 2018

Background:

Opioid misuse occurs commonly among obese patients and after bariatric surgery. However, the risk of new persistent use following postbariatric body contouring procedures remains unknown.

Methods:

The authors examined insurance claims from Clinformatics Data Mart (OptumInsight, Eden Prairie, Minn.) between 2001 and 2015 for opioid-naive patients undergoing five body contouring procedures: abdominoplasty/panniculectomy, breast reduction, mastopexy, brachioplasty, and thighplasty (n = 11,257). Their primary outcomes included both new persistent opioid use, defined as continued prescription fills between 90 and 180 days after surgery, and the prevalence of high-risk prescribing. They used multilevel logistic regression to assess the risk of new persistent use, adjusting for relevant covariates.

Results:

In this cohort, 6.1 percent of previously opioid-naive patients developed new persistent use, and 12.9 percent were exposed to high-risk prescribing. New persistent use was higher in patients with high-risk prescribing (9.2 percent). New persistent use was highest after thighplasty (17.7 percent; 95 percent CI, 0.03 to 0.33). Increasing Charlson comorbidity indices (OR, 1.11; 95 percent CI, 1.05 to 1.17), mood disorders (OR, 1.27; 95 percent CI, 1.05 to 1.54), anxiety (OR, 1.41; 95 percent CI, 1.16 to 1.73), tobacco use (OR, 1.22; 95 percent CI, 1.00 to 1.49), neck pain (OR, 1.23; 95 percent CI, 1.04 to 1.46), arthritis (OR, 1.30; 95 percent CI, 1.08 to 1.58), and other pain disorders (OR, 1.36; 95 percent CI, 1.16 to 1.60) were independently associated with persistent use.

Conclusions:

Similar to other elective procedures, 6 percent of opioid-naive patients developed persistent use, and 12 percent were exposed to high-risk prescribing practices. Plastic surgeons should remain aware of risk factors and offer opioid alternatives.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
To Bot or Not? Challenging the Top Social Media Influencers in #PlasticSurgery
Authors: Fan Kenneth L. , Economides James M. , Song David H.
Published: December 2018

Background:

The influence of social media on plastic surgery continues to be explored. Prospective patients may seek out surgeons with greater number of followers. Recently, companies selling Twitter bots have been exposed. The authors sought to examine the number of fake users, practice types, and the content of tweets broadcasted by top influencers in plastic surgery.

Methods:

Top 100 influencers were identified. The influencers were categorized into academic versus private practice and sorted according to their board-certification status. Among each board-certification status, the top five influencers of each category (American Board of Plastic Surgery, American Academy of Facial Plastic and Reconstructive Surgery, international plastic surgeon, other physician, nonphysician) were determined, and their 300 most recent tweets were analyzed for educational, promotional, or personal content. Fake bots among respective followers were identified by TwitterAudit.

Results:

Private practice surgeons represented 68 percent of the top tweeters. Academicians were only 8 percent. American board-certified surgeons represented 55 percent of the top tweeters. Compared with American board-certified surgeons, nonphysicians had a higher number of fake bots. Among the 7500 tweets that were analyzed, nonphysicians were more likely to have promotional and less likely to have educational posts when comparing to board-certified American or international plastic surgeons.

Conclusions:

Plastic surgeons are quick to adapt to the dynamic and evolving nature of social media. However, academic surgeons are poorly represented among the top influencers. Although top influencers are board-certified plastic surgeons, they continue to occupy only a fraction of the total discourse on plastic surgery.
Economic Analysis Based on the Use of Closed-Incision Negative-Pressure Therapy after Postoperative Breast Reconstruction
Authors: Gabriel Allen , Maxwell G. Patrick
Published: December 2018

Background:

Breast cancer accounts for 30% of all new cancer diagnoses in women. Although more options are now available regarding breast reconstruction, the risk of complications (eg, infection, dehiscence, and expander exposure) is also prevalent and must be considered when choosing a reconstruction option because the cost for complications can be substantial.

Methods:

A hypothetical cost model was applied to clinical outcomes of a previous retrospective study comparing the use of closed-incision negative-pressure therapy (ciNPT) and standard of care (SOC) over breast incisions after immediate reconstruction. The adjusted complication cost for a mastectomy with reconstruction was a mean of $10,402 and was calculated using a database of inpatient, outpatient, and carrier claims.

Results:

The previous retrospective study included data on 665 breasts (ciNPT = 331, SOC = 334) and 356 female patients (ciNPT = 177, SOC = 179) and reported on complication rates at the breast level: 8.5% (28/331) for the ciNPT breast group versus 15.9% (53/334) for the SOC group (P = 0.0092). In the ciNPT group, 24/177 patients (13.6%) had a complication, whereas in the SOC group, 38/179 patients (21.2%) had a complication. Based on the adjusted mean complication cost of $10,402, total complication cost for the ciNPT group was $250,000 versus $395,000 for the SOC group with a per-patient cost savings of $218.00 with ciNPT.

Conclusion:

The authors’ preliminary findings show potential cost savings with the use of ciNPT over breast incisions and warrant further study regarding the cost-effectiveness of ciNPT compared with standard of care after immediate breast reconstruction.
Meta-Analysis of Comparative Trials Evaluating a Single-Use Closed-Incision Negative-Pressure Therapy System
Authors: Singh Devinder P. , Gabriel Allen , Parvizi Javad , Gardner Michael J. , D’Agostino Ralph
Published: December 2018

Background:

Surgical site infections (SSIs) pose a significant surgical complication. Application of closed-incision negative-pressure therapy (ciNPT) has been associated with reduced SSI rates in published literature. This meta-analysis examines the effect of ciNPT use over closed incisions in reducing SSIs versus traditional dressings.

Methods:

A systematic literature search using PubMed, The Cochrane Library, OVID, EMBASE, ScienceDirect, and QUOSA was performed focusing on publications between January 1, 2005, and April 30, 2018. Characteristics of study participants, surgical procedure, type of dressing used, duration of treatment, incidence of SSI, and length of follow-up were extracted. Weighted odds ratios and 95% CIs were calculated to pool study and control groups in each publication for analysis. Treatment effects were combined using Mantel-Haenszel odds ratios as the summary statistics, and a fixed-effects model was used for each analysis performed. The chi-square test was used to statistically assess heterogeneity. For each meta-analysis performed, the more conservative random-effects models were conducted as sensitivity analyses.

Results:

For all meta-analyses (randomized controlled trial only, observational studies only, colorectal/abdominal, obstetrics, lower extremity, groin/vascular, cardiac), heterogeneity tests were nonsignificant (P > 0.05). All fixed-effects meta-analyses were significant in favor of ciNPT use over traditional dressings (P < 0.05). When the random-effects analyses were performed, all analyses except obstetrics remained significant (P < 0.05).

Conclusion:

For all meta-analyses performed using the fixed-effects approach, ciNPT usage demonstrated a statistically significant reduction in incidence of SSI relative to traditional dressings.
Infectious Disease Transmission in Solid Organ Transplantation: Donor Evaluation, Recipient Risk, and Outcomes of Transmission
Authors: White Sarah L. , Rawlinson William , Boan Peter , Sheppeard Vicky , Wong Germaine , Waller Karen , Opdam Helen , Kaldor John , Fink Michael , Verran Deborah , Webster Angela , Wyburn Kate , Grayson Lindsay , Glanville Allan , Cross Nick , Irish Ashley , Coates Toby , Griffin Anthony , Snell Greg , Alexander Stephen I. , Campbell Scott , Chadban Steven , Macdonald Peter , Manley Paul , Mehakovic Eva , Ramachandran Vidya , Mitchell Alicia , Ison Michael
Published: December 2018

In 2016, the Transplantation Society of Australia and New Zealand, with the support of the Australian Government Organ and Tissue authority, commissioned a literature review on the topic of infectious disease transmission from deceased donors to recipients of solid organ transplants. The purpose of this review was to synthesize evidence on transmission risks, diagnostic test characteristics, and recipient management to inform best-practice clinical guidelines. The final review, presented as a special supplement in Transplantation Direct, collates case reports of transmission events and other peer-reviewed literature, and summarizes current (as of June 2017) international guidelines on donor screening and recipient management. Of particular interest at the time of writing was how to maximize utilization of donors at increased risk for transmission of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, given the recent developments, including the availability of direct-acting antivirals for hepatitis C virus and improvements in donor screening technologies. The review also covers emerging risks associated with recent epidemics (eg, Zika virus) and the risk of transmission of nonendemic pathogens related to donor travel history or country of origin. Lastly, the implications for recipient consent of expanded utilization of donors at increased risk of blood-borne viral disease transmission are considered.
De novogenome assembly of the olive fruit fly (Bactrocera oleae) developed through a combination of linked-reads and long-read technologies
Authors: Djambazian Haig , Bayega Anthony , Tsoumani Konstantina T. , Sagri Efthimia , Gregoriou Maria-Eleni , Giorda Kristina , Tsiamis George , Bourtzis Kostas , Oikonomopoulos Spyridon , Dewar Ken , Church Deanna , Mathiopoulos Kostas D. , Ragoussis Jiannis
Published: December 2018

Long-read sequencing has greatly contributed to the generation of high quality assemblies, albeit at a high cost. It is also not always clear how to combine sequencing platforms. We sequenced the genome of the olive fruit fly (Bactrocera oleae), the most important pest in the olive fruits agribusiness industry, using Illumina short-reads, mate-pairs, 10x Genomics linked-reads, Pacific Biosciences (PacBio), and Oxford Nanopore Technologies (ONT). The 10x linked-reads assembly gave the most contiguous assembly with an N50 of 2.16 Mb. Scaffolding the linked-reads assembly using long-reads from ONT gave a more contiguous assembly with scaffold N50 of 4.59 Mb. We also present the most extensive transcriptome datasets of the olive fly derived from different tissues and stages of development. Finally, we used the Chromosome Quotient method to identify Y-chromosome scaffolds and show that the long-reads based assembly generates very highly contiguous Y-chromosome assembly.

JR is a member of the MinION Access Program (MAP) and has received free-of-charge flow cells and sequencing kits from Oxford Nanopore Technologies for other projects. JR has had no other financial support from ONT.

AB has received re-imbursement for travel costs associated with attending Nanopore Community meeting 2018, a meeting organized my Oxford Nanopore Technologies.
Structure of the tripartite motif of KAP1/TRIM28 identifies molecular interfaces required for transcriptional silencing of retrotransposons
Authors: Stoll Guido A. , Oda Shun-ichiro , Chong Zheng-Shan , Yu Minmin , McLaughlin Stephen H. , Modis Yorgo
Published: December 2018

Transcription of transposable elements is tightly regulated to prevent damage to the genome. The family of KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize specific retrotransposon sequences and recruit KAP1, which controls the assembly of an epigenetic silencing complex including histone H3K9 methyltransferase SETDB1. The chromatin remodeling activities of this complex repress transcription of the targeted transposable element and any adjacent genes. Here, we use biophysical and structural approaches to show that the tripartite motif (TRIM) of KAP1 forms antiparallel dimers, which further assemble into tetramers and higher-order oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 domain prevented higher-order oligomerization without a significant loss of retrotransposon silencing activity in a cell-based assay, indicating that, in contrast to other TRIM family members, self-assembly is not essential for the function of KAP1. The crystal structure of the KAP1 RBCC dimer identifies the KRAB domain binding site, in the coiled-coil domain near the dyad. Mutations at this site abolished KRAB binding and transcriptional silencing activity of KAP1. This work identifies the interaction interfaces in the KAP1 RBCC motif responsible for self-association and KRAB binding and establishes their role in retrotransposon silencing.
Polygenic adaptation to an environmental shift: temporal dynamics of variation under Gaussian stabilizing selection and additive effects on a single trait
Authors: Thornton Kevin R.
Published: December 2018

Predictions about the effect of natural selection on patterns of linked neutral variation are largely based on models involving the rapid fixation of unconditionally beneficial mutations. However, when phenotypes adapt to a new optimum trait value, the strength of selection on individual mutations decreases as the population adapts. Here, I use explicit forward simulations of a single trait with additive-effect mutations adapting to an optimum shift. Detectable “hitch-hiking” patterns are only apparent if i. the optimum shifts are large with respect to equilibrium variation for the trait, ii. mutation rates to large-effect mutations are low, and iii., large-effect mutations rapidly increase in frequency and eventually reach fixation, which typically occurs after the population reaches the new optimum. For the parameters simulated here, partial sweeps do not appreciably affect patterns of linked variation, even when the mutations are strongly selected. The contribution of new mutations versus standing variation to fixation depends on the mutation rate affecting trait values. Given the fixation of a strongly-selected variant, patterns of hitch-hiking are similar on average for the two classes of sweeps because sweeps from standing variation involving large-effect mutations are rare when the optimum shifts. The distribution of effect sizes of new mutations has little effect on the time to reach the new optimum, but reducing the mutational variance increases the magnitude of hitch-hiking patterns. In general, populations reach the new optimum prior to the completion of any sweeps, and the times to fixation are longer for this model than for standard models of directional selection. The long fixation times are due to a combination of declining selection pressures during adaptation and the possibility of interference among weakly selected sites for traits with high mutation rates.
Impact of modular mitochondrial epistatic interactions on the evolution of human subpopulations
Authors: Shinde Pramod , Whitwell Harry J. , Verma Rahul Kumar , Ivanchenko Mikhail , Zaikin Alexey , Jalan Sarika
Published: December 2018

Investigation of human mitochondrial (mt) genome variation has been shown to provide insights to the human history and natural selection. By analyzing 24,167 human mt-genome samples, collected for five continents, we have developed a co-mutation network model to investigate characteristic human evolutionary patterns. The analysis highlighted richer co-mutating regions of the mt-genome, suggesting the presence of epistasis. Specifically, a large portion of COX genes was found to co-mutate in Asian and American populations, whereas, in African, European, and Oceanic populations, there was greater co-mutation bias in hypervariable regions. Interestingly, this study demonstrated hierarchical modularity as a crucial agent for these co-mutation networks. More profoundly, our ancestry-based co-mutation module analyses showed that mutations cluster preferentially in known mitochondrial haplogroups. Contemporary human mt-genome nucleotides most closely resembled the ancestral state, and very few of them were found to be ancestral-variants. Overall, these results demonstrated that subpopulation-based biases may favor mitochondrial gene specific epistasis.
Strong Patterns of Intraspecific Variation and Local Adaptation in Great Basin Plants Revealed Through a Review of 75 Years of Experiments
Authors: Baughman Owen W. , Agneray Alison C. , Forister Matthew L. , Kilkenny Francis F. , Espeland Erin K. , Fiegener Rob , Horning Matthew E. , Johnson Richard C. , Kaye Thomas N. , Ott Jeffrey E. , Clair J. Bradley St. , Leger Elizabeth A.
Published: December 2018

Variation in natural selection across heterogenous landscapes often produces 1) among-population differences in phenotypic traits, 2) trait-by-environment associations, and 3) higher fitness of local populations. Using a broad literature search, we documented the frequency of these three signatures in plants native to North America’s Great Basin and asked which traits and environmental variables were involved. We also asked, independent of geographic distance, whether populations from more similar environments had more similar traits. From 327 experiments testing 121 taxa in 170 studies, we found 95.1% of 305 experiments reported among-population differences, and 81.4% of 161 experiments reported trait-by-environment associations. Locals showed greater survival in 67% of 24 reciprocal experiments that reported survival, and higher fitness in 90% of 10 reciprocal experiments that reported reproductive output. Variation in eight commonly-measured traits was associated with mean annual precipitation and mean annual temperature at the source location, with notably strong relationships for flowering phenology, leaf size, and survival, among others. Although the Great Basin is sometimes perceived as environmentally homogenous, our results demonstrate widespread habitat-related population differentiation and local adaptation, suggesting that locally-sourced plants likely harbor restoration-relevant adaptations, and that certain key traits and environmental variables should be prioritized in future assessments of plants.
Global invasion history of the world’s most abundant pest butterfly: a citizen science population genomics study
Authors: Ryan Sean F. , Lombaert Eric , Espeset Anne , Vila Roger , Talavera Gerard , Dincă Vlad , Renshaw Mark A. , Eng Matthew W. , Doellman Meredith M. , Hornett Emily A. , Li Yiyuan , Pfrender Michael E. , Shoemaker DeWayne
Published: December 2018

A major goal of invasion and climate change biology research is to understand the ecological and evolutionary responses of organisms to anthropogenic disturbance, especially over large spatial and temporal scales. One significant, and sometimes unattainable, challenge of these studies is garnering sufficient numbers of relevant specimens, especially for species spread across multiple continents. We developed a citizen science project, “Pieris Project”, to successfully amass thousands of specimens of the invasive agricultural pestPieris rapae, the small cabbage white butterfly, from 32 countries worldwide. We then generated and analyzed genomic (ddRAD) and mitochondrial DNA sequence data for these samples to reconstruct and compare different global invasion history scenarios. Our results bolster historical accounts of the global spread and timing ofP. rapaeintroductions. The spread ofP. rapaeover the last ∼160 years followed a linear series of at least four founding events, with each introduced population serving as the source for the next. We provide the first molecular evidence supporting the hypothesis that the ongoing divergence of the European and Asian subspecies ofP. rapae(∼1,200 yrBP) coincides with the domestication of brassicaceous crops. Finally, the international success of the Pieris Project allowed us to nearly double the geographic scope of our sampling (i.e., add >1,000 specimens from 13 countries), demonstrating the power of the public to aid scientists in collections-based research addressing important questions in ecology and evolutionary biology.

Non-technical summary

We provide genetic evidence that the success of the small cabbage white butterfly—its rise to one of the most widespread and abundant butterflies on the planet— was largely facilitated by human activities, through the domestication of its food plants and the accidental movement of the butterfly by means of trade and human movement (migration). Through an international citizen science project—Pieris Project—people from around the world helped to unravel the global invasion history of this agricultural pest butterfly by collecting samples for DNA analysis. The success of this citizen science project demonstrates the power of the public to aid in collections-based research that address important questions related to ecology and evolutionary biology.
A Toolkit for Rapid Modular Construction of Biological Circuits in Mammalian Cells
Authors: Fonseca João Pedro , Bonny Alain R. , Kumar G. Renuka , Ng Andrew H. , Town Jason , Wu Qiu Chang , Aslankoohi Elham , Chen Susan Y. , Harrigan Patrick , Osimiri Lindsey C. , Kistler Amy L. , El-Samad Hana
Published: December 2018

The ability to rapidly assemble and prototype cellular circuits is vital for biological research and its applications in biotechnology and medicine. Current methods that permit the assembly of DNA circuits in mammalian cells are laborious, slow, expensive and mostly not permissive of rapid prototyping of constructs. Here we present the Mammalian ToolKit (MTK), a Golden Gate-based cloning toolkit for fast, reproducible and versatile assembly of large DNA vectors and their implementation in mammalian models. The MTK consists of a curated library of characterized, modular parts that can be easily mixed and matched to combinatorially assemble one transcriptional unit with different characteristics, or a hierarchy of transcriptional units weaved into complex circuits. MTK renders many cell engineering operations facile, as showcased by our ability to use the toolkit to generate single-integration landing pads, to create and deliver libraries of protein variants and sgRNAs, and to iterate through Cas9-based prototype circuits. As a biological proof of concept, we used the MTK to successfully design and rapidly construct in mammalian cells a challenging multicistronic circuit encoding the Ebola virus (EBOV) replication complex. This construct provides a non-infectious biosafety level 2 (BSL2) cellular assay for exploring the transcription and replication steps of the EBOV viral life cycle in its host. Its construction also demonstrates how the MTK can enable important and time sensitive applications such as the rapid testing of pharmacological inhibitors of emerging BSL4 viruses that pose a major threat to human health.
Simulation of transcranial magnetic stimulation in head model with morphologically-realistic cortical neurons
Authors: Aberra Aman , Wang Boshuo , Grill Warren M , Peterchev Angel V
Published: December 2018

Transcranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements it activates and how stimulation parameters affect the neural response. We integrated detailed neuronal models with TMS-induced electric fields in the human head to quantify the effects of TMS on cortical neurons. TMS activated with lowest intensity layer 5 pyramidal cells at their intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 2/3 pyramidal cells and inhibitory basket cells may be activated too, whereas direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, contrary to theories implicating the field component normal to the cortical surface. Varying the induced current's direction caused a waveform-dependent shift in the activation site and provided a mechanistic explanation for experimentally observed differences in thresholds and latencies of muscle responses. This biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other forms of cortical stimulation.
A Rat Model of Somatosensory-Evoked Reflex Seizures Induced by Peripheral Stimulation
Authors: Bortel Aleksandra , Yao Ze Shan , Shmuel Amir
Published: December 2018

Objective

We introduce a novel animal model of somatosensory stimulation-induced reflex seizures which generates focal seizures without causing damage to the brain.

Methods

Specifically, we electrically stimulated digits or forepaws of adult rats sedated with dexmedetomidine while imaging cerebral blood volume and recording neurophysiological activity in cortical area S1FL. For the recordings, we either inserted a linear probe into the D3 digit representation or we performed surface electrocorticography (ECoG) recordings.

Results

Peripheral stimulation of a digit or the forepaw elicited seizures that were followed by a refractory period with decreased neuronal activity, or another seizure or a normal response. LFP amplitudes in response to electrical pulses during the seizures (0.28 ± 0.03 mV) were higher than during normal evoked responses (0.25 ± 0.05 mV) and refractory periods (0.2 ± 0.08 mV). Seizures generated during the stimulation period showed prolonged after-discharges that were sustained for 20.9±1.9 s following the cessation of the stimulus. High-frequency oscillations were observed prior to and during the seizures, with amplitudes higher than those associated with normal evoked responses. The seizures were initially focal. Optical imaging of the cerebral blood volume response showed that they propagated from the onset zone to adjacent cortical areas, beyond the S1FL representation of the stimulated digit or forepaw. The spatial extent during seizures was on average 1.74 times larger during the stimulation and 4.1 times following its cessation relative to normal evoked responses. Seizures were recorded not only by probes inserted into cortex but also with ECoG arrays (24.1±5.8 seizures per rat) placed over the dura matter, indicating that the seizures were not induced by damage caused by inserting the probes to cortex. Stimulation of the forepaw elicited more seizures (18.8±8.5 seizures per rat) than stimulation of a digit (1.7±0.7). Unlike rats sedated with dexmedetomidine, rats anesthetized with urethane showed no seizures, indicating that the seizures may depend on the use of the mild sedative dexmedetomidine.

Significance

Our proposed animal model generates seizures induced by electrical sensory stimulation free of artifacts and brain damage. It can be used for studying the mechanisms underlying the generation and propagation of reflex seizures and for evaluating antiepileptic drugs.

HIGHLIGHTS

Peripheral stimulation of the rat forepaw or digits induces seizures

Seizures are evoked with no direct application of convulsants, electro-stimulation or damage to the brain

Seizures are focal at onset, then spread beyond the spatial representation of the digit or forepaw

Seizures persist following the cessation of the stimulus

Proposed animal model may support the study of reflex seizures and improving therapeutic interventions
Anticipatory coadaptation of ankle stiffness and sensorimotor gain for standing balance
Authors: Le Mouel Charlotte , Brette Romain
Published: December 2018

External perturbation forces may compromise standing balance. The nervous system can intervene only after a delay greater than 100 ms, during which the body falls freely. With ageing, sensorimotor delays are prolonged, posing a critical threat to balance. We study a generic model of stabilisation with neural delays to understand how the organism should adapt to challenging balance conditions. The model suggests that ankle stiffness should be increased in anticipation of perturbations, for example by muscle co-contraction, so as to slow down body fall during the neural response delay. Increased ankle muscle co-contraction is indeed observed in young adults when standing in challenging balance conditions, and in older relative to young adults during normal stance. In parallel, the analysis of the model shows that increases in either stiffness or neural delay must be coordinated with decreases in spinal sensorimotor gains, otherwise the feedback itself becomes destabilizing. Accordingly, a decrease in spinal feedback is observed in challenging conditions, and with age-related increases in neural delay. These observations have been previously interpreted as indicating an increased reliance on cortical rather than spinal control of balance, despite the fact that cortical responses have a longer latency. Our analysis challenges this interpretation by showing that these observations are consistent with a functional coadaptation of spinal feedback gains to functional changes in stiffness and neural delay.

Author summary

Being able to stand still can be difficult when faced with an unexpected push. It takes the nervous system more than a tenth of a second to respond to such a perturbation, and during this delay the body falls under the influence of its own weight. By co-contracting their ankle muscles in anticipation of a perturbation, subjects can increase their ankle stiffness, which slows down their fall during the neural delay. Young subjects indeed adopt this strategy when they need to remain particularly still (for example when they stand in front of a cliff). Older subjects adopt this strategy even during normal standing. We present a model of standing balance that shows that this postural strategy provides partial compensation for the increase in neural delays with ageing. According to our model, increasing ankle stiffness only improves balance if it is accompanied by a decrease in sensorimotor gain. This provides a novel and functional interpretation for the decrease in spinal feedback observed during ageing, and observed in young subjects when they stand in challenging balance conditions.
A Darwinian Uncertainty Principle
Authors: Gascuel Olivier , Steel Mike
Published: December 2018

Reconstructing ancestral characters and traits along a phylogenetic tree is central to evolutionary biology. It is the key to understanding morphology changes among species, inferring ancestral biochemical properties of life, and recovering migration routes in phylogeography. The goal is twofold: to reconstruct the character state at the tree root (e.g. the region of origin of some species), and to understand the process of state changes along the tree (e.g. species flow between countries). Although each goal can be achieved with high accuracy individually, we use mathematics and simulations to demonstrate that it is generally impossible to accurately estimate both the root state and the rates of state changes along the tree branches from the observed data at the tips of the tree. This inherent ‘Darwinian uncertainty principle’ concerning the simultaneous estimation of ‘pattern’ and ‘process’ governs ancestral reconstructions in biology. Increasing the number of tips improves the joint estimation accuracy for certain tree shapes that arise in evolutionary models, however, for other trees shapes it does not.
Pedigree-based estimation of human mobile element retrotransposition rates
Authors: Feusier Julie , Watkins W. Scott , Thomas Jainy , Farrell Andrew , Witherspoon David J. , Baird Lisa , Ha Hongseok , Xing Jinchuan , Jorde Lynn B.
Published: December 2018

Germline mutation rates in humans have been estimated for a variety of mutation types, including single nucleotide and large structural variants. Here we directly measure the germline retrotransposition rate for the three active retrotransposon elements: L1, Alu, and SVA. We utilized three tools for calling Mobile Element Insertions (MEIs) (MELT, RUFUS, and TranSurVeyor) on blood-derived whole genome sequence (WGS) data from 603 CEPH individuals, comprising 33 three-generation pedigrees. We identified 27 de novo MEIs in 440 births. The retrotransposition rate estimates for Alu elements, one in 40, is roughly half the rate estimated using phylogenetic analyses, a difference in magnitude similar to that observed for single nucleotide variants. The L1 retrotransposition rate is one in 62 births and is within range of previous estimates (1:20-1:200 births). The SVA retrotransposition rate, one in 55 births, is much higher than the previous estimate of one in 900 births. Our large, three-generation pedigrees allowed us to assess parent-of-origin effects and the timing of insertion events in either gametogenesis or early embryonic development. We find a statistically significant paternal bias in Alu retrotransposition. Our study represents the first in-depth analysis of the rate and dynamics of human retrotransposition from WGS data in three-generation human pedigrees.
Structural and functional impact of non- synonymous SNPs in the CST complex subunit TEN1: Structural genomics approach
Authors: Amir Mohd. , Kumar Vijay , Mohammad Taj , Dohare Ravins , Rehman Md. Tabish , Alajmi Mohamed F. , Hussain Afzal , Ahmad Faizan , Hassan Md. Imtaiyaz
Published: December 2018

TEN1 protein is a key component of CST complex, implicated in maintaining the telomere homeostasis, and provide stability to the eukaryotic genome. Mutations in TEN1 gene have higher chances of deleterious impact; thus, interpreting the number of mutations and their consequential impact on the structure, stability and function is essentially important. Here, we have investigated the structural and functional consequences of nsSNPs in the TEN1 gene. A wide array of sequence- and structure-based computational prediction tools were employed to identify the effects of 78 nsSNPs on the structure and function of TEN1 protein and deleterious nsSNPs were identified. These deleterious or destabilizing nsSNPs are scattered throughout the structure of TEN1. However, major mutations were observed in the α1-helix (12-16) and β5-strand (88-96). We further observed that mutations at C-terminal region were have higher tendency to form aggregate. In-depth structural analysis of these mutations reveals that the pathogenecity of these mutations are driven mainly through larger structural changes because of alterations in non-covalent interactions. This work provides a blue print to pinpoint the possible consequences of pathogenic mutations in the CST complex subunit TEN1.
Coding advantage of grid cell orientation under noisy conditions
Authors: Chen Dong , Sun Kai-Jia , Wang Liang , Zhang Zhanjun , Lai Ying-Cheng , Axmacher Nikolai , Wang Wen-Xu
Published: December 2018

Grid cells constitute a crucial component of the “GPS” in the mammalian brain. Recent experiments revealed that grid cell activity is anchored to environmental boundaries. More specifically, these results revealed a slight yet consistent offset of 8 degrees relative to boundaries of a square environment. The causes and possible functional roles of this orientation are still unclear. Here we propose that this phenomenon maximizes the spatial information conveyed by grid cells. Computer simulations of the grid cell network reveal that the universal grid orientation at 8 degrees optimizes spatial coding specifically in the presence of noise. Our model also predicts the minimum number of grid cells in each module. In addition, analytical results and a dynamical reinforcement learning model reveal the mechanism underlying the noise-induced orientation preference at 8 degrees. Together, these results suggest that the experimentally observed common orientation of grid cells serves to maximize spatial information in the presence of noise.
Searching the optimal folding routes of a Complex Lasso protein
Authors: Perego Claudio , Potestio Raffaello
Published: December 2018

Understanding how polypeptides can efficiently and reproducibly attain a self-entangled conformation is a compelling biophysical challenge, which might shed new light on our general knowledge of protein folding. Complex Lassos, namely self-entangled protein structures characterized by a covalent loop sealed by a cysteine bridge, represent an ideal test system in the framework of entangled folding. Indeed, as cysteine bridges form in oxidizing conditions, they can be used as on/off switches of the structure topology, to investigate the role played by the backbone entanglement in the process.

In the present work we have used molecular dynamics to simulate the folding of a complex lasso glycoprotein, Granulocyte-macrophage colony-stimulating factor, modeling both reducing and oxidizing conditions. Together with a well-established Go-like description, we have employed the elastic folder model, a Coarse-Grained, minimalistic representation of the polypeptide chain, driven by a structure-based angular potential. The purpose of this study is to assess the kinetically optimal pathways, in relation to the formation of the native topology. To this end we have implemented an evolutionary strategy that tunes the elastic folder model potentials to maximize the folding probability within the early stages of the dynamics. The resulting protein model is capable of folding with high success rate, avoiding the kinetic traps that hamper the efficient folding in the other tested models. Employing specifically designed topological descriptors, we could observe that the selected folding routes avoid the topological bottleneck by locking the cysteine bridge after the topology is formed.

These results provide valuable insights on the selection of mechanisms in self-entangled protein folding while, at the same time, the proposed methodology can complement the usage of established minimalistic models, and draw useful guidelines for more detailed simulations.
Temporal modulation of host aerobic glycolysis determines the outcome of M. marinum infection
Authors: Meng Lu , Xie Lingling , Kan Yuanqing , Liu Lixia , Dong Wenyue , Feng Jintao , Yan Yuchen , Peng Gang , Lu Mingfang , Yang Chen , Niu Chen
Published: December 2018

Macrophages are the first-line host defense where the invading Mycobacterium tuberculosis (Mtb) encounters. It has been recently reported that host aerobic glycolysis was elevated post the infection by a couple of virulent mycobacterial species. However, whether this metabolic transition is required for host defense against intracellular pathogens and the underlying mechanisms remain to be further investigated. By analyzing carbon metabolism, we found that macrophages infected by M. marinum, a surrogate mycobacterial specie to Mtb, showed a strong elevation of glycolysis. Next, three glycolysis inhibitors were examined for their ability to inhibit mycobacterial proliferation inside RAW264.7, a murine macrophage-like cell line. Among them, a glucose analog, 2-deoxyglucose (2-DG) displayed a protective effect on assisting host to resist mycobacterial infection, which was further validated in zebrafish-infection model. The phagocytosis of M. marinum was significantly decreased in macrophages pre-treated with 2-DG at concentrations of 0.5 and 1 mM, at which no inhibitory effect was posed on M. marinum growth in vitro. Moreover, 2-DG pre-treatment exerted a significant protective effect on zebrafish larvae to limit the proliferation of M. marinum, and such effect was correlated to tumor necrosis factor alpha (TNF-α). On the contrary, the 2-DG treatment post infection did not restrain proliferation of M. marinum in WT zebrafish, and even accelerated bacterial replication in TNF-α-/- zebrafish. Together, modulation of glycolysis prior to infection boosts host immunity against M. marinum infection, indicating a potential intervention strategy to control mycobacterial infection.
Pathogenicity and selective constraint on variation near splice sites
Authors: Lord Jenny , Gallone Giuseppe , Short Patrick J. , McRae Jeremy F. , Ironfield Holly , Wynn Elizabeth H. , Gerety Sebastian S. , He Liu , Kerr Bronwyn , Johnson Diana S. , McCann Emma , Kinning Esther , Flinter Frances , Temple I. Karen , Clayton-Smith Jill , McEntagart Meriel , Lynch Sally Ann , Joss Shelagh , Douzgou Sofia , Dabir Tabib , Clowes Virginia , McConnell Vivienne P.M. , Lam Wayne , Wright Caroline F. , FitzPatrick David R. , Firth Helen V. , Barrett Jeffrey C. , Hurles Matthew E. ,   on behalf of the Deciphering Developmental Disorders study
Published: December 2018

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband–parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%–40% of pathogenic variants in noncanonical splice site positions are missing from public databases.