bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term taper and growth reductions following pruning intensity treatments in giant sequoia (Sequoiadendron giganteum)
Authors: York Robert A.
Published: June 2019

A high degree of stem taper limits the potential value of giant sequoia (Sequoiadendron giganteum (Lindl.) J. Buchholz) when grown for timber. I measured the effects of pruning to different height targets (0, 2.0, 3.5, and 5.5 m), resulting in the removal of 25%–85% of crown length, on the growth of 360 S. giganteum trees over 17 years. Height growth and growth of diameter at breast height were both negatively related to pruning intensity to a similar degree. Within the 17 years following pruning, repeated measurements of stem growth at different heights above the ground revealed that radial stem growth reductions were localized on the stems from which branches were removed. The higher up that trees were pruned, the more that stem radial growth was reduced compared with control trees, with the greatest reductions occurring at stem bases. The effects of pruning decreased over time, but there were still significant differences after 17 years. Girard form class was only influenced by the most intense pruning at a stem height of 5.5 m. A benefit of pruning was reduced taper, but this came at the cost of reduced stem growth. Pruning in S. giganteum must be done carefully with respect to its timing, intensity, and interactions with other management treatments on young stands.
User click fraud detection method based on Top-Rank-k frequent pattern mining
Authors: Pan Lijiao , Mu Shibiao , Wang Yingyan
Published: June 2019

A user click fraud detection method based on Top-Rank-k frequent pattern mining algorithm is presented to solve the click fraud problem appearing in current online advertising. Firstly, this method combines the click frequency of event samples, calculates the real evaluation score of click stream, and the click stream density function and evaluation score expression under multi-dimensional variables, and further obtains the time complexity of the next user’s click fraud process. Secondly, according to the Top-Rank-k frequent pattern, the process of click fraud detection algorithm is designed, and the click fraud user is analyzed and obtained. The results show that this method has good efficiency and correctness, and is superior to other similar algorithms.
Dimensional analysis of two-dimensional turbulence
Authors: Campanelli Leonardo
Published: June 2019

We study the scaling properties of two-dimensional turbulence using dimensional analysis. In particular, we consider the energy spectrum both at large and small scales and in the “inertial ranges” for the cases of freely decaying and forced turbulence. We also investigate the properties of an “energy condensate” at large scales in spatially finite systems. Finally, an analysis of a possible inverse cascade in freely decaying turbulence is presented.
Deciphering the Sardic (Ordovician) and Variscan deformations in the Eastern Pyrenees, SW Europe
Authors: Puddu Claudia , Álvaro J. Javier , Carrera Núria , Casas Josep Maria
Published: June 2019

Detailed geological mapping of the La Cerdanya area (Canigó unit, Eastern Pyrenees) provides new data characterizing the different structural styles exhibited by Cambrian–Lower Ordovician (Jujols Group) and Upper Ordovician successions. Their unconformable contact, related to the Sardic Phase, ranges from 0° (paraconformity) to 90° (angular discordance). The Jujols Group rocks topped by the unconformity are affected by Sardic foliation-free open folds. The pre-Sardic succession, the Sardic Unconformity and the lower part of the post-Sardic succession (Rabassa Conglomerate and Cava formations) are cut and offset by several Late Ordovician NNE–SSW-trending synsedimentary extensional faults associated with hydrothermal activity, which dramatically affected the thickness of the lower part of the Upper Ordovician succession. We relate (1) the Mid-Ordovician Sardic uplift and erosion, and (2) a Mid- to Late-Ordovician upward propagating extensional fault system bounding the outline of half-grabens, subsequently infilled by alluvial deposits, to a thermal doming event (about 475–450 Ma) that led to the uplift and stretching of the Ordovician lithosphere. Thermal doming may be caused by mafic magma underplating and responsible for the coeval calc-alkaline magmatic activity broadly developed in the Eastern Pyrenees. We discuss the similarities between the Mid-Ordovician Sardic Unconformity and other Early Paleozoic unconformities described in neighbouring areas. Finally, we suggest a geodynamic scenario in which a regional-scale thermal event was related to the opening of the Rheic Ocean that led to the drift of Avalonia from the SW European margin of Gondwana.
Celebrating 50 years since the publication of
Folding and Fracturing of Rocks
by J. G. Ramsay
Authors: Bond Clare E. , Lebit Hermann D.
Published: June 2019

John G. Ramsay's book
Folding and Fracturing of Rocks
was first published in 1967. It set the research agenda for, and the approaches to, modern structural geology. It is recognized as one of the most influential texts in the subject area and was underpinned by significant research publications by the author; its weight added to by later texts and articles. John was also an enthusiastic teacher of structural geology, and many of his tutees have gone on to forge their own careers in structural geology, inspired to do so by John, his teaching and approaches. This Special Publication serves as a golden 50 year celebration of the book, and also of John's life-long work and career as an innovative scientist, inspiring mentor, excellent teacher, and great field structural geologist.
New View of the Solar Chromosphere
Authors: Carlsson Mats , De Pontieu Bart , Hansteen Viggo H.
Published: June 2019

The solar chromosphere forms a crucial, yet complex and until recently poorly understood, interface between the solar photosphere and the heliosphere. ▪ Advances in high-resolution instrumentation, adaptive optics, image reconstruction techniques, and space-based observatories allow unprecedented high-resolution views of the finely structured and highly dynamic chromosphere. ▪ Dramatic progress in numerical computations allows 3D radiative magnetohydrodynamic forward models to take the place of the previous generation of 1D semiempirical atmosphere models. These new models provide deep insight into complex nonlocal thermodynamic equilibrium chromospheric diagnostics and enable physics-based interpretations of observations. ▪ This combination of modeling and observations has led to new insights into the role of shock waves, transverse magnetic waves, magnetic reconnection and flux emergence in the chromospheric energy balance, the formation of spicules, the impact of ion-neutral interactions, and the connectivity between chromosphere and transition region. ▪ During the next few years, the advent of new instrumentation (integral-field-unit spectropolarimetry) and observatories (ALMA, DKIST), coupled with novel inversion codes and expansion of existing numerical models to deal with ever more complex physical processes (including multifluid approaches), is expected to lead to major new insights into the dominant heating processes in the chromosphere and beyond.
The Organizing Principles of Eukaryotic Ribosome Recruitment
Authors: Pelletier Jerry , Sonenberg Nahum
Published: June 2019

The stage at which ribosomes are recruited to messenger RNAs (mRNAs) is an elaborate and highly regulated phase of protein synthesis. Upon completion of this step, a ribosome is positioned at an appropriate initiation codon and primed to synthesize the encoded polypeptide product. In most circumstances, this step commits the ribosome to translate the mRNA. We summarize the knowledge regarding the initiation factors implicated in this activity as well as review different mechanisms by which this process is conducted.
The Every Day Work of Studying the Law in Everyday Life
Authors: Silbey Susan S.
Published: June 2019

Susan Silbey began her academic training in political science and in the course of her studies became a sociologist of law, the last two decades as a member of the Massachusetts Institute of Technology's anthropology department and management school. The disciplinary transformations ground, in part, her attention to the ways in which the everyday life of scholarship has led her to study the everyday life of the law. In this article, she describes her scholarly life through seven chapters of relatively distinct challenges and themes. Across the arc of her life, she identifies the recurrent influence of both serendipity and theoretical inference acting within the immediate constraints of family and personal capacity. Reading across descriptions of her work on regulatory enforcement, dispute negotiation and mediation, and popular legal culture and consciousness, she points to the necessity of reconciling on-the-ground vicissitudes of doing legal work with the theories and narratives social scientists construct to make sense of institutions and history. She muses on theoretical attempts to align the particular and the general, the micro and macro forces working in legal cultures, and concludes by celebrating the ubiquity of social ordering whose own momentum both seduces and frustrates social scientists.
Ecology and Evolution of the Sudden Oak Death Pathogen Phytophthora ramorum
Authors: Grünwald Niklaus J. , LeBoldus Jared M. , Hamelin Richard C.
Published: June 2019

The sudden oak and sudden larch death pathogen Phytophthora ramorum emerged simultaneously in the United States on oak and in Europe on Rhododendron in the 1990s. This pathogen has had a devastating impact on larch plantations in the United Kingdom as well as mixed conifer and oak forests in the Western United States. Since the discovery of this pathogen, a large body of research has provided novel insights into the emergence, epidemiology, and genetics of this pandemic. Genetic and genomic resources developed for P. ramorum have been instrumental in improving our understanding of the epidemiology, evolution, and ecology of this disease. The recent reemergence of EU1 in the United States and EU2 in Europe and the discovery of P. ramorum in Asia provide renewed impetus for research on the sudden oak death pathogen.
Dams: Effects of Hydrological Infrastructure on Development
Authors: Dillon Andrew , Fishman Ram
Published: June 2019

Hydrological investments, particularly irrigation dams, have multiple potential benefits for economic development. Dams also have financial, environmental, and distributional impacts that can affect their benefits and costs. This article reviews the evidence on the impact of dams on economic development, focusing on the levels and variability of agricultural productivity, and its effect on poverty, health, electricity generation, and flood control. We also review the evidence on irrigation efficiency and collective action of dam maintenance. Throughout the discussion, we highlight the empirical challenges that restrict the body of causally interpretable impact estimates and areas in which the evidence is particularly thin. We conclude with a discussion of emerging issues pertaining to the long-term sustainability of dams’ impacts and suggest directions for future research.
Universal Mechanisms and the Development of the Face Network: What You See Is What You Get
Authors: Arcaro Michael J. , Schade Peter F. , Livingstone Margaret S.
Published: June 2019

Our assignment was to review the development of the face-processing network, an assignment that carries the presupposition that a face-specific developmental program exists. We hope to cast some doubt on this assumption and instead argue that the development of face processing is guided by the same ubiquitous rules that guide the development of cortex in general.
The Retinal Basis of Vertebrate Color Vision
Authors: Baden T. , Osorio D.
Published: June 2019

The jawless fish that were ancestral to all living vertebrates had four spectral cone types that were probably served by chromatic-opponent retinal circuits. Subsequent evolution of photoreceptor spectral sensitivities is documented for many vertebrate lineages, giving insight into the ecological adaptation of color vision. Beyond the photoreceptors, retinal color processing is best understood in mammals, especially the blueON system, which opposes short- against long-wavelength receptor responses. For other vertebrates that often have three or four types of cone pigment, new findings from zebrafish are extending older work on teleost fish and reptiles to reveal rich color circuitry. Here, horizontal cells establish diverse and complex spectral responses even in photoreceptor outputs. Cone-selective connections to bipolar cells then set up color-opponent synaptic layers in the inner retina, which lead to a large variety of color-opponent channels for transmission to the brain via retinal ganglion cells.
Central and peripheral factors mechanistically linked to exercise intolerance in heart failure with reduced ejection fraction
Authors: Craig Jesse C. , Colburn Trenton D. , Caldwell Jacob T. , Hirai Daniel M. , Tabuchi Ayaka , Baumfalk Dryden R. , Behnke Bradley J. , Ade Carl J. , Musch Timothy I. , Poole David C.
Published: June 2019

Exercise intolerance is a primary symptom of heart failure (HF); however, the specific contribution of central and peripheral factors to this intolerance is not well described. The hyperbolic relationship between exercise intensity and time to exhaustion (speed-duration relationship) defines exercise tolerance but is underused in HF. We tested the hypotheses that critical speed (CS) would be reduced in HF, resting central functional measurements would correlate with CS, and the greatest HF-induced peripheral dysfunction would occur in more oxidative muscle. Multiple treadmill-constant speed runs to exhaustion were used to quantify CS and D′ (distance coverable above CS) in healthy control (Con) and HF rats. Central function was determined via left ventricular (LV) Doppler echocardiography [fractional shortening (FS)] and a micromanometer-tipped catheter [LV end-diastolic pressure (LVEDP)]. Peripheral O2 delivery-to-utilization matching was determined via phosphorescence quenching (interstitial Po2, Po2 is) in the soleus and white gastrocnemius during electrically induced twitch contractions (1 Hz, 8V). CS was lower in HF compared with Con (37 ± 1 vs. 44 ± 1 m/min, P < 0.001), but D′ was not different (77 ± 8 vs. 69 ± 13 m, P = 0.6). HF reduced FS (23 ± 2 vs. 47 ± 2%, P < 0.001) and increased LVEDP (15 ± 1 vs. 7 ± 1 mmHg, P < 0.001). CS was related to FS ( r = 0.72, P = 0.045) and LVEDP ( r = −0.75, P = 0.02) only in HF. HF reduced soleus Po2 is at rest and during contractions (both P < 0.01) but had no effect on white gastrocnemius Po2 is ( P > 0.05). We show in HF rats that decrements in central cardiac function relate directly with impaired exercise tolerance (i.e., CS) and that this compromised exercise tolerance is likely due to reduced perfusive and diffusive O2 delivery to oxidative muscles.

NEW & NOTEWORTHY We show that critical speed (CS), which defines the upper boundary of sustainable activity, can be resolved in heart failure (HF) animals and is diminished compared with controls. Central cardiac function is strongly related with CS in the HF animals, but not controls. Skeletal muscle O2 delivery-to-utilization dysfunction is evident in the more oxidative, but not glycolytic, muscles of HF rats and is explained, in part, by reduced nitric oxide bioavailability.
Impact of pulmonary endarterectomy on pulmonary arterial wave propagation and reservoir function
Authors: Su Junjing , Hughes Alun D. , Simonsen Ulf , Nielsen-Kudsk Jens Erik , Parker Kim H. , Howard Luke S. , Mellemkjaer Soren
Published: June 2019

High wave speed and large wave reflection in the pulmonary artery have previously been reported in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the impact of pulmonary endarterectomy (PEA) on pulmonary arterial wave propagation and reservoir function in patients with CTEPH. Right heart catheterization was performed using a combined pressure and Doppler flow sensor-tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in eight patients with CTEPH before and 3 mo after PEA. Wave intensity and reservoir-excess pressure analyses were then performed. Following PEA, mean pulmonary arterial pressure (PAPm; ∼49 vs. ∼32 mmHg), pulmonary vascular resistance (PVR; ∼11.1 vs. ∼5.1 Wood units), and wave speed (∼16.5 vs. ∼8.1 m/s), i.e., local arterial stiffness, markedly decreased. The changes in the intensity of the reflected arterial wave and wave reflection index (pre: ∼28%; post: ∼22%) were small, and patients post-PEA with and without residual pulmonary hypertension (i.e., PAPm ≥ 25 mmHg) had similar wave reflection index (∼20 vs. ∼23%). The reservoir and excess pressure decreased post-PEA, and the changes were associated with improved right ventricular afterload, function, and size. In conclusion, although PVR and arterial stiffness decreased substantially following PEA, large wave reflection persisted, even in patients without residual pulmonary hypertension, indicating lack of improvement in vascular impedance mismatch. This may continue to affect the optimal ventriculoarterial interaction, and further studies are warranted to determine whether this contributes to persistent symptoms in some patients.

NEW & NOTEWORTHY We performed wave intensity analysis in the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension before and 3 mo after pulmonary endarterectomy. Despite substantial reduction in pulmonary arterial pressures, vascular resistance, and arterial stiffness, large pulmonary arterial wave reflection persisted 3 mo postsurgery, even in patients without residual pulmonary hypertension, suggestive of lack of improvement in vascular impedance mismatch.
Children with orthostatic intolerance exhibit elevated markers of inflammation in the dorsal medulla
Authors: Wagoner Ashley L. , Olson John D. , Westwood Brian M. , Fortunato John E. , Diz Debra I. , Shaltout Hossam A.
Published: June 2019

Children with orthostatic intolerance (OI) have exaggerated decreases in heart rate variability (HRV) and suppression of baroreflex sensitivity (BRS) with standing. Accompanying brain transmitter and metabolite profiles are unknown. In this study, we used proton (1H) magnetic resonance spectroscopy (1H-MRS) to quantify markers of neuronal and glial integrity in a pilot study of children with OI compared with asymptomatic controls. Eighteen participants ages 10–18 yr were evaluated for blood pressure, heart rate (HR), and calculated indexes of autonomic function in supine and upright positions and, within an average of 2 wk, underwent1H-MRS scans of dorsal medulla on a clinical 3T magnet while supine. As a result, of the 18 participants, 11 tested positive for OI and 7 did not. OI subjects exhibited higher HR and lower HRV and high-frequency α-index (HFα), an index of parasympathetic vagal tone, during standing compared with non-OI. HRV, sequence all (Seq All), high- and low-frequency (HFα and LFα) estimates of the spontaneous BRS decreased significantly, while BP variabilty increased significantly during standing only in subjects with OI. OI subjects had higher myoinositol (mIns) and total choline (tCho), markers of glial inflammation. Upright HFα and Seq All inversely correlated to supine tCho and mIns, respectively, independent of age and sex. In conclusions, in this pilot study, children with OI exhibit higher mIns and tCho in the dorsal medulla while supine that may reflect the well-established impairment in regulation of the autonomic nervous system upon standing. Neuroinflammation as an underlying cause or consequence of autonomic dysfunction is an intriguing possibility requiring further study.

NEW & NOTEWORTHY (1H) magnetic resonance spectroscopy detected elevated markers of neuroinflammation in the dorsal medulla in children with impaired autonomic responses to head upright tilt. This first report of altered brain metabolites in this population provides a basis for future clinical studies using this methodology to aide in understanding complex autonomic disease states.
Mechanisms of inspiration that modulate cardiovascular control: the other side of breathing
Authors: Convertino Victor A.
Published: June 2019

The objective of this minireview is to describe the physiology and potential clinical benefits derived from inspiration. Recent animal and clinical studies demonstrate that one of the body’s natural mechanisms associated with inspiration is to harness the respiratory pump to enhance circulation to vital organs. There is evidence that large reductions in intrathoracic pressure (>20 cmH2O) caused by some inspiration maneuvers (e.g., Mueller maneuver) or pathophysiology (e.g., heart failure, chronic obstructive lung disease) can result in adverse hemodynamic effects. However, the respiratory pump can improve cardiovascular functions when a “sweet spot” for generation of negative intrathoracic pressure during inspiration can be maintained at or less than 10 cmH2O below normal inspiration. These beneficial physiological effects include greater cardiac filling and output, lower intracranial pressure, cardiac baroreflex resetting, greater cerebral blood flow oscillatory patterns, increased vascular pressure gradients, and promoting sustained feedback between sympathetic nerve activity and arterial pressure. In addition to promoting gas exchange, data obtained from numerous animal and human experiments have provided new insights into “the other side of breathing”: the modulation of circulation by reduced intrathoracic pressure generated during inspiration. The translation of these physiological relationships form the basis for the development and application of technologies designed to optimize the intrathoracic pump for treatment of clinical conditions associated with hypovolemia including cardiac arrest, orthostatic hypotension, hemorrhagic shock, and traumatic brain injury. Harnessing these fundamental mechanisms that control cardiopulmonary physiology provides opportunities to use inspiration as a potential tool to help treat significant and often life-threatening circulatory disorders.
Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma
Authors: Katagi Hiroaki , Louis Nundia , Unruh Dusten , Sasaki Takahiro , He Xingyao , Zhang Ali , Ma Quanhong , Piunti Andrea , Shimazu Yosuke , Lamano Jonathan B. , Carcaboso Angel M. , Tian Xiao , Seluanov Andrei , Gorbunova Vera , Laurie Kathryn L. , Kondo Akihide , Wadhwani Nitin R. , Lulla Rishi , Goldman Stewart , Venneti Sriram , Becher Oren J. , Zou Lihua , Shilatifard Ali , Hashizume Rintaro
Published: June 2019

Purpose:

Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.

Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts.

Results:

GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy.

Conclusions:

Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
Prognostic Implications of PD-L1 Expression in Breast Cancer: Systematic Review and Meta-analysis of Immunohistochemistry and Pooled Analysis of Transcriptomic Data
Authors: Matikas Alexios , Zerdes Ioannis , Lövrot John , Richard François , Sotiriou Christos , Bergh Jonas , Valachis Antonios , Foukakis Theodoros
Published: June 2019

Purpose:

Conflicting data have been reported on the prognostic value of PD-L1 protein and gene expression in breast cancer.

Experimental Design: Medline, Embase, Cochrane Library, and Web of Science Core Collection were searched, and data were extracted independently by two researchers. Outcomes included pooled PD-L1 protein positivity in tumor cells, immune cells, or both, per subtype and per antibody used, and its prognostic value for disease-free and overall survival. A pooled gene expression analysis of 39 publicly available transcriptomic datasets was also performed.

Results:

Of the initial 4,184 entries, 38 retrospective studies fulfilled the predefined inclusion criteria. The overall pooled PD-L1 protein positivity rate was 24% (95% CI, 15%–33%) in tumor cells and 33% (95% CI, 14%– 56%) in immune cells. PD-L1 protein expression in tumor cells was prognostic for shorter overall survival (HR, 1.63; 95% CI, 1.07–2.46; P = 0.02); there was significant heterogeneity (I2 = 80%, Pheterogeneity < 0.001). In addition, higher PD-L1 gene expression predicted better survival in multivariate analysis in the entire population (HR, 0.82; 95% CI, 0.74–0.90; P < 0.001 for OS) and in basal-like tumors (HR, 0.64; 95% CI, 0.52–0.80; P < 0.001 for OS; Pinteraction 0.005).

Conclusions:

The largest to our knowledge meta-analysis on the subject informs on PD-L1 protein positivity rates and its prognostic value in breast cancer. Standardization is needed prior to routine implementation. PD-L1 gene expression is a promising prognostic factor, especially in basal-like breast cancer. Discrepant prognostic information might be related to PD-L1 gene expression in the stroma.
MEN1309/OBT076, a First-In-Class Antibody–Drug Conjugate Targeting CD205 in Solid Tumors
Authors: Merlino Giuseppe , Fiascarelli Alessio , Bigioni Mario , Bressan Alessandro , Carrisi Corrado , Bellarosa Daniela , Salerno Massimiliano , Bugianesi Rossana , Manno Rosanna , Bernadó Morales Cristina , Arribas Joaquin , Bisht Arnima , Kaplan Angelo , Boyd Robert , Do Uyen T. , Swaminathan Sudha , Attanasio Nickolas , Lou San Lin , Dusek Rachel L. , Ackroyd James E. , Pham Phuoc Huy , Awdew Rahel , Aud Dee , Trang Michael , Lynch Carmel M. , Terrett Jonathan , Wilson Keith E. , Rohlff Christian , Manzini Stefano , Pellacani Andrea , Binaschi Monica
Published: June 2019

CD205 is a type I transmembrane glycoprotein and is a member of the C-type lectin receptor family. Analysis by mass spectrometry revealed that CD205 was robustly expressed and highly prevalent in a variety of solid malignancies from different histotypes. IHC confirmed the increased expression of CD205 in pancreatic, bladder, and triple-negative breast cancer (TNBC) compared with that in the corresponding normal tissues. Using immunofluorescence microscopy, rapid internalization of the CD205 antigen was observed. These results supported the development of MEN1309/OBT076, a fully humanized CD205-targeting mAb conjugated to DM4, a potent maytansinoid derivate, via a cleavable N-succinimidyl-4-(2-pyridyldithio) butanoate linker. MEN1309/OBT076 was characterized in vitro for target binding affinity, mechanism of action, and cytotoxic activity against a panel of cancer cell lines. MEN1309/OBT076 displayed selective and potent cytotoxic effects against tumor cells exhibiting strong and low to moderate CD205 expression. In vivo, MEN1309/OBT076 showed potent antitumor activity resulting in durable responses and complete tumor regressions in many TNBC, pancreatic, and bladder cancer cell line–derived and patient-derived xenograft models, independent of antigen expression levels. Finally, the pharmacokinetics and pharmacodynamic profile of MEN1309/OBT076 was characterized in pancreatic tumor–bearing mice, demonstrating that the serum level of antibody–drug conjugate (ADC) achieved through dosing was consistent with the kinetics of its antitumor activity. Overall, our data demonstrate that MEN1309/OBT076 is a novel and selective ADC with potent activity against CD205-positive tumors. These data supported the clinical development of MEN1309/OBT076, and further evaluation of this ADC is currently ongoing in the first-in-human SHUTTLE clinical trial.
Antileukemia Effects of Notch-Mediated Inhibition of Oncogenic PLK1 in B-Cell Acute Lymphoblastic Leukemia
Authors: Kannan Sankaranarayanan , Aitken Marisa J.L. , Herbrich Shelley M. , Golfman Leonard S. , Hall Mandy G. , Mak Duncan H. , Burks Jared K. , Song Guangchun , Konopleva Marina , Mullighan Charles G. , Chandra Joya , Zweidler-McKay Patrick A.
Published: June 2019

In B-cell acute lymphoblastic leukemia (B-ALL), activation of Notch signaling leads to cell-cycle arrest and apoptosis. We aimed to harness knowledge acquired by understanding a mechanism of Notch-induced cell death to elucidate a therapeutically viable target in B-ALL. To this end, we identified that Notch activation suppresses Polo-like kinase 1 (PLK1) in a B-ALL–specific manner. We identified that PLK1 is expressed in all subsets of B-ALL and is highest in Philadelphia-like (Ph-like) ALL, a high-risk subtype of disease. We biochemically delineated a mechanism of Notch-induced PLK1 downregulation that elucidated stark regulation of p53 in this setting. Our findings identified a novel posttranslational cascade initiated by Notch in which CHFR was activated via PARP1-mediated PARylation, resulting in ubiquitination and degradation of PLK1. This led to hypophosphorylation of MDM2Ser260, culminating in p53 stabilization and upregulation of BAX. shRNA knockdown or pharmacologic inhibition of PLK1 using BI2536 or BI6727 (volasertib) in B-ALL cell lines and patient samples led to p53 stabilization and cell death. These effects were seen in primary human B-ALL samples in vitro and in patient-derived xenograft models in vivo. These results highlight PLK1 as a viable therapeutic target in B-ALL. Efficacy of clinically relevant PLK1 inhibitors in B-ALL patient-derived xenograft mouse models suggests that use of these agents may be tailored as an additional therapeutic strategy in future clinical studies.
Impact of Preoperative Left Atrial Dimension on Outcome in Patients in Sinus Rhythm Undergoing Surgical Valve Repair for Severe Mitral Regurgitation due to Mitral Valve Prolapse
Authors: Szymanski Catherine , Bohbot Yohann , Rusinaru Dan , Touati Gilles , Tribouilloy Christophe
Published: June 2019

Background: Left atrial (LA) enlargement has been previously identified as a predictor of mortality in patients with medically managed mitral regurgitation (MR) due to mitral valve prolapse (MVP). No study has specifically assessed the prognostic value of LA size in patients undergoing mitral valve repair (MVRp). Objective: We aimed to investigate the relationship between LA area and mortality in patients in sinus rhythm (SR) undergoing MVRp for MVP. Methods: We included 305 patients in SR who underwent MVRp for MVP. Median follow-up time was 7.9 years. Patients were divided into 3 groups: LA area ≤25 cm2 (reference group), LA 26–30 cm2, and LA >30 cm2. Results: Compared with patients with an LA area ≤25 cm2, those with an LA area >30 cm2 had a lower 10-year survival (98 ± 2 vs. 86 ± 4%; p = 0.037). In multivariate analysis, after adjustment for established outcome predictors including age, symptoms, EuroSCORE, and left ventricular size and function, LA enlargement >30 cm2 was associated with increased mortality (adjusted HR = 2.20, 95% CI 1.03–4.90; p = 0.042), whereas LA enlargement between 26 and 30 cm2 was not (adjusted HR = 1.37, 95% CI 0.56–3.56; p = 0.52). Conclusion: LA enlargement is independently predictive of long-term mortality after MVRp in patients in SR with severe MR due to MVP. Our findings suggest that MVRp should be considered before the LA area exceeds 30 cm2.
Associations between Frailty and Delirium among Older Patients Admitted to an Emergency Department
Authors: Choutko-Joaquim Sandra , Tacchini-Jacquier Nadine , Pralong D’Alessio Géraldine , Verloo Henk
Published: June 2019

Background: Switzerland’s demographic trends show, as elsewhere on the planet, increasing numbers of older and very old adults. This suggests that its healthcare system will suffer serious repercussions, including in the use of care and especially the use of emergency services. Significant numbers of older adults will be at risk of developing multiple chronic conditions including one or more geriatric syndromes, such as frailty and delirium. Few studies to date have documented associations between frailty and delirium. Aim: To explore the relationships between frailty and delirium in older adult patients consulting (n = 114) at an emergency department (ED) in Switzerland. Method: A cross-sectional study was conducted in a peripheral hospital ED in the French-speaking part of Switzerland. Frailty was assessed using the Tilburg Frailty Indicator (TFI). Delirium was assessed using the Confusion Assessment Method (CAM). Participants’ cognitive states were assessed using the 6-item Cognitive Impairment Test (6CIT) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQ-CODE), completed by the participant’s most significant informal caregiver. Results: The mean participant age was 77.6 years (SD = 7.7); the majority of the subjects were women (54%). The participants took an average of 4.7 different medications a day (SD = 3.2, median = 4). More than half (62%) of the participants were frail; 2 and 14% presented signs and symptoms of delirium and subsyndromal delirium, respectively. A weak but significant association between scores for frailty and delirium (p < 0.05) was demonstrated, and clinical observation confirmed this. A 4-h follow-up measurement of delirium in the ED revealed no significant or clinical difference. Conclusion: Although the literature describes strong associations between frailty and delirium in surgical units and community care settings, the present study only demonstrated a weak-to-moderate association between frailty and delirium in our ED.
Adult Atopic Dermatitis in Hospitalized Patients: Comparison between Those with Childhood-Onset and Late-Onset Disease
Authors: Baum Sharon , Porat Sharon  , Lyakhovitsky Anna , Astman Nadav , Barzilai Aviv 
Published: June 2019

Atopic eczema is one of the most prevalent diseases worldwide. It is a common dermatological disorder that affects 17.8 million individuals in the USA, up to 20% of children and up to 3% of adults. Recent data show that the incidence of the disease is still rising, both in children and adults, especially in low-income countries. Atopic dermatitis in adults consists of childhood-onset (COAD) and adult or late-onset types (LOAD). Prior research has described differences in clinical features, laboratory data, and response to treatment between COAD and LOAD. Most studies have been done on an ambulatory population that mostly contains patients with mild to moderate disease. Objective: The aim of the study was to describe the differences between adults hospitalized with COAD and LOAD. Methods: Data were analyzed from a retrospective cohort of 107 adult AD patients who were hospitalized from 2009 to 2017. Analysis of data included epidemiology, clinical and laboratory characteristics, and response to treatment. Results: Of the total sample, 87 (81%) patients were diagnosed with LOAD, and 20 (19%) patients were diagnosed with COAD. The median age was 66 years for all patients, 42 years for COAD patients, and 77 years for LOAD patients. The prevalence of atopy was lower in the LOAD group than in the COAD group (33.8 vs. 68.8% for family history, 35.5 vs. 84.8% for personal history). A higher incidence of head, neck, and flexural involvement was found in COAD patients. LOAD patients had lower immunoglobulin E levels and responded better to phototherapy. Conclusions: Elderly patients with LOAD constitute the majority of adults hospitalized with AD. As in ambulatory AD patients, there are significant differences in medical background, clinical picture, laboratory characteristics, and response to treatment between hospitalized LOAD and COAD patients. There is a need to determine diagnostic criteria and treatment guidelines for these patients.
Mass Cytometry Reveals the Immaturity of Circulating Neutrophils during SIV Infection
Authors: Lemaitre Julien , Cosma Antonio , Desjardins Delphine , Lambotte Olivier , Le Grand Roger
Published: June 2019

The infected host fails to eradicate HIV-1, despite significant control of viral replication by combinational antiretroviral therapy. Here, we assessed the impact of HIV infection on immune-cell compartments in a SIVmac251 nonhuman primate infection model, which allowed the choice of contamination route, time of infection, and treatment follow-up. We performed high-throughput multiparameter single-cell phenotyping by mass cytometry to obtain a global vision of the immune system in blood and bone marrow. Circulating polymorphonuclear neutrophils (PMNs) with impaired phagocytosis had altered surface expression of CD62L and CD11b during early chronic infection. The initiation of combinational antiretroviral treatment during primary infection did not restore PMN function. The maturation state of PMNs was highly altered during late chronic SIV infection, showing a primarily immature phenotype. Our results provide new insights into PMN involvement in the pathogenesis of HIV infection and may play a role in the establishment and maintenance of chronic immune activation.
Persistent Leptin Signaling in the Arcuate Nucleus Impairs Hypothalamic Insulin Signaling and Glucose Homeostasis in Obese Mice
Authors: Balland Eglantine , Chen Weiyi , Tiganis Tony , Cowley Michael A.
Published: June 2019

Background: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. Objectives: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. Methods and Results: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. Conclusions: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis.
Irradiation-Related Lymphopenia for Bone Metastasis from Hepatocellular Carcinoma
Authors: Park Sangjoon , Byun Hwa Kyung , Seong Jinsil
Published: June 2019

Background/Aim: In the era of immunotherapy, treatment-related lymphopenia (TRL) is gaining attention. In this study, TRL was investigated in patients with bone metastasis from hepatocellular carcinoma (HCC) treated with radiotherapy (RT). Methods: Clinical data of 302 patients receiving RT for 511 bone metastases from HCC between 2005 and 2018 were reviewed. Data on absolute lymphocyte count (ALC) from pre-RT to 12 months post-RT were collected. Severe TRL was defined as ALC <500 cells/mm3 and evaluated using ALC 2 months after initiating RT. Factors associated with TRL were analyzed, which include the amount of active bone marrow within the RT field. The amount of active bone marrow included in the RT field was calculated as the product of the percentage of the bone compartment included in the RT field and the active bone marrow percentage of the bone compartment. Results: Overall, 33.4% of patients developed TRL 2 months after initiating RT. The mean ALC decreased after initiating RT and remained persistently low during 12 months of observation. Overall survival (OS) was significantly worse in patients with TRL than in those without (median OS: 3.7 vs. 6.5 months, p < 0.001). In the prognostic factor analysis, TRL was an independent prognostic factor of OS (p = 0.036), along with known prognostic factors of HCC. The percentage of active bone marrow within the RT field was the only significant factor associated with TRL (p < 0.001). Conclusion: TRL was observed in patients receiving RT for bone metastasis from HCC, and it was associated with poor survival. The percentage of active bone marrow within the RT field significantly affected TRL development. The results suggest that a new strategy is required to prevent TRL.
A Formula to Predict the Magnitude of Achilles Tendon Lengthening Required to Correct Equinus Deformity
Authors: Ozyalvac Osman Nuri , Akpinar Evren , Gur Volkan , Beng Kubilay , Yagmurlu Mehmet Firat , Bayhan Avni Ilhan
Published: June 2019

Objectives: Achilles tendon lengthening (ATL) is one of the most commonly performed procedures in paediatric orthopaedic surgery. An appropriate adjustment of the amount of ATL is crucial to avoid insufficient or excessive lengthening. However, there is currently no effective method to preoperatively calculate the tendon length needed for equinus deformity correction. Thus, in this study we evaluated the accuracy of a calculation using a mathematical model based on the law of cosines. Methods: A total of 16 feet of 14 patients who were scheduled for ATL surgery due to equinus deformity were included in the study. ATL surgery was performed using a standard Z-plasty technique. Calculation of the amount of ATL using the law of cosines, and assessments of intraoperative lengthening of the tendon, were performed in a double-blind manner. The extent of lengthening resulting from the two methods was then compared. Results: The mean ATL determined intraoperatively was 23.67 ± 8.7 mm, and that obtained using the cosine-based method was 22.49 ± 8.6 mm. Thus, the new method showed excellent statistical agreement with the actual lengthening performed during surgery. Conclusions: The required dimension of ATL can be calculated preoperatively using the mathematical formula presented here. The advantages of this approach are that it allows accurate tendon lengthening and reduces the size of the surgical incision.
MALUNGOS E PARENTES: "SUMÁRIO CONTRA OS PRETOS DE ANGOLA DO CONTINENTE DE PERNAMBUCO" (1779)
Authors: Rodrigues Aldair
Published: June 2019

Entre inúmeros processos e denúncias da Inquisição portuguesa conservados no Arquivo da Torre do Tombo, há o inédito "Sumário contra os pretos de Angola do continente de Pernambuco", de 1779, aqui transcrito e publicado. O documento é constituído por um conjunto de denúncias ricas em informações sobre as práticas sociais, culturais, identitárias e religiosas da comunidade formada em Pernambuco pelos africanos de nação Angola. Além disso, o Sumário oferece evidências sobre as dinâmicas subjacentes à emergência do vocábulo "Malungo" no léxico do português brasileiro do século XVIII.
CN-DBpedia2: An Extraction and Verification Framework for Enriching Chinese Encyclopedia Knowledge Base
Authors: Xu Bo , Liang Jiaqing , Xie Chenhao , Liang Bin , Chen Lihan , Xiao Yanghua
Published: June 2019

Knowledge base plays an important role in machine understanding and has been widely used in various applications, such as search engine, recommendation system and question answering. However, most knowledge bases are incomplete, which can cause many downstream applications to perform poorly because they cannot find the corresponding facts in the knowledge bases. In this paper, we propose an extraction and verification framework to enrich the knowledge bases. Specifically, based on the existing knowledge base, we first extract new facts from the description texts of entities. But not all newly-formed facts can be added directly to the knowledge base because the errors might be involved by the extraction. Then we propose a novel crowd-sourcing based verification step to verify the candidate facts. Finally, we apply this framework to the existing knowledge base CN-DBpedia and construct a new version of knowledge base CN-DBpedia2, which additionally contains the high confidence facts extracted from the description texts of entities.
Neoapterocis, a new genus of apterous Ciidae (Coleoptera: Tenebrionoidea) from Chile and Mexico
Authors: LOPES-ANDRADE CRISTIANO
Published: June 2019

Neoapterocis gen. nov. is described based on two species: Neoapterocis mexicanus sp. nov. (type species) from the state of Oaxaca (Mexico); and Neoapterocis chilensis sp. nov. from Concepción Province (VIII Biobío Region), Chile. Diagnostic characters of the genus include the distinct oval, highly convex body, small eyes and scutellum, absence of hind wings, short prosternum and metaventrite, and first abdominal ventrite longer than the next two together. Comparisons are made with other apterous and micropterous ciid genera, particularly Apterocis Perkins, Lipopterocis Miyatake, Nipponapterocis Miyatake and Polynesicis Zimmerman. The new genus is placed in the tribe Ciini. A key to males of the species of Neoapterocis gen. nov. is provided, together with descriptions of external morphology of adults, morphology of male genitalia of both species and the female genitalia of Neo. mexicanus sp. nov. Neoapterocis gen. nov. is the first apterous ciid genus to be described from continental lands