bluuebunny/crossref_metadata_2025 huggingface dataset:
Past-Year Racial Discrimination and Allostatic Load Among Indigenous Adults in Canada: The Role of Cultural Continuity
Authors: Currie Cheryl L. , Copeland Jennifer L. , Metz Gerlinde A. , Chief Moon-Riley Kat , Davies Colleen M.
Published: October 2019

Objective

This study aimed to examine the association between racial discrimination and allostatic load (AL) and whether this association was moderated by cultural continuity among Indigenous adults.

Methods

Data were collected from Indigenous adults attending university in a small city in western Canada between 2015 and 2017 (mean age = 27.8 years). The Experience of Discrimination Situation Score and the Vancouver Index Enculturation Subscale were used to assess racial discrimination and cultural continuity, respectively. AL was measured as a composite of seven biomarkers assessing neuroendocrine, cardiovascular, metabolic, and immune system function. Bias-corrected and accelerated bootstrapped linear regression models were used to examine associations adjusting for confounders (n = 104; 72.5% women).

Results

Across the full sample, racial discrimination was associated with a linear, dose-response increase in AL score after adjustment for confounders. Among adults with low cultural continuity, past-year discrimination was associated with increased AL and explained 22% (adjusted R
2) of the variance in AL score. Taken together, the full model including age, sex, and income explained 38% of the variance in AL score in this subgroup. Among adults with high cultural continuity, racial discrimination was not associated with AL, whereas age remained significant and explained 13% of the variance in AL score.

Conclusions

Past-year racial discrimination was associated with early and more pronounced wear and tear on stress response systems among Indigenous adults relative to peers. Indigenous cultural continuity served as an important buffer that promoted biological resilience against the adverse effects of racial discrimination on physiologic regulation among Indigenous adults.
Brief Report: Zinc Supplementation and Inflammation in Treated HIV
Authors: Dirajlal-Fargo Sahera , Yu Jiao , Kulkarni Manjusha , Sattar Abdus , Funderburg Nicholas , Barkoukis Hope , Mccomsey Grace A.
Published: October 2019

Objective:

In this study, we explored the effect of zinc supplementation on markers of inflammation and monocyte activation in antiretroviral therapy–treated HIV infection.

Methods:

This is a phase I open-labeled randomized double-arm study, exploring the efficacy and safety of zinc supplementation on inflammation in ≥18-year-old people living with HIV in the US, on stable antiretroviral therapy and with zinc levels ≤75 µg/dL in the last 60 days. Patients were randomized 1:1 to zinc gluconate capsules at a dose of 45 mg (low-dose), or 90 mg (high-dose) elemental zinc daily for 16 weeks. We assessed inflammatory and gut integrity biomarkers at baseline and 16 weeks.

Results:

Overall, a total of 52 participants were enrolled (25 participants in the low-dose arm and 27 participants in the high-dose arm). Median (Interquartile range) age was 49 (38, 60) years, 77% were men and 73% were African Americans. At baseline, median zinc levels were 73 (64, 86) µg/dL. Median circulating zinc levels increased to 91 µg/dL in the low-dose arm and to 100 µg/dL in the high-dose arm. Overall, 48%–60% of participants experienced a reduction in biomarkers levels. The margin of reduction ranged between 8% and 21%. This change was meaningful with large effect size (Cohen D ranging from 5 to 19).

Conclusions:

In this pilot study, we found that zinc supplementation is effective at increasing circulating zinc levels. In addition, our findings provide novel data suggesting that zinc can affect a biological signature in people living with HIV and modulate biomarkers associated with clinical comorbidities.
Switching to Fixed-Dose Bictegravir, Emtricitabine, and Tenofovir Alafenamide (B/F/TAF) in Virologically Suppressed HIV-1 Infected Women: A Randomized, Open-Label, Multicenter, Active-Controlled, Phase 3, Noninferiority Trial
Authors: Kityo Cissy , Hagins Debbie , Koenig Ellen , Avihingsanon Anchalee , Chetchotisakd Ploenchan , Supparatpinyo Khuanchai , Gankina Natalya , Pokrovsky Vadim , Voronin Evgeny , Stephens Jeffrey L. , DeJesus Edwin , Wang Hui , Acosta Rima K. , Cao Huyen , Quirk Erin , Martin Hal , Makadzange Tariro
Published: October 2019

Background:

Bictegravir, coformulated with emtricitabine/tenofovir alafenamide as a fixed-dose combination (B/F/TAF), is recommended for treatment of HIV-1-infection. Multiple studies of B/F/TAF in treatment-naive and virologically suppressed cohorts have shown high efficacy and tolerability with no treatment-emergent resistance through 48 weeks. Participants in these studies have been predominantly men. We report 48-week results from a phase 3 study evaluating switching to B/F/TAF, specifically in a globally distributed trial population of women.

Methods:

In this multicenter, randomized, open-label, active-controlled, noninferiority trial (ClinicalTrials.gov NCT02652624), women living with HIV who were virologically suppressed (HIV-1 RNA levels <50 copies/mL) on a regimen containing either TAF or tenofovir disoproxil fumarate were randomly assigned (1:1) to switch to B/F/TAF (50/200/25 mg) or stay on baseline regimen (SBR) once daily for 48 weeks. Primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (U.S. Food and Drug Administration snapshot algorithm); prespecified noninferiority margin was 4%.

Findings:

We randomized 472 participants and treated 470 (234 B/F/TAF, 236 SBR). Switching to B/F/TAF was noninferior to SBR for the primary outcome, as 1.7% (4/234) vs 1.7% (4/236) had HIV-1 RNA ≥50 copies/mL at week 48 (difference 0.0%, 95.001% confidence interval: −2.9% to 2.9%). No individual receiving B/F/TAF developed treatment-emergent resistance. Both treatments were well-tolerated; no participant discontinued treatment because of an adverse event.

Interpretation:

Fixed-dose combination B/F/TAF provides a safe and efficacious option for ongoing treatment of HIV in women. This study contributes important data on safety, tolerability, and outcomes of antiretroviral therapy among women living with HIV.
A Modification of the Posterior Perichondrio-Adipo-Dermal Flap for Protruding Ear Correction
Authors: Ersen Burak
Published: October 2019

Prominent ear deformity is a common congenital deformity of the external ear affecting 5% of the general population. Because of the deformity's displeasing nature, corrective prominent ear surgery is widely common and performed as a prophylactic surgery. More than 200 surgical techniques for the correction of prominent ear deformity have been described to improve the cosmetic outcome and decrease complication rates. The aim of the study was to present a modified post auricular flap technique that increases the control of reshaping the ear cartilages, decreases the operation time, and provides a symmetrical long-lasting cosmetic outcome.

One hundred sixty-two patients (141 male and 21 female) had ear correction surgeries performed by the same surgeon using the described technique between January 2015 and January 2018. One hundred sixty patients were gone through bilateral ear correction, whereas only 2 patients had unilateral ear correction procedures. A modified posterior perichondrio-adipo-dermal flap technique for protruding ear correction was applied to all patients.

The patients' ages ranged from 18 to 40 years, with a median of 28.3 years. The mean follow-up time was 22.5 months (6–36 months). Total operation time was 35 minutes on average (25–45 minutes). As more experience was gained in flap harvesting, operation time became shorter. The mean preoperative upper third ear proportion-scalp distance was 33.1 mm and the middle third ear proportion—scalp distance was 29.8 mm. At the sixth month of the surgery, the measurements were 9.8 and 11.6 mm.

Measuring and adjusting flap's width provided to achieve symmetry in initial technique. Locating the postoperative scar along the posterior surface of the helical groove also provides a natural view. Different from traditional posterior fascial flap, the width of the flap was narrowed to 8 to 10 mm. In the traditional technique, the flap was dissected along the incision margins. Narrowing the width of the flap decreased the operation time. The preserved skin between the helix and the mastoid bone has the same width with perichondrio-adipo-dermal flap. That increases the control over the helix-mastoid distance and posterior auricular fold not to mention provides permanent results. The previously mentioned method can be a simple, useful, and practical technique for protruding ear deformity.
Macrophage Transplantation Fails to Improve Repair of Critical-Sized Calvarial Defects
Authors: Borrelli Mimi R. , Hu Michael S. , Hong Wan Xing , Oliver Jeremie D. , Duscher Dominik , Longaker Michael T. , Lorenz Hermann Peter
Published: October 2019

Introduction:

Over 500,000 bone grafting procedures are performed every year in the United States for neoplastic and traumatic lesions of the craniofacial skeleton, costing $585 million in medical care. Current bone grafting procedures are limited, and full-thickness critical-sized defects (CSDs) of the adult human skull thus pose a substantial reconstructive challenge for the craniofacial surgeon. Cell-based strategies have been shown to safely and efficaciously accelerate the rate of bone formation in CSDs in animals. The authors recently demonstrated that supraphysiological transplantation of macrophages seeded in pullalan–collagen composite hydrogels significantly accelerated wound healing in wild type and diabetic mice, an effect mediated in part by enhancing angiogenesis. In this study, the authors investigated the bone healing effects of macrophage transplantation into CSDs of mice.

Methods:

CD1 athymic nude mice (60 days of age) were anesthetized, and unilateral full-thickness critical-sized (4 mm in diameter) cranial defects were created in the right parietal bone, avoiding cranial sutures. Macrophages were isolated from FVB-L2G mice and seeded onto hydroxyapatite-poly (lactic-co-glycolic acid) (HA-PLGA) scaffolds (1.0 × 106 cells per CSD). Scaffolds were incubated for 24 hours before they were placed into the CSDs. Macrophage survival was assessed using three-dimensional in vivo imaging system (3D IVIS)/micro-CT. Micro-CT at 0, 2, 4, 6, and 8 weeks was performed to evaluate gross bone formation, which was quantified using Adobe Photoshop. Microscopic evidence of bone regeneration was assessed at 8 weeks by histology. Bone formation and macrophage survival were compared at each time point using independent samples t tests.

Results:

Transplantation of macrophages at supraphysiological concentration had no effect on the formation of bones in CSDs as assessed by either micro-CT data at any time point analyzed (all P > 0.05). These results were corroborated by histology. 3D IVIS/micro-CT demonstrated survival of macrophages through 8 weeks.

Conclusion:

Supraphysiologic delivery of macrophages to CSDs of mice had no effect on bone formation despite survival of transplanted macrophages through to 8 weeks posttransplantation. Further research into the physiological effects of macrophages on bone regeneration is needed to assess whether recapitulation of these conditions in macrophage-based therapy can promote the healing of large cranial defects.
Outcomes of Surgical Management of Palatal Fistulae in Patients With Repaired Cleft Palate
Authors: Denadai Rafael , Zanco Guilherme Luis , Raposo-Amaral Cesar Augusto , Buzzo Celso Luiz , Raposo-Amaral Cassio Eduardo
Published: October 2019

Background:

The palatal fistula is an important surgical challenge within the longitudinal follow-up of patients with repaired cleft palate as the success rate of palatal fistula reconstruction by adopting several surgical techniques is variable and often unsatisfactory. The purpose of this retrospective study was to report the clinical outcomes of an algorithm for the surgical management of palatal fistulae in patients with repaired cleft palate.

Methods:

Consecutive patients (n = 101) with repaired cleft palate and palatal fistula-related symptoms who were treated according to a specific algorithm between 2009 and 2017 were included. Based on the anatomical location (Pittsburgh fistula types II–V), amount of scarring (minimal or severe scarred palate), and diameter of the fistula (≤5 mm or >5 mm), 1 of 3 approaches (local flaps [62.4%], buccinator myomucosal flaps [20.8%], or tongue flaps [16.8%]) was performed. For clinical outcome assessment, symptomatic and anatomical parameters (fistula-reported symptoms and residual fistula, respectively) were combined as follows: complete fistula closure with no symptoms; asymptomatic narrow fistula remained; or failure to repair the fistula (“good,” “fair,” or “poor” outcomes, respectively). Surgical-related complication data were also collected.

Results:

Most patients (91.1%) presented “good” clinical outcomes, ranging from 86.2% to 100% (86.2%, 100%, and 100% for local flaps, buccinator flaps, and tongue flaps, respectively). All (8.9%) “fair” and “poor” outcomes were observed in fistulae reconstructed by local flaps. All “poor” (5%) outcomes were observed in borderline fistulae (4–5 mm). No surgical-related complications (dehiscence, infections, or necrosis) were observed, except for an episode of bleeding after the 1st stage of tongue flap-based reconstruction (1.0%).

Conclusion:

A high rate of fistula resolution was achieved using this algorithm for surgical management of palatal fistulae in patients with repaired cleft palate.
An Accurate Volumetric Analysis Method for Evaluating Outcomes of Alveolar Cleft Reconstruction
Authors: Liu Bing , Chen Shu X. , Li Bing H. , Yin Ning B. , Xiao Ran , Wang Yong Q.
Published: October 2019

An accurate volumetric analysis method for evaluating the outcomes of different types of alveolar cleft reconstruction is essential because it can help determine which graft material is more effective, confirm favorable times for alveolar bone grafting, and improve surgical techniques. This study aimed to introduce a novel method of precisely calculating the bone formation ratio using computer-aided engineering after surgery. A patient with a unilateral alveolar cleft who was treated with anterior iliac crest bone grafting was enrolled in this study. Helical computed tomography scans were performed preoperatively and 12 months postoperatively. The Digital Imaging and Communications in Medicine (DICOM) data were reconstructed as three-dimensional images and saved in the STL format by using Mimics software. STL data were processed by Geomagic Wrap 2017, using the Boolean operation, the newly formed bone of the alveolar was segmented by identifying the differences between the preoperative and the postoperative three-dimensional images. For this patient, the mean volume of the newly formed bone was 0.387 cm3, the morphology was clear, the bone formation ratio was 41.4%, the mean time required for calculating the newly formed bone volume was 23 minutes, and the bone survival ratio was 38.7%. This method is a clinically practical, accurately measurement and time-saving method to evaluate the outcome of alveolar cleft reconstruction. Both the volumetric assessment and morphological analysis of the newly formed bone could be determined in a precise manner.
Identification of Stress Fields in a Customized Mandibular Reconstruction Based on a Photoelastic Model
Authors: Moreno-Garibaldi Pablo , Beltrán-Fernández Juan-Alfonso , Yescas-Hernandez Jorge-Arturo , González-Rebattu Mauricio , Carrera-Espinoza Rafael , Hernández-Gómez Luis-Héctor , López-Liévano Daniel-Ramon , Pava-Chipol Nefi-David , Pava-Chipol Joel Francisco , Urriolagoitia-Calderon Guillermo Manuel
Published: October 2019

Tumors, trauma and infections are the main reasons for subjecting a patient to a bone reconstruction made with the use of bone grafts or prosthetic elements, using for example components such as osteosynthesis plates, meshes and screws for their stabilization.

This study focuses on the photoelastic analysis of a customized prosthesis of the jaw for a patient diagnosed with osteonecrosis. A resin model was manufactured as follows: DICOM files were processed in ScanIP software to obtain an STL file that was used to generate an antagonist model of the healthy section of the jaw using CATIA software, then, models were printed in Acrylonitrile Butadiene Styrene (ABS). Following the resin casting technique, the printed model of the jaw was used to construct a resin model, which is tested to determine its mechanical behavior.

After carrying out the photoelastic analysis, it was found that the assembly process generates stress concentration zones. Here, the stress reaches a maximum value after the application of a bite force of 130.9 N in the premolars. In this study near the premolars, 3 stress concentration zones were identified and overlap of stress fields is reveled.

The results show the importance of planning in the design and assembly process to obtain the best results in the reconstruction, reducing in this way the risk of a surgical reoperation due to problems of rupture or loosening of the prosthesis.
Management of Congenital Melanocytic Nevus on Face Using Multiple Re-expansion Method: Aesthetic and Psychosocial Results
Authors: Lee Hojune , Eom Yeseul , Oh Kap Sung
Published: October 2019

Background:

Congenital giant melanocytic nevus on the face is a challenging condition, especially in the pediatric population. It can produce significant cosmetic deformity with negative psychosocial effects in pediatric patients even after treatment. The objective of this study was to report aesthetic and psychosocial results in the management of congenital melanocytic nevus on the face using multiple reexpansion.

Methods:

Data of 6 patients with congenital melanocytic nevus on the face who underwent excision and multiple reexpansion at our center from September 2004 to August 2017, were retrospectively reviewed. To evaluate aesthetic outcomes, preoperative and final photographs of each patient were reviewed by 3 other plastic surgeons and 4 laypersons. For comparison, 6 other patients who were treated with conventional surgery during the same period were reviewed. After final reconstruction surgery, the authors surveyed patients’ satisfaction via telephone.

Results:

Six patients were followed up for an average of 87.66 months (range, 55–123 months). The mean number of tissue expander insertions was 3.33 and the mean number of total expanders inserted was 4.83. Complication associated with expander exposure occurred in 1 patient during the fifth expansion. The average score of aesthetic outcome in the multiple reexpansion group was superior to that of the conventional group (2.60 versus 2.10, P = 0.03). During the telephone survey, patients did not rate their appearance as positive, although they were comparatively satisfied with the surgical procedure.

Conclusion:

Considering the low rate of malignancy involving congenital melanocytic nevus in childhood, multiple reexpansion is an attractive option to obtain better results compared with other reconstructive methods.
Applications of artificial intelligence in neuro-oncology
Authors: Aneja Sanjay , Chang Enoch , Omuro Antonio
Published: October 2019

Purpose of review

To discuss recent applications of artificial intelligence within the field of neuro-oncology and highlight emerging challenges in integrating artificial intelligence within clinical practice.

Recent findings

In the field of image analysis, artificial intelligence has shown promise in aiding clinicians with incorporating an increasing amount of data in genomics, detection, diagnosis, classification, risk stratification, prognosis, and treatment response. Artificial intelligence has also been applied in epigenetics, pathology, and natural language processing.

Although nascent, applications of artificial intelligence within neuro-oncology show significant promise. Artificial intelligence algorithms will likely improve our understanding of brain tumors and help drive future innovations in neuro-oncology.
Age effect on functional connectivity changes of right anterior insula after partial sleep deprivation
Authors: Long Zhiliang , Cheng Fei
Published: October 2019

Neuroimaging studies revealed that emotion and cognition dysfunction after sleep deprivation is associated with the disturbance of the salience network. However, the age effect on the functional connectivity changes of the network after sleep deprivation remains unclear. The current study investigated the functional connectivity changes of the right anterior insula after partial sleep deprivation in young and old adults by using resting-state functional magnetic resonance imaging. We found a significant age × deprivation interaction effect on the functional connectivity between the right ventral anterior insula and the right ventral lateral prefrontal cortex and between the right dorsal anterior insula and the right anterior temporoparietal junction and left medial prefrontal cortex. Post-hoc analysis indicated that only young adults showed reduced functional connectivity of the right anterior insula. The changes in the functional connectivity between the right anterior insula and the right ventral lateral prefrontal cortex and anterior temporoparietal junction were negatively correlated with the insomnia severity index. Results suggested that sleep deprivation affects the salience network of young and old adults differently and highlighted the crucial role of age in sleep deprivation-related studies.
Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode
Authors: Dell’Osso Bernardo , Cremaschi Laura , Arici Chiara , Altamura A. Carlo , Hooshmand Farnaz , Do Dennis , Shah Saloni , Gershon Anda , Holsinger Alex , Yeon Park Dong , Miller Shefali , Wang Po W. , Ketter Terence A.
Published: October 2019

Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management.
Mycobacterium chelonae bacteraemia in a patient with myasthenia gravis receiving long-term steroid therapy
Authors: Samaddar Arghadip , Srivastava Saumya , Khan Salman , Tak Vibhor , Sharma Anuradha , Nag Vijaya Lakshmi , Bohra Gopal Krishna
Published: October 2019

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms found in soil and water. Infections caused by NTM are increasing with conditions ranging from harmless colonization to invasive infections, the latter being more common in immunocompromised hosts. In this report, we present a case of bacteraemia caused by

Mycobacterium chelonae

, a rapidly growing NTM belonging to Class IV in the Runyon classification, in a 71-year-old male with ocular myasthenia gravis undergoing treatment with oral prednisolone. Gram staining of these organisms from blood culture can be easily overlooked or confused with diptheroids. Detection of Gram-positive bacilli should prompt Ziehl–Neelsen staining to distinguish diphtheroids from rapidly growing mycobacteria in immunosuppressed patients. In addition, speciation and antimicrobial susceptibility testing are of paramount importance in such cases as there is considerable variation in the resistance patterns between different species of NTM. Line probe assay provides a rapid and reliable method for identification of NTM to the species level, which can guide treatment with appropriate antibiotics. This case report highlights the importance of early detection of such cases so as to optimize management and improve patient outcomes.
HRT Atlas v1.1 database: redefining human and mouse housekeeping genes and candidate reference transcripts by mining massive RNA-seq datasets
Authors: Hounkpe Bidossessi Wilfried , Chenou Francine , Lima Franciele , de Paula Erich Vinicius
Published: October 2019

Housekeeping (HK) genes are constitutively expressed genes that are required for the maintenance of basic cellular functions. Despite their importance in the calibration of gene expression, as well as the understanding of many genomic and evolutionary features, important discrepancies have been observed in studies that previously identified these genes. Here, we present Housekeeping Transcript Atlas (HRT Atlas v1.0, www.housekeeping.unicamp.br) a web-based database which addresses some of the previously observed limitations in the identification of these genes, and offers a more accurate database of human and mouse HK genes and transcripts. The database was generated by mining massive human and mouse RNA-seq data sets, including 12,482 and 507 high-quality RNA-seq samples from 82 human non-disease tissues/cells and 15 healthy tissues/cells of C57BL/6 wild type mouse, respectively. User can visualize the expression and download lists of 2,158 human HK transcripts from 2,176 HK genes and 3,024 mouse HK transcripts from 3,277 mouse HK genes. HRT Atlas also offers the most stable and suitable tissue selective candidate reference transcripts for normalization of qPCR experiments. Specific primers and predicted modifiers of gene expression for some of these HK transcripts are also proposed. HRT Atlas has also been integrated with regulatory elements from Epiregio server. All of these resources can be accessed and downloaded from any computer or small device web browsers.
Cell segmentation-free inference of cell types fromin situtranscriptomics data
Authors: Park Jeongbin , Choi Wonyl , Tiesmeyer Sebastian , Long Brian , Borm Lars E. , Garren Emma , Nguyen Thuc Nghi , Tasic Bosiljka , Codeluppi Simone , Graf Tobias , Schlesner Matthias , Stegle Oliver , Eils Roland , Ishaque Naveed
Published: October 2019

Multiplexed fluorescencein situhybridization techniques have enabled cell-type identification, linking transcriptional heterogeneity with spatial heterogeneity of cells. However, inaccurate cell segmentation reduces the efficacy of cell-type identification and tissue characterization. Here, we present a novel method called Spot-based Spatial cell-type Analysis by Multidimensional mRNA density estimation (SSAM), a robust cell segmentation-free computational framework for identifying cell-types and tissue domains in 2D and 3D. SSAM is applicable to a variety ofin situtranscriptomics techniques and capable of integrating prior knowledge of cell types. We apply SSAM to three mouse brain tissue images: the somatosensory cortex imaged by osmFISH, the hypothalamic preoptic region by MERFISH, and the visual cortex by multiplexed smFISH. We found that SSAM detects regions occupied by known cell types that were previously missed and discovers new cell types.
The transcriptional landscape of the murine middle ear epithelium in vitro
Authors: Mulay Apoorva , Chowdhury Md Miraj K , James Cameron , Bingle Lynne , Bingle Colin D
Published: October 2019

Otitis media (OM) is the most common paediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology, it is clear that epithelial abnormalities underpin the disease. The mechanisms underpinning epithelial remodelling in OM remain unclear. We recently described a novel in vitro model of mouse middle ear epithelial cells (mMEECs) that undergoes mucociliary differentiation into the varied epithelial cell populations seen in the middle ear cavity. We now describe genome wide gene expression profiles of mMEECs as they undergo differentiation. We compared the gene expression profiles of original (uncultured) middle ear cells, confluent cultures of undifferentiated cells (day 0 of ALI) and cells that had been differentiated for 7 days at an ALI. >5000 genes were differentially expressed among the three groups of cells. Approximately 4000 genes were differentially expressed between the original cells and day 0 of ALI culture. The original cell population was shown to contain a mix of cell types, including contaminating inflammatory cells that were lost on culture. Approximately 500 genes were upregulated during ALI induced differentiation. These included some secretory genes and some enzymes but most were associated with the process of ciliogenesis. Our in vitro model of differentiated murine middle ear epithelium exhibits a transcriptional profile consistent with the mucociliary epithelium seen within the middle ear. Knowledge of the transcriptional landscape of this epithelium will provide a basis for understanding the phenotypic changes seen in murine models of OM.
Sequential and efficient neural-population coding of complex task information
Authors: Koay Sue Ann , Charles Adam S. , Thiberge Stephan Y. , Brody Carlos D. , Tank David W.
Published: October 2019

Recent work has highlighted that many types of variables are represented in each neocortical area. How can these many neural representations be organized together without interference, and coherently maintained/updated through time? We recorded from large neural populations in posterior cortices as mice performed a complex, dynamic task involving multiple interrelated variables. The neural encoding implied that correlated task variables were represented by uncorrelated neural-population modes, while pairs of neurons exhibited a variety of signal correlations. This finding relates to principles of efficient coding for task-specific information, with neural-population modes as the encoding unit, and applied across posterior cortical regions and layers 2/3 and 5. Remarkably, this encoding function was multiplexed with sequential neural dynamics as well as reliably followed changes in task-variable correlations through time. We suggest that neural circuits can implement time-dependent encoding in a simple way by using random sequential dynamics as a temporal scaffold.
Neuro-Computational Foundations of Moral Preferences
Authors: Ugazio Giuseppe , Grueschow Marcus , Polania Rafael , Lamm Claus , Tobler Philippe N. , Ruff Christian C.
Published: October 2019

Moral preferences pervade many aspects of our lives, dictating how we ought to behave, whom we can marry, and even what we eat. Despite their relevance, one fundamental question remains unanswered: Where do individual moral preferences come from? It is often thought that all types of preferences reflect properties of domain-general neural decision mechanisms that employ a common “neural currency” to value choice options in many different contexts. This assumption, however, appears at odds with the observation that many humans consider it intuitively wrong to employ the same scale to compare moral value (e.g., of a human life) with material value (e.g., of money). In this paper, we directly challenge the common-currency hypothesis by comparing the neural mechanisms that represent moral and financial subjective values. In a study combining fMRI with a novel behavioral paradigm, we identify neural representations of the subjective values of human lives or financial payoffs by means of structurally identical computational models. Correlating isomorphic model variables from both domains with brain activity reveals specific patterns of neural activity that selectively represent values in the moral (in the rTPJ) or financial (in the vmPFC) domain. Thus, our findings show that human lives and money are valued in distinct neural currencies, supporting theoretical proposals that human moral behavior is guided by processes that are distinct from those underlying behavior driven by personal material benefit.
Characterisation of an inflammation-related epigenetic score and its association with cognitive ability
Authors: Stevenson Anna J. , McCartney Daniel L. , Hillary Robert F. , Campbell Archie , Morris Stewart W. , Bermingham Mairead L. , Walker Rosie M. , Evans Kathryn L. , Boutin Thibaud S. , Hayward Caroline , McRae Allan F. , McColl Barry W. , Spires-Jones Tara L. , McIntosh Andrew M. , Deary Ian J. , Marioni Riccardo E.
Published: October 2019

Results from large cohort studies investigating the association between inflammation and cognition have been mixed, possibly due to methodological disparities. However, a key issue in research utilising inflammatory biomarkers is their typically phasic responses. C-reactive protein (CRP) is widely used to investigate the association between chronic inflammation and cognition, but its plasma concentrations can markedly deviate in response to acute infection. Recently a large-scale epigenome-wide association study identified DNA methylation correlates of CRP. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. Here, we generate an epigenetic CRP score and investigate its trajectories with age, and associations with cognitive ability, in comparison to serum CRP in two cohorts: a longitudinal study of older adults (the Lothian Birth Cohort 1936, n=889) and a large, cross-sectional cohort (Generation Scotland, n=7,028).

We identified differing trajectories of serum CRP across the cohorts, with no homogeneous trends seen with age. Conversely, the epigenetic score was consistently found to increase with age, and to do so more rapidly in males compared to females. Higher levels of serum CRP were found to associate with poorer cognition in Lothian Birth Cohort 1936, but not in Generation Scotland. However, a consistent negative association was identified between cognition and the epigenetic score in both cohorts. Furthermore, the epigenetic score accounted for a greater proportion of variance in cognitive ability.

Our results suggest that epigenetic signatures of acute inflammatory markers may provide an enhanced signature of chronic inflammation, allowing for more reliable stratification of individuals, and thus clearer inference of associations with incident health outcomes.
Impact of higher-order network structure on emergent cortical activity
Authors: Nolte Max , Gal Eyal , Markram Henry , Reimann Michael W.
Published: October 2019

Synaptic connectivity between neocortical neurons is highly structured. The network structure of synaptic connectivity includes first-order properties that can be described by pairwise statistics, such as strengths of connections between different neuron types and distance-dependent connectivity, and higher-order properties, such as an abundance of cliques of all-to-all connected neurons. The relative impact of first- and higher-order structure on emergent cortical network activity is unknown. Here, we compare network structure and emergent activity in two neocortical microcircuit models with different synaptic connectivity. Both models have a similar first-order structure, but only one model includes higher-order structure arising from morphological diversity within neuronal types. We find that such morphological diversity leads to more heterogeneous degree distributions, increases the number of cliques, and contributes to a small-world topology. The increase in higher-order network structure is accompanied by more nuanced changes in neuronal firing patterns, such as an increased dependence of pairwise correlations on the positions of neurons in cliques. Our study shows that circuit models with very similar first-order structure of synaptic connectivity can have a drastically different higher-order network structure, and suggests that the higher-order structure imposed by morphological diversity within neuronal types has an impact on emergent cortical activity.
Dopamine D2 receptors modulate intrinsic properties and synaptic transmission of parvalbumin interneurons in the mouse primary motor cortex
Authors: Cousineau Jérémy , Lescouzères Léa , Taupignon Anne , Delgado-Zabalza Lorena , Valjent Emmanuel , Baufreton Jérôme , Bon-Jégo Morgane Le
Published: October 2019

Dopamine (DA) plays a crucial role in the control of motor and higher cognitive functions such as learning, working memory and decision making. The primary motor cortex (M1), which is essential for motor control and the acquisition of motor skills, receives dopaminergic inputs in its superficial and deep layers from the midbrain. However, the precise action of DA and DA receptor subtypes on the cortical microcircuits of M1 remains poorly understood. The aim of this work was to investigate how DA, through the activation of D2 receptors (D2R), modulates the cellular and synaptic activity of M1 parvalbumin-expressing interneurons (PVINs) which are crucial to regulate the spike output of pyramidal neurons (PNs). By combining immunofluorescence, ex vivo electrophysiology, pharmacology and optogenetics approaches, we show that D2R activation increases neuronal excitability of PVINs and GABAergic synaptic transmission between PVINs and PNs in layer V of M1. Our data reveal a mechanism through which cortical DA modulates M1 microcircuitry and might participate in the acquisition of motor skills.

Significance Statement

Primary motor cortex (M1), which is a region essential for motor control and the acquisition of motor skills, receives dopaminergic inputs from the midbrain. However, precise action of dopamine and its receptor subtypes on specific cell types in M1 remained poorly understood. Here, we demonstrate in M1 that dopamine D2 receptors (D2R) are present in parvalbumin interneurons (PVINs) and their activation increases the excitability of the PVINs, which are crucial to regulate the spike output of pyramidal neurons (PNs). Moreover the activation of the D2R facilitates the GABAergic synaptic transmission of those PVINs on layer V PNs. These results highlight how cortical dopamine modulates the functioning of M1 microcircuit which activity is disturbed in hypo- and hyperdopaminergic states.
Regulatory dynamic enzyme-cost flux balance analysis: A unifying framework for constraint-based modeling
Authors: Liu Lin , Bockmayr Alexander
Published: October 2019

Integrated modeling of metabolism and gene regulation continues to be a major challenge in computational biology. While there exist approaches like regulatory flux balance analysis (rFBA), dynamic flux balance analysis (dFBA), resource balance analysis (RBA) or dynamic enzyme-cost flux balance analysis (deFBA) extending classical flux balance analysis (FBA) in various directions, there have been no constraint-based methods so far that allow predicting the dynamics of metabolism taking into account both macromolecule production costs and regulatory events.

In this paper, we introduce a new constraint-based modeling framework named regulatory dynamic enzyme-cost flux balance analysis (r-deFBA), which unifies dynamic modeling of metabolism, cellular resource allocation and transcriptional regulation in a hybrid discrete-continuous setting.

With r-deFBA, we can predict discrete regulatory states together with the continuous dynamics of reaction fluxes, external substrates, enzymes, and regulatory proteins needed to achieve a cellular objective such as maximizing biomass over a time interval. The dynamic optimization problem underlying r-deFBA can be reformulated as a mixed-integer linear optimization problem, for which there exist efficient solvers.
Exome Sequencing Reveals a High Prevalence ofBRCA1andBRCA2Founder Variants in a Diverse Population-Based Biobank
Authors: Abul-Husn Noura S. , Soper Emily R. , Odgis Jacqueline A. , Cullina Sinead , Bobo Dean , Moscati Arden , Rodriguez Jessica E. ,   CBIPM Genomics Team,   Regeneron Genetics Center, Loos Ruth J.F. , Cho Judy H. , Belbin Gillian M. , Suckiel Sabrina A. , Kenny Eimear E.
Published: October 2019

Pathogenic variants inBRCA1andBRCA2(BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant positive individuals in the general population are unaware of their risk, and little is known about the prevalence of pathogenicBRCA1/2variants in non-European populations. We investigatedBRCA1/2prevalence and impact using exome sequencing and electronic health record (EHR) data from 30,223 adult participants of the BioMeBiobank in New York City. There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. In sub-populations defined by genetic ancestry, the highest prevalence was in individuals of Ashkenazi Jewish (AJ; 1 in 49), Filipino and Southeast Asian (1 in 81), and Non-AJ European (1 in 103) descent. Among 218 variant positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1c.5266dupC and c.68_69delAG, andBRCA2c.5946delT), 7 had a Puerto Rican founder variant (BRCA2c.3922G>T), and 25 had one of 19 other founder variants. Non-European populations were more likely to harborBRCA1/2variants that were not classified in ClinVar, or that had uncertain or conflicting evidence for pathogenicity. Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion African genetic ancestry and the likelihood of harboring aBRCA1/2variant with uncertain or conflicting evidence for pathogenicity. Based on EHR and participant questionnaire data, ∼28% of variant positive individuals had a personal history, and ∼45% a personal or family history ofBRCA1/2-associated cancers. Approximately 27% of variant positive individuals had evidence of prior clinical genetic testing forBRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (38%) than those with other pathogenic variants (19%). These findings deepen our knowledge aboutBRCA1/2variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.
Response modality-dependent abstract choice representations for vibrotactile comparisons
Authors: Wu Yuan-hao , Velenosi Lisa A. , Blankenburg Felix
Published: October 2019

Previous electrophysiological studies in monkeys and humans suggest that premotor regions are the primary loci for the encoding of perceptual choices during vibrotactile comparisons. However, these studies employed paradigms wherein choices were inextricably linked with the physical properties of the stimuli and action selection. It raises the question what brain regions represent choices at a more abstract level, independent of the sensorimotor components of the task. To address this question, we used fMRI-MVPA and a variant of the vibrotactile frequency discrimination task which enabled the isolation of choice-related signals from those related to stimulus properties and selection of the manual decision reports. We identified the left, contralateral dorsal premotor cortex (PMd) and intraparietal sulcus (IPS) as carrying information about abstract choices. Notably, our previous work using an oculomotor variant of the task also reported abstract choice representation in intraparietal and premotor regions. However, the informative premotor cluster was centered in the frontal eye fields rather than in the PMd, providing empirical support for a response effector-dependent organization of abstract choice representation in the context of vibrotactile comparisons. Considering our results together with findings from recent studies in animals, we speculate that the premotor region likely serves as a temporary storage site for information necessary for the specification of concrete manual movements, while the IPS might be more directly involved in the computation of choice.
Inserting small molecules across membrane mixtures: Insight from the potential of mean force
Authors: Centi Alessia , Dutta Arghya , Parekh Sapun H. , Bereau Tristan
Published: October 2019

Small solutes have been shown to alter the lateral organization of cell membranes and reconstituted phospholipid bilayers; however, the mechanisms by which these changes happen are still largely unknown. Traditionally, both experiment and simulation studies have been restricted to testing only a few compounds at a time, failing to identify general molecular descriptors or chemical properties that would allow extrapolating beyond the subset of considered solutes. In this work, we probe the competing energetics of inserting a solute in different membrane environments by means of the potential of mean force. We show that these calculations can be used as a computationally-efficient proxy to establish whether a solute will stabilize or destabilize domain phase separation. Combined with umbrella sampling simulations and coarse-grained molecular dynamics simulations, we are able to screen solutes across a wide range of chemistries and polarities. Our results indicate that, for the system under consideration, preferential partitioning and therefore effectiveness in altering membrane phase separation are strictly linked to the location of insertion in the bilayer (i.e., midplane or interface). Our approach represents a fast and simple tool for obtaining structural and thermodynamic insight into the partitioning of small molecules between lipid domains and its relation to phase separation, ultimately providing a platform for identifying the key determinants of this process.

SIGNIFICANCE

In this work we explore the relationship between solute chemistry and the thermodynamics of insertion in a mixed lipid membrane. By combining a coarse-grained resolution and umbrella-sampling simulations we efficiently sample conformational space to study the thermodynamics of phase separation. We demonstrate that measures of the potential of mean force—a computationally-efficient quantity—between different lipid environments can serve as a proxy to predict a compound’s ability to alter the thermodynamics of the lipid membrane. This efficiency allows us to set up a computational screening across many compound chemistries, thereby gaining insight beyond the study of a single or a handful of compounds.