bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective Comparative Study of ACL Reconstruction Between Using Hamstring Autograft and Soft Tissue Allograft
Authors: Song Eun Kyoo , Seon Jong Keun , Kim Hasung
Published: August 2014

Objectives:

Nowadays, two most commonly used grafts in the anterior cruciate ligament reconstruction are hamstring autograft and soft tissue allograft. Although the short-term clinical outcomes between two grafts were similar, only a few studies reported mid-term clinical outcomes. The purpose of this prospective study was to compare clinical outcomes of ACL reconstruction between using hamstring autograft and soft tissue allograft after mid-term follow-up.

Methods:

One-hundred sixty-one patients that underwent ACL reconstruction (78 in the hamstring group and 83 in the fresh frozen soft tissue (tibialis anterior) allograft) were followed up for a minimum of 4 years.We compared clinical outcomes (IKDC scores and Tegner activity scores, and Lachman and pivot shift test findings) For the radiologic evaluation, we determined the degree of osteoarthritis based on Kellgren and Lawrence grade system at the time of final follow-up and compared the number of patient with progression of osteoarthritis more than grade I. The muscle strength and position sense using iso-kinetic dynamometer was compared at the final follow-up. We also compared complication rate including graft failures and infection during the follow-up. Among them, we did the 2nd-look arthroscopies to evaluate the partial rupture and extent of synovial coverage on grafts for 27 patients in each group.

Results:

Stability results of the Lachman test, pivot-shift test, and knee joint laxity test failed to reveal any significant inter-group differences (P > 0.05). In the pivot-shift result, autograft group showed 7 cases of grade II and allograft group11 cases of grade II (p=0.09). The clinical outcomes, including Lysholm knee and Tegner activity scores, showed no significant differences between the two groups. Concerning osteoarthritis at the final follow-up, seven patients in the autograft group and eight patients in the allograft group progressed osteoarthritis more than one Kellgren-Lawrence grade at final follow-up (P=0.82). Moreover, extension and flexion muscle power deficits and position sense were similar in both groups. However, the complications were more in allograft group (5 failures and 2 infection in the allograft group and 2 failures and no infection in the autograft group) during the follow-up (P = 0.06). We observed the less partial rupture and better synovial coverage of graft in autograft than allograft under 2nd look arthroscopic findings.

Conclusion:

Although hamstring autograft and soft tissue allograft ACL reconstruction showed similar functional and radiological outcomes after mid-term follow-up, hamstring autograft group showed fewer complications including failure and better arthroscopic findings compared with soft tissue allograft group.
Gated Auditory Speech Perception in Elderly Hearing Aid Users and Elderly Normal-Hearing Individuals: Effects of Hearing Impairment and Cognitive Capacity
Authors: Moradi Shahram , Lidestam Björn , Hällgren Mathias , Rönnberg Jerker
Published: August 2014

This study compared elderly hearing aid (EHA) users and elderly normal-hearing (ENH) individuals on identification of auditory speech stimuli (consonants, words, and final word in sentences) that were different when considering their linguistic properties. We measured the accuracy with which the target speech stimuli were identified, as well as the isolation points (IPs: the shortest duration, from onset, required to correctly identify the speech target). The relationships between working memory capacity, the IPs, and speech accuracy were also measured. Twenty-four EHA users (with mild to moderate hearing impairment) and 24 ENH individuals participated in the present study. Despite the use of their regular hearing aids, the EHA users had delayed IPs and were less accurate in identifying consonants and words compared with the ENH individuals. The EHA users also had delayed IPs for final word identification in sentences with lower predictability; however, no significant between-group difference in accuracy was observed. Finally, there were no significant between-group differences in terms of IPs or accuracy for final word identification in highly predictable sentences. Our results also showed that, among EHA users, greater working memory capacity was associated with earlier IPs and improved accuracy in consonant and word identification. Together, our findings demonstrate that the gated speech perception ability of EHA users was not at the level of ENH individuals, in terms of IPs and accuracy. In addition, gated speech perception was more cognitively demanding for EHA users than for ENH individuals in the absence of semantic context.
Sonographic Evaluation of the Carotid Intima-media Complex Thickness in Nigerian Chronic Kidney Disease Patients
Authors: Ajiboye Olubukola K. , Bello Babawale , Adeyomoye Adekunle A. , Olowoyeye Omodele A. , Irurhe Nicholas K.
Published: August 2014

Atherosclerotic cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease (CKD). Measurement of the carotid artery intima-media thickness (CIMT) is being used by many investigators to detect an increased risk of coronary artery atherosclerotic disease and document treatment effects. This study compares CIMT measurements in 75 patients with chronic kidney disease to a matched cohort of 75 subjects with normal kidney function. In plaque-free arterial segments, the CIMT was measured manually in the longitudinal plane from the far walls of a segment of the common carotid artery 3 cm in length adjacent to the carotid bifurcation. Patients with CKD had a significantly higher mean CIMT compared to those with normal renal function (0.86 ± 0.42 mm vs 0.69 ± 0.21 mm; P < .01). Mean CIMT values did not differ significantly between patients with different stages of CKD (stage 3: 0.88 ± 0.14 mm; stage 4: 0.89 ± 0.18 mm; and stage 5: 0.87 ± 0.14 mm, P = .94). These data indicate that CIMT is significantly higher in patients with CKD compared with controls, regardless of the stage of their disease, and may be a readily available noninvasive means of further assessing cardiovascular risk in CKD patients.
Sonographic Confirmation of Bilateral Invasive Ductal Carcinoma Undetected on Mammogram
Authors: Cheung Renee M.
Published: August 2014

Invasive ductal carcinoma of the breast is cancer that originates in the ducts and subsequently invades the fatty tissue of the breast outside the duct. It is the most common form of breast cancer, representing 80% of all breast cancers. Invasive ductal carcinoma has the potential to metastasize via the bloodstream and lymph nodes, making early diagnosis critical. In the case presented, a rare instance of bilateral primary invasive ductal carcinoma is discussed: It was identified by magnetic resonance imaging, and it was visualized, confirmed, and located by sonography; yet, it was undetected by mammography.
A Rare Case of Papillary Bladder Neoplasm Detected by Sonography in a Young Male
Authors: Morales Steven A. , Abu-Yousef Monzer M. , Tracy Chad R.
Published: August 2014

Bladder tumors are extremely rare in young adults and are usually linked to tobacco abuse, chronic infections, or occupational exposure to carcinogens. We present a case of a papillary urothelial neoplasm in a 19-year-old man with no significant risk factors, initially detected by sonography and later confirmed with computed tomographic urography and cystoscopy. The tumor was quickly resected and mitomycin C instilled in the bladder prophylactically. This is an atypical situation in a patient with none of the common risk factors.
SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma
Authors: Palomero Jara , Vegliante Maria Carmela , Rodríguez Marta Leonor , Eguileor Álvaro , Castellano Giancarlo , Planas-Rigol Ester , Jares Pedro , Ribera-Cortada Inmaculada , Cid Maria C. , Campo Elias , Amador Virginia
Published: August 2014

Key Points

SOX11 mediates regulation of angiogenesis via the PDGFA signaling pathway in MCL. SOX11-dependent increased angiogenesis contributes to a more aggressive MCL phenotype.
CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo
Authors: Alshahrani Musaed M. , Yang Eunice , Yip Jana , Ghanem Simona S. , Abdallah Simon L. , deAngelis Anthony M. , O’Malley Cindy J. , Moheimani Fatemeh , Najjar Sonia M. , Jackson Denise E.
Published: August 2014

Key Points

CEACAM2 is a novel platelet immunoreceptor. CEACAM2 negatively regulates platelet-collagen interactions and thrombus growth and stability in vitro, in vivo and CLEC-2 pathways.
Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting
Authors: Jaka Hyasinta , Mshana Stephen E , Rambau Peter F , Masalu Nestory , Chalya Phillipo L , Kalluvya Samuel E
Published: August 2014

Background

Hepatocellular carcinoma is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries. There is a paucity of published data regarding hepatocellular carcinoma in Tanzania, and the study area in particular. This study describes the clinicopathological profile of hepatocellular carcinoma in our local setting and highlights the challenging problems in the management of this disease.

Methods

This was a retrospective study of histopathologically confirmed cases of hepatocellular carcinoma seen at Bugando Medical Center between March 2009 and February 2013.

Results

A total of 142 patients (M: F = 2.2: 1) were studied representing 4.6% of all malignancies. The median age of patients was 45 years. Hepatitis B virus infection (66.2%) and heavy alcohol consumption (60.6%) were the most frequently identified risk factors for hepatocellular carcinoma. The majority of patients (88.0%) presented late with advanced stages. HBsAg was positive in 66.2% of the patients and Hepatitis C Virus antibody in 16.9%. Thirteen (9.2%) patients tested positive for HIV infection. Most patients (52.8%) had both right and left lobe involvement. The trabecular pattern (47.9%) was the most frequent histopathological type. None of patients had curative therapy because of the advanced nature of the disease. Coagulopathy (45.7%) was the most common complications. The overall mortality rate was 46.5% and it was significantly associated with comorbidity, HIV positivity, CD4+ count <200 cells/μl, high histological grade, advanced stage of the tumor, presence of distant metastases at the time of diagnosis, and associated complications (P < 0.001). The overall median duration of hospital stay was 14 days. The majority of patients (71.1%) were lost to follow-up at the end of the follow-up period.

Conclusions

Hepatocellular carcinoma patients in this region are relatively young at diagnosis and the majority of them present late with an advanced stage and high rate of distant metastasis. Lack of awareness of the disease, poor accessibility to healthcare facilities, and lack of screening programs in this region may contribute to advanced disease at the time of diagnosis. There is a need for early detection, adequate treatment, and proper follow-up to improve treatment outcome.
Error concealment algorithm using inter-view correlation for multi-view video
Authors: Kuan Yuan-Kai , Li Gwo-Long , Chen Mei-Juan , Tai Kuang-Han , Huang Pin-Cheng
Published: August 2014

This paper proposes an error concealment algorithm for whole frame loss for multi-view video decoding. In our proposal, the relationship between motion vectors and disparity vectors is exploited first. Based on the parallelogram-like motion relationship, the motion vectors of error frames can be indirectly derived by projecting the disparity vectors from the counterpart view. In addition, to further improve the concealing results, a joint sum of the absolute difference (SAD) minimization approach is also proposed to find the block for the purpose of concealing the current error block by jointly considering motion vectors and disparity vectors. Experimental results show that our proposed algorithm provides better video quality than previous work and reduces error propagation.
Peroxidase activity in scutella of maize in association with anatomical changes during germination and grain storage
Authors: Corona-Carrillo José Isaac , Flores-Ponce Mitzi , Chávez-Nájera Gerardo , Díaz-Pontones David Manuel
Published: August 2014

The embryo of the maize grain (Zea mays L.) is separated from the starchy endosperm by a fibrous structure, which is called the fibrous layer (FL). Using histochemical staining, it was determined that the FL is composed of collapsed cellular layers that contain phenols, neutral lipids, and 1,3-β-glucan. Due to its composition, the FL prevents free diffusion and separates the embryo from the endosperm during germination. Twenty-four hours after imbibition, the scutellum epidermis initiated a series of asynchronous spatial modifications, including cell growth, the perforation of cell walls, increased peroxidase activity in the apoplastic space, and elevated levels of superoxide, phenols, and other components that interact with the fibrous layer, enabling its transformation in addition to the free flow between compartments. During storage at high relative humidity levels, which leads to fast or slow deterioration depending on the temperature, the activity of phenol peroxidase in the scutellum was associated with a loss of vigor and reduced germination capacity when compared with low temperature and low relative humidity conditions. Such deterioration is associated with alterations in autofluorescent emissions from endogenous compounds in the scutellum, indicating changes in the microenvironment or in the differential proportions of epidermal and FL components.
New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0
Authors: Clark Alex M , Sarker Malabika , Ekins Sean
Published: August 2014

Background

We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible.

Results

We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a näive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets.

Conclusions

TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool.
Physician payment methods: A focus on quality and cost control
Authors: Rudmik Luke , Wranik Dominika , Rudisill-Michaelsen Caroline
Published: August 2014

With rising health care costs, governments must develop innovative methods to deliver efficient and equitable health care services. With physician remuneration being the third largest health care expense, the design of remuneration methods is a priority in health care policy. Otolaryngology-Head and Neck surgeons should have an understanding of the behavioural incentives associated with different physician payment methods. This article will outline the different physician payment methods with a focus on discussing the impact on quality of care and health care costs.
Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells
Authors: Thorn Mitchell , Point Gary R , Burga Rachel A , Nguyen Cang T , Joseph Espat N , Katz Steven C
Published: August 2014

LM escape immune surveillance, in part, as a result of the expansion of CD11b+MC, which alter the intrahepatic microenvironment to promote tumor tolerance. HBC make up a significant proportion of liver lymphocytes and appear to delay tumor progression; however, their significance in the setting of LM is poorly defined. Therefore, we characterized HBC and HBC/CD11b+MC interactions using a murine model of LM. Tumor-bearing livers showed a trend toward elevated absolute numbers of CD19+ HBC. A significant increase in the frequency of IgMloIgDhi mature HBC was observed in mice with LM compared with normal mice. HBC derived from tumor-bearing mice demonstrated increased proliferation in response to TLR and BCR stimulation ex vivo compared with HBC from normal livers. HBC from tumor-bearing livers exhibited significant down-regulation of CD80 and were impaired in inducing CD4+ T cell proliferation ex vivo. We implicated hepatic CD11b+MC as mediators of CD80 down-modulation on HBC ex vivo via a CD11b-dependent mechanism that required cell-to-cell contact and STAT3 activity. Therefore, CD11b+MC may compromise the ability of HBC to promote T cell activation in the setting of LM as a result of diminished expression of CD80. Cross-talk between CD11b+MC and HBC may be an important component of LM-induced immunosuppression.
Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531
Authors: Gamis Alan S. , Alonzo Todd A. , Meshinchi Soheil , Sung Lillian , Gerbing Robert B. , Raimondi Susana C. , Hirsch Betsy A. , Kahwash Samir B. , Heerema-McKenney Amy , Winter Laura , Glick Kathleen , Davies Stella M. , Byron Patti , Smith Franklin O. , Aplenc Richard
Published: August 2014

Purpose

To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.

Patients and Methods

Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).

Results

There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P = .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).

Conclusion

GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.
The tattered curtain hypothesis revised: Coastal jets limit cross‐shelf larval transport
Authors: Harrison Cheryl S. , Siegel David A.
Published: August 2014

Lay Abstract

This biophysical modeling study examined how ocean currents control transport of simulated larvae and the relationship of coastal larval retention to wind forcing. We found that offshore transport was limited when an alongshore coastal jet of water was in place. This jet exhibited complex topology, remaining parallel to the coast for wide sections while simultaneously meandering and “tattering” in other regions. After long periods of strong wind forcing, the jet broke up and larvae moved offshore in complex patterns. However, the integrated strength of the wind only moderately predicted coastal retention of simulated larvae, suggesting that the jet dynamics are intrinsically nonlinear. Coastal jets are expected to exert a strong control on coastal transport in a variety of settings.
Rab35 promotes the recruitment of Rab8, Rab13 and Rab36 to recycling endosomes through MICAL-L1 during neurite outgrowth
Authors: Kobayashi Hotaka , Etoh Kan , Ohbayashi Norihiko , Fukuda Mitsunori
Published: August 2014

Small GTPase Rab35 is an important molecular switch for endocytic recycling that regulates various cellular processes, including cytokinesis, cell migration, and neurite outgrowth. We previously showed that active Rab35 promotes nerve growth factor (NGF)-induced neurite outgrowth of PC12 cells by recruiting MICAL-L1, a multiple Rab-binding protein, to Arf6-positive recycling endosomes. However, the physiological significance of the multiple Rab-binding ability of MICAL-L1 during neurite outgrowth remained completely unknown. Here we report that Rab35 and MICAL-L1 promote the recruitment of Rab8, Rab13, and Rab36 to Arf6-positive recycling endosomes during neurite outgrowth. We found that Rab35 functions as a master Rab that determines the intracellular localization of MICAL-L1, which in turn functions as a scaffold for Rab8, Rab13, and Rab36. We further showed by functional ablation experiments that each of these downstream Rabs regulates neurite outgrowth in a non-redundant manner downstream of Rab35 and MICAL-L1, e.g. by showing that knockdown of Rab36 inhibited recruitment of Rab36-specific effector JIP4 to Arf6-positive recycling endosomes, and caused inhibition of neurite outgrowth without affecting accumulation of Rab8 and Rab13 in the same Arf6-positive area. Our findings suggest the existence of a novel mechanism that recruits multiple Rab proteins at the Arf6-positive compartment by MICAL-L1.
Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors
Authors: Gallina Donika , Zelinka Christopher , Fischer Andy J.
Published: August 2014

Identification of the signaling pathways that influence the reprogramming of Müller glia into neurogenic retinal progenitors is key to harnessing the potential of these cells to regenerate the retina. Glucocorticoid receptor (GCR) signaling is commonly associated with anti-inflammatory responses and GCR agonists are widely used to treat inflammatory diseases of the eye, even though the cellular targets and mechanisms of action in the retina are not well understood. We find that signaling through GCR has a significant impact upon the ability of Müller glia to become proliferating Müller glia-derived progenitor cells (MGPCs). The primary amino acid sequence and pattern of GCR expression in the retina is highly conserved across vertebrate species, including chickens, mice, guinea pigs, dogs and humans. In all of these species we find GCR expressed by the Müller glia. In the chick retina, we find that GCR is expressed by progenitors in the circumferential marginal zone (CMZ) and is upregulated by Müller glia in acutely damaged retinas. Activation of GCR signaling inhibits the formation of MGPCs and antagonizes FGF2/MAPK signaling in the Müller glia. By contrast, we find that inhibition of GCR signaling stimulates the formation of proliferating MGPCs in damaged retinas, and enhances the neuronal differentiation while diminishing glial differentiation. Given the conserved expression pattern of GCR in different vertebrate retinas, we propose that the functions and mechanisms of GCR signaling are highly conserved and are mediated through the Müller glia. We conclude that GCR signaling directly inhibits the formation of MGPCs, at least in part, by interfering with FGF2/MAPK signaling.
Ptch2 mediates the Shh response in Ptch1−/− cells
Authors: Alfaro Astrid C. , Roberts Brock , Kwong Lina , Bijlsma Maarten F. , Roelink Henk
Published: August 2014

The Hedgehog (Hh) signaling response is regulated by the interaction of three key components that include the sonic hedgehog (Shh) ligand, its receptor patched 1 (Ptch1) and the pathway activator smoothened (Smo). Under the prevailing model of Shh pathway activation, the binding of Shh to Ptch1 (the key Shh receptor) results in the release of Ptch1-mediated inhibition of Smo, leading to Smo activation and subsequent cell-autonomous activation of the Shh response. Consistent with this model, Ptch1−/− cells show a strong upregulation of the Shh response. Our finding that this response can be inhibited by the Shh-blocking antibody 5E1 indicates that the Shh response in Ptch1–/– cells remains ligand dependent. Furthermore, we find that Shh induces a strong response in Ptch1–/–;Shh–/– cells, and that Ptch1–/– fibroblasts retain their ability to migrate towards Shh, demonstrating that Ptch1–/– cells remain sensitive to Shh. Expression of a dominant-negative Ptch1 mutant in the developing chick neural tube had no effect on Shh-mediated patterning, but expression of a dominant-negative form of patched 2 (Ptch2) caused an activation of the Shh response. This indicates that, at early developmental stages, Ptch2 functions to suppress Shh signaling. We found that Ptch1–/–;Ptch2–/– cells cannot further activate the Shh response, demonstrating that Ptch2 mediates the response to Shh in the absence of Ptch1.
Ntf3 acts downstream of Sip1 in cortical postmitotic neurons to control progenitor cell fate through feedback signaling
Authors: Parthasarathy Srinivas , Srivatsa Swathi , Nityanandam Anjana , Tarabykin Victor
Published: August 2014

Cortical progenitors undergo progressive fate restriction, thereby sequentially producing the different layers of the neocortex. However, how these progenitors precisely change their fate remains highly debatable. We have previously shown the existence of cortical feedback mechanisms wherein postmitotic neurons signal back to the progenitors and promote a switch from neurogenesis to gliogenesis. We showed that Sip1 (Zeb2), a transcriptional repressor, controls this feedback signaling. A similar mechanism was also suggested to control neuronal cell type specification; however, the underlying mechanism was not identified. Here, we provide direct evidence that in the developing mouse neocortex, Ntf3, a Sip1 target neurotrophin, acts as a feedback signal between postmitotic neurons and progenitors, promoting both apical progenitor (AP) to basal progenitor (BP) and deep layer (DL) to upper layer (UL) cell fate switches. We show that specific overexpression of Ntf3 in neocortical neurons promotes an overproduction of BP at the expense of AP. This shift is followed by a decrease in DL and an increase in UL neuronal production. Loss of Ntf3, by contrast, causes an increase in layer VI neurons but does not rescue the Sip1 mutant phenotype, implying that other parallel pathways also control the timing of progenitor cell fate switch.
Obituary: Walter J. Gehring (1939-2014)
Authors: Schier Alexander F.
Published: August 2014

Alex Schier looks back at the life and research of his graduate mentor and friend Walter Gehring.
A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer
Authors: Burman Jonathon L. , Itsara Leslie S. , Kayser Ernst-Bernhard , Suthammarak Wichit , Wang Adrienne M. , Kaeberlein Matt , Sedensky Margaret M. , Morgan Philip G. , Pallanck Leo J.
Published: August 2014

Mutations affecting mitochondrial complex I, a multi-subunit assembly that couples electron transfer to proton pumping, are the most frequent cause of heritable mitochondrial diseases. However, the mechanisms by which complex I dysfunction results in disease remain unclear. Here, we describe a Drosophila model of complex I deficiency caused by a homoplasmic mutation in the mitochondrial-encoded NADH dehydrogenase subunit 2 (ND2) gene. We show that ND2 mutants exhibit phenotypes that resemble symptoms of mitochondrial disease, including shortened lifespan, progressive neurodegeneration, diminished neural mitochondrial membrane potential, and lower levels of neural ATP. Our biochemical studies of ND2 mutants reveal that complex I is unable to efficiently couple electron transfer to proton pumping. Thus, our study provides evidence that the ND2 subunit participates directly in the proton pumping mechanism of complex I. Together, our findings support the model that diminished respiratory chain activity, and consequent energy deficiency, are responsible for the pathogenesis of complex I-associated neurodegeneration.
Modelling of a targeted nanotherapeutic ‘stroma’ to deliver the cytokine LIF, or XAV939, a potent inhibitor of Wnt–β-catenin signalling, for use in human fetal dopaminergic grafts in Parkinson’s disease
Authors: Zhao Jing-Wei , Dyson Sean C. , Kriegel C. , Tyers Pam , He Xiaoling , Fahmy Tarek M. , Metcalfe Su M. , Barker Roger A.
Published: August 2014

The endogenous reparative capacity of the adult human brain is low, and chronic neurodegenerative disorders of the central nervous system represent one of the greatest areas of unmet clinical need in the developing world. Novel therapeutic strategies to treat them include: (i) growth factor delivery to boost endogenous repair and (ii) replacement cell therapy, including replacing dopaminergic neurons to treat Parkinson's disease (PD). However, these approaches are restricted not only by rapid degradation of growth factors, but also by the limited availability of cells for transplant and the poor survival of implanted cells that lack the necessary stromal support. We therefore hypothesised that provision of a transient artificial stroma for paracrine delivery of pro-survival factors could overcome both of these issues. Using leukaemia inhibitory factor (LIF) - a proneural, reparative cytokine - formulated as target-specific poly(lactic-co-glycolic acid) (PLGA) nano-particles (LIF-nano-stroma), we discovered that attachment of LIF-nano-stroma to freshly isolated fetal dopaminergic cells improved their survival fourfold: furthermore, in vivo, the number of surviving human fetal dopaminergic cells tended to be higher at 3 months after grafting into the striatum of nude rats, compared with controls treated with empty nanoparticles. In addition, we also analysed the effect of a novel nano-stroma incorporating XAV939 (XAV), a potent inhibitor of the developmentally important Wnt-β-catenin signalling pathway, to investigate whether it could also promote the survival and differentiation of human fetal dopaminergic precursors; we found that the numbers of both tyrosine-hydroxylase-positive neurons (a marker of dopaminergic neurons) and total neurons were increased. This is the first demonstration that LIF-nano-stroma and XAV-nano-stroma each have pro-survival effects on human dopaminergic neurons, with potential value for target-specific modulation of neurogenic fate in cell-based therapies for PD
Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming
Authors: Zwaans Bernadette M. M. , Lombard David B.
Published: August 2014

In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.
Isolating the role of elevated Phlda2 in asymmetric late fetal growth restriction in mice
Authors: Tunster Simon J. , Van De Pette Matthew , John Rosalind M.
Published: August 2014

Pleckstrin homology-like domain family A member 2 (PHLDA2) is a maternally expressed imprinted gene whose elevated expression has been linked to fetal growth restriction in a number of human studies. In mice, Phlda2 negatively regulates placental growth and limits the accumulation of placental glycogen. We previously reported that a three-copy transgene spanning the Phlda2 locus drove a fetal growth restriction phenotype late in gestation, suggesting a causative role for PHLDA2 in human growth restriction. However, in this mouse model, Phlda2 was overexpressed by fourfold, alongside overexpression of a second imprinted gene, Slc22a18. Here, we genetically isolate the role of Phlda2 in driving late fetal growth restriction in mice. We furthermore show that this Phlda2-driven growth restriction is asymmetrical, with a relative sparing of the brain, followed by rapid catch-up growth after birth, classic features of placental insufficiency. Strikingly, fetal growth restriction showed strain-specific differences, being apparent on the 129S2/SvHsd (129) genetic background and absent on the C57BL6 (BL6) background. A key difference between these two strains is the placenta. Specifically, BL6 placentae possess a more extensive endocrine compartment and substantially greater stores of placental glycogen. Taken together, these data support a direct role for elevated Phlda2 in limiting fetal growth but also suggest that growth restriction only manifests when there is limited placental reserve. These findings should be taken into account in interpreting the results from human studies.
Comparison of Dictyostelium LvsB and endosomal fission defect mutants support a fusion regulatory role for LvsB
Authors: Falkenstein Kristin , De Lozanne Arturo
Published: August 2014

Defects in human Lyst are associated with the lysosomal disorder Chediak Higashi Syndrome. The absence of Lyst results in the formation of enlarged lysosome related compartments but the mechanism for how these compartments arise is not well established. Two opposing models have been proposed to explain Lyst function. The fission model describes Lyst as a positive regulator of fission from lysosomal compartments, while the fusion model identifies Lyst as a negative regulator of fusion between lysosomal vesicles. Here we used assays that can distinguish between defects in vesicle fusion versus fission. We compared the phenotype of Dictyostelium cells defective in LvsB, the ortholog of Lyst, with that of two known fission defect mutants (μ3 and WASH null mutants). We found that the temporal localization characteristics of the post-lysosomal marker vacuolin, as well as vesicular acidity and fusion dynamics of LvsB null cells are distinct from those of both μ3 and WASH null fission defect mutants. These distinctions are predicted by the fusion defect model and implicate LvsB as a negative regulator of vesicle fusion.
A critical role for beta2 integrins in podosome formation, dynamics and TLR-signaled disassembly in dendritic cells
Authors: Gawden-Bone Christian , West Michele A. , Morrison Vicky L. , Edgar Alexander J. , McMillan Sarah J. , Dill Brian D. , Trost Matthias , Prescott Alan , Fagerholm Susanna C. , Watts Colin
Published: August 2014

The dynamic properties of podosomes, their ability to degrade the underlying matrix and their modulation by TLR-signalling in dendritic cells (DC) suggests they may have an important role in migration. Integrins are thought to participate in podosome formation and dynamics but the multiplicity of integrins in podosomes has made this difficult to assess. We report that murine DC lacking β2 integrins fail to form podosomes. Re-expression of β2 integrins restored podosomes but not when either the membrane proximal or distal NPxF motifs or when an intervening triplet of threonine residues were mutated. We show that β2 integrins are remarkably long-lived in podosome clusters forming a persistent framework that hosted multiple actin core formation events at the same or adjacent sites. When β2 integrin residues 745 or 756 were mutated from serine to alanine, podosomes became resistant to TLR-signaled dissolution. TLR signalling did not detectably modulate phosphorylation at these sites but mutation of either residue to phospho-mimetic aspartic acid increased β2 integrin turnover in podosomes, indicating that phosphorylation at one or both sites may establish permissive conditions for TLR-signaled podosome disassembly.
Differential binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation
Authors: Huet-Calderwood Clotilde , Brahme Nina N. , Kumar Nikit , Stiegler Amy L. , Raghavan Srikala , Boggon Titus J. , Calderwood David A.
Published: August 2014

Kindlins are essential FERM domain-containing focal adhesion (FA) proteins required for proper integrin activation and signaling. Despite the widely accepted importance of each of the three mammalian kindlins in cell adhesion, the molecular basis for their function has yet to be fully elucidated, and the functional differences between isoforms have generally not been examined. Here we report functional differences between kindlin-2 and -3; GFP-tagged kindlin-2 localizes to FA while kindlin-3 does not, and kindlin-2, but not kindlin-3, can rescue α5β1 integrin activation defects in kindlin-2-knockdown fibroblasts. Using chimeric kindlins, we show that the relatively uncharacterized kindlin-2 F2 subdomain drives FA targeting and integrin activation. We find that the integrin-linked kinase (ILK)-PINCH-parvin complex binds strongly to the kindlin-2 F2 subdomain, but poorly to that of kindlin-3. Using a point-mutated kindlin-2 we establish that efficient kindlin-2-mediated integrin activation and FA targeting require binding to the ILK complex. Thus, ILK-complex binding is crucial for normal kindlin-2 function and differential ILK binding contributes to kindlin isoform specificity.
The use of MRI in pre-operative evaluation of anterior talofibular ligament in chronic ankle instability
Authors: Kanamoto T. , Shiozaki Y. , Tanaka Y. , Yonetani Y. , Horibe S.
Published: August 2014

Objectives

To evaluate the applicability of MRI for the quantitative assessment of anterior talofibular ligaments (ATFLs) in symptomatic chronic ankle instability (CAI).

Methods

Between 1997 and 2010, 39 patients with symptomatic CAI underwent surgical treatment (22 male, 17 female, mean age 25.4 years (15 to 40)). In all patients, the maximum diameters of the ATFLs were measured on pre-operative T2-weighted MR images in planes parallel to the path of the ATFL. They were classified into three groups based on a previously published method with modifications: ‘normal’, diameter = 1.0 - 3.2 mm; ‘thickened’, diameter > 3.2 mm; ‘thin or absent’, diameter < 1.0 mm. Stress radiography was performed with the maximum manual force in inversion under general anaesthesia immediately prior to surgery. In surgery, ATFLs were macroscopically divided into two categories: ‘thickened’, an obvious thickened ligament and ‘thin or absent’. The imaging results were compared with the macroscopic results that are considered to be of a gold standard.

Results

Agreement was reached when comparison was made between groups, based on MRI and macroscopic findings. ATFLs were abnormal in all 39 cases and classified as ten ‘thickened’ and 29 ‘thin or absent’. As to talar tilt stress radiography, a clear cut-off angle, which would allow discrimination between ‘thickened’ and ‘thin or absent’ patients, was not identified.

Conclusion

MRI is valuable as a pre-operative assessment tool that can provide the quantitative information of ATFLs in patients with CAI. Cite this article Bone Joint Res 2014;3:241–5.
Parents’ involvement and university students’ independence
Authors: Lewis Jane , West Anne , Roberts Jonathan , Noden Philip
Published: August 2014

Living away from home at university has long been seen as a first step on the road to fully independent living, but considerable concern has been expressed by some commentators that involved parenting – sometimes termed ‘helicopter parenting’ – threatens the transition to independence. We approached students and parents at two pre-1992 universities and interviewed 29 parent-student dyads. The paper focuses on non-financial support and the analysis takes the parents’ standpoint. Four categories of parental involvement are identified and described. The article finds no evidence to suggest that involved parenting routinely becomes ‘helicopter parenting’. Most parents wanted to balance support on the one hand, and the encouragement of their children to become more independent on the other, but a majority expressed anxieties about doing so. Students were more optimistic than their parents about becoming independent.
Gender differences and age-related changes in body fat mass in Tibetan children and teenagers: an analysis by the bioelectrical impedance method
Authors: Zhang Hai-Long , Fu Qiang , Li Wen-Hui , Liu Su-Wei , Zhong Hua , Duoji Bai-Ma , Zhang Mei-Zhi , Lv Po , Xi Huan-Jiu
Published: August 2014

We aimed to obtain the fat base value and the fat distribution characteristics of Tibetan children and teenagers by estimating their body fat content with the bioelectrical impedance method.

We recruited 1427 healthy children and teenagers by a stratified cluster sampling method. By using bioelectrical impedance analysis, we obtained various values relevant to fat.

We found that total body fat mass and the fat mass of various body parts increased with age in boys and girls. Yet there were no differences between age groups until 11 years. However, fat mass increased quickly between 11 and 18 years, and significant differences were seen between adolescent boys and girls; all fat indices were higher in girls than in boys (p<0.05).

The characteristics of fat in Tibetan children and teenagers in Tibet is related to age and gender related hormone secretion, which reflects the physiological characteristics in different developmental stages.
Negative control of BAK1 by protein phosphatase 2A during plant innate immunity
Authors: Segonzac Cécile , Macho Alberto P , Sanmartín Maite , Ntoukakis Vardis , Sánchez‐Serrano José Juan , Zipfel Cyril
Published: August 2014

Recognition of pathogen‐associated molecular patterns (PAMPs) by surface‐localized pattern‐recognition receptors (PRRs) activates plant innate immunity, mainly through activation of numerous protein kinases. Appropriate induction of immune responses must be tightly regulated, as many of the kinases involved have an intrinsic high activity and are also regulated by other external and endogenous stimuli. Previous evidences suggest that PAMP‐triggered immunity (PTI) is under constant negative regulation by protein phosphatases but the underlying molecular mechanisms remain unknown. Here, we show that protein Ser/Thr phosphatase type 2A (PP2A) controls the activation of PRR complexes by modulating the phosphostatus of the co‐receptor and positive regulator BAK1. A potential PP2A holoenzyme composed of the subunits A1, C4, and B’η/ζ inhibits immune responses triggered by several PAMPs and anti‐bacterial immunity. PP2A constitutively associates with BAK1 in planta. Impairment in this PP2A‐based regulation leads to increased steady‐state BAK1 phosphorylation, which can poise enhanced immune responses. This work identifies PP2A as an important negative regulator of plant innate immunity that controls BAK1 activation in surface‐localized immune receptor complexes.
UBL5 is essential for pre‐mRNA splicing and sister chromatid cohesion in human cells
Authors: Oka Yasuyoshi , Varmark Hanne , Vitting‐Seerup Kristoffer , Beli Petra , Waage Johannes , Hakobyan Anna , Mistrik Martin , Choudhary Chunaram , Rohde Mikkel , Bekker‐Jensen Simon , Mailand Niels
Published: August 2014

UBL5 is an atypical ubiquitin‐like protein, whose function in metazoans remains largely unexplored. We show that UBL5 is required for sister chromatid cohesion maintenance in human cells. UBL5 primarily associates with spliceosomal proteins, and UBL5 depletion decreases pre‐mRNA splicing efficiency, leading to globally enhanced intron retention. Defective sister chromatid cohesion is a general consequence of dysfunctional pre‐mRNA splicing, resulting from the selective downregulation of the cohesion protection factor Sororin. As the UBL5 yeast orthologue, Hub1, also promotes spliceosome functions, our results show that UBL5 plays an evolutionary conserved role in pre‐mRNA splicing, the integrity of which is essential for the fidelity of chromosome segregation.
Murine Langerin+ dermal dendritic cells prime CD8+T cells while Langerhans cells induce cross‐tolerance
Authors: Flacher Vincent , Tripp Christoph H , Mairhofer David G , Steinman Ralph M , Stoitzner Patrizia , Idoyaga Juliana , Romani Nikolaus
Published: August 2014

Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C‐type lectin Langerin/CD207 are cross‐presented to CD8+ T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin+ dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti‐CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)‐coupled anti‐Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin+ dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8+ T‐cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross‐presentation to CD8+ T cells. Langerin/OVA combined with imiquimod could not prime CD8+ T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin+ dDCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8+ T‐cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.