bluuebunny/crossref_metadata_2025 huggingface dataset:
Orthokeratology With a New Contact Lens Design in Hyperopia: A Pilot Study
Authors: Sánchez-García Alicia , Batres-Valderas Laura , Piñero David P.
Published: April 2019

Purpose:

To evaluate the preliminary clinical outcomes of a new contact lens design for orthokeratology in hyperopia.

Methods:

Prospective pilot study including 8 hyperopic eyes of 4 nonpresbyopic patients (24–44 years) undergoing orthokeratology with the Alexa H contact lens (Tiedra Pharmaceutical, Madrid, Spain), which is an aspheric pentacurve design. Visual, refractive, corneal topographic, and aberrometric changes were evaluated during a 1-month follow-up. Likewise, the presence of ocular surface alterations was evaluated by slit-lamp biomicroscopy during this follow-up.

Results:

Mean noncyclopegic sphere decreased significantly from a mean prefitting value of 2.94±0.95 D to mean values of 1.18±1.19 (P=0.01) and 0.25±0.85 D (P=0.04) at 1 week and 1 month of lens wear, respectively. Statistically significant changes were detected at 1 week of use of the lenses in keratometry (P=0.03), asphericity (Q) (P=0.01), and the Zernike term for corneal spherical aberration (SA) (P=0.01). However, no significant changes were observed in uncorrected (P=0.68) and best-corrected distance visual acuity (P=0.18). Superficial corneal staining was observed after the first night of use in only 1 patient who was resolved spontaneously. Likewise, the induction of a “toroid-like” topographic pattern leading to poor visual outcome and suboptimal correction was observed in four eyes at the beginning of the treatment. This condition was solved in all cases by reducing the lens diameter.

Conclusion:

The Alexa H lens seems to be useful for providing an orthokeratologic correction of hyperopia, with generation of increased negative Q and SA, and central steepening. However, fitting guides must be improved to avoid suboptimal outcomes as those related to the “toroid-like” topographic pattern defined.
Therapeutic Implications of Inherited Thrombophilia in Pregnancy
Authors: Trasca Livia Florentina , Patrascu Natalia , Bruja Ramona , Munteanu Octavian , Cirstoiu Monica , Vinereanu Dragos
Published: April 2019

Background:

Inherited (hereditary) thrombophilia is a genetic disorder that affects coagulation, being responsible for more than 60% of idiopathic (spontaneous or unprovoked) thromboembolic events. Association of inherited thrombophilia with pregnancy increases the risk of thromboembolic disease, and it may be related to many complications, such as preeclampsia, recurrent miscarriage intrauterine growth restriction, early detachment of placenta, and prematurity.

Areas of Uncertainty:

Interpretation of a positive test for thrombophilia in pregnant women is difficult because they have many natural changes in the coagulation system. Genetic diagnosis of thrombophilia, after a thrombotic event or during a pregnancy complication, has a major importance, not only to define its etiology but also to determine the duration of anticoagulant treatment and risk stratification for prophylaxis treatment.

Data sources:

Literature search was performed using electronic database (PubMed) between April 1981 and November 2018. We used different keywords and MeSH terms to generate the most relevant results related to the inherited thrombophilia and its impact on pregnancy.

Results:

Screening for inherited thrombophilia in young women is recommended in case of personal history of venous thromboembolism, first-degree relatives with a history of high-risk thrombophilia, or personal history of second-trimester miscarriage. Decision to recommend thromboprophylaxis with anticoagulant treatment in pregnant women with inherited thrombophilia is determined by history of venous thromboembolism, type and associated risk of inherited thrombophilia, and presence of additional risk factors. Low-molecular-weight heparins are the preferred agents for prophylaxis in pregnancy, while the doses vary depending on thrombophilia type, personal history, and associated risk factors.

Conclusions:

Association between 2 procoagulant conditions, inherited thrombophilia and pregnancy, has an important impact for the mother and fetus. This review will summarize the impact of each inherited prothrombotic factor on cardiovascular and pregnancy outcomes and will discuss the role of anticoagulation treatment for women diagnosed with inherited thrombophilia.
Development of an Antibiotic Guideline for Children With Suspected Ventilator-Associated Infections*
Authors: Shein Steven L. , Karam Oliver , Beardsley Andrew , Karsies Todd , Prentice Elizabeth , Tarquinio Keiko M. , Willson Douglas F.
Published: April 2019

Objectives:

To develop a guideline for the decision to continue or stop antibiotics at 48–72 hours after their initiation in children with suspected ventilator-associated infection.

Design:

Prospective, multicenter observational data collection and subsequent development of an antibiotic guideline.

Setting:

Twenty-two PICUs.

Patients:

Children less than 3 years old receiving mechanical ventilation who underwent clinical testing and initiation of antibiotics for suspected ventilator-associated infection.

Interventions:

None.

Measurements and Main Results:

Phase 1 was a prospective data collection in 281 invasively ventilated children with suspected ventilator-associated infection. The median age was 8 months (interquartile range, 4–16 mo) and 75% had at least one comorbidity. Phase 2 was development of the guideline scoring system by an expert panel employing consensus conferences, literature search, discussions with institutional colleagues, and refinement using phase 1 data. Guideline scores were then applied retrospectively to the phase 1 data. Higher scores correlated with duration of antibiotics (p < 0.001) and higher PEdiatric Logistic Organ Dysfunction 2 scores (p < 0.001) but not mortality, PICU-free days or ventilator-free days. Considering safety and outcomes based on the phase 1 data and aiming for a 25% reduction in antibiotic use, the panel recommended stopping antibiotics at 48–72 hours for guideline scores less than or equal to 2, continuing antibiotics for scores greater than or equal to 6, and offered no recommendation for scores 3, 4, and 5. The acceptability and effect of these recommendations on antibiotic use and outcomes will be prospectively tested in phase 3 of the study.

Conclusions:

We developed a scoring system with recommendations to guide the decision to stop or continue antibiotics at 48–72 hours in children with suspected ventilator-associated infection. The safety and efficacy of the recommendations will be prospectively tested in the planned phase 3 of the study.
Hypertensive Disorders of Pregnancy and Symptoms of Depression and Anxiety as Related to Gestational Age at Birth: Findings From the All Our Families Study
Authors: Horsley Kristin J. , Tomfohr-Madsen Lianne M. , Ditto Blaine , Tough Suzanne C.
Published: April 2019

Objective

The aim of the study was to investigate whether symptoms of depression or state anxiety changed the strength or nature of the association between hypertensive disorders of pregnancy (HDP) and gestational age at birth.

Methods

We conducted a secondary analysis of data from the All Our Families Cohort, a prospective pregnancy cohort study based in Calgary, Alberta, Canada. Self-reported depressive symptoms and state anxiety were assessed between 3 and 5 months of gestation, and obstetrical information, including diagnosis of HDP, parity, type of delivery, and gestational age at birth, was retrieved from the maternal discharge abstract. All models were adjusted for sociodemographic and obstetric confounders.

Results

Of 2763 women who had a singleton pregnancy and live birth, 247 (9%) were diagnosed with HDP. Women with HDP had significantly shorter gestational length relative to those without the diagnosis (M = 37.87 versus M = 38.99 weeks of gestation), t(2761) = 9.43, p < .001. Moderation analyses showed significant HDP by depressive symptoms and HDP by state anxiety interactions, such that the strength of the association between HDP and gestational age at birth increased alongside greater depressive symptom and state anxiety severity.

Conclusions

Results suggest that depressive symptoms and state anxiety may add to the increased risk for shortened gestation associated with HDP. Women at high risk of cardiovascular complications during pregnancy may benefit from additional resources to manage symptoms of depression or anxiety.
18F-FDG PET/CT for Staging and Evaluation of Therapy in a Patient With Unusual Hairy Cell Leukemia Presentation
Authors: Doma Andrej , Škerget Matevž , Žagar Ivana
Published: April 2019

Hairy cell leukemia is a rare hematologic malignancy characterized by splenomegaly, pancytopenia, and susceptibility to infections. We report a case of a 66-year-old man, diagnosed with hairy cell leukemia, without severe cytopenias and splenomegaly, but with an extensive pathological retroperitoneal mass and infiltration of the spleen and skeletal involvement. All findings were highly avid on pretreatment 18F-FDG PET/CT scan. Treatment response evaluation 18F-FDG PET/CT scan showed normalization of FDG uptake on all previously pathological sites.
Typical and Atypical 18FDG PET/CT Findings in Two Cases of Cat Scratch Disease
Authors: Zhou Wei , Gong Lianggeng , Zuo Changjing , Zhang Jian
Published: April 2019

Cat scratch disease (CSD) is a rare zoonotic infection disease, and the imaging performance for evaluation varies. We present FDG PET/CT images of two cases of CSD. In one case, images showed typical findings of regional lymph node enlargement. In another case, images showed atypical findings of extensive superficial and deep lymph node enlargement.
Intradermal-Stress-Lymphoscintigraphy in Early Detection and Clinical Management of Secondary Lymphedema
Authors: Tartaglione Girolamo , Visconti Giuseppe , Bartoletti Roberto , Gentileschi Stefano , Ieria Francesco Pio , Colletti Patrick M. , Rubello Domenico , Salgarello Marzia
Published: April 2019

Stress-lymphoscintigraphy evaluates the effects of exercise on lymph drainage. Results may predict outcomes of complex physical therapy as a first-line lymphedema treatment. Microsurgical approaches are best in patients with lymphangectasia or dermal backflow. Lymphatic pathway mapping helps plan lympho-venous anastomoses. For improved lymphatic visualization, we suggest a scan at rest, after a quick exercise (stepping or weight lifting for 2 min) and delayed scanning after prolonged symptom limited exercise (walking or hand squeezing for 30–40 min). In advanced lymphedema, identification of lymph pathways and residual regional lymph nodes might be difficult. In these patients, lymph node transplant is suggested.
FDG PET/CT of Spinal Brucellosis
Authors: Alduraibi Alaa Khalid , Naddaf Sleiman , Alzayed Mohammed Fahad
Published: April 2019

A 17-year-old adolescent boy’s known case of classical seminoma stage IB for which he underwent right radical orchiectomy. At the first-year follow-up, CT abdomen and pelvis was performed and showed lytic vertebral lesion with left paravertebral necrotic mass that warranted further investigation to exclude disease recurrence. FDG PET/CT scan was performed to evaluate the extent of disease and showed high uptake in the same areas. A biopsy was obtained from the hypermetabolic soft tissue lesion and did not reveal malignant cells. Subsequently, serologic tests were suggestive of brucellosis.
Comparison of l-Methyl-11C-Methionine PET With Magnetic Resonance Spectroscopy in Detecting Newly Diagnosed Glioma
Authors: Kebir Sied , Lazaridis Lazaros , Weber Manuel , Deuschl Cornelius , Stoppek Ann-Kathrin , Schmidt Teresa , Mönninghoff Christoph , Blau Tobias , Keyvani Kathy , Umutlu Lale , Pierscianek Daniela , Forsting Michael , Stuschke Martin , Antoch Gerald , Sure Ulrich , Kleinschnitz Christoph , Scheffler Björn , Colletti Patrick M. , Rubello Domenico , Herrmann Ken , Glas Martin
Published: April 2019

Aims

Amino acid PET and magnetic resonance spectroscopy (MRS) are at the forefront of noninvasive imaging techniques used for detection and subtyping of glioma-suspicious lesions. In this pilot study, we compare l-methyl-11C-methionine PET and MRS for their ability to predict glioma subtypes.

Methods

Nineteen patients with histologically, confirmed newly diagnosed glioma underwent preoperative l-methyl-11C-methionine PET and MRS in 1 diagnostic session. According to the molecular portfolio and histopathologic diagnosis, patients were subdivided in isocitrate dehydrogenase (IDH) wild-type glioblastoma, IDH wild-type grade II/III glioma, IDH-mutant grade II/III glioma without 1p/19q codeletion, and with 1p/19q codeletion subgroups. Maximum tumor-to-brain ratio (TBRmax), creatine, choline, and N-acetyl aspartate peaks were correlated with postoperative histopathologic tumor diagnoses.

Results

Maximum tumor-to-brain ratio was highest in glioblastoma patients (4.18) followed by patients with IDH wild-type grade II and III glioma (3.41). The latter TBRmax values were higher compared with those in patients with IDH-mutant grade II/III glioma without 1p/19q codeletion (1.95) and in patients with IDH-mutant 1p/19q codeleted grade II and III glioma (2.79). Magnetic resonance spectroscopy marker distribution showed no clear trend. Receiver operating characteristic analysis revealed TBRmax to be the best performing parameter in identifying IDH status (area under the curve, 0.67) and all spectroscopy markers combined in identifying glioma subgroups (area under the curve, 0.68), respectively.

Conclusions

l-Methyl-11C-methionine PET and MRS bear limited potential in glioma subgrouping. l-Methyl-11C-methionine PET appears to be superior in differentiating IDH status, whereas MRS is more helpful in glioma subgrouping.
Clinical Application of 18F-AlF-NOTA-Octreotide PET/CT in Combination With 18F-FDG PET/CT for Imaging Neuroendocrine Neoplasms
Authors: Long Tingting , Yang Nengan , Zhou Ming , Chen Dengming , Li Yulai , Li Jian , Tang Yongxiang , Liu Zhaoqian , Li Zibo , Hu Shuo
Published: April 2019

Objectives

The study is to evaluate biodistribution, dosimetry, safety, and clinical usefulness of 18F-AlF-NOTA-octreotide (18F-OC) PET/CT in combination with 18F-FDG PET/CT for detection of neuroendocrine neoplasms (NENs).

Methods

The biodistribution, dosimetry, and safety of 18F-OC were evaluated in 3 healthy volunteers. Twenty-two NEN patients underwent PET/CT at 60 minutes after intravenous injection of 3.7 to 4.44 MBq (0.1–0.12 mCi) per kilogram of body weight of 18F-OC. This was followed by 18F-FDG PET/CT within a 2-week period.

Results

18F-OC was well tolerated by all healthy volunteers and NEN patients. The calculated effective dose of 18F-OC was 0.023 ± 0.002 mSv/MBq. In NEN patients, we observed prominent 18F-OC tumor uptake and high tumor-to-background ratios. Tumor uptake of 18F-OC was greater than that of 18F-FDG, and this was particularly evident in G2 NENs (median SUVmax, 45.6 vs 4.3; P < 0.015). Tumor uptake of 18F-OC or 18F-FDG was significantly correlated with tumor differentiation (P < 0.05). Dual tracer PET/CT detected more lesions and also yielded information on the biological status of tumors.

Conclusions

The tracer 18F-OC exhibited favorable safety and dosimetry profiles. 18F-OC provided superior imaging of well-differentiated NENs and significantly higher tumor-to-background ratio compared with 18F-FDG. Combining 18F-FDG with 18F-OC PET/CT has the potential to improve NEN staging and management of patient treatment.
Preperitoneal balloon tamponade and resuscitative endovascular balloon occlusion of the aorta: Alternatives to open packing for pelvic fracture-associated hemorrhage
Authors: Do Woo S. , Forte Dominic M. , Sheldon Rowan R. , Weiss Jessica B. , Barron Morgan R. , Sokol Kyle K. , Black George E. , Hegge Sara R. , Eckert Matthew J. , Martin Matthew J.
Published: April 2019

BACKGROUND

The objective of this study was to compare the efficacy of preperitoneal balloon tamponade (PPB), resuscitative endovascular balloon occlusion of the orta (REBOA), and open preperitoneal packing (OP) in a realistic animal model of pelvic fracture-associated hemorrhage.

METHODS

Thirty-nine swine underwent creation of open-book pelvic fracture and iliac vascular injury. Animals were randomized to no intervention (n = 7), OP (n = 10), PPB (n = 9), zone 1 REBOA (n = 7), and zone 3 REBOA (n = 6) at a mean arterial pressure less than 40 mm Hg from uncontrolled hemorrhage. Primary outcome was survival at 1 hour. Secondary outcomes included survival in the immediate 10 m following intervention reversal, peak preperitoneal pressure (PP), blood loss, bleed rate, and peak lactate.

RESULTS

Prior to injury, no difference was measured between groups for weight, hemodynamics, lactate, and hematocrit (all p = NS). The injury was uniformly lethal without intervention, with survival time (mean) of 5 m, peak PP of 14 mm Hg, blood loss of 960 g, bleed rate of 450 g/m, and peak lactate of 2.6 mmol/L. Survival time (m) was extended to 44 with OP, 60 with PPB, and 60 with REBOA (p < 0.01). Peak PP (mm Hg) was 19 with OP, 23 with PPB, 10 with zone 1 REBOA, and 6 with zone 3 REBOA (p < 0.05). Blood loss (g) was 850 with OP, 930 with PPB, 610 with zone 1 REBOA, and 370 with zone 3 REBOA (p < 0.01). Peak lactate (mmol/L) was 3.3 with OP, 4.3 with PPB, 13.4 with zone 1 REBOA, and 5.3 with zone 3 REBOA (p < 0.01). Only 33% of zone 1 REBOA animals survived the initial 10 m after balloon deflation, compared to 60% for OP, 67% for PPB, and 100% for zone 3 REBOA (p < 0.01).

CONCLUSION

Preperitoneal balloon tamponade and zone 3 REBOA are effective alternatives to OP in this animal model of lethal pelvic fracture-associated hemorrhage. Zone 1 REBOA extends survival time but with high mortality upon reversal.
Prehospital adenosine, lidocaine, and magnesium has inferior survival compared with tactical combat casualty care resuscitation in a porcine model of prolonged hemorrhagic shock
Authors: How Remealle A. , Glaser Jacob J. , Schaub Leasha J. , Fryer Darren M. , Ozuna Kassandra M. , Morgan Clifford G. , Sams Valerie G. , Cardin Sylvain
Published: April 2019

BACKGROUND

Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized prehospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the golden hour.

METHODS

Swine were randomized to: (1) TCCC, (2) 2 mL·kg−1 vehicle control (VC), (3) 2 mL·kg−1 ALM + drip, (4) 4 mL·kg−1 ALM + drip, 5) 4 mL·kg−1 ALM + delayed drip at 0.5 mL·kg−1·h−1, 6) 4 mL/kg VC, 7) 4 mL·kg−1 ALM for 15 minutes + delayed drip at 3 mL·kg−1·h−1. Animals underwent pressure controlled hemorrhage to mean arterial pressure (MAP) of 30 mm Hg (S = 0). Treatment was administered at T = 0. After 120 minutes of simulated prehospital care (T = 120) blood product resuscitation commenced. Physiologic variables were recorded and laboratories were drawn at specified time points.

RESULTS

Tactical Combat Casualty Care demonstrated superior survival to all other agents. The VC and ALM groups had lower MAPs and systolic blood pressures compared with TCCC. Except for the VC groups, lactate levels remained similar with correction of base deficit after prehospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared with baseline values, TCCC demonstrated significant hypocoagulability.

CONCLUSION

Adenosine, lidocaine, and magnesium, as administered in this study, are inferior to current Hextend-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower systolic blood pressures and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. Adenosine, lidocaine, and magnesium do not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.
Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome
Authors: Utami Kagistia Hana , Skotte Niels H. , Colaço Ana R. , Yusof Nur Amirah Binte Mohammad , Sim Bernice , Yeo Xin Yi , Bae Han-Gyu , Garcia-Miralles Marta , Radulescu Carola I. , Chen Qiyu , Chaldaiopoulou Georgia , Liany Herty , Nama Srikanth , Sampath Prabha , Jung Sangyong , Mann Matthias , Pouladi Mahmoud A.
Published: April 2019

Fragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing ofFMR1and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenicFMR1knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation inFMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenicFMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that theFMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.
Neogenin-1 distinguishes between myeloid-biased and balancedHoxb5+mouse long-term hematopoietic stem cells
Authors: Gulati Gunsagar S. , Zukowska Monika , Noh Joseph , Zhang Allison , Sinha Rahul , George Benson M. , Wesche Daniel J. , Weissman Irving L. , Szade Krzysztof
Published: April 2019

Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single-cell transplants (1–3) and lineage tracing (4, 5) suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled withHoxb5, a specific reporter of long-term HSCs (LT-HSCs) (6). We show that NEO1+Hoxb5+LT-HSCs expand with age and respond to myeloablative stress, while NEO1−Hoxb5+LT-HSCs exhibit no significant change in number. NEO1+Hoxb5+LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1−Hoxb5+LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+Hoxb5+LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution, while NEO1−Hoxb5+LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression comparison reveals increased expression of cell cycle genes and evidence of lineage-priming in the NEO1+fraction. Finally, transplanted NEO1+Hoxb5+LT-HSCs rarely generate NEO1−Hoxb5+LT-HSCs, while NEO1−Hoxb5+LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced, NEO1−Hoxb5+LT-HSCs can hierarchically precede active, myeloid-biased NEO1+Hoxb5+LT-HSCs.

SIGNIFICANCE STATEMENT

Hematopoietic stem cells (HSCs) are rare cells that have the unique ability to regenerate themselves and produce all blood cells throughout life. However, HSCs are functionally heterogeneous and several studies have shown that HSCs can differ in their contribution to major blood lineages. In this study, we discovered that the surface marker, Neogenin-1, can divide mouse HSCs into two subpopulations—one that is more active but biased towards producing myeloid cells and another that is more dormant and capable of equally producing all blood lineages. Neogenin-1 reveals the diversity and hierarchical relationship of HSCs in the mouse bone marrow, enables the prospective isolation of myeloid-biased and balanced HSCs, and opens opportunities to do the same in humans.
Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy
Authors: Simon Christian M. , Van Alstyne Meaghan , Lotti Francesco , Bianchetti Elena , Tisdale Sarah , Mentis George Z. , Pellizzoni Livio
Published: April 2019

Reduced expression of the SMN protein causes spinal muscular atrophy (SMA) – an inherited neurodegenerative disease characterized by multiple synaptic deficits and motor neuron loss. Here, we show that AAV9-mediated delivery of Stasimon – a gene encoding an ER-resident transmembrane protein regulated by SMN – improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons of SMA mice, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In SMA motor neurons, Stasimon suppresses the neurodegenerative process by selectively reducing phosphorylation but not upregulation of the tumor suppressor p53, both of which are converging events required to trigger neuronal death. We further show that Stasimon deficiency synergizes with SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of cellular pathways that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.
Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types
Authors: Wang Xuewei , Xu Yide , Chang Yuting , Ju Sihan , Yang Liu , Qian Qufei , Chen Yao , Chen Shuaizhou , Qin Na , Ma Zijian , Dai Juncheng , Ma Hongxia , Jin Guangfu , Zhang Erbao , Wang Cheng , Hu Zhibin
Published: April 2019

The meiosis stage of spermatogenesis and the aneuploidy generation in tumorigenesis are highly linked. Cancer-testis genes (CT genes) were specifically expressed in testis and cancers and may serve as the molecular basis of the shared features between spermatogenesis and tumorigenesis. In the present study, we integrated multi-omics data from bulk samples and cell lines, and single cell RNA-Seq data from testis and two tumors to systematically investigate the association between CT genes and aneuploidy. After ranking genes according to their association with aneuploidy level, we found that CT genes, especially CT genes specifically expressed in meiosis, showed a consistently positive correlation with aneuploidy and homologous recombination deficiency (HRD) level. Similar results were also found in the CT non-coding genes. Then, we constructed a regulatory network based on the single cell RNA-seq data and revealed that the gain of accelerator transcriptional factors (TFs) E2F7 and E2F8 and the loss of the stabilizer TFs RFX2 and NFYA aberrantly activated CT genes in the cancers and were associated with the increase of HRD level. Finally, we found that the association between CT genes and cytotoxic infiltrating lymphocytes can be influenced by the HRD level. In sum, our results revealed the evidence of pseudomeiotic functions of CT genes in the aneuploidy generation process in the cancer cells. The results may help illuminate the origin of aneuploidy in cancers and guide future immunotherapy targeting CT antigens.
Differential Requirements for the RAD51 Paralogs in Genome Repair and Maintenance in Human Cells
Authors: Garcin Edwige B. , Gon Stéphanie , Prakash Rohit , Sullivan Meghan R. , Brunette Gregory J. , De Cian Anne , Concordet Jean-Paul , Giovannangeli Carine , Dirks Wilhelm G. , Eberth Sonja , Bernstein Kara A. , Jasin Maria , Modesti Mauro
Published: April 2019

Deficiency in several of the classical human RAD51 paralogs [RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3] is associated with cancer predisposition and Fanconi anemia. To investigate their functions, isogenic disruption mutants for each were generated in non-transformed MCF10A mammary epithelial cells and in transformed U2OS and HEK293 cells. In U2OS and HEK293 cells, viable ablated clones were readily isolated for each RAD51 paralog; in contrast, with the exception of RAD51B, RAD51 paralogs are cell-essential in MCF10A cells. Underlining their importance for genomic stability, mutant cell lines display variable growth defects, impaired sister chromatid recombination, reduced levels of stable RAD51 nuclear foci, and hypersensitivity to mitomycin C and olaparib. Altogether these observations underscore the contributions of RAD51 paralogs in diverse DNA repair processes, and demonstrate essential differences in different cell types. Finally, this study will provide useful reagents to analyze patient-derived mutations and to investigate mechanisms of chemotherapeutic resistance deployed by cancers.
The Drosophila Afadin and ZO-1 homologs Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling
Authors: Manning Lathiena A. , Perez-Vale Kia Z. , Schaefer Kristina N. , Sewell Mycah T. , Peifer Mark
Published: April 2019

During morphogenesis cells must change shape and move without disrupting tissue integrity. This requires cell-cell junctions to allow dynamic remodeling while resisting force generated by the actomyosin cytoskeleton. Multiple proteins play roles in junctional-cytoskeletal linkage, but the mechanisms by which they act remain unclear. Drosophila Canoe maintains adherens junction-cytoskeletal linkage during gastrulation. Canoe’s mammalian homolog Afadin plays similar roles in cultured cells, working in parallel with ZO-1 proteins, particularly at multicellular junctions. We took these insights back into the fly embryo, exploring how cells maintain epithelial integrity when challenged by adherens junction remodeling during germband extension and dorsal closure. We found Canoe helps cells maintain junctional-cytoskeletal linkage when challenged by the junctional remodeling inherent in mitosis, cell intercalation and neuroblast invagination, or by forces generated by the actomyosin cable at the leading edge. However, even in the absence of Canoe many cells retain epithelial integrity. This is explained by a parallel role played by the ZO-1 homolog Polychaetoid. In embryos lacking both Canoe and Polychaetoid, cell junctions fail early, with multicellular junctions especially sensitive, leading to widespread loss of epithelial integrity. Our data suggest Canoe and Polychaetoid stabilize Bazooka/Par3 at cell-cell junctions, helping maintain balanced apical contractility and tissue integrity.
Integrating Protein Localization with Automated Signaling Pathway Reconstruction
Authors: Youssef Ibrahim , Law Jeffrey , Ritz Anna
Published: April 2019

Understanding cellular responses via signal transduction is a core focus in systems biology. Tools to automatically reconstruct signaling pathways from protein-protein interactions (PPIs) can help biologists generate testable hypotheses about signaling. However, automatic reconstruction of signaling pathways suffers from many interactions with the same confidence score leading to many equally good candidates. Further, some reconstructions are biologically misleading due to ignoring protein localization information. We proposeLocPL, a method to improve the automatic reconstruction of signaling pathways from PPIs by incorporating information about protein localization in the reconstructions. The method relies on a dynamic program to ensure that the proteins in a reconstruction are localized in cellular compartments that are consistent with signal transduction from the membrane to the nucleus.LocPLand existing reconstruction algorithms are applied to two PPI networks and assessed using both global and local definitions of accuracy.LocPLproduces more accurate and biologically meaningful reconstructions on a versatile set of signaling pathways.LocPLis a powerful tool to automatically reconstruct signaling pathways from PPIs that leverages cellular localization information about proteins. The underlying dynamic program and signaling model are flexible enough to study cellular signaling under different settings of signaling flow across the cellular compartments.
Biofluid modeling of the coupled eye-brain system and insights into simulated microgravity conditions
Authors: Salerni Fabrizia , Repetto Rodolfo , Harris Alon , Pinsky Peter , Prud’homme Christophe , Szopos Marcela , Guidoboni Giovanna
Published: April 2019

This work aims at investigating the interactions between the flow of fluids in the eyes and the brain and their potential implications in the development of visual impairment in astronauts, a condition also known as spaceflight associated neuro-ocular syndrome (SANS). To this end, we propose a reduced (0-dimensional) mathematical model of fluid flow in the eyes and brain, which is embedded into a simplified whole-body circulation model. In particular, the model accounts for: (i) the flows of blood and aqueous humor in the eyes; (ii) the flows of blood, cerebrospinal fluid and interstitial fluid in the brain; and (iii) their interactions. The model is used to simulate variations in intraocular pressure, intracranial pressure and blood flow due to microgravity conditions, which are thought to be critical factors in SANS. Specifically, the model predicts that both intracranial and intraocular pressures increase in microgravity, even though their respective trends may be different. In such conditions, ocular blood flow is predicted to decrease in the choroid and ciliary body circulations, whereas retinal circulation is found to be less susceptible to microgravity-induced alterations, owing to a purely mechanical component in perfusion control associated with the venous segments. These findings indicate that the particular anatomical architecture of venous drainage in the retina may be one of the reasons why most of the SANS alterations are not observed in the retina but, rather, in other vascular beds, particularly the choroid. Thus, clinical assessment of ocular venous function may be considered as a determinant SANS factor, for which astronauts could be screened on earth and in-flight.
Evidence for Early European Neolithic Dog Dispersal: New Data on South-Eastern European subfossil dogs from Prehistory and Antiquity Ages
Authors: Marinov Miroslav , Yankova Iskra , Neov Boyko , Petrova Maria , Spassov Nikolai , Hristov Peter , Radoslavov Georgi
Published: April 2019

Objectives

The history of dog domestication is still under debate, but doubtlessly, it is a process of an ancient partnership between dogs (Canis familiaris) and humans. Although data on ancient DNA dog diversity are scarce, it is clear that several regional dog populations had been formed in Eurasia up to the Holocene. During the Neolithic Revolution and the transition from hunter-gatherer to farmer societies, followed by civilization changes in the Antiquity period, the dog population structure also changed. This process was due to replacement with newly formed dog breeds.

Methods

In this study we have presented for the first time mitochondrial data about South-Eastern Europe (the Balkans) ancient dog remains from the Early Neolithic (8 000 years BP) to the Late Antiquity ages (up to 3th century AD). A total of 25 samples were analyzed using the mitochondrial D-loop region (HVR1).

Results

The results have shown the presence of A (70%) and B (25%) clades throughout the whole investigated period. In order to clarify the position of our results within the ancient dog population in Eneolithic Eurasia, we performed phylogenetic analysis with the available genetic data sets. This data revealed a similarity of the Bulgarian dogs’ structure to that of ancient Italian dogs (A, B, and C clades), which suggests a new prehistoric and historic Mediterranean dog population. A clear border can be seen between South-European genetic dog structure, on the one hand, and, on the other hand, Central-West (clade C), East (clade D) and North Europe (clades A and C). This corresponds to genetic data for European humans during the same period without admixture between dog populations.

Conclusions

Our data have shown for the first time the presence of clade B in ancient Eurasia. This is not unexpected as the B haplogroup is widely distributed in extant Balkan dogs and wolves. The presence of this clade both in dogs and in wolves on the Balkans may be explained with hybridization events before the Neolithic period. The spreading of this clade across Europe together with the A clade is related to the possible dissemination of newly formed dog breeds from Ancient Greece, Thrace and the Roman Empire.
Promotion of adipogenesis by JMJD6 requires the AT hook-like domain and is independent of its catalytic function
Authors: Reyes-Gutierrez Pablo , Carrasquillo-Rodríguez Jake W. , Imbalzano Anthony N.
Published: April 2019

JMJD6 is a member of the Jumonji C domain containing enzymes that demethylate and/or hydroxylate substrate proteins. It is a multi-functional protein that has been implicated in disparate aspects of transcriptional and post-transcriptional control of gene expression, including but not limited to enhancer and promoter binding, release of paused RNA polymerase II, control of splicing, and interaction with the translation machinery. JMJD6 contributes to multiple aspects of animal development, including adipogenesis modeled in culture. We mutated proposed or characterized domains in the JMJD6 protein to better understand the requirement for JMJD6 in adipogenic differentiation. Mutation of JMJD6 amino acids that mediate binding of iron and 2-oxogluterate, which are required cofactors for enzymatic activity, had no impact on JMJD6 function, showing that catalytic activity is not required for JMJD6 contributions to adipogenic differentiation. In addition, we documented the formation of JMJD6 oligomers and showed that catalytic activity is not required for oligomerization, as has been reported previously. We also observed no effect of mutations in the sumoylation site and in the poly-serine stretch. In contrast, mutation of the AT hook-like structure, which mediates interaction with DNA and/or RNA, compromised JMJD6 function. The ability of JMJD6 to interact with nucleic acids may be a critical requirement for its function in adipogenic differentiation. The requirement for the AT hook-like domain and the lack of requirement for catalytic activity giving rise to the idea that JMJD6 may be functioning as a scaffold protein that supports the interactions of other critical regulators.
Epidemiology of drug-resistant tuberculosis in Chongqing, China: a retrospective observational study from 2010 to 2017
Authors: Wu Bo , Yu Ya , Du Changting , Liu Ying , Hu Daiyu
Published: April 2019

China is one of the top 30 countries with high multidrug-resistant tuberculosis (MDR-TB) and rifampin-resistant tuberculosis (RR-TB) burden. Chongqing is a southwest city of China with a large rural population. A retrospective observational study has been performed based on routine tuberculosis (TB) surveillance data in Chongqing from 2010 to 2017. The MDR/RR-TB notification rate increased from 0.03 cases per 100,000 population in 2010 to 2.09 cases per 100,000 population in 2017. The extensively drug-resistant TB (XDR-TB) notification rate has increased to 0.09 cases per 100,000 population in 2017. There was a decreasing detection gap between the number of notified MDR/RR-TB cases and the estimate number of MDR/RR-TB cases among all notified TB cases. The treatment success rate of MDR/RR-TB was 50.66% in this period. The rate of MDR/RR-TB in new TB cases was 6.23%, and this rate in previously treated TB cases was 32.7%. Despite the progress achieved, the prevalence of MDR/RR-TB was still high facing challenges including detection gaps, the regional disparity, and the high risk for MDR/RR-TB in elderly people and farmers. Sustained government financing and policy support should be guaranteed in the future.
Experimental station Bernina at SwissFEL: condensed matter physics on femtosecond time scales investigated by X-ray diffraction and spectroscopic methods
Authors: Ingold Gerhard , Abela Rafael , Arrell Christopher , Beaud Paul , Böhler Pirmin , Cammarata Marco , Deng Yunpei , Erny Christian , Esposito Vincent , Flechsig Uwe , Follath Rolf , Hauri Christoph , Johnson Steven , Juranic Pavle , Mancini Giulia Fulvia , Mankowsky Roman , Mozzanica Aldo , Oggenfuss Roland Alex , Patterson Bruce D. , Patthey Luc , Pedrini Bill , Rittmann Jochen , Sala Leonardo , Savoini Matteo , Svetina Cristian , Zamofing Thierry , Zerdane Serhane , Lemke Henrik Till
Published: April 2019

The Bernina instrument at the SwissFEL Aramis hard X-ray free-electron laser is designed for studying ultrafast phenomena in condensed matter and material science. Ultrashort pulses from an optical laser system covering a large wavelength range can be used to generate specific non-equilibrium states, whose subsequent temporal evolution can be probed by selective X-ray scattering techniques in the range 2–12 keV. For that purpose, the X-ray beamline is equipped with optical elements which tailor the X-ray beam size and energy, as well as with pulse-to-pulse diagnostics that monitor the X-ray pulse intensity, position, as well as its spectral and temporal properties. The experiments can be performed using multiple interchangeable endstations differing in specialization, diffractometer and X-ray analyser configuration and load capacity for specialized sample environment. After testing the instrument in a series of pilot experiments in 2018, regular user operation begins in 2019.
The role of client participation and psychological comfort in driving perceptions of audit quality
Authors: Sampet Jomjai , Sarapaivanich Naruanard , Patterson Paul
Published: April 2019

Purpose

With increased competition under the establishment of the ASEAN Economic Community (AEC) in December 2015, CPA and Tax Auditors are free to export their services within AEC partner countries. Hence, it is crucial that the growing numbers of auditors in the region differentiate themselves by providing superior perceived audit quality and client value in order to retain (and attract) clients. Based on theoretical foundations of service-dominant logic and culture theory, the purpose of this paper is to investigate the role of client involvement in the audit process and client psychological comfort in influencing client perceptions of audit quality.

Design/methodology/approach

A survey was used to collect data from firms listed on the Thai Stock Exchange. The unit of analysis was the client firm. A key informant method was used whereby a senior manager, heavily involved in the auditor assessment and selection process answered all questions on behalf of their company. Data from 190 firms are subsequently analyzed with structural equation modeling.

Findings

Both client level of involvement and psychological comfort impact their perceptions of three dimensions of audit quality: service quality, independence and competence. Audit quality in turn is strongly associated with overall client satisfaction.

Originality/value

While various scholarly works have examined audit quality, this study does so in an emerging, highly collectivist culture (Thailand) where due to cultural norms, relationships take on added importance. More importantly, for the first time, the study shines the spotlight on the role that client involvement in the audit process, and client psychological comfort, play in influencing client perceptions of audit quality.
Could sustainability improve the promotion of luxury products?
Authors: Dekhili Sihem , Achabou Mohamed Akli , Alharbi Fatmah
Published: April 2019

Purpose

This paper aims to examine the extent to which sustainability information unfavorably impacts consumers’ behavior in the case of luxury. In particular, it explores the effect of social and environmental attributes on the perceived quality.

Design/methodology/approach

A between-subject experimental design involving 973 French and Saudi consumers has been conducted.

Findings

The results indicate that sustainability information negatively impacts the perceived quality of luxury products. However, this result varies regarding the consumers’ country of origin. While no significant effect was observed in the case of French respondents, Saudi consumers lower the evaluation of quality when social information is provided. In addition, the negative effect of sustainability information is moderated by the consumers’ degree of liking of luxury and by the brand corporate social responsibility image.

Research limitations/implications

This research fills a gap occurred in the previous literature. In effect, limited studies examined perceptions of the association between luxury and sustainability. In addition, it enriches the limited literature on sustainable consumption in the context of developing countries. However, further studies should focus on specific dimensions of quality and examine different sustainable practices and luxury goods.

Practical implications

From a practical point of view, this study suggests new applications with respect to the link between luxury and sustainability.

Originality/value

No study to date, as per the authors’ knowledge, has investigated empirically the impact of sustainability information on the perceived quality of luxury products. Contrary to the literature indicating a positive effect of sustainable attributes on consumers’ behavior, this study confirms the incompatibility between luxury and sustainability.
The moderating effect of corporate reputation on inter-firm alliance impact on company performance
Authors: Liu Xiaoyu , Vredenburg Harrie , Daellenbach Urs
Published: April 2019

Purpose

The purpose of this paper is to untangle the impacts of a firm’s corporate reputation and its alliance partners’ social capital on its financial performance, drawing on the relational and the network points of view.

Design/methodology/approach

This paper explored the moderating effect of corporate reputation on the relationship between partners’ social capital (e.g. resource heterogeneity, structural relations and partners’ social ties) and a focal firm’s performance. An OLS three-step regression model (controls, main effects and interaction effects) was used to test the proposed hypotheses based on 265 US joint ventures.

Findings

The influence of partners’ social capital on a focal firm’s performance is negatively moderated by the focal firm’s reputation at the firm and network levels; larger and more prestigious firms listed inFortunedatabase tend to choose partners with a higher level of resource heterogeneity, whereas smaller firms tend to choose partners in similar industries to increase economies of scale. The social capital factors of the partners will have different effects on the focal firm performance.

Originality/value

The value of this paper is in providing insight into the importance and nuances of corporate reputation in offsetting the advantages of inter-firm alliances and their impact on firm performance. In particular, the performance benefits of inter-firm alliance partners’ social ties and heterogeneous resources are negatively affected by the corporate reputation of a firm.