bluuebunny/crossref_metadata_2025 huggingface dataset:
CHOROIDEREMIA ASSOCIATED WITH A NOVEL SYNONYMOUS MUTATION IN GENE ENCODING REP-1
Authors: Sengillo Jesse D. , Lee Winston , Bakhoum Mathieu F. , Cho Galaxy Y. , Chiang John (P-W) , Tsang Stephen H.
Published: October 2017

Purpose:

To report a novel synonymous mutation in CHM and the associated phenotype in an affected man and carrier mother.

Methods:

Case report.

Results:

A 34-year-old man with a long history of progressive night blindness and visual field constriction was diagnosed with choroideremia based on ocular examination and multimodal retinal imaging. Extensive chorioretinal degeneration was noted on spectral domain optical coherence tomography and fundus autofluorescence imaging. Candidate CHM gene sequencing revealed a hemizygous c.1359C>T, p.(S453S) variant. This variant was heterozygous in the mother of the proband who exhibited the classic carrier phenotype of choroideremia on fundus autofluorescence imaging.

Conclusion:

A novel c.1359C>T, p.(S453S) variant in CHM is the first-identified synonymous mutation associated with disease manifestation in an affected man and carrier phenotype in a heterozygous mother.
Influence of Socioeconomic Deprivation on Visual Acuity in Patients Undergoing Corneal Transplantation
Authors: Robbie Scott J. , Jones Mark N. A. , Larkin Daniel F. P. ,   on behalf of the NHS Blood and Transplant Ocular Tissue Advisory Group and Contributing Ophthalmologists (OTAG Audit Study 22)
Published: October 2017

Purpose:

To determine whether there is an association between socioeconomic status and best-corrected visual acuity (BCVA) in patients undergoing corneal transplantation in the United Kingdom.

Methods:

Retrospective cohort study of 4306 patients registered on the national United Kingdom Transplant Registry and undergoing penetrating keratoplasty, anterior lamellar keratoplasty, or endothelial keratoplasty in 2002, 2008, and 2013. Socioeconomic status was determined by applying a validated deprivation index to generate a score based on 5 categories. Patients' demographic details, preoperative BCVA, copathology, surgical center volume, and socioeconomic status were analyzed for univariate effects of categorical and continuous variables. Binary logistic regression was used to determine whether preoperative BCVA was affected by socioeconomic status after adjusting for other factors.

Results:

A larger percentage of the most deprived group was female in each period compared with the least deprived, but this was only significant in 2002 (48.7% vs. 40.3%; P = 0.04). There was no interaction between socioeconomic status and the preoperative BCVA in the grafted eye. However, BCVA in the fellow eye was poorer for the most economically deprived patients compared with the least deprived in 2013 (P = 0.01).

Conclusions:

We found no evidence of a relationship between socioeconomic deprivation and BCVA in the transplant recipient eye. However, there was clear evidence of an association between socioeconomic deprivation and reduced acuity in fellow eyes, for which barriers to access or low patient demand may be possible contributors.
Treatment and Resolution of Filamentary Keratitis in a Patient with Stiff Person Syndrome
Authors: Bae Steven S. , Yeung Sonia N. , Chan Clara C.
Published: October 2017

Purpose:

To report a rare case of filamentary keratitis associated with stiff person syndrome.

Methods:

Case report.

Results:

A 26-year-old woman with several autoimmune conditions was referred because of filamentary keratitis. Conservative management using lubrication, mucolytics, and bandage contact lenses failed to adequately relieve symptoms. Despite the addition of oral prednisone, cyclosporine, and azathioprine, the patient's condition persisted with numerous filaments and severe dry eye. One month later, the patient had an episode of sudden muscle cramps in her back, for which she was hospitalized. Investigations revealed a diagnosis of stiff person syndrome, positive for glutamic acid decarboxylase autoantibodies. Plasmapheresis and high-dose intravenous steroids were provided as initial therapy. On follow-up, her filamentary keratitis resolved and at the last visit, her ocular symptoms had completely resolved.

Conclusions:

Filamentary keratitis is a chronic, recurrent condition that can be challenging to treat. Effective management requires careful consideration of possible predisposing causes, especially in refractory cases.
Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor
Authors: Gerson James N. , Witteles Ronald M. , Chang Daniel T. , Beygui Ramin E. , Iagaru Andrei H. , Kunz Pamela L.
Published: October 2017

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms. These tumors can produce a wide variety of hormones that can lead to syndromes of hormone excess, such as carcinoid syndrome. We present the case of a 47-year-old man who presented with right upper quadrant abdominal pain and emesis. He was found to have metastatic pancreatic NET and was treated with systemic chemotherapy. He subsequently developed dyspnea on exertion and was found to have severe right-sided heart disease secondary to elevated levels of serum serotonin. He was successfully treated with surgical tricuspid and pulmonic valve replacement. True carcinoid syndrome with pancreatic NETs is rare, but, as a treatable complication of the disease, is an important entity for which oncologists should be familiar.
Fatty Pancreas
Authors: Majumder Shounak , Philip Nissy A. , Takahashi Naoki , Levy Michael J. , Singh Vijay P. , Chari Suresh T.
Published: October 2017

The metabolic consequences of visceral fat deposition are well known, and the presence of intrapancreatic fat (IPF) has been recognized for decades. However, our knowledge about the distribution of fat in the pancreas and its clinical implications is in a nascent stage. Various terms have been proposed to describe IPF; for the purpose of this narrative review, we chose the general termfatty pancreas. Herein, we describe the radiologic, endoscopic, and histopathologic aspects of diagnosing fatty pancreas and provide an overview of the diseases associated with this condition. Our purpose is to highlight diagnostic challenges and identify specific clinical questions that would benefit from further study. As evident in this review, IPF is associated with various metabolic diseases, pancreatitis, pancreatic cancer, and precancer—yet establishing causality needs careful, further study.
Autoimmune Hepatitis and Autoimmune Hepatitis Overlap With Sclerosing Cholangitis
Authors: Ferri Priscila M. , Simões e Silva Ana C. , Torres Karen C.L. , Silva Soraya L.C. , Aquino Diego J.Q. , Ferreira Maria L.M. , Fagundes Eleonora D.T. , Miranda Débora M. , Ferreira Alexandre R.
Published: October 2017

Objective:

The pathophysiology of autoimmune hepatitis (AIH) may involve the activation of immune cells and changes in the expression of cellular markers. The aim of the present study was to characterize the immunophenotype markers of lymphocytes and monocytes in the peripheral blood of children and adolescents with type 1 AIH and AIH overlap with sclerosing cholangitis (overlap syndrome [OS]).

Methods:

This is a cross‐sectional study of 20 children and adolescents diagnosed with type 1 AIH and 19 with OS. Fifteen healthy subjects were included as controls. Flow cytometric analysis was used to identify markers of inflammation and autoimmunity.

Results:

The total number of CD4+ T cells was higher in the AIH patients compared with the controls. The number of CD4+ T cells expressing CCR3 and CD28 was higher in the AIH group than in the control group. CD45RO was more highly expressed in the AIH group, whereas CD45RA was more highly expressed in the OS group. In regard to CD8+ T lymphocytes, the CCR3 expression was higher in both groups of patients. Patients with OS had the highest expression of CD45RA and CD25. In monocytes, human leukocyte antigen DR (HLA‐DR) was less expressed in both groups of patients.

Conclusions:

Complex phenotype features may be involved in the pathophysiology of AIH, accounting for changes in immune system regulation mechanisms. In conclusion, even after good response to treatment, patients still have immune activity signals at the cellular level.
Epidemiology and Predictors of Orbital Fractures in Children
Authors: Miller Andrew F. , Elman Daniel M. , Aronson Paul L. , Kimia Amir A. , Neuman Mark I.
Published: October 2017

Objectives

Data regarding clinical predictors of orbital fractures in children are limited. We sought to describe the epidemiology of pediatric orbital fractures and identify the signs and symptoms of orbital fractures in children.

Methods

We performed a retrospective cohort study of children younger than 22 years who underwent a facial or orbital computed tomography (CT) scan to evaluate for orbital fracture. We included patients presenting to an emergency department of a tertiary care children's hospital between January 2009 and May 2013. The presence of an orbital fracture was assessed using the final interpretation of the CT by an attending radiologist in the electronic medical record.

Results

Among 326 children who underwent facial or orbital CT during the study period, 133 (41%) had an orbital fracture. The presence of nausea or vomiting, orbital tenderness, swelling, or ecchymosis and limitation of extraocular movement were each associated with the presence of an orbital fracture (P < 0.05 for each). Twenty-two children (6.7% of cohort and 16.5% of children with orbital fractures) underwent surgical repair for an orbital fracture. In the absence of orbital tenderness, swelling, or ecchymosis, there was 1 child with an orbital fracture who underwent operative intervention.

Conclusions

Fewer than half of children undergoing CT have an orbital fracture identified, and fewer than 7% have a fracture that requires operative intervention. In the absence of orbital tenderness, swelling, or ecchymosis, only 1 child had an orbital fracture requiring surgical repair.
Toxic Shock Syndrome
Authors: Gossack-Keenan Kira L. , Kam April J.
Published: October 2017

Background

Toxic shock syndrome (TSS) is an acute, severe, toxin-mediated disease, characterized by fever, hypotension, and multiorgan system involvement. Toxic shock syndrome has made headlines because of its high associated morbidity and mortality rate in previously healthy young females. Incidence peaked in the early 1980s owing to increased usage of ultra-absorbent tampons. After improved patient education and tampon labeling, the incidence of menstrual TSS has declined.

Case

A previously healthy 14-year-old girl presented to an urgent care center with a 2-day history of fever, erythematous maculopapular rash, vomiting, diarrhea, and malaise. She was found to be tachycardic and hypotensive. Investigations revealed thrombocytopenia, an elevated white count and lactate, and acute kidney injury, consistent with septic shock. Recent tampon usage with menstruation was reported, and a pelvic examination revealed purulent vaginal discharge. The patient was transferred to a pediatric intensive care unit for antibiotic and vasopressor therapy. Vaginal swabs later tested positive for Staphylococcus aureus and TSS toxin-1.

Conclusions

Although the incidence of TSS has decreased in recent years, it is crucial that clinicians rapidly recognize and treat this life-threatening condition. Emergency physicians should always have a high index of suspicion for TSS in young females presenting without another obvious cause of shock. A pelvic examination should always be completed in these cases.
Brief Report: CD52 Expression on CD4+ T Cells in HIV-Positive Individuals on cART
Authors: Vojdeman Fie Juhl , Gaardbo Julie Christine , Hartling Hans Jakob , Gelpi Marco , Hove-Skovsgaard Malene , Pedersen Anders Elm , Nielsen Susanne Dam
Published: October 2017

Background:

HIV persists in a latent state in quiescent CD4+ T cells preventing eradication of HIV. CD52 is a surface molecule modulated by HIV. We aimed at examining factors related to CD52 expression on CD4+ T cells in HIV-positive individuals and the impact of initiation of combination antiretroviral therapy (cART).

Methods:

Peripheral blood mononuclear cells from 18 HIV-positive individuals and 10 uninfected age- and sex-matched controls were examined by flow cytometry for CD38 and CD52 expression on CD4+ T cells. Stimulation assays were performed on 8 healthy blood donors to determine a cutoff for CD52 expression.

Results:

All examined CD4+ T cells expressed CD52. However, both CD4+ T cells with higher (CD52++) and with lower CD52 expression (CD52dim) were found in HIV-positive individuals compared to uninfected controls. Two % CD52dim cells defined groups of high and low CD52: the group of individuals with high CD52 had higher CD4 counts at baseline (447 vs. 54 cells/µL, P = 0.02) and higher increase in CD4 counts during follow-up compared with low CD52 (P = 0.02). After 12 months of cART, CD52 increased (median fluorescence intensity 4846 vs. 5621, P < 0.05), whereas CD38 decreased (median fluorescence intensity 1519 vs. 730, P < 0.0001).

Conclusions:

All HIV-positive individuals in this cohort had CD4+ T cells that expressed CD52. Higher CD4 counts were found in those with high CD52. Furthermore, an increase in CD52 was found after 12 months of cART, indicating that anti-CD52 antibodies may be more efficient for depletion of CD4+ T cells in HIV-positive individuals on cART.
Brief Report: AIDS-Defining Events and Deaths in HIV-Infected Children and Adolescents on Antiretrovirals: A 14-Year Study in Thailand
Authors: Traisathit Patrinee , Delory Tristan , Ngo-Giang-Huong Nicole , Somsamai Rosalin , Techakunakorn Pornchai , Theansavettrakul Sookchai , Kanjanavanit Suparat , Mekmullica Jutarat , Ngampiyaskul Chaiwat , Na-Rajsima Sathaporn , Lallemant Marc , Cressey Tim R. , Jourdain Gonzague , Collins Intira Jeannie , Le Coeur Sophie
Published: October 2017

Background:

Data are scarce on the long-term clinical outcomes of perinatally HIV-infected children and adolescents receiving antiretroviral therapy (ART) in low/middle-income countries. We assessed the incidence of mortality before (early) and after (late) 6 months of ART and of the composite outcome of new/recurrent AIDS-defining event or death >6 months after ART start (late AIDS/death) and their associated factors.

Methods:

Study population was perinatally HIV-infected children (≤18 years) initiating ART within the Program for HIV Prevention and Treatment observational cohort (NCT00433030). Factors associated with late AIDS/death were assessed using competing risk regression models accounting for lost to-follow-up and included baseline and time-updated variables.

Results:

Among 619 children, “early” mortality incidence was 99 deaths per 1000 person-years of follow-up [95% confidence interval (CI): 69 to 142] and “late” mortality 6 per 1000 person-years of follow-up (95% CI: 4 to 9). Of the 553 children alive >6 months after ART initiation, median age at ART initiation was 6.4 years, CD4% 8.2%, and HIV-RNA load 5.1 log10 copies/mL. Thirty-eight (7%) children developed late AIDS/death after median time of 3.3 years: 24 died and 24 experienced new/recurrent AIDS-defining events (10 subsequently died). Factors independently associated with late AIDS/death were current age ≥13 years (adjusted subdistribution hazard ratio 4.9; 95% CI: 2.4 to 10.1), HIV-RNA load always ≥400 copies/mL (12.3; 95% CI: 4.0 to 37.6), BMI-z-score always <−2 SD (13.7; 95% CI: 3.4 to 55.7), and hemoglobin <8 g/dL at least once (4.6; 95% CI: 2.0 to 10.5).

Conclusions:

After the initial 6 months of ART, being an adolescent, persistent viremia, poor nutritional status, and severe anemia were associated with poor clinical outcomes. This supports the need for novel interventions that target children, particularly adolescents with poor growth and uncontrolled viremia.
Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons
Authors: Koethe John R. , McDonnell Wyatt , Kennedy Arion , Abana Chike O. , Pilkinton Mark , Setliff Ian , Georgiev Ivelin , Barnett Louise , Hager Cindy C. , Smith Rita , Kalams Spyros A. , Hasty Alyssa , Mallal Simon
Published: October 2017

Background:

Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8+ T cells represent an expanded, oligoclonal population.

Methods:

We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4+ and CD8+ T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8+ cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue.

Results:

Adipose tissue had a higher percentage of CD3+CD8+ T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8+HLA-DR+ T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8+CD57+ T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8+ T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05).

Conclusions:

Adipose tissue is enriched for activated and late-differentiated CD8+ T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.
Proof of Concept Study for the Design, Manufacturing, and Testing of a Patient-Specific Shape Memory Device for Treatment of Unicoronal Craniosynostosis
Authors: Borghi Alessandro , Rodgers Will , Schievano Silvia , Ponniah Allan , Jeelani Owase , Dunaway David
Published: October 2017

Treatment of unicoronal craniosynostosis is a surgically challenging problem, due to the involvement of coronal suture and cranial base, with complex asymmetries of the calvarium and orbit. Several techniques for correction have been described, including surgical bony remodeling, early strip craniotomy with orthotic helmet remodeling and distraction. Current distraction devices provide unidirectional forces and have had very limited success. Nitinol is a shape memory alloy that can be programmed to the shape of a patient-specific anatomy by means of thermal treatment.

In this work, a methodology to produce a nitinol patient-specific distractor is presented: computer tomography images of a 16-month-old patient with unicoronal craniosynostosis were processed to create a 3-dimensional model of his skull and define the ideal shape postsurgery. A mesh was produced from a nitinol sheet, formed to the ideal skull shape and heat treated to be malleable at room temperature. The mesh was afterward deformed to be attached to a rapid prototyped plastic skull, replica of the patient initial anatomy. The mesh/skull construct was placed in hot water to activate the mesh shape memory property: the deformed plastic skull was computed tomography scanned for comparison of its shape with the initial anatomy and with the desired shape, showing that the nitinol mesh had been able to distract the plastic skull to a shape close to the desired one.

The shape-memory properties of nitinol allow for the design and production of patient-specific devices able to deliver complex, preprogrammable shape changes.
The Pantheon Variant of the Classic Cathedral Dome Procedure for Parieto-Occipital Skull Deformities
Authors: Eibach Sebastian , Le Hop N. , Zovickian John , Pang Dachling
Published: October 2017

Objective:

To describe a new technique for the reconstruction of parieto-occipital skull deformities.

Methods and Results:

The technique is a variant of the previously described “cathedral dome procedure” used for frontal skull deformities. The authors apply the same principle of remodeling by making meridional slat craniotomies surrounding the depressed dome of the posterior skull deformity, followed by “green-stick fracture-reshaping” of the meridional slats to elevate and support the excised depressed dome. The authors present an illustrative patient with a follow-up of 2 years and an excellent cosmetic result.

Conclusion:

The authors introduce a new operative technique for the reconstruction of parieto-occipital skull deformities with excellent long-term results. The freshly reconstructed occiput resembles the dome of the pantheon in Rome, Italy, whose unique features inspired us to name this procedure the “Pantheon” variant of the cathedral dome operation.
Untreated Relative Hypotension Measured as Perfusion Pressure Deficit During Management of Shock and New-Onset Acute Kidney Injury—A Literature Review
Authors: Panwar Rakshit
Published: October 2017

Maintaining an optimal blood pressure (BP) during shock is a fundamental tenet of critical care. Optimal BP targets may be different for different patients. In current practice, too often, uniform BP targets are pursued which may result in inadvertently accepting a degree of untreated relative hypotension, i.e., the deficit between patients’ usual premorbid basal BP and the achieved BP, during vasopressor support. Relative hypotension is a common but an under-recognized and an under-treated sign among patients with potential shock state. From a physiological perspective, any relative reduction in the net perfusion pressure across an organ (e.g., renal) vasculature has a potential to overwhelm autoregulatory mechanisms, which are already under stress during shock. Such perfusion pressure deficit may consequently impact organs’ ability to function or recover from an injured state. This review discusses such pathophysiologic mechanisms in detail with a particular focus on the risk of new-onset acute kidney injury (AKI). To review current literature, databases of Medline, Embase, and Google scholar were searched to retrieve articles that either adjusted BP targets based on patients’ premorbid BP levels or considered relative hypotension as an exposure endpoint and assessed its association with clinical outcomes among acutely ill patients. There were no randomized controlled trials. Only seven studies could be identified and these were reviewed in detail. These studies indicated a significant association between the degree of relative hypotension that was inadvertently accepted in real-world practice and new-onset organ dysfunction or subsequent AKI. However, this is not a high-quality evidence. Therefore, well-designed randomized controlled trials are needed to evaluate whether adoption of individualized BP targets, which are initially guided by patient's premorbid basal BP and then tailored according to clinical response, is superior to conventional BP targets for vasopressor therapy, particularly among patients with vasodilatory shock states.
Has molecular imaging delivered to drug development?
Authors: Murphy Philip S. , Patel Neel , McCarthy Timothy J.
Published: October 2017

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Protonation of carboxyl groups in EuDOTA-tetraamide complexes results in catalytic prototropic exchange and quenching of the CEST signal
Authors: Zhang Lei , Evbuomwan Osasere M. , Tieu Michael , Zhao Piyu , Martins Andre F. , Sherry A. Dean
Published: October 2017

The CEST properties of EuDOTA-tetraamide complexes bearing pendant carboxylate and carboxyl ethyl esters were measured as a function of pH. The CEST signal from the Eu
3+
-bound water molecule decreased in intensity between pH 8.5 and 4.5 while the proton exchange rates (
k
ex
) increased over this same pH range. In comparison, the CEST signal in the corresponding carboxyl ester derivatives was nearly constant. Both observations are consistent with stepwise protonation of the four carboxylic acid groups over this same pH range. This indicates that negative charges on the carboxyl groups above pH 6 facilitate the formation of a strong hydrogen-bonding network in the coordination second sphere above the single Eu
3+
-bound water molecule, thereby decreasing prototropic exchange of protons on the bound water molecule with bulk water protons. The percentage of square antiprismatic versus twisted square antiprism coordination isomers also decreased as the appended carboxylic acid groups were positioned further away from the amide. The net effect of lowering the pH was an overall increase in
k
ex
and a quenching of the CEST signal.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Phosphate starvation induces replacement of phospholipids with the betaine lipid diacylglycerol-N,N,N-trimethylhomoserine in the human fungal pathogenCandida albicans
Authors: Naik Surabhi , Cahoon Rebecca , Tripp Bridget , Elowsky Christian , Alvarez Sophie , Liu Kan , Zhang Chi , Riekhof Wayne
Published: October 2017

We have previously demonstrated that phosphate starvation induces replacement of phosphatidylcholine with the betaine lipid diacylglyceryl-N,N,N-trimethylhomoserine (DGTS) in fungi. InNeurospora crassa, theBTA1gene encodes the betaine lipid synthase, which is necessary and sufficient for DGTS synthesis. BTA1 expression and DGTS accumulation are part of the fungal phosphorus (Pi) deprivation (PHO) regulon, mediated by the NUC-1/Pho4p transcription factor. We now demonstrate that the human pathogenCandida albicansencodes aBTA1ortholog (CaBTA1), which is activated during Piscarcity. TheCaBTA1 gene is also induced under certain biofilm-promoting conditions independent of Pistarvation. RNA-seq and qRT-PCR showed a significant increase inCaBTA1 expression in response to Pilimitation. Thin-layer chromatography and LC-ESI-MS/MS confirmed the replacement of PC with DGTS in wild-type under low Piand showed the absence of DGTS in thebta1ΔΔmutant.

Pilimitation in the gut of critically ill patients also triggers the switching ofC. albicansinto an invasive filamentous form. To assess the role of BTA1 and DGTS in the pathogenicity ofC. albicans in vitro, we compared the growth and morphology ofbta1ΔΔand wild type in hyphaeinducing media and observed defects in biofilm formation and invasive growth in thebta1ΔΔmutant. This observation is complemented by RNA-seq data demonstrating that Pistarvation in planktonicC. albicanscells induces the expression of virulence-associated cell surface proteins. Taken together, these results show novel functional interactions between lipid metabolism and remodeling, biofilm formation, and the phosphate starvation response ofC. albicans.
Ade novomissense mutation inTUBA1Aresults in reduced neural progenitor survival and differentiation
Authors: Driver Ashley M. , Pitstick Amy L. , Mayhew Chris N. , Kline-Fath Beth , Saal Howard M. , Stottmann Rolf W.
Published: October 2017

Mutations in tubulins have been implicated in numerous human neurobiological disorders collectively known as “tubulinopathies.” We identified a patient with severe cortical dysgenesis and a novelde novoheterozygous missense mutation inTubulin Alpha 1a(TUBA1A, c.1225 G>T). Induced pluripotent stem cells derived from this individual were differentiated into two dimensional neural rosette clusters to identify underlying mechanisms for the severe cortical dysgenesis phenotype. Patient-derived clones showed evidence of impaired neural progenitor survival and differentiation with abnormal neural rosette formation, increases in cell death, and fewer post-mitotic neurons. These features correlate with the drastically underdeveloped cortical tissues seen in the proband. This is the first experimental evidence in human tissue suggesting a mechanism underlying the role forTUBA1Ain cortical development.

SUMMARY STATEMENT

Variants in tubulin genes often lead to severe congenital brain malformations. Here we identify a new mutation inTUBA1Aand use iPSCS to show this alters proliferation, differentiation and survival of neural progenitors.
Homeostatic feedback modulates the development of two-state patterned activity in a model serotonin motor circuit inCaenorhabditis elegans
Authors: Ravi Bhavya , Garcia Jessica , Collins Kevin M.
Published: October 2017

Neuron activity accompanies synapse formation and maintenance, but how early circuit activity contributes to behavior development is not well understood. Here, we use theCaenorhabditis elegansegg-laying motor circuit as a model to understand how coordinated cell and circuit activity develops and drives a robust two-state behavior in adults. Using calcium imaging in behaving animals, we find the serotonergic Hermaphrodite Specific Neurons (HSNs) and vulval muscles show rhythmic calcium transients in L4 larvae before eggs are produced. HSN activity in L4 is tonic and lacks the alternating burst-firing/quiescent pattern seen in egg-laying adults. Vulval muscle activity in L4 is initially uncoordinated but becomes synchronous as the anterior and posterior muscle arms meet at HSN synaptic release sites. However, coordinated muscle activity does not require presynaptic HSN input. Using reversible silencing experiments, we show that neuronal and vulval muscle activity in L4 is not required for the onset of adult behavior. Instead, the accumulation of eggs in the adult uterus renders the muscles sensitive to HSN input. Sterilization or acute electrical silencing of the vulval muscles inhibits presynaptic HSN activity, and reversal of muscle silencing triggers a homeostatic increase in HSN activity and egg release that maintains ~12-15 eggs in the uterus. Feedback of egg accumulation depends upon the vulval muscle postsynaptic terminus, suggesting a retrograde signal sustains HSN synaptic activity and egg release. Our results show that egg-laying behavior inC. elegansis driven by a homeostat that scales serotonin motor neuron activity in response to postsynaptic muscle feedback.

Significance Statement

The functional importance of early, spontaneous neuron activity in synapse and circuit development is not well understood. Here we show that in the nematodeC. elegans, the serotonergic Hermaphrodite Specific Neurons (HSNs) and postsynaptic vulval muscles show activity during circuit development, well before the onset of adult behavior. Surprisingly, early activity is not required for circuit development or the onset of adult behavior, and the circuit remains unable to drive egg laying until fertilized embryos are deposited into the uterus. Egg accumulation potentiates vulval muscle excitability, but ultimately acts to promote burst firing in the presynaptic HSNs during which eggs are laid. Our results suggest that mechanosensory feedback acts at three distinct steps to initiate, sustain, and terminateC. elegansegg-laying circuit activity and behavior.
Virulence evolution of a parasite infecting male and female hosts
Authors: Wardlaw Alison M. , Agrawal Aneil F.
Published: October 2017

Parasites experience different tradeoffs between transmission and virulence in male and female hosts if the sexes vary in life history or disease-related traits. We determine the evolutionarily stable levels of exploitation by pathogens under two scenarios: an unconstrained pathogen that expresses different exploitation rates within each host type as well as a pathogen constrained to express the same exploitation rate in each sex. We show that an unconstrained horizontally-transmitted parasite evolves to express the same sex-specific exploitation rate within each sex as it would in a host population composed entirely of hosts with that sex’s resistance and intrinsic death rate. In contrast, the ESS exploitation rate of a constrained pathogen is affected by sex-differences in susceptibility and non-random contact patterns between host types that differ in resistance. As the amount of within-sex transmission increases, the ESS shifts closer to the optimum trait value in the more susceptible sex. Allowing for some degree of vertical transmission, the exploitation rate expressed in females (but not males) changes with contact pattern even in unconstrained pathogens. Differences in contact pattern and susceptibility play an important role in determining the ESS exploitation rate by shifting the reproductive value of each host type.
sigQC: A procedural approach for standardising the evaluation of gene signatures
Authors: Dhawan Andrew , Barberis Alessandro , Cheng Wei-Chen , Domingo Enric , West Catharine , Maughan Tim , Scott Jacob G. , Harris Adrian L. , Buffa Francesca M.
Published: October 2017

With the increase in next generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools, poised to make a large impact on the diagnosis, management and prognosis for a number of diseases. Increasingly, it is becoming necessary to determine whether a gene expression signature may apply to a dataset, but no standard quality control methodology exists. In this work, we introduce the first protocol, implemented in an R package sigQC, enabling a streamlined methodological and standardised approach for the quality control validation of gene signatures on independent data sets. The emphasis in this work is in showing the critical quality control steps involved in the generation of a clinically and biologically useful, transportable gene signature, including ensuring sufficient expression, variability, and autocorrelation of a signature. We demonstrate the application of the protocol in this work, showing how the outputs created from sigQC may be used for the evaluation of gene signatures on large-scale gene expression data in cancer.
Slower environmental change hinders adaptation from standing genetic variation
Authors: Guzella Thiago S. , Dey Snigdhadip , Chelo Ivo M. , Pino-Querido Ania , Pereira Veronica F. , Proulx Stephen R. , Teotónio Henrique
Published: October 2017

Evolutionary responses to environmental change depend on the time available for adaptation before environmental degradation leads to extinction. Explicit tests of this relationship are limited to microbes where adaptation depends on the order of mutation accumulation, excluding standing genetic variation which is key for most natural species. When adaptation is determined by the amount of heritable genotype-by-environment fitness variance then genetic drift and/or maintenance of similarly fit genotypes may deter adaptation to slower the environmental changes. To address this hypothesis, we perform experimental evolution with self-fertilizing populations of the nematode Caenorhabditis elegans and develop a new inference model that follows pre-existing genotypes to describe natural selection in changing environments. Under an abrupt change, we find that selection rapidly increases the frequency of genotypes with high fitness in the most extreme environment. In contrast, under slower environmental change selection favors those genotypes that are worse at the most extreme environment. We further demonstrate with a second set of evolution experiments that, as a consequence of slower environmental change, population bottlenecks and small population sizes lead to the loss of beneficial genotypes, while maintenance of polymorphism impedes their fixation in large populations. Taken together, these results indicate that standing variation for genotype-by-environment fitness interactions alters the pace and outcome of adaptation under environmental change.
Atmospheric CO2availability does not equate to increased nodularin production in diazotrophic cyanobacteria, but does induce varying responses in net photosynthesis and N2fixation rates
Authors: Wannicke Nicola , Gehringer Michelle M.
Published: October 2017

Increasing levels of CO2in the atmosphere are suggested to favour increased incidences of cyanobacterial blooms in water bodies, with a potential concomitant increase in toxin production. As nitrogen fixing cyanobacteria are independent of nitrate and ammonium, this pilot study investigated whether elevated atmospheric CO2levels (eCO2), could increase toxin production and net photosynthesis (NP) rates in both terrestrial and aquatic diazotrophic cyanobacteria. Both toxin and non-toxin producing strains ofNostocandNodulariawere grown at present atmospheric levels (PAL) of CO2or near future elevated (eCO2) and net photosynthesis (NP) determined. Short term responses demonstrated CO2associated increases and decreases in NP, withN. harveyanaSAG44.85 showing little change in its NP at eCO2. Long term responses recorded increases in NP for all species in response to eCO2, except forN. harveyanaon day 7. Nitrogen fixation rates were significantly higher by approx. 10 fold in the aquaticNodulariaspecies compared to the terrestrialNostocspecies tested. Moreover, nitrogen fixation rates were not significantly higher at eCO2, except forN. harveyana. There was no direct correlation between increased nodularin production and eCO2in neither aquatic, nor terrestrial nodularin producing species, however there was a significant correlation between nodularin content and POC:PON ratio for the terrestrialNostocsp. 73.1 not observed for the aquaticNodularia spumigenaCCY9414.
Deciphering the regulation mechanism in biochemical networks by a systems-biology approach
Authors: Mello Bernardo A. , Tu Yuhai
Published: October 2017

To decipher molecular mechanisms in biological systems from system-level input-output data is challenging especially for complex processes that involve interactions among multiple components. Here, we study regulation of the multi-domain (P1-5) histidine kinase CheA by the MCP chemoreceptors. We develop a network model to describe dynamics of the system treating the receptor complex with CheW and P3P4P5 domains of CheA as a regulated enzyme with two substrates, P1 and ATP. The model enables us to search the hypothesis space systematically for the simplest possible regulation mechanism consistent with the available data. Our analysis reveals a novel dual regulation mechanism wherein besides regulating ATP binding the receptor activity has to regulate one other key reaction, either P1 binding or phosphotransfer between P1 and ATP. Furthermore, our study shows that the receptors only control kinetic rates of the enzyme without changing its equilibrium properties. Predictions are made for future experiments to distinguish the remaining two dual-regulation mechanisms. This systems-biology approach of combining modeling and a large input-output data-set should be applicable for studying other complex biological processes.
Super-Resolution Ultrasound Bubble Tracking for Preclinical and Clinical Multiparametric Tumor Characterization
Authors: Opacic Tatjana , Dencks Stefanie , Theek Benjamin , Piepenbrock Marion , Ackermann Dimitri , Rix Anne , Lammers Twan , Stickeler Elmar , Delorme Stefan , Schmitz Georg , Kiessling Fabian
Published: October 2017

Super-resolution imaging methods promote tissue characterization beyond the spatial resolution limits of the devices and bridge the gap between histopathological analysis and non-invasive imaging. Here, we introduce Ultrasound Bubble Tracking (UBT) as an easily applicable and robust new tool to morphologically and functionally characterize fine vascular networks in tumors at super-resolution. In tumor-bearing mice and for the first time in patients, we demonstrate that within less than one minute scan time UBT can be realized using conventional preclinical and clinical ultrasound devices. In this context, next to highly detailed images of tumor microvascularization and the reliable quantification of relative blood volume and perfusion, UBT provides access to multiple new functional and morphological parameters that showed superior performance in discriminating tumors with different vascular phenotypes. Furthermore, our initial clinical results indicate that UBT is a highly translational technology with strong potential for the multiparametric characterization of tumors and the assessment of therapy response.
Degeneracy in hippocampal physiology and plasticity
Authors: Rathour Rahul Kumar , Narayanan Rishikesh
Published: October 2017

Degeneracy, defined as the ability of structurally disparate elements to perform analogous function, has largely been assessed from the perspective of maintaining robustness of physiology or plasticity. How does the framework of degeneracy assimilate into an encoding system where the ability to change is an essential ingredient for storing new incoming information? Could degeneracy maintain the balance between the apparently contradictory goals of the need to change for encoding and the need to resist change towards maintaining homeostasis? In this review, we explore these fundamental questions with the mammalian hippocampus as an example encoding system. We systematically catalog lines of evidence, spanning multiple scales of analysis, that demonstrate the expression of degeneracy in hippocampal physiology and plasticity. We assess the potential of degeneracy as a framework to achieve the conjoint goals of encoding and homeostasis without cross-interferences. We postulate that biological complexity, involving interactions among the numerous parameters spanning different scales of analysis, could establish disparate routes towards accomplishing these conjoint goals. These disparate routes then provide several degrees of freedom to the encoding-homeostasis system in accomplishing its tasks in an input- and state-dependent manner. Finally, the expression of degeneracy spanning multiple scales offers an ideal reconciliation to several outstanding controversies, through the recognition that the seemingly contradictory disparate observations are merely alternate routes that the system might recruit towards accomplishment of its goals. Against the backdrop of the ubiquitous prevalence of degeneracy and its strong links to evolution, it is perhaps apt to add a corollary to Theodosius Dobzhansky’s famous quote and state “nothing in physiology makes sense except in the light of degeneracy”.

Highlights

Degeneracy is the ability of structurally distinct elements to yield similar function

We postulate a critical role for degeneracy in the emergence of stable encoding systems

We catalog lines of evidence for the expression of degeneracy in the hippocampus

We suggest avenues for research to explore degeneracy in stable encoding systems

Dobzhansky wrote: “nothing in biology makes sense except in the light of evolution”

A corollary: “nothing in physiology makes sense except in the light of degeneracy”
HTX: a tool for the exploration and visualization of high-throughput image assays
Authors: Arteta Carlos , Lempitsky Victor , Zak Jaroslav , Lu Xin , Alison Noble J. , Zisserman Andrew
Published: October 2017

High-throughput screening (HTS) techniques have enabled large scale image-based studies, but extracting biological insights from the imaging data in an exploratory setting remains a challenge. Existing packages for this task either require expert annotations, which can bias the outcome of the study, or are completely unsupervised, failing to leverage the information present in the assay design. We present HTX, an interactive tool to aid in the exploration of large microscopy data sets by allowing the visualization of entire image-based assays according to visual similarities between the samples in an intuitive and navigable manner. Underlying HTX are a collection of novel algorithmic techniques for deep texture descriptor learning, 2D data visualization, adversarial suppression of batch effects, and backprop-based image saliency estimation.

We demonstrate that HTX can exploit the screen meta-data in order to learn screen-specific image descriptors, which are then used to quantify the visual similarity between samples in the assay. Given these similarities and the different visualization resources of HTX, it is shown that screens of small-molecule libraries on cell data can be easily explored, reproducing the results of previous studies where highly-specific domain knowledge was required.
How structural elements added by evolution from bacterial transporters to human SLC6 homologs have enabled new functional properties
Authors: Razavi Asghar M. , Khelashvili George , Weinstein Harel
Published: October 2017

Much of the structure-based mechanistic understandings of the function of SLC6A neurotransmitter transporters emerged from the study of their bacterial LeuT-fold homologs. It has become evident, however, that structural differences such as the long N- and C-termini of the eukaryotic neurotransmitter transporters impart an expanded set of functional properties to the eukaryotic transporters, which are not shared by the bacterial homologs that lack the structural elements that appeared later in evolution. However, mechanistic insights into some of the measured functional properties of the eukaryotic transporters, that have been suggested to involve these structural elements, are sparse. To learn how the structural elements added in evolution enable mechanisms of the eukaryotic transporters in ways not shared with their bacterial LeuT-like homologs, we focused on the human dopamine transporter (hDAT) as a prototype. We present the results of a study employing large-scale molecular dynamics simulations and comparative Markov State Model analysis of experimentally determined properties of the wild type and mutant hDAT constructs, which reveal a rich spectrum of interactions of the hDAT N-terminus and the mechanisms by which these contribute to regulation (e.g., by phosphorylation), or to entirely new phenotypes (e.g., reverse uptake – efflux) added in evolution. We reveal separate roles for the distal and proximal segments of the much larger N-terminus shared by the eukaryotic transporters compared to the bacterial ones, consistent with the proposal that the size of this region increased during evolution to enable more, and different, modes of regulation that are not shared with the bacterial homologs.