bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing the Staging/Restaging Performance of 68Ga-Labeled Prostate-Specific Membrane Antigen and 18F-Choline PET/CT in Prostate Cancer
Authors: Lin Chun-Yi , Lee Ming-Tsung , Lin Cheng-Li , Kao Chia-Hung
Published: March 2019

Purpose

PET/CT using prostate-specific membrane antigen (PSMA) and choline radiotracers is widely used for diagnosis of prostate cancer. However, the roles of and differences in diagnostic performance between these 2 radiotracers for prostate cancer are unclear. The aim of this study was to compare the staging and restaging performance of 68Ga-labeled PSMA and 18F-choline PET/CT imaging in prostate cancer.

Methods

A comprehensive search was performed in PubMed for studies reporting the staging performance of 68Ga-PSMA and 18F-choline PET/CT in prostate cancer from the inception of the database to October 1, 2018, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Thirty-five studies were included in this systematic review and meta-analysis. Pooled estimates of patient- and lesion-based sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) for 68Ga-PSMA and 18F-choline PET/CT were calculated alongside 95% confidence intervals. Summary receiver operating characteristic curves were plotted, and the area under the summary receiver operating characteristic curve (AUC) was determined alongside the Q* index.

Results

The patient-based overall pooled sensitivity, specificity, PLR, NLR, DOR, and AUC of 68Ga-PSMA PET/CT for staging in prostate cancer (13 studies) were 0.92, 0.94, 7.91, 0.14, 79.04, and 0.96, respectively, whereas those of 18F-choline PET/CT (16 studies) were 0.93, 0.83, 4.98, 0.10, 68.27, and 0.95. The lesion-based overall pooled sensitivity, specificity, PLR, NLR, DOR, and AUC of 68Ga-PSMA PET/CT for staging in prostate cancer (9 studies) were 0.83, 0.95, 23.30, 0.17, 153.58, and 0.94, respectively, and those of 18F-choline PET/CT (4 studies) were 0.81, 0.92, 8.59, 0.20, 44.82, and 0.98. In both patient- and lesion-based imaging, there was no statistically significant difference in the abilities of detecting or excluding prostate cancer between 68Ga-PSMA PET/CT and 18F-choline PET/CT.

Conclusions

For staging and restaging performance in patients with prostate cancer, there was no significant difference between 68Ga-PSMA PET/CT and 18F-choline PET/CT. 68Ga-PSMA PET/CT and 18F-choline PET/CT have demonstrated high diagnostic performance for accurate staging and restaging in patients with prostate cancer, and thus both should be considered for staging in this disease.
Malignant Peripheral Nerve Sheath Tumor With Bilateral Adrenal Metastases
Authors: Tripathy Sarthak , Passah Averilicia , Singhal Abhinav , Prashanth Arun , Kumar Rakesh
Published: March 2019

MPNSTs (malignant peripheral nerve sheath tumors) are a highly malignant group of soft tissue sarcomas and carry a very poor prognosis. Metastasis to bilateral adrenal glands is very rare in such group of neoplasms. We discuss a case of 85-year-old man who was diagnosed with MPNST from prevertebral mass with metastases to bilateral adrenal glands and bone marrow from the beginning and role of serial 18F-FDG PET/CT scans in response assessment first to sunitinib (tyrosine kinase inhibitor) and then to liposomal doxorubicin.
Detection of Local Relapse of Prostate Cancer With 18F-PSMA-1007
Authors: Seifert Robert , Schafigh Darius , Bögemann Martin , Weckesser Matthias , Rahbar Kambiz
Published: March 2019

Prostate-specific membrane antigen (PSMA)–targeted PET/CT has become a fundamental tool in the management of patients with prostate cancer, especially to rule out local recurrence after surgery or radiation. However, the assessment of the prostatic fossa is difficult due to the renal excretion of PSMA-targeted radionuclides. PET/CT studies using 68Ga-PSMA-11 PET/CT and 18F-PSMA-1007 of a 61-year-old man after radical prostatectomy are presented. This case illustrates that 18F-PSMA-1007 is an ideal radionuclide for the detection of local recurrence of prostate cancer and is superior to 68Ga-PSMA-11, especially in case of pelvic lesions.
A Drain-free Technique for Female-to-Male Gender Affirmation Chest Surgery Decreases Morbidity
Authors: Gallagher Sidhbh , Rahmani Farrah , Russell Arielle , Duquette Stephen
Published: March 2019

Purpose

One of the most common surgical procedures for gender affirmation surgery of the chest is mastectomy. The aims of this article are to review the outcomes of a single surgeon's experience with a drainless technique, which we named “masculoplasty” and compare morbidity in this group to previously published outcomes where drains were used.

Methods

A retrospective chart review was undertaken of all patients presenting to a single surgeon for gender-affirming chest surgery. A literature review was completed, compiling data from previously published studies of mastectomy with free nipple graft for the transgender patient. Outcomes of this drain-free group were compared with historical data, where drains were known to have been used.

Results

One hundred fifty-three patients underwent 306 masculoplasties in a university teaching hospital. The mean age of patients was 30 years (17–66 years). Sixty-five (42%) had 1 or more chronic medical comorbidities with 17 diabetic patients (11%). The mean body mass index was 32 kg/m2 (18–57 kg/m2), and 83 (54%) were obese. Forty-two (27%) of the patients had a history of smoking. Mean operative time was 136 minutes (74–266 minutes).

Hematoma occurred in 1 patient (0.3%). Infections occurred in 7 masculoplasties (2%) with wound dehiscence in 3 (1%). Two masculoplasties (0.7%) had partial nipple necrosis. Two patients (0.7%) developed a symptomatic pneumothorax. There were 0 seromas, and no procedures were performed to drain fluid. Eight masculoplasties (3%) underwent secondary corrections. Median follow-up was 9 months.

Outcomes from this drain-free technique were compared with previously published outcomes of mastectomy where drains were known to be used. When compared with previously published series (n = 1334), the drain-free group had statistically significantly lower rates of hematoma (1/306 vs 39/1334, P = 0.0036) and acute reoperation (1/306 vs 42/1334, P = 0.0024). There was a shorter length of hospital stay in the drain-free group with a statistically significantly lower revision rate (8/306 vs 116/1334, P = 0.0001).

Conclusions

Gender affirmation chest surgery can be safely offered using a drain-free or “masculoplasty” technique. Compared with historical data, the use of progressive tension sutures decreases the incidence of hematoma, the need for acute reoperation, and other complications.
Delayed Diagnosis and Treatment of Cerebrospinal Fluid Leakage in Current Practice
Authors: Li Mingxian , Mao Song , Tang Ru , Lin Hai , Li Dawei , Ye Haibo , Su Kaiming , Chen Zhengnong , Zhang Weitian
Published: March 2019

As delayed diagnosis and treatment of cerebrospinal fluid (CSF) leakage are common in current practice, this study was performed to determine associated factors and discuss appropriate strategies to deal with these problems. A retrospective analysis of all cases of CSF leakage in our hospital from 2007 to 2018, including 41 patients with CSF rhinorrhea and 5 with CSF otorhinorrhea, was performed. Symptoms, associated diseases, misdiagnoses, history of skull base repair surgical, previous medical costs, and number of hospital visits before visiting our institution were reviewed. The diagnoses, surgical reconstruction methods, and prognoses of the patients were analyzed. In 18 patients, CSF leakage was spontaneous, in 14 the cause was trauma, and in the remaining 14 the origin was iatrogenic. Twelve patients had been misdiagnosed with allergic rhinitis, rhinosinusitis, or otitis media. Twelve cases had intracranial infection and 14 suffered airway infection. Six had undergone unsuccessful craniotomy, endonasal endoscopic surgery, or ear surgery for treatment of CSF leakage before visiting our institute. This resulted in an average of 5.13 ± 1.32 referrals and medical costs of up to 20,795.7 ± 4553.80 RMB. The success rate was 97.83% after repairing CSF fistulae in our hospital. The septal floor flap (SFF) method (based on ethmoidal arteries) to treat CSF rhinorrhea showed a success rate of 100% in 12 patients. Therefore, early localization, clinical diagnosis, and appropriate repair surgery can avoid the occurrence of delayed events. Pedicled flaps, including SFF, are recommended to manage challenging CSF rhinorrhea.
An Interdisciplinary Approach to Treatment of Adult Facial Arteriovenous Malformations: A Review of the Literature and A Single Institution's Experience With “Late” Surgical Resection and Aesthetic Reconstruction
Authors: Pedreira Rachel , Lopez Joseph , Ostrander Benjamin T. , Pearl Monica , Puttgen Katherine , Tekes Aylin , Dorafshar Amir H.
Published: March 2019

Background:

Arteriovenous malformations (AVMs) are high flow vascular anomalies that are difficult to manage given their high recurrence rate. At this time, the optimal treatment of AVMs involves embolization and surgical resection. However, few studies have examined patient outcomes after a delayed surgical resection approach.

Methods:

A retrospective chart review of all patients presenting to a single institution with vascular malformations from 2000 to 2016 was performed. Patients with facial AVMs that underwent operative management were included. Records were reviewed for patient characteristics, lesion natural history, operative timing after embolization (<72 vs >72 hours), and outcomes.

Results:

11 patients fulfilled the inclusion/exclusion criteria. Nine patients were female, with an average age at resection of 29.1 years. Three patients had hemi/mid-facial AVMs, 1 patient had a nasal AVM, 3 patients had labial AVMs, 1 patient had an AVM on the chin, and 1 had a periorbital AVM. Average time between embolization and primary resection was 8.6 days (range 1–24). No complications requiring reoperation occurred in any patient. Average follow-up was 32.6 months, with 2 recurrences at a mean of 47.6 months. Timing of resection, Schobinger stage, and resection completeness did not significantly affect recurrence (P >0.05). Lesion size >6 cm in any dimension was significantly associated with recurrence (P = 0.018).

Conclusion:

Compared to early resection, delayed (>72 h) surgical resection after embolization of facial AVMs is a viable treatment option and results in non-inferior recurrence rates (25 vs 14% respectively over a 40-month period).
Kimura's Disease
Authors: Wang Xizhong , Ma Ying , Wang Zhiming
Published: March 2019

Kimura's disease (KD) is a benign, rare and chronic inflammatory disorder of unknown etiology and it affects subcutaneous tissues, lymph nodes, and salivary glands. The clinical manifestation of cases reported is mainly small neoplasms or enlarged lymph nodes, while cases for large masses are rarely reported. This case reveals a female patient of KD with large masses in the head and neck region. The scope of the tumor is huge, which seriously affects the facial shape and psychology of the patient, thereby affecting the daily life of the patient. Although the patient had surgically removed the same site tumor 8 years ago, it was not possible to determine whether it was a recurrent case because the postoperative pathological diagnosis of first treatment was not confirmed. Under the general anesthesia, the right head and neck masses were removed. During the operation, the facial nerve branches were wrapped by the masses. After consulting the family members, it was agreed that the facial nerve should not be preserved for maximum extent removal of the tumor. Although the patient has facial paralysis symptoms after surgery, the facial shape and patient's psychology are greatly improved, and the patient is satisfied with the treatment effect. Surgical treatment is one of the effective ways to treat huge tumors in the head and neck of KD. This study has certain guiding significance for clinicians to treat huge tumors of head and neck in KD.
Ophthalmic Changes Following Maxillectomy With or Without Postoperative Radiation Therapy
Authors: Sweeney Adam R. , Walker Brian , Bhrany Amit D. , Chang Shu-Hong , Jian-Amadi Arash
Published: March 2019

Purpose:

To evaluate ophthalmic complications and quantitatively assess anatomic changes following maxillectomy with or without adjuvant radiotherapy in patients with midface malignancy.

Methods:

Twenty-four patients who underwent maxillectomy for sinus and/or paranasal cancer were included for retrospective review. Patients with complete ophthalmic examinations were evaluated for postoperative findings corresponding to sequelae of treatment. When available, anatomical changes including eyelid position were quantified from preoperative and postoperative full-face photos using computer software.

Results:

The most common complications identified in patients after maxillectomy were retraction/ectropion (50%), epiphora (29%), and exposure keratopathy/dry eye syndrome (25%). Patients treated with maxillectomy with adjuvant radiation therapy were more frequently found to have ophthalmic complications following treatment. In patients with available postoperative photos (n = 10), the mean ipsilateral margin reflex distance (MRD)2 and inferior scleral show were 8.4 mm and 2.4 mm, respectively. In patients with available preoperative photos (n = 5), the mean change in MRD2 and inferior scleral show following maxillectomy was 3.4 mm and 2.8 mm, respectively.

Conclusion:

Patients undergoing maxillectomy for the treatment of head and neck malignancy may be at significant risk for development of specific periocular complications. Lower eyelid malposition was the most significant postoperative quantitative eyelid change following maxillectomy, which may be exacerbated by adjuvant radiotherapy and inferior orbital rim removal.
The Natural Growth Rate of Skull Base Meningiomas Compared With Non-Skull Base Meningiomas
Authors: Yao Xiang , Wei Ting , Zhang Haoran , Li Jialin , Tang Aiwen , Ren Ke
Published: March 2019

In the present study, the authors assessed the differences in natural growth rates between skull base and non-skull base meningiomas by meta-analysis. Studies investigating meningioma growth rate were compiled from PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature database, and the China National Knowledge Infrastructure databases. A systematic review and meta-analysis of the collected literature were conducted using Stata 12.0 software. A total of 7 observational cohort studies, including 361 patients with untreated meningiomas, were included in the study. Meta-analysis showed that the weighted mean difference for absolute growth rate (years), relative growth rate (years), and doubling time (month) were 0.42 (95% confidence interval [CI]: 0.20–0.64, P <.0001), 1.08 (95%CI: 0.85–1.32, P <.0001), and −0.56 [95%CI: (−0.78)–(−0.33), P <.0001)] respectively. These findings indicate that the natural growth rate of skull base meningioma is less than that of non-skull base meningioma.
Reconstruction of Full-Thickness Defects of the Lower Lip With a Double Overlying Cervical Flap
Authors: Copelli Chiara , Manfuso Alfonso , Pederneschi Nicola , Hanna Karim Tewfik , Cassano Lazzaro , Cocchi Roberto
Published: March 2019

Reconstruction of full-thickness total or subtotal lower lip defects represents a challenge for the reconstructive surgeon because of the difficulty to create a functional and aesthetically good lip. Many surgical techniques, going from local to free flaps, have been reported, each of them having its own advantages and disadvantages. In particular, the free fascio-cutaneous flaps in most cases are the first reconstructive option, even though several disadvantages such as the complexity of the procedure, longer operative times, morbidity, longer hospitalization, and conspicuous donor-site scar. To avoid these problems, especially in aged patients and in presence of low compliance and/or comorbidities, the Authors propose a single stage reconstruction with a double overlying cervical flap.
Use of Calcium Phosphate Cement for Repairing Bone Defects: Histomorphometric and Immunohistochemical Analyses
Authors: Gulinelli Jéssica Lemos , Queiroz Thallita Pereira , Hochuli-Vieira Eduardo , Okamoto Roberta , Mattos João Marcos Borges , Calcagnotto Thiago , Santos Pâmela Leticia dos
Published: March 2019

This study aimed to assess the repair of surgically created bone defects filled with blood clot, autogenous bone, and calcium phosphate cement, by histomorphometric and immunohistochemical analyses. Ten adult male rabbits were used. Three bone defects were prepared with an 8-mm diameter trephine bur in the parietal region of each animal and filled with blood clot (Group BC), autogenous bone (Group AB), and calcium phosphate bone cement (Group CPC). The animals were euthanized at 40 and 90 postoperative days. The sections were subjected to histomorphometric analysis of the new bone formed inside the calvarial defects and immunohistochemical staining to determine the expression of osteocalcin (OC), osteopontin (OP), and tartrate-resistant acid phosphatase (TRAP) proteins. Histomorphometric data were analyzed statistically by analysis of variance and Tukey's post hoc test at 5% significance level. In the results at 40 and 90 days, Group AB differed significantly from Group CPC regarding the area of newly formed bone. The immunohistochemical analysis revealed expression of OP, OC, and TRAP proteins in all groups. Group AB showed prevalence of OC and OP, and lower TRAP expression. Therefore, the calcium phosphate bone cement assessed in the present study did not accelerate the protein expression dynamics during bone healing, compared with the autogenous group.
Chimerism, Transplant Tolerance, and Beyond
Authors: Messner Franka , Etra Joanna W. , Dodd-o Jeffrey M. , Brandacher Gerald
Published: March 2019

The present review discusses current developments in tolerance induction for solid organ transplantation with a particular emphasis on chimerism-based approaches. It explains the basic mechanisms of chimerism-based tolerance and provides an update on ongoing clinical tolerance trials. The concept of “delayed tolerance” is presented, and ongoing preclinical studies in the nonhuman primate setting—including current limitations and hurdles regarding this approach—are illustrated. In addition, a brief overview and update on cell-based tolerogenic clinical trials is provided. In a critical approach, advantages, limitations, and potential implications for the future of these different regimens are discussed.
Different genetic and morphological outcomes for phages targeted by single or multiple CRISPR-Cas spacers
Authors: Watson B. N. J. , Easingwood R. A. , Tong B. , Wolf M. , Salmond G. P. C. , Staals R. H. J. , Bostina M. , Fineran P. C.
Published: March 2019

CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against genetic invaders, such as bacteriophages. The systems integrate short sequences from the phage genome into the bacterial CRISPR array. These ‘spacers’ provide sequence-specific immunity but drive natural selection of evolved phage mutants that escape the CRISPR-Cas defence. Spacer acquisition occurs by either naive or primed adaptation. Naive adaptation typically results in the incorporation of a single spacer. By contrast, priming is a positive feedback loop that often results in acquisition of multiple spacers, which occurs when a pre-existing spacer matches the invading phage. We predicted that single and multiple spacers, representative of naive and primed adaptation, respectively, would cause differing outcomes after phage infection. We investigated the response of two phages, ϕTE and ϕM1, to the
Pectobacterium atrosepticum
type I-F CRISPR-Cas system and observed that escape from single spacers typically occurred via point mutations. Alternatively, phages escaped multiple spacers through deletions, which can occur in genes encoding structural proteins. Cryo-EM analysis of the ϕTE structure revealed shortened tails in escape mutants with tape measure protein deletions. We conclude that CRISPR-Cas systems can drive phage genetic diversity, altering morphology and fitness, through selective pressures arising from naive and primed acquisition events.

This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
Natural diversity of CRISPR spacers ofThermus: evidence of local spacer acquisition and global spacer exchange
Authors: Lopatina Anna , Medvedeva Sofia , Artamonova Daria , Kolesnik Matvey , Sitnik Vasily , Ispolatov Yaroslav , Severinov Konstantin
Published: March 2019

We investigated the diversity of CRISPR spacers ofThermuscommunities from two locations in Italy, two in Chile and one location in Russia. Among the five sampling sites, a total of more than 7200 unique spacers belonging to different CRISPR-Cas systems types and subtypes were identified. Most of these spacers are not found in CRISPR arrays of sequencedThermusstrains. Comparison of spacer sets revealed that samples within the same area (separated by few to hundreds of metres) have similar spacer sets, which appear to be largely stable at least over the course of several years. While at further distances (hundreds of kilometres and more) the similarity of spacer sets is decreased, there are still multiple common spacers inThermuscommunities from different continents. The common spacers can be reconstructed in identical or similar CRISPR arrays, excluding their independent appearance and suggesting an extensive migration of thermophilic bacteria over long distances. Several newThermusphages were isolated in the sampling sites. Mapping of spacers to bacteriophage sequences revealed examples of local acquisition of spacers from some phages and distinct patterns of targeting of phage genomes by different CRISPR-Cas systems.

This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
Why put up with immunity when there is resistance: an excursion into the population and evolutionary dynamics of restriction–modification and CRISPR-Cas
Authors: Gurney James , Pleška Maroš , Levin Bruce R.
Published: March 2019

Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction–modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions under which selection mediated by lytic phage will favour such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the number of steps in the coevolutionary arms race between the bacteria-acquiring spacers and the phage-generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered.

This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
CRISPR-Cas immunity leads to a coevolutionary arms race between
Streptococcus thermophilus
and lytic phage
Authors: Common Jack , Morley Daniel , Westra Edze R. , van Houte Stineke
Published: March 2019

CRISPR-Cas is an adaptive prokaryotic immune system that prevents phage infection. By incorporating phage-derived ‘spacer’ sequences into CRISPR loci on the host genome, future infections from the same phage genotype can be recognized and the phage genome cleaved. However, the phage can escape CRISPR degradation by mutating the sequence targeted by the spacer, allowing them to re-infect previously CRISPR-immune hosts, and theoretically leading to coevolution. Previous studies have shown that phage can persist over long periods in populations of
Streptococcus thermophilus
that can acquire CRISPR-Cas immunity, but it has remained less clear whether this coexistence was owing to coevolution, and if so, what type of coevolutionary dynamics were involved. In this study, we performed highly replicated serial transfer experiments over 30 days with
S. thermophilus
and a lytic phage. Using a combination of phenotypic and genotypic data, we show that CRISPR-mediated resistance and phage infectivity coevolved over time following an arms race dynamic, and that asymmetry between phage infectivity and host resistance within this system eventually causes phage extinction. This work provides further insight into the way CRISPR-Cas systems shape the population and coevolutionary dynamics of bacteria–phage interactions.

This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
The ethics of genome editing in non-human animals: a systematic review of reasons reported in the academic literature
Authors: de Graeff Nienke , Jongsma Karin R. , Johnston Josephine , Hartley Sarah , Bredenoord Annelien L.
Published: March 2019

In recent years, new genome editing technologies have emerged that can edit the genome of non-human animals with progressively increasing efficiency. Despite ongoing academic debate about the ethical implications of these technologies, no comprehensive overview of this debate exists. To address this gap in the literature, we conducted a systematic review of the reasons reported in the academic literature for and against the development and use of genome editing technologies in animals. Most included articles were written by academics from the biomedical or animal sciences. The reported reasons related to seven themes: human health, efficiency, risks and uncertainty, animal welfare, animal dignity, environmental considerations and public acceptability. Our findings illuminate several key considerations about the academic debate, including a low disciplinary diversity in the contributing academics, a scarcity of systematic comparisons of potential consequences of using these technologies, an underrepresentation of animal interests, and a disjunction between the public and academic debate on this topic. As such, this article can be considered a call for a broad range of academics to get increasingly involved in the discussion about genome editing, to incorporate animal interests and systematic comparisons, and to further discuss the aims and methods of public involvement.

This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
Characterization of Fowlpox virus in chickens and bird-biting mosquitoes: a molecular approach to investigating Avipoxvirus transmission
Authors: Yeo Gladys , Wang Yifan , Chong Shin Min , Humaidi Mahathir , Lim Xiao Fang , Mailepessov Diyar , Chan Sharon , How Choon Beng , Lin Yueh Nuo , Huangfu Taoqi , Fernandez Charlene Judith , Hapuarachchi Hapuarachchige Chanditha , Yap Grace
Published: March 2019

Avian pox is a highly contagious avian disease, yet relatively little is known about the epidemiology and transmission of Avipoxviruses. Using a molecular approach, we report evidence for a potential link between birds and field-caught mosquitoes in the transmission of Fowlpox virus (FWPV) in Singapore. Comparison of fpv167 (P4b), fpv126 (VLTF-1), fpv175–176 (A11R-A12L) and fpv140 (H3L) gene sequences revealed close relatedness between FWPV strains obtained from cutaneous lesions of a chicken and four pools of Culex pseudovishnui, Culex spp. (vishnui group) and Coquellitidea crassipes caught in the vicinity of the study site. Chicken-derived viruses characterized during two separate infections two years later were also identical to those detected in the first event, suggesting repeated transmission of closely related FWPV strains in the locality. Since the study location is home to resident and migratory birds, we postulated that wild birds could be the source of FWPV and that bird-biting mosquitoes could act as bridging mechanical vectors. Therefore, we determined whether the FWPV-positive mosquito pools (n=4) were positive for avian DNA using a polymerase chain reaction-sequencing assay. Our findings confirmed the presence of avian host DNA in all mosquito pools, suggesting a role for Cx. pseudovishnui, Culex spp. (vishnui group) and Cq. crassipes mosquitoes in FWPV transmission. Our study exemplifies the utilization of molecular tools to understand transmission networks of pathogens affecting avian populations, which has important implications for the design of effective control measures to minimize disease burden and economic loss.
Stringent structural plasticity of dendritic spines revealed by two-photon glutamate uncaging in adult mouse neocortex in vivo
Authors: Noguchi Jun , Nagaoka Akira , Hayama Tatsuya , Ucar Hasan , Yagishita Sho , Takahashi Noriko , Kasai Haruo
Published: March 2019

Two-photon uncaging of glutamate is widely utilized to characterize structural plasticity in brain slice preparations in vitro. In this study, we investigated spine plasticity by using, for the first time, glutamate uncaging in the neocortex of adult mice in vivo. Spine enlargement was successfully induced in a smaller fraction of spines in the neocortex (22%) than in young hippocampal slices (95%), even under a low magnesium condition. Once induced, the time course and mean amplitudes of long-term enlargement were the same (81%) as those in vitro. However, low-frequency (1–2 Hz) glutamate uncaging caused spine shrinkage in a similar fraction (34%) of spines as in vitro, but spread to the neighboring spines less frequently than in vitro. Thus, we found that structural plasticity can occur similarly in the adult neocortex in vivo as in the hippocampus in vitro, although it happens stringently in a smaller subset of spines.
A novel averaging principle provides insights in the impact of intratumoral heterogeneity on tumor progression
Authors: Leocata Marta , Alfonso J. C. L. , Kavallaris Nikos I. , Hatzikirou Haralampos
Published: March 2019

Typically stochastic differential equations (SDEs) involve an additive or multiplicative noise term. Here, we are interested in stochastic differential equations for which the white noise is non-linearly integrated in the corresponding evolution term, typically termed as random ordinary differential equations (RODEs). The classical averaging methods fail to treat such RODEs. Therefore, we introduce a novel averaging method appropriate to be applied on RODEs. To exemplify the importance of our method, we apply it in an important biomedical problem, i.e. the assessment of intratumoral heterogeneity impact on tumor dynamics. In particular, we model gliomas according to a well-known Go or Grow (GoG) model and tumor heterogeneity is modelled as a stochastic process. It has been shown that this GoG model exhibits an emerging Allee effect (bistability). We analytically and computationally show that the introduction of white noise, as a model of intratumoral heterogeneity, leads to a monostable tumor growth. This monostability behaviour is also derived even when spatial cell diffusion is taking into account.
MS Atlas - A molecular map of brain lesion stages in progressive multiple sclerosis
Authors: Frisch Tobias , Elkjaer Maria L. , Reynolds Richard , Michel Tanja Maria , Kacprowski Tim , Burton Mark , Kruse Torben A. , Thomassen Mads , Baumbach Jan , Illes Zsolt
Published: March 2019

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder of the central nervous system with an untreatable late progressive phase in a high percentage of patients. Molecular maps of different stages of brain lesion evolution in patients with progressive MS (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate of PMS on lesion basis. The MS Atlas gives means for testing research hypotheses, validating candidate biomarkers and drug targets. The MS Atlas data base comprises comprehensive high-quality transcriptomic profiles of 73 brain white matter lesions at different stages of lesion evolution from 10 PMS patients and 25 control white matter samples from five patients with non-neurological disease. The MS Atlas was assembled from next generation RNA sequencing ofpost mortemsamples using strict, conservative preprocessing as well as advanced statistical data analysis. It comes with a user-friendly web interface, which allows for querying and interactively analyzing the PMS lesion evolution. It fosters bioinformatics methods forde novonetwork enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures. We also demonstrate how its interface can interactively condense and visualize the atlas’ content. This compendium of mechanistic PMS white matter lesion profiles is an invaluable resource to fuel future multiple sclerosis research and a new basis for treatment development.
ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin
Authors: Lin Quy Xiao Xuan , Rebbani Khadija , Jha Sudhakar , Benoukraf Touati
Published: March 2019

Background

ZBTB33, also known as Kaiso, is a member of the zinc finger and BTB/POZ family. In contrast to many transcription factors, ZBTB33 has the ability to bind both a sequence-specific consensus and methylated DNA. Although these dual binding preferences enable ZBTB33 to function as an active as well as repressive regulator of gene expression, little is known about the underlining molecular mechanisms.

Results

In this study, we aimed to investigate the role of ZBTB33 as a methylated DNA binding factor. We took advantage of the latest releases of the ENCODE sequencing datasets, including ZBTB33 ChIP- seq, whole genome bisulfite sequencing (WGBS), histone mark ChIP-seq and sequencing assays determining the chromatin states, to characterize the chromatin landscapes surrounding methylated ZBTB33 binding sites. Interestingly, our integrative analyses demonstrated that the majority of methylated ZBTB33 binding sites were located within condensed chromatin, which are inaccessible to DNase I and Tn5 transposase. Moreover, these sites were carrying a newly revealed histone post-translational modification signature, with significant enrichment of mono-methylation at lysine 4 of histone 3 (H3K4me1) and a complete absence of other active or expected repressive histone marks.

Conclusions

Overall, our analyses revealed that ZBTB33 has the unique ability to bind methylated DNA across heterochromatin in a transition state, suggesting a potential role for ZBTB33 in heterochromatin priming.
GWAS of 19,629 individuals identifies novel genetic variants for regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits
Authors: Zhao Bingxin , Luo Tianyou , Li Tengfei , Li Yun , Zhang Jingwen , Shan Yue , Wang Xifeng , Yang Liuqing , Zhou Fan , Zhu Ziliang , Zhu Hongtu
Published: March 2019

Volumetric variations of human brain are heritable and are associated with many brain-related complex traits. Here we performed genome-wide association studies (GWAS) and post-GWAS analyses of 101 brain volumetric phenotypes using the UK Biobank (UKB) sample including 19,629 participants. GWAS identified 287 independent SNPs exceeding genome-wide significance threshold of 4.9*10−10, adjusted for testing multiple phenotypes. Gene-based association study found 142 associated genes (113 new) and functional gene mapping analysis linked 122 more genes. Many of the discovered genetic variants have previously been implicated with cognitive and mental health traits (such as cognitive performance, education, mental disease/disorders), and significant genetic correlations were detected for 29 pairs of traits. The significant SNPs discovered in the UKB sample were supported by a joint analysis with other four independent studies (total sample size 2,192), and we performed a meta-analysis of five samples to provide GWAS summary statistics with sample size larger than 20,000. Using genome-wide polygenic risk scores prediction, up to 4.36% of phenotypic variance (p-value=2.97*10−22) in the four independent studies can be explained by the UKB GWAS results. In conclusion, our study identifies many new genetic variants at SNP, locus and gene levels and advances our understanding of the pleiotropy and genetic co-architecture between brain volumes and other traits.
From bud formation to flowering: transcriptomic state defines the cherry developmental phases of sweet cherry bud dormancy
Authors: Vimont Noémie , Fouché Mathieu , Campoy José Antonio , Tong Meixuezi , Arkoun Mustapha , Yvin Jean-Claude , Wigge Philip A. , Dirlewanger Elisabeth , Cortijo Sandra , Wenden Bénédicte
Published: March 2019

Background

Bud dormancy is a crucial stage in perennial trees and allows survival over winter to ensure optimal flowering and fruit production. Recent work highlighted physiological and molecular events occurring during bud dormancy in trees. However, they usually examined bud development or bud dormancy in isolation. In this work, we aimed to further explore the global transcriptional changes happening throughout bud development and dormancy onset, progression and release.

Results

Using next-generation sequencing and modelling, we conducted an in-depth transcriptomic analysis for all stages of flower buds in several sweet cherry (Prunus avium L.) cultivars that are characterized for their contrasted dates of dormancy release. We find that buds in organogenesis, paradormancy, endodormancy and ecodormancy stages are defined by the expression of genes involved in specific pathways, and these are conserved between different sweet cherry cultivars. In particular, we found that DORMANCY ASSOCIATED MADS-box (DAM), floral identity and organogenesis genes are up-regulated during the pre-dormancy stages while endodormancy is characterized by a complex array of signalling pathways, including cold response genes, ABA and oxidation-reduction processes. After dormancy release, genes associated with global cell activity, division and differentiation are activated during ecodormancy and growth resumption. We then went a step beyond the global transcriptomic analysis and we developed a model based on the transcriptional profiles of just seven genes to accurately predict the main bud dormancy stages.

Conclusions

Overall, this study has allowed us to better understand the transcriptional changes occurring throughout the different phases of flower bud development, from bud formation in the summer to flowering in the following spring. Our work sets the stage for the development of fast and cost effective diagnostic tools to molecularly define the dormancy stages. Such integrative approaches will therefore be extremely useful for a better comprehension of complex phenological processes in many species.
Is there an intrinsic relationship between LFP beta oscillation amplitude and firing rate of individual neurons in monkey motor cortex?
Authors: Confais Joachim , Malfait Nicole , Brochier Thomas , Riehle Alexa , Kilavik Bjørg Elisabeth
Published: March 2019

It is a long-standing controversial issue whether an intrinsic relationship between the local field potential (LFP) beta oscillation amplitude and the spike rate of individual neurons in the motor cortex exists. Beta oscillations are prominent in motor cortical LFPs, and their relationship to the local neuronal spiking activity has been extensively studied. Many studies demonstrated that the spikes of individual neurons lock to the phase of LFP beta oscillations. However, the results concerning whether there is also an intrinsic relationship between the amplitude of LFP beta oscillations and the firing rate of individual neurons are contradictory. Some studies suggest a systematic mapping of spike rates onto LFP beta amplitude, and others find no systematic relationship. To resolve this controversy, we correlated the amplitude of LFP beta oscillations recorded in motor cortex of two male macaque monkeys with spike counts of individual neurons during visuomotor behavior, in two different manners. First, in an analysis termed task-related correlation, data obtained across all behavioral task epochs was included. These task-related correlations were frequently significant, and in majority of negative sign. Second, in an analysis termed trial-by-trial correlation, only data from a fixed pre-cue task epoch was included, and correlations were calculated across trials. Such trial-by-trial correlations were weak and rarely significant. We conclude that there is no intrinsic relationship between the firing rate of individual neurons and LFP beta oscillation amplitude in macaque motor cortex, beyond each of these signals being modulated by external factors such as the behavioral task.

SIGNIFICANCE STATEMENT

We addressed the long-standing controversial issue of whether there is an intrinsic relationship between the local field potential (LFP) beta oscillation amplitude and the spike rate of individual neurons in the motor cortex. In two complementary analyses of data from macaque monkeys, we first demonstrate that the unfolding behavioral task strongly affects both the LFP beta amplitude and the neuronal spike rate, creating task-related correlations between the two signals. However, when limiting the influence of the task, by restricting our analysis to a fixed task epoch, correlations between the two signals were largely eliminated. We conclude that there is no intrinsic relationship between the firing rate of individual neurons and LFP beta oscillation amplitude in motor cortex.
Modulation of visual cortex by hippocampal signals
Authors: Fournier Julien , Saleem Aman B , Diamanti E Mika , Wells Miles J , Harris Kenneth D , Carandini Matteo
Published: March 2019

Neurons in primary visual cortex (V1) are influenced by the animal’s position in the environment and encode positions that correlate with those encoded by hippocampus (CA1). Might V1’s encoding of spatial positions be inherited from hippocampal regions? If so, it should depend on non-visual factors that affect the encoding of position in hippocampus, such as the physical distance traveled and the phase of theta oscillations. We recorded V1 and CA1 neurons while mice ran through a virtual corridor and confirmed these predictions. Spatial representations in V1 and CA1 were correlated even in the absence of visual cues. Moreover, similar to CA1 place cells, the spatial responses of V1 neurons were influenced by the physical distance traveled and the phase of hippocampal theta oscillations. These results reveal a modulation of cortical sensory processing by non-sensory estimates of position that might originate in hippocampal regions.
Negative calorie foods: An empirical examination of what is fact or fiction
Authors: Buddemeyer Katherine M. , Alexander Ashley E. , Secor Stephen M.
Published: March 2019

A proposed weight loss strategy is to include in one’s diet foods that are deemed “negative calorie”. In theory, negative-calorie foods are foods for which more energy is expended in their digestion and assimilation than is consumed, thereby resulting in an energy deficit. Commonly listed negative calorie foods are characterized by a high water and fiber content and little fat. Although the existence of negative calorie foods has been largely argued against, no empirical study has fully addressed the validity of foods being negative calorie. We conducted such a study using the omnivorous lizard the bearded dragon(Pogona vitticeps)and celery as the tested food. Celery tops many lists of negative calorie foods due to its high fiber and low caloric content. Following their consumption of celery meals equaling in mass to 5% of their body mass, we measured from each lizard their postprandial metabolic rates to calculate specific dynamic action (SDA). Feces and urate were collected after meals to determine the energy lost to excretion. The specific energy of the celery meals, feces, and urate was determined by bomb calorimetry. Lizards lost on average 29% and 14% of meal energy to feces and urate, respectively, and an additional 33% to SDA, leaving a net gain of 24% of the meal’s energy. When considering that only a portion of fecal energy stems from the celery meal, the net gain is expectedly higher. Although this study debunks the validity of celery and other proposed foods as negative calorie, these foods will contribute to generating a negative energy budget and thus the loss of body weight.

This empirical study refutes the existence of negative-calorie foods; however such foods will contribute to a negative energy balance, and thus the loss of body mass.
Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis
Authors: Chang Hui-Hsin , Ho Ching-Huang , Tomita Beverly , Silva Andrea A. , Sparks Jeffrey A. , Karlson Elizabeth W. , Rao Deepak A. , Lee Yvonne C. , Ho I-Cheng
Published: March 2019

Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response in a drug-specific manner.