bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of Micropulse Transscleral Cyclophotocoagulation in Eyes With Good Central Vision
Authors: Varikuti Venkata N.V. , Shah Parth , Rai Oshin , Chaves Ariel C. , Miranda Alex , Lim Boon-Ang , Dorairaj Syril K. , Sieminski Sandra F.
Published: August 2019

Precis:

This study is the first to report micropulse transscleral cyclophotocoagulation (MP-TSCPC) use in only good vision patients. MP-TSCPC significantly reduced intraocular pressure (IOP) and glaucoma medication use without any significant reduction in visual acuity at every postoperative follow-up point.

Purpose:

To evaluate outcomes of MP-TSCPC in eyes with baseline best-corrected visual acuity (BCVA) of ≥20/60.

Methods:

A retrospective review of patients who underwent MP-TSCPC at Mayo Clinic and Ross Eye Institute from July 2016 to August 2017 with BCVA of ≥20/60, and a minimum of 3 months follow-up.

Results:

A total of 61 eyes of 46 patients (68.80±17.12 y) underwent MP-TSCPC with a mean follow-up of 10.2±3.1 months. Mean IOP and mean number of glaucoma medications used were significantly reduced from baseline at every follow-up time point (P<0.0001). At month 12, mean IOP was reduced 40.2% from baseline with 85.4% of the patients having an IOP reduction of ≥20%, and mean glaucoma medication use reduced by 0.82±0.53 with 79.6% of the patients having a reduction of ≥1 medication. There was no significant reduction in BCVA from baseline at any follow-up point (P>0.05), except for 10 eyes with a vision loss of ≥2 lines and 5 out of 10 eyes had cataract progression. The probability of complete success (IOP range, 6 to 21 mm Hg or ≥20% IOP reduction; BCVA loss ≤2 lines, no reoperation for glaucoma) was 74.14%, 83.61%, 84.21%, and 75.0% at months 1, 3, 6, 12, respectively. The probability of qualified success (above criteria for IOP, no reoperation and BCVA loss >2 lines) was 81.03%, 91.80%, 94.74%, and 93.75% at months 1, 3, 6, 12, respectively.

Conclusions:

MP-TSCPC should be considered earlier in the management of glaucoma and can possibly be offered as an alternative to incisional glaucoma surgeries.
Video Technology to BOOST Preceptor Recruitment: A Mixed Methods Study
Authors: Nunes D'Aquila Mitzi , Richter Lagha Regina , Tramel Janice , Lie Désirée A.
Published: August 2019

Purpose

This study's aim was to examine the impact of a brief video presentation for changing clinician knowledge and attitude about precepting physician assistant (PA) students.

Methods

In this mixed methods study, we developed a 12-minute video and made presentations to potential preceptors. Change in knowledge and attitudes was assessed with a pre/post survey. We conducted focus groups (FGs) to elicit barriers and motivators for precepting PA students and assessed acceptability and impact of the video.

Results

Twenty-three preceptors participated in three 45-minute presentations. Participants showed significant knowledge increase in 7 of 10 survey questions. After the presentation, willingness to precept PA students was high. Major FG themes were: teaching is motivating, need clarity about PA students' needs, need support to teach, prefer video presentation to email, and similarities with medical student teaching is positive.

Conclusions

A brief in-person video presentation is acceptable and is associated with increased knowledge and comfort in precepting PA students.
Role of ultrafast-acting insulin analogues in the management of diabetes
Authors: Kruger Davida F. , Novak Lucia M.
Published: August 2019

To control both fasting and prandial plasma glucose levels in people with diabetes, insulin therapy must mimic “normal” physiological insulin secretion as much as possible. This is achieved with a long-acting insulin injected once or twice daily and a bolus of insulin injected before every meal. Prandial (bolus) insulin can either be regular human insulin (RHI) or a rapid-acting insulin analogue (RAIA). Although the efficacy of RHI has been established over approximately 35 years of clinical use, RAIAs offer several clinical advantages over RHI, namely that they have been engineered with a reduced tendency to aggregate as hexamers, which allows for rapid dissociation and absorption after a subcutaneous injection. Conventional RAIAs include insulin lispro, insulin aspart, and insulin glulisine. The more recently developed fast-acting insulin aspart (faster aspart) is an ultrafast-acting mealtime insulin that contains the conventional insulin aspart in a new formulation with the excipients niacinamide and l-arginine to achieve faster insulin absorption than RHI and the conventional insulin aspart formulation. This article reviews the clinical evidence supporting the use of RAIAs as part of a basal–bolus regimen in patients with diabetes, with a focus on new formulations whose pharmacological profiles more closely mimic the endogenous prandial insulin secretion pattern that is seen in individuals without diabetes. This review also provides a clinical perspective to help guide health care professionals in the use of RAIAs.
Blood-sparing removal technique of extracorporeal membrane oxygenation circuit in a Jehovah Witness patient
Authors: Park Sang Min , Lee Bom , Kim Christopher Y.
Published: August 2019

Rationale:

Percutaneous cardiopulmonary support (PCPS) using extracorporeal membrane oxygenation (ECMO) is widely used in the critical patients with cardiopulmonary collapse. It is a representative blood-consuming procedure. In limited situations in which the option of blood transfusion is unavailable, there is no general agreement as to whether ECMO is contraindicated.

Patient concerns:

A 61-year-old male Jehovah Witness with acute respiratory collapse and loss of consciousness was rushed to our emergency room. Throughout his hospital course, the patient's family refused any type of blood transfusion even at the risk of death.

Diagnosis:

The clinical situations were secondary to a massive pulmonary thromboembolism

Interventions:

The patient underwent veno-venous ECMO via both femoral veins. The patient was recovered by intensive medical care although the level of hemoglobin (Hb) and hematocrit (Hct) was gradually decreased from 15.8 g/dl and 46.8% to 11.7 g/dl and 36.5%, respectively.

Outcomes:

On hospital day 3, ECMO was successfully removed using a blood-sparing ECMO removal technique involving the recycling of blood within the circuit by continuous saline infusion. There was no significant change in level of Hb/Hct and hemodynamic profile. At 2 days after ECMO removal, the level of Hb/Hct was elevated up to 9.2 g/dl and 30.0%, respectively without any transfusion.

Lessons:

Our blood-sparing removal technique of ECMO appears to be feasible and led to no significant adverse impact on hemodynamic status. The technique might be helpful for critical patients who cannot receive blood transfusion due to any cause.
Infection in xenotransplantation: opportunities and challenges
Authors: Fishman Jay A.
Published: August 2019

Purpose of review

Posttransplantation infections are common. It is anticipated that infection will be no less common in xenotransplantation recipients. Prolonged xenograft survivals have resulted from advances in immunosuppressive strategies and development of swine that decrease host immune responses via genetic manipulation, notably CRISPR/cas9 manipulation. As prospects for clinical trials improve, consideration of the unique infectious risks posed by xenotransplantation reemerge.

Recent findings

Organisms likely to cause infection in human recipients of porcine xenografts are unknown in advance of clinical trials. Microbiological screening of swine intended as xenograft donors can be more intensive than is currently feasible for human allograft donors. Monitoring infection in recipients will also be more intensive. Key opportunities in infectious diseases of xenotransplantation include major technological advances in evaluation of the microbiome by unbiased metagenomic sequencing, assessments of some risks posed by porcine endogenous retroviruses (PERVs) including antiretroviral susceptibilities, availability of swine with deletion of genomic PERVs, and recognition of the rapidly changing epidemiology of infection in swine worldwide.

Unknown infectious risks in xenotransplantation requires application of advanced microbiological techniques to discern and prevent infection in graft recipients. Clinical trials will provide an opportunity to advance the safety of all of organ transplantation.
The potential role of 3D-bioprinting in xenotransplantation
Authors: Li Ping , Zhang Wenjun , Smith Lester J. , Ayares David , Cooper David K.C. , Ekser Burcin
Published: August 2019

Purpose of review

To review the impact of a new technology, 3D-bioprinting, in xenotransplantation research.

Recent findings

Genetically engineered pigs, beginning with human (h) CD55-transgenic and Gal-knockout pigs, have improved the outcomes of xenotransplantation research. Today, there are more than 30 different genetically engineered pigs either expressing human gene(s) or lacking pig gene(s). CRIPSR/cas9 technology has facilitated the production of multigene pigs (up to nine genes in a single pig), which lack multiple pig xenoantigens, and express human transgenes, such as hCD46, hCD55, hThrombomodulin, hCD39, etc. Although recent studies in nonhuman primates (NHPs) have demonstrated prolonged survival after life-supporting pig kidney, heart, and islet xenotransplantation, researchers have difficulty determining the best genetic combination to test in NHPs because of a potential greater than 100 000 genetic combinations. 3D-bioprinting of genetically engineered pig cells: is superior to 2D in-vitro testing, enables organ-specific testing, helps to understand differences in immunogenicity between organs, and is faster and cheaper than testing in NHPs. Moreover, 3D-bioprinted cells can be continuously perfused in a bioreactor, controlling for all variables, except the studied variable.

3D-bioprinting can help in the study of the impact of specific genes (human or pig) in xenotransplantation in a rapid, inexpensive, and reliable way.
Knockdown of PAK1 Inhibits the Proliferation and Invasion of Non–Small Cell Lung Cancer Cells Through the ERK Pathway
Authors: Wang Si , Wang Si-Yao , Du Feng , Han Qiang , Wang En-Hua , Luo En-Jie , Liu Yang
Published: August 2019

The p21-activated kinase (PAK) family of serine/threonine kinases plays a pivotal role in various human tumors, as supported by our previous report on the overexpressed PAK isoforms in non–small cell lung cancer (NSCLC). To better understand the role of PAKs in tumorigenesis, the authors examined PAK1 expression patterns and its significance in NSCLC. It was demonstrated by immunohistochemical staining that PAK1 was increased and localized in the cytoplasm in 151 of 207 cases. High levels of PAK1 expression correlated with a histologic type of tumor (squamous cell carcinoma), tumor node metastasis stage, and lymph nodal status. We also examined the biological role of PAK1 in lung cancer cell lines transfected with PAK1-small interfering RNA. Decreased expression of PAK1 inhibited lung cancer cell proliferation and invasion, which is the major cause of lung cancer malignancy. Downregulated expression of PAK1 hampered rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase pathway activity but did not affect Wnt/β-catenin signaling. Our findings suggest that PAK1 is an important oncogene in NSCLC, as decreased expression of PAK1 inhibited the proliferation and invasion of NSCLC cells by blocking the ERK pathway. These results provide evidence for using PAK1 inhibition as potential anticancer therapy.
Letermovir for Difficult to Treat Cytomegalovirus Infection in Lung Transplant Recipients
Authors: Veit Tobias , Munker Dieter , Kauke Teresa , Zoller Michael , Michel Sebastian , Ceelen Felix , Schiopu Sanziana , Barton Jürgen , Arnold Paola , Milger Katrin , Behr Jürgen , Kneidinger Nikolaus
Published: August 2019

Background.

Cytomegalovirus (CMV)-infection remains a major cause of morbidity and mortality after lung transplantation. Treatment with currently available drugs poses treatment difficulties in some patients due to drug resistance or intolerability.

Methods.

We report a series of 4 lung transplant recipients with CMV-infection and treatment failure upon standard care due to antiviral drug resistance and treatment-limiting side effects. As rescue therapy letermovir recently approved for the prophylaxis of CMV-infection in patients after hematopoietic stem cell transplantation was initiated. Patients received 480 mg/day for a follow up of 36.1 ± 12.9 weeks. Efficacy and tolerability were assessed retrospectively.

Results.

Mild nausea, vomiting, and diarrhea were the only side effects of letermovir reported by a single patient. A small adjustment of the tacrolimus dose was mandatory upon treatment initiation with letermovir. CMV viral load could be decreased and cleared subsequently in all patients. CMV clearance was observed after 17.7 ± 12.6 weeks despite lack of CMV-immunity.

Conclusions.

CMV-infection and -disease were successfully managed with letermovir. Letermovir was well tolerated and effective in treating CMV-infections in lung transplant recipients failing on currently available antiviral agents.
Impact of Tocilizumab (Anti–IL-6R) Treatment on Immunoglobulins and Anti-HLA Antibodies in Kidney Transplant Patients With Chronic Antibody-mediated Rejection
Authors: Shin Bong-Ha , Everly Matthew J. , Zhang Hao , Choi J. , Vo Ashley , Zhang Xiaohai , Huang Edmund , Jordan Stanley C. , Toyoda Mieko
Published: August 2019

Background.

Chronic antibody-mediated rejection (cAMR) results in the majority of renal allograft losses. Currently, there are no approved therapies. We recently reported on clinical use of tocilizumab (TCZ) for treatment of cAMR in HLA-sensitized kidney transplant patients. IgG1 and IgG3 subclasses of IgG are potent effectors of complement- and antibody-dependent cellular cytotoxicity, which are critical mediators of AMR. Here, we examined the impact of TCZ treatment for cAMR on total IgG, IgG1-4 subclasses, and anti–HLA-IgG (total and subclasses).

Methods.

Archived plasma obtained pre- and post-TCZ treatment (8 mg/kg, 6×, monthly) from 12 cAMR patients who failed standard of care treatment with intravenous immune globulin + rituximab with or without plasma exchange were tested for total IgG and IgG1-4 by ELISA, anti–HLA-total IgG, IgG3 and IgG4, and donor-specific antibody by Luminex assay. Archived plasma from 14 cAMR patients treated with the standard of care were included as controls.

Results.

Total IgG and IgG1-3 were significantly reduced post-TCZ, whereas no reduction was seen post-treatment in the control group. Of 11 patients, 8 (73%) showed reduction of anti–HLA-total IgG and IgG3 post-TCZ, but this was not statistically significant.

Conclusions.

TCZ reduced total IgG and IgG1-3 and anti–HLA-total IgG and IgG3 levels, suggesting that TCZ suppresses Ig production in B cells nonspecifically, likely through inhibition of interleukin 6–mediated signaling to B cells and plasma cells. This may be a contributing factor for the beneficial effect of TCZ on cAMR observed in this patient population.
H
3
+
, the ideal probe for
in situ
measurement of the Galactic cosmic rays
Authors: Oka Takeshi
Published: August 2019

The reason why

H

3

+

is an ideal probe for
in situ
measurement of cosmic ray energy density in the Galaxy is discussed. The variation of measured values of cosmic ray ionization rate
ζ
of H
2
since the theoretical prediction by Spitzer & Tomasko (Spitzer & Tomasko 1968
Astrophys. J.
152
, 971–986) is reviewed. How the measurements by

H

3

+

established
ζ
as of the order of 10
−17
 s
−1
for dense clouds, 10
−16
 s
−1
for diffuse clouds in the Galactic disc, and 10
−14
 s
−1
for warm and diffuse gas in the Galactic centre is discussed.

This article is part of a discussion meeting issue ‘Advances in hydrogen molecular ions: H
3
+
, H
5
+
and beyond’.
Mental Health in UK Biobank Revised – development, implementation and results from an online questionnaire completed by 157,366 participants
Authors: Davis Katrina A. S. , Coleman Jonathan R. I. , Adams Mark , Allen Naomi , Breen Gerome , Cullen Breda , Dickens Chris , Fox Elaine , Graham Nick , Holliday Jo , Howard Louise M , John Ann , Lee William , McCabe Rose , McIntosh Andrew , Pearsall Robert , Smith Daniel J. , Sudlow Cathie , Ward Joey , Zammit Stan , Hotopf Matthew
Published: August 2019

This paper corrects and updates a paper published in BJPsych Open 2018 “Mental Health in UK Biobank” (https://doi.org/10.1192/bjo.2018.12) that was voluntarily retracted following the finding of errors in the coding of the variable for alcohol use disorder. Notably, the percentage of participants reaching threshold for alcohol use disorder on the Alcohol Use Disorder Identification Tool increased from 7% to 21%.

Background

UK Biobank is a well-characterised cohort of over 500,000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants expands the potential for research into mental disorders.

Methods

An expert working group designed the questionnaire, using established measures where possible, and consulting with a service user group regarding acceptability. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and alcohol use disorders.

Results

157,366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was the most common finding in 24% of participants (37,434), with current alcohol use disorder criteria met by 21% (32,602), while other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.

Conclusions

The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed due to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
How Top-Down and Bottom-Up Regulation in Fronto-Amygdalar Network Changes over Time during Drug Cue-Exposure: An fMRI Study among Abstinent Heroin User
Authors: Zare-Sadeghi Arash , Oghabian Mohammad Ali , Zare-Bidoky Mehran , Batouli Seyed Amir Hossein , Ekhtiari Hamed
Published: August 2019

Top-down regulation is one of the major neural cores in drug-craving management and relapse prevention. The dynamic temporal behavior of top-down regulation between the dorso-lateral and ventro-medial prefrontal cortices (DLPFC and VMPFC) and amygdala during drug cue-exposure has not been studied yet. Fifteen abstinent participants with heroin use disorder were scanned using drug cue-induced craving fMRI task. Using Dynamic Causal Modelling (DCM), the winning model showed a significant reciprocal connection between the VMPFC and DLPFC while there was a one-way effect of the VMPFC on the amygdala. There is also a top-down modulation by DLPFC on the VMPFC-Amygdala connection. Craving contrast input only modulated amygdala directly. Using sliding-window for temporal evaluation, craving input to amygdala increased over time, simultaneously, DLPFC top-down modulatory effect on VMPFC-amygdala connection decreased. Temporal changes in the network connectivity during cue exposure with enhancement in craving input to amygdala and reduction in top-down modulatory effects of DLPFC, could provide us with new insights towards the dynamic nature of the cue-reactivity and failure to control its motivational consequences. Dynamic response of top-down regulatory networks during cue exposure can be considered as a new potential biomarker in the future addiction fMRI studies.
Conformational Transition Pathways in Major Facilitator Superfamily Transporters
Authors: Ogden Dylan , Immadisetty Kalyan , Sauve Stephanie , Moradi Mahmoud
Published: August 2019

The major facilitator superfamily (MFS) of transporters contains three classes of membrane transporters: symporters, uniporters, and antiporters. Despite utilizing a variety of transport methods, MFS transporters are believed to undergo similar conformational changes within their distinct transport cycles. Although the similarities regarding conformational changes between the classes of MFS transporters are noteworthy, the differences are also valuable because they may explain the distinct functions of the classes within the MFS. Here, we have performed a variety of equilibrium and non-equilibrium all-atom molecular dynamics (MD) simulations of the bacterial proton-coupled oligopeptide transporter (GkPOT) and the human glucose transporter 1 (GluT1). To compare the similarities and differences of the conformational dynamics found within the three different classes of transporters we have also referenced previous simulations involving the glycerol-3-phosphate (GlpT) transporter. All of the proteins discussed here were simulated in the {\it apo} state in explicit membrane environments. Our results suggest a very similar conformational transition for all transporter types involving interbundle salt-bridge formation/disruption coupled with the orientation changes of transmembrane (TM) helices, specifically H1/H7 and H5/H11, resulting in an alternation in the accessibility of water at the cyto- and periplasmic gates.
Differential expression of soluble receptor for advanced glycation end-products (sRAGE) in mice susceptible or resistant to chronic colitis
Authors: Bramhall Michael , Rich Kevin , Chakraborty Ajanta , Logunova Larisa , Han Namshik , Wilson James , Booth Catherine , Mclaughlin John , Brass Andy , Cruickshank Sheena M.
Published: August 2019

Aims

Identifying the factors that contribute to chronicity in inflamed colitic tissue is not trivial. However, in mouse models of colitis, we can investigate at preclinical timepoints. We sought to validate murine Trichuris muris infection as a model for identification of factors that promote development of chronic colitis.

Methods

We compared preclinical changes in mice with a resolving immune response to T. muris (resistant) versus mice that fail to expel the worms and develop chronic colitis (susceptible). Findings were then validated in healthy controls and patients with suspected or confirmed IBD.

Results

The Receptor for Advanced Glycation End Products (Rage) was highly dysregulated between resistant and susceptible mice prior to the onset of any pathological signs. Increased soluble RAGE (sRAGE) in the serum and faeces of resistant mice correlated with reduced colitis scores. Mouse model findings were validated in a preliminary clinical study: faecal sRAGE was differentially expressed in patients with active IBD compared with IBD in remission, patients with IBD excluded or healthy controls.

Conclusion

Pre-clinical changes in mouse models can identify early pathways in the development of chronic inflammation that human studies cannot. We identified the decoy receptor sRAGE as a potential mechanism for protection against chronic inflammation in colitis in mice and humans. We propose that the RAGE pathway is clinically relevant in the onset of chronic colitis, and that further study of sRAGE in IBD may provide a novel diagnostic and therapeutic target.
SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1.1
Authors: Simonet Nicolás G. , Thackray Joshua K. , Vazquez Berta N. , Ianni Alessandro , Espinosa-Alcantud Maria , Morales-Sanfrutos Julia , Hurtado-Bagès Sarah , Sabidó Eduard , Buschbeck Marcus , Tischfield Jay , de la Torre Carolina , Esteller Manel , Braun Thomas , Olivella Mireia , Serrano Lourdes , Vaquero Alejandro
Published: August 2019

Sirtuins are key players in the response to oxidative, metabolic and genotoxic stress, and are involved in genome stability, metabolic homeostasis and aging. Originally described as NAD+-dependent deacetylases, some sirtuins are also characterized by a poorly understood mono-ADP-ribosyltransferase (mADPRT) activity. Here we report that the deacetylase SirT7 is a dual sirtuin as it also features auto-mADPRT activity. Molecular and structural evidence suggests that this novel activity occurs at a second previously undefined active site that is physically separated in another domain. Specific abrogation of this activity alters SirT7 chromatin distribution, suggesting a role for this modification in SirT7 chromatin binding specificity. We uncover an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader macroH2A1.1, a histone variant involved in chromatin organization, metabolism and differentiation. Glucose starvation (GS) boosts this interaction and promotes SirT7 relocalization to intergenic regions in a macroH2A1-dependent manner. Both SirT7 activities are in turn required to promote GS-dependent enrichment of macroH2A1 in a subset of nearby genes, which results in their specific up- or downregulation. Consistently, the expression changes of these genes associated to calorie restriction (CR) or aging are abrogated in SirT7-/- mice, reinforcing the link between Sirtuins, CR and aging. Our work provides a novel perspective about sirtuin duality and suggests a key role for SirT7/macroH2A1.1 axis in mammalian glucose homeostasis, calorie restriction signaling and aging.
A Galaxy-based training resource for single-cell RNA-seq quality control and analyses
Authors: Etherington Graham J , Soranzo Nicola , Mohammed Suhaib , Haerty Wilfried , Davey Robert P , Di Palma Federica
Published: August 2019

Background

It is not a trivial step to move from single-cell RNA-seq (scRNA-seq) data production to data analysis. There is a lack of intuitive training materials and easy-to-use analysis tools, and researchers can find it difficult to master the basics of scRNA-seq quality control and analysis.

Results

We have developed a range of easy-to-use scripts, together with their corresponding Galaxy wrappers, that make scRNA-seq training and analysis accessible to researchers previously daunted by the prospect of scRNA-seq analysis. The simple command-line tools and the point-and-click nature of Galaxy makes it easy to assess, visualise, and quality control scRNA-seq data.

Conclusion

We have developed a suite of scRNA-seq tools that can be used for both training and more in-depth analyses.
Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice
Authors: Frye Hannah E. , Williams Sidney B. , Trousdale Christopher R. , Nelson Elliot C. , Dougherty Joseph D. , Morón Jose A.
Published: August 2019

Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein that traffics AMPARs to the postsynaptic membrane and potentiates AMPAR signaling. AMPARs are key components of hippocampal synaptic plasticity and memory formation, however the role of CNIH3 in memory has yet to be elucidated. To study the role of CNIH3 on mouse behavior, we bred and characterized a line of Cnih3-/- mice from C57BL/6 Cnih3tm1a(KOMP)Wtsi mice obtained from the Knockout Mouse Project (KOMP). In agreement with previous studies of CNIH3 in the brain, we observed concentrated expression of Cnih3 in the dorsal hippocampus, a region associated with spatial learning and memory. Therefore, we tested Cnih3+/+, Cnih3+/-, and Cnih3-/- mice in the Barnes maze paradigm to measure spatial memory. We observed no change in spatial memory in male Cnih3+/- and Cnih3-/- mice compared to male Cnih3+/+ controls, however, Cnih3-/- female mice made significantly more primary errors, had a higher primary latency, and took less efficient routes to the target in the maze compared to Cnih3+/+ female mice. Next, to investigate an enhancement of spatial memory by Cnih3 overexpression, specifically in the dorsal hippocampus, we developed an AAV5 viral construct to express wild-type Cnih3 in excitatory neurons. Female mice overexpressing Cnih3 made significantly fewer errors, had a lower primary latency to the target, and took more efficient routes to the maze target compared to YFP expressing control females. No change in spatial memory was observed in male Cnih3 overexpression mice. This study, the first to identify sex-specific effects of the AMPAR auxiliary protein CNIH3 on spatial memory, provides the groundwork for future studies investigating the role of CNIH3 on sexually dimorphic AMPAR-dependent behavior and hippocampal synaptic plasticity.
Evolutionary increases in catecholamine signaling may underlie the emergence of adaptive traits and behaviors in the blind cavefish, Astyanax mexicanus
Authors: Gallman Kathryn , Rivera Daihana , Soares Daphne
Published: August 2019

Evolutionary changes in catecholamine neurotransmitters such as dopamine and noradrenaline can lead to habitat specific behaviors. We used tyrosine hydroxylase, a conserved precursor to the biosynthesis of dopamine and noradrenaline, to compare catecholaminergic neurons in the brain of a species undergoing allopatric speciation. The teleost fish Astyanax mexicanus is extant in two readily available forms, an ancestral river dwelling form (surface) and various derived blind cave forms (cavefish). Adaptation to nutrient poor cave life without predation has led to marked differences in the behavior of this species. The cavefish has lost defensive responses, such as stimulus aversion, found in the ancestral surface fish and instead displays enhanced food seeking behaviors. This is reflected by an increase in catecholamine immunoreactivity in the cavefish brain in regions associated with non-visual sensory perception, motor control pathways, attention, and endocrine release. These neuroanatomical regions include the olfactory system, the basal telencephalon, the preoptic nuclei, the posterior tuberculum, caudal hypothalamus, and isthmus. These results indicate that the evolutionary shift from aversive defensive responses to attractive exploratory behaviors was driven by increases in the size and/or quantity of catecholaminergic neurons in the cavefish brain.
Maximizing Ecosystem Services Provided to the New Oil Crop Brassica carinata Through Landscape and Arthropod Diversity
Authors: Stiles Shane , Lundgren Jon , Fenster Charles , Nottebrock Henning
Published: August 2019

Prairies, once spanning the Upper Midwest, have now largely been replaced by agriculture. The lack of resources available to pollinators in agricultural fields and practices commonly employed has led to a decline in insect diversity. To enhance sustainable practices, we must better understand how ecosystem services such as pest control and pollination services provided by a diverse insect and pollinator community scale to current farming practices as related to crop yield and how landscape features may positively contribute to insect and pollinator diversity. We examined how landscape heterogeneity relates to insect and pollinator diversity, as well as how insect and pollinator diversity relates to crop yield across common farming practices. We planted 35 single acre sites of Brassica carinata, a generalist flower possibly capable of supporting a diverse insect community. We randomly assigned each site with a combination of three common farming practices: tilling (yes/no), added honey bee hives (yes/no), and treatment with systemic neonicotinoids (yes/no). Insect and pollinator diversity and the surrounding landscape at multiple spatial scales were calculated. We observed a significant positive relationship between insect (and pollinator) diversity with yield in the absence of any farming practice. All farming practices will increase yield. However, farming practices alter the relationship between yield and diversity. The addition of seed treatment or tillage negates the relationship between insect (and pollinator) diversity with yield. Seed treatment alone results in a flat relationship between diversity and yield for all insects and a negative relationship for pollinators. Increased landscape heterogeneity results in a positive relationship between insect diversity at the 1000 m scale and pollinator diversity at the 3000 m scale, suggesting large-scale heterogeneity contributes to overall insect diversity. Our results show that increasing large-scale landscape heterogeneity increases diversity serving as a substitute for common farming practices such as application of pesticides, tilling, or bee hives. Increased heterogeneity could save farmers from the input cost of treatment or tillage, by way of increased insect diversity, while still providing similar yields.
Dynamic 3D chromosomal landscapes in acute leukemia
Authors: Kloetgen Andreas , Thandapani Palaniraja , Ntziachristos Panagiotis , Ghebrechristos Yohana , Nomikou Sofia , Lazaris Charalampos , Chen Xufeng , Hu Hai , Bakogianni Sofia , Wang Jingjing , Fu Yi , Boccalatte Francesco , Zhong Hua , Paietta Elisabeth , Trimarchi Thomas , Zhu Yixing , van Vlierberghe Pieter , Inghirami Giorgio G , Lionnet Timothee , Aifantis Iannis , Tsirigos Aristotelis
Published: August 2019

Three-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD “fusion” event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

One Sentence Summary

3D chromatin alterations in T cell leukemia are accompanied by changes in insulation and oncogene expression and can be partially restored by targeted drug treatments.
Computational mapping of the differentially expressed gene-lncRNA pairs present at the root nodule developmental stages of Arachis hypogaea
Authors: Rizvi Ahsan Z. , Dhusia Kalyani
Published: August 2019

RNA-sequencing (RNA-seq) data analysis of the different stages of root nodules formation in peanut Arachis hypogaea investigate the genetic features. Genes related to the root nodules formations in this plant are extensively studied [1] [2] [3] [4] [5], but less information is present for their relations with long noncoding RNAs (lncRNAs). Bioinformatics techniques are utilised here to identify the novel lncRNAs present in the publically available RNA-seq data reported [6] for the different stages of root nodules formation in this plant. Highly correlated, significant, and Differentially Expressed (DE) gene-lncRNA pairs are also detected to understand the epigenetic control of lncRNA. These pairs are further differentiated between cis and trans antisense lncRNAs and lincRNAs based on their functions and positions from the genes. Obtained results are the catalogue for the highly correlated and significant DE gene-lncRNA pairs related to root nodules formation in A. hypogaea.
Eye movements during visuomotor adaptation represent only part of the explicit learning
Authors: Bromberg Zohar , Donchin Opher , Haar Shlomi
Published: August 2019

Visuomotor rotations are learned through a combination of explicit strategy and implicit recalibration. However, measuring the relative contribution of each remains a challenge and the possibility of multiple explicit and implicit components complicates the issue. Recent interest has focused on the possibility that eye movements reflect explicit strategy. Here we compared eye movements during adaptation to two accepted measures of explicit learning - verbal report and the exclusion test. We found that while reporting, all subjects showed a match between all three measures. However, when subjects did not report their intention, the eye movements of some subjects suggested less explicit adaptation than what was measured in an exclusion test. Interestingly, subjects whose eye movements did match their exclusion could be clustered into two subgroups: fully implicit learners showing no evidence of explicit adaptation and explicit learners with little implicit adaptation. Subjects showing a mix of both explicit and implicit adaptation were also those where eye movements showed less explicit adaptation than did exclusion. Thus, our results support the idea of multiple components of explicit learning as only part of the explicit learning is reflected in the eye movements. Individual subjects may use explicit components that are reflected in the eyes or those that are not or some mixture of the two. Analysis of reaction times suggests that the explicit components reflected in the eye-movements involve longer reaction times. This component, according to recent literature, may be related to mental rotation.

Significance Statement

Visuomotor adaptation involves both explicit and implicit components: aware re-aiming and unaware error correction. Recent studies suggest that eye movements could be used to capture the explicit component, a method that would have significant advantages over other approaches. We show that eye movements capture only one component of explicit adaptation. This component scales with reaction time while the component unrelated to eye movements does not. Our finding has obvious practical implications for the use of eye movements as a proxy for explicit learning. However, our results also corroborate recent findings suggesting the existence of multiple explicit components, and, specifically, their decomposition into components correlated with reaction time and components that are not.
Metabolic responses in opposite sun-exposed Antarctic cryptoendolithic communities
Authors: Coleine Claudia , Gevi Federica , Fanelli Giuseppina , Onofri Silvano , Timperio Anna Maria , Selbmann Laura
Published: August 2019

Antarctic cryptoendolithic communities are self-supporting borderline ecosystems spreading across the extreme conditions of the Antarctic desert and represent the most predominant life-form in the ice-free desert of McMurdo Dry Valleys, accounted as the closest terrestrial Martian analogue. Components of these communities are very adapted extremophiles and extreme-tolerant microorganisms, among the most resistant known to date. Recent advances started to investigate the biodiversity and community composition in these microbial ecosystems but the metabolic activity of the metacommunity has never been investigated to date. In this study, we explored the stress-response, spreading in two different sites of the same location, subjected to increasing environmental pressure due to opposite sun exposure, to verify the effect of sunlight on settlement and adaptation strategies. Results indicated that the metabolic responses are shaped according to external conditions; in the overall 252 altered metabolites (56 and 196 unique for north and south, respectively), distinguished the two differently exposed communities. We also selected 10 metabolites and performed two-stage Receiver Operating Characteristic (ROC) analysis to test them as potential biomarkers. We focused further on melanin and allantoin as protective substances; their concentration was highly different in the community in the shadow or in the sun.
Morphogenesis is transcriptionally coupled to neurogenesis during peripheral olfactory organ development
Authors: Aguillon Raphaël , Madelaine Romain , Guturu Harendra , Link Sandra , Dufourcq Pascale , Lecaudey Virginie , Bejerano Gill , Blader Patrick , Batut Julie
Published: August 2019

Sense organs acquire their distinctive shapes concomitantly with the differentiation of sensory cells and neurons necessary for their function. While our understanding of the mechanisms controlling morphogenesis and neurogenesis in these structures has grown, how these processes are coordinated remains largely unexplored. Neurogenesis in the zebrafish olfactory epithelium requires the bHLH proneural transcription factor Neurogenin1 (Neurog1). To address whether Neurog1 also controls morphogenesis in this system, we analysed the morphogenetic behaviour of early olfactory neural progenitors inneurog1mutant embryos. Our results indicate that the oriented movements of these progenitors are disrupted in this context. Morphogenesis is similarly affected by mutations in the chemokine receptor gene,cxcr4b, suggesting it is a potential Neurog1 target gene. We find that Neurog1 directly regulatescxcr4bthrough an E-boxes cluster located just upstream of thecxcr4btranscription start site. Our results suggest that proneural transcription factors, such as Neurog1, directly couple distinct aspects of nervous system development.

One Sentence Summary

Neurog1 controls olfactory organ morphogenesis viacxcr4b
Meta-transcriptomic comparison of the RNA viromes of the mosquito vectors Culex pipiens and Culex torrentium in northern Europe
Authors: Pettersson John H.-O. , Shi Mang , Eden John-Sebastian , Holmes Edward C. , Hesson Jenny C.
Published: August 2019

There is mounting evidence that mosquitoes harbour an extensive diversity of ‘insect-specific’ RNA viruses in addition to those important to human and animal health. However, because most studies of the mosquito virome have been conducted at lower latitudes there is a major knowledge gap on the genetic diversity, evolutionary history, and spread of RNA viruses sampled from mosquitoes in northern latitudes. Here, we determined and compared the RNA virome of two common northern Culex mosquito species, Cx. pipiens and Cx. torrentium, known vectors of West Nile virus and Sindbis virus, respectively, collected in south-central Sweden. Following bulk RNA-sequencing (meta-transcriptomics) of 12 libraries, comprising 120 specimens of Cx. pipiens and 150 specimens of Cx. torrentium, we identified 40 viruses (representing 14 virus families) of which 28 were novel based on phylogenetic analysis of the RNA-dependent RNA polymerase (RdRp) protein. Hence, we found similar levels of virome diversity as in mosquitoes sampled from the more biodiverse lower latitudes. Four libraries, all from Cx. torrentium, had a significantly higher abundance of viral reads, spanning ∼7– 36% of the total amount of reads. Many of these viruses were also related to those sampled on other continents, indicative of widespread global movement and/or long host-virus co-evolution. Importantly, although the two mosquito species investigated have overlapping geographical distributions and share many viruses, approximately one quarter of the viruses were only found at a specific location, such that geography must play an important role in shaping the diversity of RNA viruses in Culex mosquitoes.

Importance

RNA viruses are found in all domains of life and all global habitats. However, the factors that determine virome composition and structure within and between organisms are largely unknown. Herein, we characterised RNA virus diversity in two common mosquito vector species, Culex pipiens and Culex torrentium, sampled from northern Europe. Our analysis revealed extensive viral diversity, including 28 novel viruses, and was comparable to the levels of diversity found in other temperate and tropical regions globally. Importantly, as well as harbouring RNA viruses that are closely related to other mosquito-derived viruses sampled in diverse global locations, we also described a number of viruses that are unique to specific sampling locations in Sweden. Hence, these data showed that geographical factors can play an important role in shaping virome structure even at local scales.
Regulation of Microtubule Disassembly by Spatially Heterogeneous Patterns of Acetylation
Authors: Aparna J S , Padinhateeri Ranjith , Das Dibyendu
Published: August 2019

Microtubules (MTs) are bio-polymers, composed of tubulin proteins, involved in several functions such as cell division, transport of cargoes within cells, maintaining cellular structures etc. Their kinetics are often affected by chemical modifications on the filament known as Post Translational Modifications (PTMs). Acetylation is a PTM which occurs on the luminal surface of the MT lattice and has been observed to reduce the lateral interaction between tubulins on adjacent protofilaments. Depending on the properties of the acetylase enzymeαTAT1 and the structural features of MTs, the patterns of acetylation formed on MTs are observed to be quite diverse. In this study, we present a multi-protofilament model with spatially heterogenous patterns of acetylation, and investigate how the local kinetic differences arising from heterogeneity affect the global kinetics of MT filaments. From the computational study we conclude that a filament with spatially uniform acetylation is least stable against disassembly, while ones with more clustered acetylation patterns may provide better resistance against disassembly. The increase in disassembly times for clustered pattern as compared to uniform pattern can be upto fifty percent for identical amounts of acetylation. Given that acetylated MTs affect several cellular functions as well as diseases such as cancer, our study indicates that spatial patterns of acetylation need to be focussed on, apart from the overall amount of acetylation.

Author Summary

Microtubules (MTs) form a crucial part of the cytoskeletal machinery which regulates several cellular processes. The basic building block of MTs are tubulin proteins. These proteins assemble in lateral and longitudinal directions to form a hollow cylindrical structure of a MT. There are chemical modifications on tubulin, known as Post Translational Modifications (PTMs), which affect the stability and dynamics of MT filaments. We computationally study how one such PTM, namely acetylation, affects the kinetics of disassembly of a MT filament. We propose a model which incorporates spatially heterogeneous patterns of acetylation on MT filament and study how they may regulate the disassembly times and velocities, a factor hitherto unexplored in studies. We conclude that there are significant differences of disassembly velocities and their fluctuations depending on the differnces in spatial patterns of acetylation.