bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital Vomer Defect Incidentally Detected on Preoperative Evaluation for Nasal Septoplasty and Turbinoplasty
Authors: Jeong Junhui , Park Jun Cheol , Hong Chang Eui , Chung Hyo Jin , Chang Jung Hyun
Published: March 2018

A perforation in posterioinferior portion of nasal septum is rare and caused by vomeral defect. We report a case of 56-year-old man who had a vomer defect, which was detected incidentally during preoperative evaluation of nasal septoplasty and turbinoplasty. The patient had a surgery of septoplasty and bilateral turbinoplasty under general anesthesia. There was no septal mucosal tear or defect during septoplasty and turbinoplasty. When the patient who has vomeral defect with nasal obstruction is planned for septoplasty and turbinoplasty, the surgery should be performed carefully to protect the mucosa.
Ophthalmologic Complications Associated With Oculofacial Plastic and Esthetic Surgeries
Authors: Baek Ji Sun , Kim Kun Hae , Lee Jung Hye , Choi Hye Sun
Published: March 2018

Purpose:

To assess the ophthalmologic complications after oculofacial plastic and esthetic surgeries, including their incidence and management.

Methods:

A retrospective study was performed on 110 patients who presented with ocular complications followed by oculofacial plastic and esthetic surgeries from January 2014 to December 2015. The incidence and management of complications after each surgery or procedure were analyzed.

Results:

For lower eyelid blepharoplasty, the common complications were chemosis and lower eyelid ectropion. There was also a case of canalicular laceration. Exposure keratitis and corneal abrasion were the most common complications after upper eyelid blepharoplasty. Chemosis frequently occurred after lateral cathoplasty, but other complications, such as ectropion, trichiasis, and lacrimal fistula, were also seen. Nasolacrimal duct obstruction occurred in some cases of orthognathic surgery, and was managed with endonasal dacryocystorhinostomy. Inflammatory lipogranuloma was a common complication after autologous fat transplantation.

Conclusion:

Complications after oculofacial plastic and esthetic surgeries are not rare. Ophthalmologists must be aware of not only common complications but also rare and possibly serious conditions that may occur after such surgeries.
Effects of platelet-sparing leukocyte reduction and agitation methods on in vitro measures of hemostatic function in cold-stored whole blood
Authors: Remy Kenneth E. , Yazer Mark H. , Saini Arun , Mehanovic-Varmaz Ajlana , Rogers Sharon R. , Cap Andrew P. , Spinella Philip C.
Published: March 2018

BACKGROUND

Agitation of platelet units stored at room temperature is performed routinely to maintain platelet function, and leukoreduction of blood products is the standard of care in many countries to reduce immune consequences of transfusion. The effect of agitation and leukoreduction on whole blood stored at 4°C requires investigation, as reductions in hemostatic capacity of whole blood may reduce its efficacy in treating trauma-induced coagulopathy and platelet dysfunction. We hypothesize that agitation of whole blood will not affect hemostatic function and that leukoreduction will reduce hemostatic function of whole blood.

METHODS

In this in vitro randomized controlled study, 21 units of leukoreduced and 20 nonleukoreduced whole blood units were each randomly assigned into four agitation groups. Hemostatic parameters were measured using viscoelastic assays (rotational thromboelastometry-Extrinsic Screening Test (ROTEM-EXTEM) and thromboelastography (TEG) platelet mapping), impedance aggregometry (agonists—adenosine phosphate, arachidonic acid, thrombin receptor activating peptide, and collagen), and a thrombin generation assay from these whole blood units before and after filtration and on 0, 5, 10, and 15 days of storage at 4°C.

RESULTS

Leukoreduction compared to nonleukoreduction reduced platelet concentration on Day 0. Viscoelastic measures and thrombin generation parameters revealed significant reduction in hemostatic function between the leukoreduced units and the nonleukoreduced units at a few time points. Leukoreduced units consistently demonstrated reduced platelet aggregation compared to the nonleukoreduced units. Agitation methods did not significantly affect any of the hemostatic parameters examined.

CONCLUSIONS

Leukoreduction of whole blood with a platelet-sparing filter caused a moderate but significant reduction in some measures of whole blood hemostatic function most evident early in storage. The benefits of leukoreduction should be weighed against the potential reduced hemostatic function of leukoreduced units. Agitation of whole blood is not required to maintain hemostatic function.

LEVEL OF EVIDENCE

In vitro randomized controlled trial, level 1.
Adenosine, lidocaine, and Mg2+ (ALM) resuscitation fluid protects against experimental traumatic brain injury
Authors: Letson Hayley L. , Dobson Geoffrey P.
Published: March 2018

BACKGROUND

Currently, no drug therapy prevents secondary injury progression after traumatic brain injury (TBI). Our aim was to investigate the effects of small-volume intravenous adenosine, lidocaine, and Mg2+ (ALM) resuscitation fluid after moderate TBI in a rat fluid–percussion injury model.

METHODS

Anesthetized, mechanically ventilated male Sprague-Dawley rats (449 ± 5 g) were randomly assigned to one of four groups: (1) sham (craniotomy without TBI), (2) no-treatment, (3) saline-control, or (4) ALM therapy groups (all n = 16). A subdural probe was implanted in eight animals per group to measure cerebral blood flow. Fifteen minutes after moderate TBI was induced with lateral fluid percussion injury (2.57 atm), a single 3% NaCl ± ALM bolus (0.7 mL/kg) was injected intravenously, and after 60 minutes (Phase 1), 0.9% NaCl ± ALM stabilization “drip” (0.5 mL/kg per hour) was administered for 3 hours (Phase 2).

RESULTS

Mortality (without subdural brain probe) was 25% (saline controls) and 0% (ALM). Sixty minutes after bolus, ALM significantly increased cardiac function, cortical blood flow (CBF; approximately threefold) and blunted systemic inflammation compared to saline controls. Three hours after infusion drip, ALM improved left ventricular function, supported higher CBF, decreased proinflammatory cytokines systemically (IL-1β, tumor necrosis factor α, and regulated on activation, normal T cell expressed and secreted [RANTES]), increased anti-inflammatory cytokines in brain tissue (IL-10, IL-4), lowered brain injury markers (neuron-specific enolase, Syndecan-1, HMGB-1), reduced coagulopathy, increased platelet aggregation, and maintained baseline fibrinogen levels. Saline-controls were proinflammatory (brain, heart, lung, and blood) and hypocoagulable with neurogenic enlargement of the right side of the heart. Survival time significantly correlated with plasma neuron-specific enolase (p = 0.001) and CBF at 180 minutes (p = 0.009), and CBF correlated with brain anti-inflammatory cytokines (p = 0.001–0.034).

CONCLUSION

After moderate TBI, ALM resuscitation fluid increased survival and protected against early secondary injury by reducing coagulopathy, inflammation, and platelet dysfunction.
Vitamin D–binding protein deficiency in mice decreases systemic and select tissue levels of inflammatory cytokines in a murine model of acute muscle injury
Authors: Kew Richard R. , Tabrizian Tahmineh , Vosswinkel James A. , Davis James E. , Jawa Randeep S.
Published: March 2018

BACKGROUND

Severe acute muscle injury results in massive cell damage, causing the release of actin into extracellular fluids where it complexes with the vitamin D–binding protein (DBP). We hypothesized that a systemic DBP deficiency would result in a less proinflammatory phenotype.

METHODS

C57BL/6 wild-type (WT) and DBP-deficient (DBP−/−) mice received intramuscular injections of either 50% glycerol or phosphate-buffered saline into thigh muscles. Muscle injury was assessed by histology. Cytokine levels were measured in plasma, muscle, kidney, and lung.

RESULTS

All animals survived the procedure, but glycerol injection in both strains of mice showed lysis of skeletal myocytes and inflammatory cell infiltrate. The muscle inflammatory cell infiltrate in DBP-deficient mice had remarkably few neutrophils as compared with WT mice. The neutrophil chemoattractant CXCL1 was significantly reduced in muscle tissue from DBP−/− mice. However, there were no other significant differences in muscle cytokine levels. In contrast, plasma obtained 48 hours after glycerol injection revealed that DBP-deficient mice had significantly lower levels of systemic cytokines interleukin 6, CCL2, CXCL1, and granulocyte colony-stimulating factor. Lung tissue from DBP−/− mice showed significantly decreased amounts of CCL2 and CXCL1 as compared with glycerol-treated WT mice. Several chemokines in kidney homogenates following glycerol-induced injury were significantly reduced in DBP−/− mice: CCL2, CCL5, CXCL1, and CXCL2.

CONCLUSIONS

Acute muscle injury triggered a systemic proinflammatory response as noted by elevated plasma cytokine levels. However, mice with a systemic DBP deficiency demonstrated a change in their cytokine profile 48 hours after muscle injury to a less proinflammatory phenotype.
Organ donation in trauma victims: A systematic review and meta-analysis
Authors: Cameron Adam , Erdogan Mete , Lanteigne Sara , Hetherington Alexandra , Green Robert S.
Published: March 2018

BACKGROUND

Although trauma patients represent a large pool of potential organ donors (PODs), the donor conversion rates (DCRs) in this population are unclear. Our primary objective was to synthesize published evidence on DCRs in trauma patients. As a secondary objective, we investigated factors that affect organ donation (OD) in the trauma population.

METHODS

We searched four electronic databases (PubMed, Embase, Web of Science, and Cochrane Library) and gray literature for articles on OD in trauma patients (PROSPERO 2017: CRD42017070388). Articles were excluded if it was not possible to calculate the DCR (actual organ donors divided by PODs). We pooled DCRs and performed subgroups analysis by trauma subpopulation, patients’ age, and study publication date.

RESULTS

We identified 27 articles with a total of 123,142 participants. Cohorts ranged in size from 28 to 120,512 patients (median, 132), with most studies performed in the United States. Conversion rates among individual studies ranged from 14.0% to 75.2% (median, 49.3%). All 27 studies were included in the meta-analysis. We found a pooled DCR of 48.1% using the random effects model. There was a high level of heterogeneity between studies (I
2 = 97.4%). Upon subgroup analysis, we found DCRs were higher in head trauma patients compared with traumatic cardiac arrest patients (45.3% vs 20.9%, p < 0.001), in pediatric patients compared with adults (61.0% vs 38.0%, p = 0.018), and in studies published after 2007 compared with those published before (50.8% vs 43.9%, p < 0.001). Few studies assessed for factors associated with OD in trauma patients.

CONCLUSIONS

We found variation in DCRs among trauma patients (range, 14.0–75.2%) and estimated a pooled DCR of 48.1%. Our results are limited by heterogeneity across studies, which may be attributable to differences in study design and population, definitions of a POD, and in the institutional criteria and processes regarding OD.

LEVEL OF EVIDENCE

Systematic reviews and meta-analyses level III.
Minimally invasive surgery techniques for the management of urgent or emergent small bowel pathology: A 2018 EAST Master Class Video Presentation
Authors: Martin Matthew J. , Pakula Andrea M.
Published: March 2018

Although minimally invasive surgery techniques have been rapidly and widely adopted among nearly all fields of elective surgery, their use by trauma and acute care surgeons for urgent or emergent pathology has somewhat lagged behind. Trauma surgeons are frequently called upon to manage traumatic or emergent surgical small bowel pathology, and many of these may be ideally suited for increased incorporation of minimally invasive surgery techniques. This surgical technique video and associated article provide a technical guide and “how-to” instructions for laparoscopic and other minimally invasive approaches that can be utilized in the management of traumatic small bowel injuries, small bowel obstructions, or other emergent small bowel pathology.
Minimally invasive approach to incarcerated or strangulated groin hernias: A 2018 EAST Master Class Video Presentation
Authors: Martin Matthew J. , Pakula Andrea M.
Published: March 2018

Groin hernia repair is one of the most common general surgical procedures performed worldwide. Although only a small percentage will become incarcerated or strangulated, this is an indication for repair. Minimally invasive surgery is becoming the standard of care for most procedures, and we believe this to be a safe and feasible approach for incarcerated or strangulated groin hernias. We present a description of our recommended approach with technical details and accompanying video clips to highlight these techniques.
Trauma surgeon performance of appendectomy in 5-year- to 10-year-old children is safe and decreases length of hospital stay
Authors: Wall Derek B. , Ortega Carlos
Published: March 2018

BACKGROUND

Even in metropolitan areas, on-call pediatric surgeons may not always be immediately available for surgical care of appendicitis, potentially leading to delays in care. In 2012, the in-house trauma group at a suburban Level 1 trauma center (none with formal pediatric fellowship training) assumed surgical care of 5-year- to 10-year-old children with appendicitis, who had previously been cared for by pediatric surgeons. We propose to compare the outcomes of the trauma and pediatric surgery groups.

METHODS

Retrospective chart review of 5-year- to 10-year-olds undergoing emergency appendectomy at a suburban Level 1 trauma center between January 2007 and December 2016 was performed. Patients were classified as having surgery performed by the trauma surgery group or the pediatric surgery group. Patient characteristics, clinical course, and outcomes were compared.

RESULTS

A total of 220 patients were identified for study, 138 in the trauma group and 82 in the pediatric surgery group. Patients cared for by the trauma group were more likely to be female (47% vs. 32%; p = 0.03), were less likely to be diagnosed without imaging (2% vs. 26%; p < 0.0001), had a shorter time from diagnosis to surgery (214 vs. 318 minutes; p = 0.01), were more likely to have laparoscopic surgery (70% vs. 55%; p = 0.04), had a shorter operative time (40 vs. 49 minutes; p < 0.0001), and had a shorter length of stay (32 vs. 41 hours; p < 0.0001), despite more of them needing to be transferred from outside hospitals (60% vs. 37%; p < 0.001). There were no significant differences in patient age, rate of perforated appendicitis, 30-day readmissions, surgical site infections, or unanticipated procedures.

CONCLUSIONS

Trauma surgeon performance of emergency appendectomy in 5-year- to 10-year-old children decreased length of hospitalization with similar complication rates as compared with pediatric surgeons.

LEVEL OF EVIDENCE

Therapeutic study, level IV.
Prehospital low-titer cold-stored whole blood: Philosophy for ubiquitous utilization of O-positive product for emergency use in hemorrhage due to injury
Authors: McGinity Ashley C. , Zhu Caroline S. , Greebon Leslie , Xenakis Elly , Waltman Elizabeth , Epley Eric , Cobb Danielle , Jonas Rachelle , Nicholson Susannah E. , Eastridge Brian J. , Stewart Ronald M. , Jenkins Donald H.
Published: March 2018

The mortality from hemorrhage in trauma patients remains high. Early balanced resuscitation improves survival. These truths, balanced with the availability of local resources and our goals for positive regional impact, were the foundation for the development of our prehospital whole blood initiative—using low-titer cold-stored O RhD-positive whole blood. The main concern with use of RhD-positive blood is the potential development of isoimmunization in RhD-negative patients. We used our retrospective massive transfusion protocol (MTP) data to analyze the anticipated risk of this change in practice. In 30 months, of 124 total MTP patients, only one female of childbearing age that received an MTP was RhD-negative. With the risk of isoimmunization very low and the benefit of increased resources for the early administration of balanced resuscitation high, we determined that the utilization of low-titer cold-stored O RhD-positive whole blood would be safe and best serve our community.
Direct to operating room trauma resuscitation decreases mortality among severely injured children
Authors: Wieck Minna M. , Cunningham Aaron J. , Behrens Brandon , Ohm Erika T. , Maxwell Bryan G. , Hamilton Nicholas A. , Adams M. Christopher , Cole Frederick J. , Jafri Mubeen A.
Published: March 2018

BACKGROUND

Expediting evaluation and intervention for severely injured patients has remained a mainstay of advanced trauma care. One technique, direct to operating room (DOR) resuscitation, for selective adult patients has demonstrated decreased mortality. We sought to investigate the application of this protocol in children.

METHODS

All DOR pediatric patients from 2009 to 2016 at a pediatric Level I trauma center were identified. Direct to OR criteria included penetrating injury, chest injuries, amputations, significant blood loss, cardiopulmonary resuscitation, and surgeon discretion. Demographics, injury patterns, interventions, and outcomes were analyzed. Observed mortality was compared with expected mortality, calculated using Trauma Injury Severity Score methodology, with two-tailed t tests, and a p value less than 0.5 was considered significant.

RESULTS

Of 2,956 total pediatric trauma activations, 82 (2.8%) patients (age range, 1 month to 17 years) received DOR resuscitation during the study period. The most common indications for DOR were penetrating injuries (62%) and chest injuries (32%). Forty-four percent had Injury Severity Score (ISS) greater than 15, 33% had Glasgow Coma Scale (GCS) score of 8 or less, and 9% were hypotensive. The most commonly injured body regions were external (66%), head (34%), chest (30%), and abdomen (27%). Sixty-seven (82%) patients required emergent procedural intervention, most commonly wound exploration/repair (35%), central venous access (22%), tube thoracostomy (19%), and laparotomy (18%). Predictors of intervention were ISS greater than 15 (odds ratio, 14; p = 0.013) and GCS < 9 (odds ratio = 8.5, p = 0.044). The survival rate to discharge for DOR patients was 84% compared with an expected survival of 79% (Trauma Injury Severity Score) (p = 0.4). The greatest improvement relative to expected mortality was seen in the subgroup with penetrating trauma (84.5% vs 74.4%; p = 0.002).

CONCLUSION

A selective policy of resuscitating the most severely injured children in the OR can decrease mortality. Patients suffering penetrating trauma with the highest ISS, and diminished GCS scores have the greatest benefit. Trauma centers with appropriate resources should evaluate implementing similar policies.

LEVEL OF EVIDENCE

Diagnostic tests or criteria, level II.
Evaluation of Vision-Related Quality of Life in Chinese Patients With Leber Hereditary Optic Neuropathy and the G11778A Mutation
Authors: Cui Shilei , Jiang Hanqiu , Peng Jingting , Wang Jiawei , Zhang Xiaojun
Published: March 2018

Objective:

To assess quality of life (QoL) measures in Chinese Leber hereditary optic neuropathy (LHON) patients with the G11778A mutation.

Methods:

Chinese LHON patients with the G11778A mutation were prospectively evaluated using the Visual Function Index (VF-14) at 6 months, 1 year, and 3 years after the involvement of the second eye. Patients who completed the VF-14 at all 3 follow-up time designations were included in the analysis.

Results:

Fifty-five patients met the inclusion criteria. The median age of patients when their vision was bilaterally affected was 16.3 years old (interquartile range: 13.9–18.3 years). In our patient cohort, 89.1% (n = 49) were male, and the ratio of males to females was 8.2:1. The median logMAR visual acuity was 2.0 (interquartile range: 1.0–2.6). The mean VF-14 scores of patients with LHON at 6-month, 1-year, and 3-year follow-ups were 18.0 ± 19.2 (range 0–85.4), 19.9 ± 20.0 (range 0–85.4), and 20.7 ± 20.2 (range 0–85.4), and the differences were statistically significant (P < 0.001). VF-14 score at 6 months was significantly correlated with visual acuity of the better eye (P < 0.001) but not with age of onset (P = 0.43). Overall, the QoL improvement was significantly correlated with age of onset (P = 0.006) but not with visual acuity of the better eye (P = 0.134). Several abilities were significantly improved at the 1-year follow-up compared with the 6-month follow-up, including seeing steps, curbs, or stairs (P < 0.01), doing handiwork (P < 0.05), playing sports (P < 0.05), cooking (P < 0.01), and watching television (P < 0.05). When these scores were further compared between 1- and 3-year follow-ups, only scores for cooking (P < 0.05) and watching television (P < 0.05) were higher at the 3-year follow-up than that at the 1-year follow-up. No changes were found during the follow-up for reading small print, reading a newspaper or book, or reading signs.

Conclusions:

Our results indicate that although most of our Chinese LHON patients with the G11778A mutation had permanent central visual loss, visual-related quality of life improved over time, especially in younger patients.
Visual Outcomes and Clinical Manifestations of Pediatric Optic Neuritis in Indian Population: An Institutional Study
Authors: Ambika Selvakumar , Padmalakshmi Krishnakumar , Venkatraman Viswanathan , Noronha Olma V.
Published: March 2018

Background:

Optic neuritis in children is an uncommon disorder which usually occurs after a viral illness or vaccination and, less frequently, occurs as a manifestation of a demyelinating disorder. Pediatric optic neuritis usually is bilateral and presents with optic disc edema, recovers rapidly with steroid therapy, and generally has low conversion rate to multiple sclerosis or neuromyelitis optica spectrum disorder. We report the clinical features and treatment outcomes of pediatric optic neuritis in Indian population, for which little data are available.

Methods:

We reviewed the medical case records of patients with optic neuritis who were younger than 18 years, from 1999 to 2016. All patients were assessed and managed in the Neuro-Ophthalmology Department of Sankara Nethralaya, a unit of Medical Research Foundation and Pediatric Neurology Department of Kanchi Kamakoti—Childs Trust Hospital, Chennai, India.

Results:

One hundred seventeen eyes of 78 children with mean age of 11.84 (±4.58) years were identified. Forty-two (53.8%) were females and 36 (46.2%) were males. Thirty-nine patients (50%) had bilateral involvement and a similar number had unilateral involvement. Fifty-nine eyes (50.4%) had optic disc edema, 20 eyes (17.1%) had disc pallor, and 38 eyes (32.4%) had normal discs. Of 63 patients who had neuroimaging, 36 had MRI, and 27 underwent computed tomography. Eighty-four eyes (of 59 patients) received steroid therapy according to the protocol of the Optic Neuritis Treatment Trial (ONTT). Thirty-three eyes that were treated with other steroid protocols were excluded from the final visual outcome analyses. Sixty of the 84 eyes (72.3%) recovered visual acuity of 20/40 or better. Visual acuity improvement was statistically significant between initial and final visual acuity (logMAR) in our patients treated with the ONTT protocol (P ≤ 0.001).

Conclusions:

Our Indian pediatric population had good visual recovery after steroid treatment for optic neuritis. Profound loss of visual acuity on presentation and bilateral involvement were significantly associated with poor visual outcome.
HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells
Authors: Harrison Hannah , Pegg Henry J , Thompson Jamie , Bates Christian , Shore Paul
Published: March 2018

Hypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.

We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.

We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.

These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.
Structure of WT1 zinc fingers bound to its cognate DNA: Implications of the KTS insert
Authors: Yengo Raymond K. , Nurmemmedov Elmar , Thunnissen Marjolein M.G.M.
Published: March 2018

WT1 is a transcription factor with a DNA binding N-terminal domain containing four C2H2-type zinc fingers. In order to perform its role as a transcription factor, WT1 needs to specifically recognize and properly bind to its target DNA. How this is done is still not completely clear. Two of WT1’s major isoforms are distinguished by the presence or absence of a 3 amino acid insert, Lysine-Threonine-Serine (KTS) in the linker between zinc-fingers 3 and 4. This KTS insert is conserved throughout all life forms expressing WT1. The –KTS isoform, which acts as a transcription factor, binds DNA with higher affinity than the +KTS isoform, which is thought to participate in RNA splicing and interaction with partner proteins. This study was aims at elucidating the effect of the KTS insert on DNA binding. Here we present the crystal structure of WT1 zinc fingers 2-4, with and without the KTS insert, bound to the WT1 9-base pair cognate DNA sequence, refined to 1.9 Å and 2.5 Å respectively. The structures show that the +KTS isoform of WT1 recognizes DNA with the same specificity as the –KTS isoform. The only differences in the DNA bound conformation of the two isoforms are found within the linker containing the KTS, and these mainly involve the loss of the C-capping interactions thought to stabilize the complex. These structures provide the molecular detail necessary for the interpretation of the WT1 transcriptional DNA recognition and validation of its transcriptional targets.
Mean-Variance QTL Mapping Identifies Novel QTL for Circadian Activity and Exploratory Behavior in Mice
Authors: Corty Robert W. , Kumar Vivek , Tarantino Lisa M. , Takahashi Joseph S. , Valdar William
Published: March 2018

We illustrate, through two case studies, that “mean-variance QTL mapping” can discover QTL that traditional interval mapping cannot. Mean-variance QTL mapping is based on the double generalized linear model, which elaborates on the standard linear model by incorporating not only a linear model for the data itself, but also a linear model for the residual variance. Its potential for use in QTL mapping has been described previously, but it remains underutilized, with certain key advantages undemonstrated until now. In the first case study, we use mean-variance QTL mapping to reanalyze a reduced complexity intercross of C57BL/6J and C57BL/6N mice examining circadian behavior and find a mean-controlling QTL for circadian wheel running activity that was not detected by traditional interval mapping. Mean-variance QTL mapping was more powerful than traditional interval mapping at the QTL because it accounted for the fact that mice homozygous for the C57BL/6N allele had less residual variance than the other mice. In the second case study, we reanalyze an intercross between C57BL/6J and C58/J mice examining anxiety-like behaviors, and identify a variance-controlling QTL for rearing behavior. This QTL was not identified in the original analysis because traditional interval mapping does not target variance QTL.
Eye-movement intervention enhances extinction via amygdala deactivation
Authors: de Voogd Lycia D. , Kanen Jonathan W. , Neville David A. , Roelofs Karin , Fernández Guillén , Hermans Erno J.
Published: March 2018

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n=24), we found that goal-directed eye movements activate a dorsal fronto-parietal network and transiently deactivate the amygdala. Connectivity analyses revealed this down-regulation engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, this reduced spontaneous fear recovery 24 hours later. Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement. In conclusion, we show that extinction learning can be improved with a non-invasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits similar to those that support cognitive control of emotion.

Significant statement

Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via non-invasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements can reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppress amygdala activity can alter retention of emotional memories.
Scaffolding of RhoA contractile signaling by anillin: a regulatory analogue of kinetic proofreading
Authors: Budnar Srikanth , Husain Kabir B. , Gomez Guillermo A. , Naghibosidat Maedeh , Verma Suzie , Hamilton Nicholas A. , Morris Richard G. , Yap Alpha S.
Published: March 2018

Scaffolding is a fundamental principle of cell signaling commonly thought to involve multi-domain proteins that tether different components of a pathway together into a complex 1,2. We now report an alternative mechanism for scaffolding that is necessary for RhoA-mediated contractile signaling. We find that anillin binding stabilizes active, GTP-RhoA, and promotes contractility at both the epithelial zonula adherens (ZA) and the cytokinetic furrow. However, anillin does not conform to the classical picture of a multi-domain tether, since its RhoA-binding AH domain alone was sufficient to promote contractile signaling. Moreover, anillin competes with contractile effectors for a common site on RhoA, presenting the conundrum of how an inhibitory interaction can otherwise promote signaling. To explain this, we propose that inactivation of RhoA is non-Poissonian, having a rate that increases with time, unless the process is reset via transient binding to anillin. Repeated cycles of binding and un-binding therefore increase cortical residence times of non-sequestered GTP-RhoA and hence the probability of engaging contractile effectors. We identify the modification of the local lipid environment as a potential mechanism underlying such non-Poisson statistics, and demonstrate agreement with a minimal cellular system. Finally, we show that Myosin II anchors anillin at the cortex to form a feedback pathway that enhances RhoA signaling. This new paradigm of scaffolding is a regulatory analogue of kinetic proofreading and may be employed by other binding proteins that do not fit the classical picture.
Phenotypic expansion in DDX3X – a common cause of intellectual disability in females
Authors: Wang Xia , Rosenfeld Jill A. , Bacino Carlos A. , Scaglia Fernando , Immken LaDonna , Harris Jill M. , Hickey Scott E. , Mosher Theresa M. , Slavotinek Anne , Zhang Jing , Beuten Joke , Leduc Magalie S. , He Weimin , Vetrini Francesco , Walkiewicz Magdalena A. , Bi Weimin , Xiao Rui , Shao Yunru , Gezdirici Alper , Jiang Yunyun , Hansen Adam W. , Pehlivan Davut , Piard Juliette , Muzny Donna M. , Hanchard Neil , Belmont John W. , van Maldergem Lionel , Gibbs Richard A. , Eldomery Mohammad K. , Akdemir Zeynep C. , Harel Tamar , Posey Jennifer E. , Adesina Adekunle M. , Chen Shan ,   members of the UDN, Lee Brendan , Lupski James R. , Eng Christine M. , Xia Fan , Yang Yaping , Graham Brett H. , Moretti Paolo
Published: March 2018

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID), one of the most common causes of ID, in females. Forty-seven patients (44 females, 3 males) have been described. We identified 29 additional individuals carrying 27 unique DDX3X variants in the setting of complex clinical presentations including developmental delay or ID. In addition to previously reported manifestations, rare or novel phenotypes were identified including respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.
Active information sampling varies across the cardiac cycle
Authors: Kunzendorf Stella , Klotzsche Felix , Akbal Mert , Villringer Arno , Ohl Sven , Gaebler Michael
Published: March 2018

Perception and cognition oscillate with fluctuating bodily states. For example, visual processing has been shown to change with alternating cardiac phases. Here, we study the heartbeat’s role for active information sampling—testing whether humans implicitly act upon their environment so that relevant signals appear during preferred cardiac phases.

During the encoding period of a visual memory experiment, participants clicked through a set of emotional pictures to memorize them for a later recognition test. By self-paced key press, they actively prompted the onset of shortly (100-ms) presented pictures. Simultaneously recorded electrocardiograms allowed us to analyse the self-initiated picture onsets relative to the heartbeat. We find that self-initiated picture onsets vary across the cardiac cycle, showing an increase during cardiac systole, while memory performance was not affected by the heartbeat. We conclude that active information sampling integrates heart-related signals, thereby extending previous findings on the association between body-brain interactions and behaviour.
Sensory Deprivation Independently Regulates Neocortical Feedforward and Feedback Excitation-Inhibition Ratio
Authors: Miska Nathaniel J. , Richter Leonidas M.A. , Cary Brian A. , Gjorgjieva Julijana , Turrigiano Gina G.
Published: March 2018

Brief (2-3d) monocular deprivation (MD) during the critical period induces a profound loss of responsiveness within layer 4 of primary visual cortex (V1). This has largely been ascribed to long-term depression (LTD) at thalamocortical synapses onto pyramidal neurons, while a contribution from intracortical inhibition has been controversial. Here we used optogenetics to probe feedforward thalamocortical and feedback intracortical excitation-inhibition (E-I) ratios following brief MD. While thalamocortical inputs onto pyramidal neurons were depressed, there was stronger depression onto PV+ interneurons, which shifted the thalamocortical-evoked E-I ratio toward excitation. In contrast, feedback intracortical E-I ratio was shifted toward inhibition, and a computational model of layer 4 demonstrated that these opposing shifts produced an overall suppression of layer 4 excitability. Thus, feedforward and feedback E-I ratios onto the same postsynaptic target can be independently regulated by visual experience, and enhanced feedback inhibition is the primary driving force behind loss of visual responsiveness.
Cell-type heterogeneity in adipose tissue is associated with complex traits and reveals disease-relevant cell-specific eQTLs
Authors: Glastonbury Craig A. , Alves Alexessander Couto , El-Sayed Moustafa Julia S. , Small Kerrin S.
Published: March 2018

Adipose tissue is comprised of a heterogeneous collection of cell-types which can differentially impact disease phenotypes. We investigated cell-type heterogeneity in two population-level subcutaneous adipose tissue RNAseq datasets (TwinsUK, N =766 and GTEx, N=326). We find that adipose cell-type composition is heritable and confirm the positive association between macrophage proportion and obesity (BMI), but find a stronger BMI-independent association with DXA-derived body-fat distribution traits. Cellular heterogeneity can confound ‘omic analyses, but is rarely taken into account in analysis of solid-tissue transcriptomes. We benchmark the impact of adipose tissue cell-composition on a range of standard analyses, including phenotypegene expression association, co-expression networks and cis-eQTL discovery. We applied G x Cell Type Proportion interaction models to identify 26 cell-type specific eQTLs in 20 genes, including 4 autoimmune disease GWAS loci, demonstrating the potential of in silico deconvolution of bulk tissue to identify cell-type restricted regulatory variants.
Dynamic Construction of Reduced Representations in the Brain for Perceptual Decision Behavior
Authors: Zhan Jiayu , Ince Robin A. A. , van Rijsbergen Nicola , Schyns Philippe G.
Published: March 2018

Current models propose that the brain uses a multi-layered architecture to reduce the high dimensional visual input to lower dimensional representations that support face, object and scene categorizations. However, understanding the brain mechanisms that support such information reduction for behavior remains challenging. We addressed the challenge using a novel information theoretic framework that quantifies the relationships between three key variables: single-trial information randomly sampled from an ambiguous scene, source-space MEG responses and perceptual decision behaviors. In each observer, behavioral analysis revealed the scene features that subtend their decisions. Independent source space analyses revealed the flow of these and other features in cortical activity. We show where (at the junction between occipital cortex and ventral regions), when (up until 170 ms post stimulus) and how (by separating task-relevant and irrelevant features) brain regions reduce the high-dimensional scene to construct task-relevant feature representations in the right fusiform gyrus that support decisions. Our results inform the occipito-temporal pathway mechanisms that reduce and select information to produce behavior.
Role of anterograde motor Kif5b in clathrin-coated vesicle uncoating and clathrin-mediated endocytosis
Authors: Ni Yan-Xiang , Xue Wen-Qian , Zhou Nan , Yung Wing-Ho , Lin Rao-Zhou , Kao Richard Yi-Tsun , Duan Zhi-Gang , Tang Xu-Ming , Liu Meng-Fei , Zhang Wen , Qi Shuang , Lu Xi-Bin , Hu Jian-jiang , Chung Sookja , Song You-Qiang , Huang Jian-Dong
Published: March 2018

Kif5b-driven anterograde transport and clathrin-mediated endocytosis (CME) are responsible for opposite intracellular trafficking, contributing to plasma membrane homeostasis. However, whether and how the two trafficking processes coordinate remain unclear. Here, we show that Kif5b directly interacts with clathrin heavy chain (CHC) at a region close to that for uncoating catalyst (Hsc70) and preferentially localizes on large clathrin-coated vesicles (CCVs). Uncoatingin vitrois decreased for CCVs from the cortex ofkif5bconditional knockout (mutant) mouse and facilitated by adding CHC-binding Kif5b fragments, while cell peripheral distribution of CHC or Hsc70 keeps unaffected by Kif5b depletion. Furthermore, cellular entry of vesicular stomatitis virus that internalized into large CCV is inhibited in cells by Kif5b depletion or introducing a dominant-negative Kif5b fragment. These findings showed a new role of Kif5b in CCV uncoating and CME, indicating Kif5b as a molecular knot connecting anterograde transport to CME.
Identify and Predict Environmental Change Effects On Tiger Mosquitos,Aedes Polynesiensis
Authors: Grziwotz Florian , Strauß Jakob Friedrich , Hsieh Chih-hao , Telschow Arndt
Published: March 2018

Summary

To control mosquito populations for managing vector-borne diseases, a critical need is to identify and predict their response to causal environmental variables. However, most existing attempts rely on linear approaches based on correlation, which cannot apply in complex, nonlinear natural systems, because correlation is neither a necessary nor sufficient condition for causation. Appling empirical dynamic modelling that acknowledges nonlinear dynamics on nine subpopulations of tiger mosquitos from three neighbouring reef islets of the Raiatea atoll, we identified temperature, precipitation, dew point, air pressure, and mean tide level as causal environmental variables. Interestingly, responses of subpopulations in close proximity (100-500 m) differed with respect to their causal environmental variables and the time delay of effect, highlighting complexity in mosquito-environment causality network. Moreover, we demonstrated how to explore the effects of changing environmental variables on number and strength of mosquito outbreaks, providing a new framework for pest control and disease vector ecology.
Chromosome compartmentalization replacement during stem cell differentiation
Authors: Eidelman Y.A. , Slanina S.V. , Pyatenko V.S. , Andreev S.G.
Published: March 2018

In this paper, changes in a large-scale 3D structure of chromosomes during stem cell differentiation is studied. The polymer coarse-grained model of a human interphase chromosome is introduced which reproduces the experimental Hi-C contact maps in chromosomes 12, 17 for both embryonic stem and differentiated cells with high accuracy. Model based analysis of Hi-C data suggests a mechanism of establishment of preferential long-range chromosomal contacts and compartmentalization replacement during cell stem differentiation. The model provides the conceptual basis for integration of data on the dynamics of chromatin interactions, the 3D structure of chromosomes and gene expression during stem cell differentiation or reprogramming.
A re-examination of responding on ratio and regulated-probability interval schedules
Authors: Pérez Omar D. , Aitken Michael R.F. , Milton Amy L. , Dickinson Anthony
Published: March 2018

The higher response rates observed on ratio than on matched interval reward schedules has been attributed to the differential reinforcement of longer inter-response times (IRTs) on the interval contingency. Some data, however, seem to contradict this hypothesis, showing that the difference is still observed when the role of IRT reinforcement is neutralized by using a regulated-probability interval schedule (RPI). Given the mixed evidence for these predictions, we re-examined this hypothesis by training three groups of rats to lever press under ratio, interval and RPI schedules across two phases while matching reward rates within triads. At the end of the first phase, the master ratio and RPI groups responded at similar rates. In the second phase, an interval group yoked to the same master ratio group of the first phase responded at a lower rate than the RPI group. Post-hoc analysis showed comparable reward rates for master and yoked schedules. The experienced response-outcome rate correlations were likewise similar, and approached zero as training progressed. We discuss these results in terms of dual-system theories of instrumental conditioning.
Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy
Authors: Das Avinash , Lee Joo Sang , Zhang Gao , Wang Zhiyong , Iglesias-Bartolome Ramiro , Tian Tian , Wei Zhi , Miao Benchun , Nair Nishanth Ulhas , Ponomarova Olga , Friedman Adam A. , Amzallag Arnaud , Moll Tabea , Kasumova Gyulnara , Greninger Patricia , Egan Regina K. , Damon Leah J. , Frederick Dennie T. , Wagner Allon , Cheng Kuoyuan , Park Seung Gu , Robinson Welles , Gardner Kevin , Boland Genevieve , Hannenhalli Sridhar , Herlyn Meenhard , Benes Cyril , Gutkind J. Silvio , Flaherty Keith , Ruppin Eytan
Published: March 2018

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involvesynthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (therescuer). Here we perform a genome-wide prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.