bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of matrix metalloprotease and tissue inhibitor of metalloprotease genes in human anterior cruciate ligament
Authors: Foos Marcus J. , Hickox John R. , Mansour Paul G. , Slauterbeck James R. , Hardy Daniel M.
Published: July 2002

Women are more susceptible to anterior cruciate ligament (ACL) injuries than men performing similar athletic activities. Because tissue remodeling may affect ligament strength, we assessed expression of tissue remodeling effector genes in the human ACL. Specifically, we surveyed ACL for RNAs encoding all known matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) by reverse transcription/polymerase chain reaction (RT‐PCR). These experiments revealed that mRNAs encoding nine of sixteen MMPs and all four TIMPs are present in the normal ACL. The nine expressed proteases were MMPs 1—3, 7, 9, 11, 14, and 17 (collagenase 1, gelatinase A, stromelysin 1, matrilysin, gelatinase B, stromelysin 3, and membrane types 1 and 4, respectively), and MMP‐18. Genes for MMPs 8, 10, 12, 13, 15, and 16 appeared not to be expressed in ACL, as their mRNAs were not detected using RT‐PCR conditions that did yield positive signals from other tissues (testis or bone). We conclude that numerous genes encoding tissue remodeling effector proteins are expressed in the human ACL. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
Retroviral manipulation of the expression of bone morphogenetic protein receptor Ia by SVZa progenitor cells leads to changes in their p19INK4d expression but not in their neuronal commitment
Authors: Coskun Volkan , Venkatraman Giri , Yang Hui , Rao Mahendra S. , Luskin Marla B.
Published: July 2002

Bone morphogenetic proteins (BMPs), a group of cytokines in the TGF‐β superfamily, have complex regulatory roles in the control of neural proliferation and cell fate decision. In this study, we analyzed the potential role(s) of BMP signaling on the regulation of the proliferation and differentiation of the unique progenitor cells of the neonatal anterior subventricular zone (SVZa). Unlike other progenitor cells of the brain, SVZa progenitor cells have the capacity to divide even though they express a neuronal phenotype. In order to augment or inhibit endogenous BMP signaling, we injected into the neonatal rat SVZa replication‐deficient retroviruses encoding for either the wild‐type BMP receptor subtype Ia (wt‐BMPR‐Ia) or a mutated dominant‐negative version of BMPR‐Ia (dn‐BMPR‐Ia) in conjunction with a reporter gene, human alkaline phosphatase (AP) and perfused the pups 1, 4 and 7 days post injection. We analyzed whether changing the expression of BMPR‐Ia has an effect on the spatial‐temporal expression pattern of the cyclin dependent kinase inhibitor, p19INK4d, or on the phenotype of SVZa derived cells. The results of our study confirmed and extended our previous findings that in control (non injected) animals, the rostral migratory stream (RMS), traversed by the SVZa‐derived cells en route to the olfactory bulb, exhibits an anteriorhigh‐posteriorlow gradient of p19INK4d expression; p19INK4d expression is essentially absent in the SVZa and highest in the subependymal zone in the middle of the olfactory bulb. However, SVZa progenitor cells encoding the wt‐BMPR‐Ia gene express p19INK4d within the SVZa, suggesting that the BMPs induce SVZa cells to ectopically undergo cell cycle exit within the SVZa. Furthermore, unlike striatal SVZ progenitor cells, which acquire an astrocytic phenotype when exposed to BMPs, SVZa progenitor cells retain their neuronal commitment under augmented BMP signaling.
Dopaminergic dysfunction in alcoholism and schizophrenia – psychopathological and behavioral correlates
Authors: Heinz A.
Published: July 2002

Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of schizophrenia as well as drug and alcohol dependence. Different drugs of abuse stimulate dopamine release in the ventral striatum and thus reinforce drug consumption. Increased subcortical dopamine release has also been associated with the pathogenesis of positive symptoms in schizophrenia and may be driven by a prefrontal dopaminergic dysfunction. These seemingly heterogeneous findings may be explained by recent research in non-human primates. According to these studies, reward anticipation but not anticipated reward consumption is accompanied by a phasic dopamine release in the striatum and prefrontal cortex. In the striatum, phasic dopamine release primarily affects motivation, psychomotor activation and reward craving, while in the prefrontal cortex, dopaminergic stimulation is involved in the activation of working memory and reward anticipation. In alcoholism, previously neutral stimuli that have been associated with alcohol intake can become conditioned cues which activate phasic dopamine release and reward craving. In schizophrenia, stress-induced or chaotic activation of dopamine release may attribute incentive salience to otherwise irrelevant stimuli and thus be involved in the pathogenesis of delusional mood and other positive symptoms. Studies in humans and non-human primates emphasize the role of dopaminergic neurotransmission in reward anticipation and its dysfunction in different neuropsychiatric diseases.
The final triumph of the Pax Americana? Western intervention in Yugoslavia and Russia's debate on the post-Cold War order
Authors: Tsygankov Andrei P.
Published: July 2002

This paper addresses the question of world order by considering how Western military actions in Yugoslavia were perceived from a different cultural perspective. It traces how the NATO-led bombing campaign during March–June of 1999 affected various visions of world order that had existed in Russia before the campaign and describes the discursive change this campaign produced. The argument is made that Russia's foreign policy elites, from Westernizers to Neo-Communists and Expansionists, perceived Western goals in Yugoslavia differently from their counterparts in the West. However, they differed in their recommendations regarding Russia's response and lessons to be drawn from the Kosovo crisis. The paper also identifies several points where the different perspectives can converge. More specifically, all Russian schools of thought viewed the NATO campaign as a dangerous precedent potentially destabilizing the existing world order. They also shared the conviction that Russia should play a larger role in world affairs and that without Russia's involvement there could be no peace and stability in the Balkans and in Europe. They point to the United Nations as the only forum for debating the legitimacy of military interventions and for preventing interventions carried out without the approval of the UN.
Comparison of different methods of functional evaluation in patients with chronic heart failure
Authors: Rostagno Carlo , Galanti Giorgio , Comeglio Marco , Boddi Vieri , Olivo Giuseppe , Serneri Gian Gastone Neri
Published: July 2002

Background:

Stratification of the severity of heart failure has major prognostic and therapeutic implications.

Aims:

To prospectively compare different methods of assessment of functional capacity in patients with chronic heart failure (CHF).

Methods and results:

We studied 143 patients (78 male and 65 female) with CHF aged less than 70 years (mean 57.3 years). Functional assessment was made clinically according to NYHA classification and according to the Goldman Activity Scale Classification (GASC). Cardiovascular performance was measured by peak O2 consumption (pVO2) and anaerobic threshold (AT) at cardiopulmonary exercise test and by the distance walked during a 6‐min walk test (6‐MWT). Clinical scales resulted significantly related. Peak VO2 and AT showed a mild relation with distance covered at 6‐MWT (r = 0.56 and r = 0.46, respectively). Concordance between NYHA classification and levels of performance at cardiopulmonary exercise test or at 6‐MWT was less than 50%.

Conclusion:

Our results suggest that none of the usually employed methods give a definitive assessment of functional capacity of cardiovascular system and a high degree of discordance exists among the results of different tests in the same patient. Although NYHA classification maintains its value in clinical evaluation of patients with CHF, the 6‐min walk test is recommended in patients with mild‐to‐moderate CHF (II–III NYHA classes) as a simple and useful screening test to select patients for further diagnostic evaluation.
Health Problems After Childbirth
Authors: Albers Leah L.
Published: July 2002

Of the entire maternity care cycle, the postpartum period occupies the lowest priority in practice, teaching, and research. Despite this, data from research outside the United States show that health problems after birth are very common, may persist over time, and are often under‐recognized by care providers. Women's health would be favorably impacted by updating patterns of postpartum care, and by obtaining baseline population data in midwifery practices on the extent of postnatal morbidity.
Cascading proton transfers are a hallmark of the catalytic mechanism of SAM‐dependent methyltransferases
Authors: Zhao Li Na , Kaldis Philipp
Published: April 2020

The S‐adenosyl methionine (SAM)‐dependent methyltransferases attach a methyl group to the deprotonated methyl lysine using SAM as a donor. An intriguing, yet unanswered, question is how the deprotonation takes place. PRDM9 with well‐defined enzyme activity is a good representative of the methyltransferase family to study the deprotonation and subsequently the methyl transfer. Our study has found that the pKa of Tyr357 is low enough to make it an ideal candidate for proton abstraction from the methyl lysine. The partially deprontonated Tyr357 is able to change its H‐bond pattern thus bridging two proton tunneling states and providing a cascading proton transfer. We have uncovered a new catalytic mechanism for the deprotonation of the methyl lysine in methyltransferases.
Theoretical Model and Outstanding Performance from Constructive Piezoelectric and Triboelectric Mechanism in Electrospun PVDF Fiber Film
Authors: Yousry Yasmin Mohamed , Yao Kui , Mohamed Ayman Mahmoud , Liew Weng Heng , Chen Shuting , Ramakrishna Seeram
Published: April 2020

Flexible materials with high electromechanical coupling performance are highly demanded for wide applications for electromechanical sensors and transducers, including mechanical energy harvesters. Here, outstanding electromechanical performance is obtained in electrospun‐aligned polyvinylidene fluoride (PVDF) fiber film. A theoretical model is developed from systematic theoretical analyses to clarify the underlying constructive piezoelectric‐triboelectric mechanism in the polarized PVDF fiber films that explains the experimental observations well. The electrospinning process induces polarization alignment and thus tunes the electron affinity for PVDF fibers with different polarization terminals, which results in the constructive piezoelectric and triboelectric responses in the obtained PVDF fiber films. Extremely large effective piezoelectric performance properties are achieved in the direct piezoelectric measurements, reaching the maximum effective piezoelectric strain and voltage coefficients of −1065 pm V−1 and −9178 V mm N−1, respectively, at 100 Hz. In the converse piezoelectric measurements without a significant contribution from reversible triboelectric effect, the maximum effective piezoelectric strain and voltage coefficients are −166 pm V−1 and −1499 V mm N−1, respectively. The theoretical analyses and experimental results show the great potential of the electrospun aligned polar PVDF fiber material for various electromechanical device applications, particularly for mechanical energy harvesting.
Tractor guidance improves production efficiency by reducing overlaps and gaps
Authors: Kharel Tulsi P. , Ashworth Amanda J. , Shew Aaron , Popp Michael P. , Owens Phillip R.
Published: April 2020

Tractor guidance (TG) systems presumably improve agricultural production efficiencies by reducing overlaps and gaps during field operations. However, replicated field studies that calculate TG gains are limited but necessary to estimate efficiencies on small farms (82% of U.S. producers). We applied fertilizer with a wheel spreader and herbicides with a boom sprayer on six and four fields, respectively, with and without TG. This study developed novel postprocessing methodology to calculate spatial coverage efficiency from TG systems. Overlap and gap estimation was implemented using the individual pass polygon method (IPPM). We propose a correction factor to adjust biased estimation of overlap area by IPPM. Results from IPPM suggest TG systems reduced overlaps (up to 6% of field area) and gaps (up to 16%) during field operations and improved overall efficiency up to 20%. Consequently, TG systems lead to reduced input use and in‐field operation time, as well as improved equipment efficiency, leading to potential economic and environmental savings for small‐scale producers.
Neuroenhancement in surgeons: benefits, risks and ethical dilemmas
Authors: Patel R , Ashcroft J , Darzi A , Singh H , Leff D R
Published: April 2020

Background

Surgeons traditionally aim to reduce mistakes in healthcare through repeated training and advancement of surgical technology. Recently, performance-enhancing interventions such as neurostimulation are emerging which may offset errors in surgical practice.

Methods

Use of transcranial direct-current stimulation (tDCS), a novel neuroenhancement technique that has been applied to surgeons to improve surgical technical performance, was reviewed. Evidence supporting tDCS improvements in motor and cognitive performance outside of the field of surgery was assessed and correlated with emerging research investigating tDCS in the surgical setting and potential applications to wider aspects of healthcare. Ethical considerations and future implications of using tDCS in surgical training and perioperatively are also discussed.

Results

Outside of surgery, tDCS studies demonstrate improved motor performance with regards to reaction time, task completion, strength and fatigue, while also suggesting enhanced cognitive function through multitasking, vigilance and attention assessments. In surgery, current research has demonstrated improved performance in open knot-tying, laparoscopic and robotic skills while also offsetting subjective temporal demands. However, a number of ethical issues arise from the potential application of tDCS in surgery in the form of safety, coercion, distributive justice and fairness, all of which must be considered prior to implementation.

Conclusion

Neuroenhancement may improve motor and cognitive skills in healthcare professions with impact on patient safety. Implementation will require accurate protocols and regulations to balance benefits with the associated ethical dilemmas, and to direct safe use for clinicians and patients.
Immediate and long-term impact of the COVID-19 pandemic on delivery of surgical services
Authors: Søreide K , Hallet J , Matthews J B , Schnitzbauer A A , Line P D , Lai P B S , Otero J , Callegaro D , Warner S G , Baxter N N , Teh C S C , Ng-Kamstra J , Meara J G , Hagander L , Lorenzon L
Published: April 2020

Background

The ongoing pandemic is having a collateral health effect on delivery of surgical care to millions of patients. Very little is known about pandemic management and effects on other services, including delivery of surgery.

Methods

This was a scoping review of all available literature pertaining to COVID-19 and surgery, using electronic databases, society websites, webinars and preprint repositories.

Results

Several perioperative guidelines have been issued within a short time. Many suggestions are contradictory and based on anecdotal data at best. As regions with the highest volume of operations per capita are being hit, an unprecedented number of operations are being cancelled or deferred. No major stakeholder seems to have considered how a pandemic deprives patients with a surgical condition of resources, with patients disproportionally affected owing to the nature of treatment (use of anaesthesia, operating rooms, protective equipment, physical invasion and need for perioperative care). No recommendations exist regarding how to reopen surgical delivery. The postpandemic evaluation and future planning should involve surgical services as an essential part to maintain appropriate surgical care for the population during an outbreak. Surgical delivery, owing to its cross-cutting nature and synergistic effects on health systems at large, needs to be built into the WHO agenda for national health planning.

Conclusion

Patients are being deprived of surgical access, with uncertain loss of function and risk of adverse prognosis as a collateral effect of the pandemic. Surgical services need a contingency plan for maintaining surgical care in an ongoing or postpandemic phase.
Combined robotic approach and enhanced recovery after surgery pathway for optimization of costs in patients undergoing proctectomy
Authors: Rouanet P , Mermoud A , Jarlier M , Bouazza N , Laine A , Mathieu Daudé H
Published: April 2020

Background

Enhanced recovery after surgery (ERAS) pathways are beneficial in proctocolectomy, but their impact on robotic low rectal proctectomy is not fully investigated. This study assessed the impact of an ERAS pathway on the outcomes and cost of robotic (RTME) versus laparoscopic (LTME) total mesorectal excision.

Methods

A retrospective review was performed of patients with rectal cancer in a single French tertiary centre for three yearly periods: 2011, LTME; 2015, RTME; and 2018, RTME with ERAS. Patient characteristics, operative and postoperative data, and costs were compared among the groups.

Results

A total of 220 consecutive proctectomies were analysed (71 LTME, 58 RTME and 91 RTME with ERAS). A prevalence of lower and locally advanced tumours was observed with RTME. The median duration of surgery increased with the introduction of RTME, but became shorter than that for LTME with greater robotic experience (226, 233 and 180 min for 2011, 2015 and 2018 respectively; P < 0·001). The median duration of hospital stay decreased significantly for RTME with ERAS (11, 10 and 8 days respectively; P = 0·011), as did the overall morbidity rate (39, 38 and 16 per cent; P = 0·002). Pathology results, conversion and defunctioning stoma rates remained stable. RTME alone increased the total cost by €2348 compared with LTME. The introduction of ERAS and improved robotic experience decreased costs by €1960, compared with RTME performed in 2015 without ERAS implementation. In patients with no co-morbidity, costs decreased by €596 for RTME with ERAS versus LTME alone.

Conclusion

ERAS is associated with cost reductions in patients undergoing robotic proctectomy.
Mapping brain–behavior networks using functional and structural connectome fingerprinting in the HCP dataset
Authors: Lin Ying‐Chia , Baete Steven H , Wang Xiuyuan , Boada Fernando E
Published: April 2020

Introduction

Connectome analysis of the human brain's structural and functional architecture provides a unique opportunity to understand the organization of the brain's functional architecture. In previous studies, connectome fingerprinting using brain functional connectivity profiles as an individualized trait was able to predict an individual's neurocognitive performance from the Human Connectome Project (HCP) neurocognitive datasets.

Materials and Methods

In the present study, we extend connectome fingerprinting from functional connectivity (FC) to structural connectivity (SC), identifying multiple relationships between behavioral traits and brain connectivity. Higher‐order neurocognitive tasks were found to have a weaker association with structural connectivity than its functional connectivity counterparts.

Results

Neurocognitive tasks with a higher sensory footprint were, however, found to have a stronger association with structural connectivity than their functional connectivity counterparts. Language behavioral measurements had a particularly stronger correlation, especially between performance on the picture language test (Pic Vocab) and both FC (r = .28, p < .003) and SC (r = 0.27, p < .00077).

Conclusions

At the neural level, we found that the pattern of structural brain connectivity related to high‐level language performance is consistent with the language white matter regions identified in presurgical mapping. We illustrate how this approach can be used to generalize the connectome fingerprinting framework to structural connectivity and how this can help understand the connections between cognitive behavior and the white matter connectome of the brain.
Buparlisib in combination with tamoxifen in pretreated patients with hormone receptor‐positive, HER2‐negative advanced breast cancer molecularly stratified for PIK3CA mutations and loss of PTEN expression
Authors: Welt Anja , Wiesweg Marcel , Theurer Sarah , Abenhardt Wolfgang , Groschek Matthias , Müller Lothar , Schröder Jan , Tewes Mitra , Chiabudini Marco , Potthoff Karin , Bankfalvi Agnes , Marschner Norbert , Schuler Martin , Breitenbücher Frank
Published: April 2020

The PIKTAM study evaluated the efficacy and safety of the PI3K inhibitor buparlisib in combination with tamoxifen in hormone receptor‐positive (HR+), HER2‐negative advanced breast cancer patients after failure of prior endocrine therapy. In this open‐label, single‐arm phase II trial, 25 patients were enrolled in 11 sites in Germany. Patients were stratified according to PIK3CA mutation status (tissue and cfDNA from serum samples) and/or loss of PTEN expression. Patients received buparlisib (100 mg) and tamoxifen (20 mg) once daily on a continuous schedule (28‐day cycle) until progression or unacceptable toxicity.

Primary endpoint was overall 6‐month progression‐free survival (PFS) rate. Key secondary endpoints included the 6‐month PFS rate in subpopulations, PFS, overall survival, overall response rate (ORR), disease control rate (DCR), and safety.

Overall, the 6‐month PFS rate was 33.3% (n/N = 7/21, one‐sided 95% CI 16.8‐100) and median PFS was 6.1 (CI 2.6‐10.6) months. The ORR and DCR were 12.5% and 44%. The PIK3CA‐mutated subgroup consistently showed the highest 6‐month PFS rate (62.5%, n/N = 5/8), median PFS (8.7 months), ORR (40%), and DCR (80%). No new safety signals emerged. Most common adverse events were gastrointestinal disorders (56%), psychiatric/mood disorders (48%), skin rash/hypersensitivity (44%), cardiovascular (40%), and hepatic (32%) events. The trial was prematurely terminated due to the substantially altered risk‐benefit profile of buparlisib. Nevertheless, PIK3CA mutations emerged as a clinically feasible and useful biomarker for combined PI3K inhibition and endocrine therapy in patients with HR+ breast cancer. Further biomarker‐stratified studies with isoform‐specific PI3K inhibitors are warranted. EudraCT No: 2014‐000599‐24.
Exploring the synergy between customer home‐based and hotel‐based water consumption and conservation behaviors: An empirical approach
Authors: Untaru Elena‐Nicoleta , Ispas Ana , Han Heesup
Published: April 2020

This study aimed to investigate the synergy between customers' home‐based and hotel‐based water conservation behaviors. A market segmentation approach based on water conservation behaviors in households and environmental concerns was undertaken to identify the distinct types of individual groups and understand the differences between segments in terms of demographic characteristics, attitudes, moral obligation, and intentions toward water conservation behavior in a hotel guestroom. Our empirical findings showed that individuals who save water at home and are more environmentally concerned have stronger attitudes, moral obligation, and water conservation intentions while staying in a hotel. The cluster analysis indicated that three distinct segments existed that are significantly different in terms of gender and age. The findings suggested that targeting the three segments, which included the environmentally concerned and active, the environmentally concerned but inactive, and the environmentally unconcerned and inactive groups, with different communication strategies may prove to be a more efficient approach for hotel managers.
Insights for increased risk of failed fibrinolytic therapy and stent thrombosis associated with COVID‐19 in ST‐segment elevation myocardial infarction patients
Authors: Lacour Thibaud , Semaan Carl , Genet Thibaud , Ivanes Fabrice
Published: April 2020

Important health resources are dedicated worldwide to the management of COVID‐19. This new disease, due to its large diffusion, may significantly hamper the prognosis of other pathologies, such as ST‐segment elevation myocardial infarction (STEMI) because of (a) a possible direct negative impact and (b) shortage of first response medical resources and increased delays to reperfusion. We report the case of a 68‐year‐old man admitted for anterior STEMI and asymptomatic COVID‐19. Due to extended transportation delays to a cathlab, he received intravenous fibrinolytic therapy, which failed. Reperfusion was achieved with rescue coronary angioplasty, but the patient experienced two episodes of acute stent thrombosis at 2‐ and 36‐hr following admission and despite optimal medical therapy. He finally died because of cardiogenic shock. This raises concerns about a possible increase in platelet aggregability associated with COVID‐19 leading to an increased risk of stent thrombosis, particularly in the context of STEMI. This pleads for the promotion of primary coronary angioplasty as the first‐choice revascularization technique in this population and the use of new generation P2Y12 inhibitors. In addition, the use of GPIIb/IIIa inhibitors may be considered in every STEMI patient with COVID‐19 to prevent the risk of acute stent thrombosis.
Malignant melanoma in submandibular gland—A rare diagnostic dilemma
Authors: Gopala Krishnan Srinish , Shehrazi S Ali Raza , Jayaram Sharan Chakkyath , Hall Rachel Clare
Published: April 2020

Diagnostic surprises such as melanoma occurring within unusual sites such as submandibular salivary glands are possible. The role of a discerning pathologist with the aid of histochemistry and MDTs is crucial in such circumstances.
Comparing nitrogen timing and sidedressing placement strategies on corn growth and yield in Michigan
Authors: Purucker T.S. , Steinke K.
Published: April 2020

Spring and summer weather volatility plus poor N use efficiency emphasize the importance of improving corn (Zea mays L.) N management strategies. Synchronizing N application with crop uptake and flexibility for in‐season sidedressing placement options may reduce N losses. Field studies in Michigan evaluated four N timing strategies: broadcast pre‐emergence (PRE), sidedressing at V4 to V6 (0:100), a 50:50 split between preplanting incorporation and sidedressing at V4 to V6 (50:50), and 40 lb N acre–1 applied 2 inches below and laterally from the seed at planting followed by sidedressing at V4 to V6 (2 × 2). Within the 0:100, 50:50, and 2 × 2 strategies, the two sidedressing placement methods included coulter injection (CInj) and Y‐drop surface application (YD). The PRE N strategy and YD placement were applied with and without a urease inhibitor (UI). During dry soil conditions following application, N timing, sidedressing placement, and their combinations did not affect grain yield. The agronomic efficiency (AE) of applied N increased by 11.2 to 13.5% with 2 × 2 and 0:100 compared with 50:50 and PRE and increased by 7.8% with CInj over YD, suggesting greater application efficiency with delayed N application and CInj placement. Grain yield, net economic return, and AE were not affected by UI. Midseason N applications allow greater flexibility and adjustments to rate and placement but uptake may be restricted with limited soil moisture. The benefits of YD surface placement may be better realized with adequate surface moisture or as late‐season rescue N applications.
Endometrial stromal sarcomas with BCOR‐rearrangement harbor MDM2 amplifications
Authors: Kommoss Felix KF , Chang Kenneth TE , Stichel Damian , Banito Ana , Jones David TW , Heilig Christoph E , Fröhling Stefan , Sahm Felix , Stenzinger Albrecht , Hartmann Wolfgang , Mechtersheimer Gunhild , Sinn Hans‐Peter , Schmidt Dietmar , Kommoss Friedrich , von Deimling Andreas , Koelsche Christian
Published: April 2020

Recently a novel subtype of endometrial stromal sarcoma (ESS) defined by recurrent genomic alterations involving BCOR has been described (HGESS‐BCOR). We identified a case of HGESS‐BCOR with a ZC3H7B‐BCOR gene fusion, which harbored an amplification of the MDM2 locus. This index case prompted us to investigate MDM2 amplification in four additional cases of HGESS‐BCOR. Tumors were analyzed for MDM2 amplification by array‐based profiling of copy number alterations (CNAs) and fluorescence in situ hybridization (FISH), as well as for MDM2 expression by immunohistochemistry (IHC). Additionally, a cohort of other mesenchymal uterine neoplasms, including 17 low‐grade ESS, 6 classical high‐grade ESS with YWHAE‐rearrangement, 16 uterine tumors resembling ovarian sex cord tumors, 7 uterine leiomyomas and 8 uterine leiomyosarcomas, was analyzed for CNAs in MDM2. Copy number profiling identified amplification of the 12q15 region involving the MDM2 locus in all five HGESS‐BCOR. Subsequent validation analyses of three tumors confirmed MDM2 amplification using MDM2 FISH. Accordingly, IHC showed MDM2 overexpression in all analyzed cases. None of the other uterine neoplasms in our series, including tumors that are in the histopathological differential diagnoses of HGESS‐BCOR, showed copy number gains of MDM2. Together, our results indicate that HGESS‐BCOR carries MDM2 amplifications, which has diagnostic implications and could potentially be used for targeted therapies in these clinically aggressive tumors.
Mechanochemical Synthesis of Porous Carbons and Their Applications in Catalysis
Authors: Zhao Li‐Yuan , Dong Xiao‐Ling , Lu An‐Hui
Published: April 2020

Porous carbons have shown considerable potential in catalysis as either as supports or metal‐free catalysts. Various methods based on solution chemistry have been intensively developed for the preparation of porous carbon‐based catalysts with controllable morphology, pore structure, surface chemical property as well as the desired active sites. Nowadays, mechanochemical synthesis, a re‐emerging strategy, has become more and more popular in the synthesis of porous carbons, due to its feasibility and high synthetic efficiency under solvent‐free condition. This Minireview presents recent advances in the mechanochemical synthesis of porous carbons by ball milling, and their applications in catalysis. It starts a brief introduction of the characteristics and work mechanism of ball milling, and then discuss the preparation of porous carbons as metal‐free catalysts and carbon‐supported metal catalysts. Finally, some issues and further opportunities for the mechanochemical synthesis of porous carbon‐based catalysts are proposed and discussed.
Benzoselenadiazole‐Based Conjugated Molecules: Active Switching Layers with Nanofibrous Morphology for Nonvolatile Organic Resistive Memory Devices
Authors: Jadhav Rohit G. , Kumar Amitesh , Kumar Sanjay , Maiti Sayan , Mukherjee Shaibal , Das Apurba K.
Published: April 2020

In this work, two symmetrical donor‐acceptor‐donor (D‐A‐D) type benzoselenadiazole (BSeD)‐based π‐conjugated molecules were synthesized and employed as an active switching layer for non‐volatile data storage applications. BSeD‐based derivatives with different donor units attached through common vinylene linkers showed different electrical and optical properties. 4,7‐Di((E)‐styryl)benzo[c][2,1,3]selenadiazole (DSBSeD) and 4,7‐bis((E)‐4‐methoxystyryl)benzo[c][2,1,3]selenadiazole (DMBSeD) are sandwiched between gallium‐doped ZnO (GZO) and metal aluminum electrodes respectively through solution‐processed spin‐coating method. The solution‐processed nanofibrous switching layer containing the DMBSeD‐based memory device showed reliable memory characteristics in terms of write and erase operations with low SET voltage than the random‐aggregated DSBSeD‐based device. The nanofibrous molecular morphology of switching layer overcomes the interfacial hole transport energy barrier at the interface of the DMBSeD thin‐film and the bottom GZO electrode. The memory device GZO/DMBSeD/Al based on nanofibrous switching layers shows switching characteristics at compliance current of 10 mA with Vset=0.79 V and Vreset=−0.55 V. This work will be beneficial for the rational design of advanced next‐generation organic memory devices by controlling the nanostructured morphology of active organic switching layer for enhanced charge‐transfer phenomenon.
Ms3 dominant genetic male sterility for wheat improvement with molecular breeding
Authors: Guttieri Mary J.
Published: April 2020

Genetic dominant male sterility (DMS) has not been widely used as a breeding tool in wheat (Triticum aestivum L.), although DMS‐facilitated backcross, mass selection, half‐sib selection, and S1 family recurrent selection strategies have been described, and Ms2‐facilitated recurrent selection has been used in China. Our objective was to revisit these strategies using the tools of molecular breeding. Development of a mechanism for seedling identification of sterile progeny was a key component of designing practical DMS‐facilitated molecular breeding systems. The DMS gene Ms3 was previously localized to the centromeric region of chromosome 5A. The centromeric location is an advantage because recombination rates are very low. Once identified, a broadly informative marker would reliably predict the male‐sterile phenotype. A set of 429 hybrids incorporating Ms3 were constructed, both within US hard winter wheats, and between these winter wheats and Asian spring wheats. Association of the male‐sterile phenotype with those polymorphic DNA sequence tags that localized to chromosome 5A was tested using case‐control association analysis. Two highly significant (logarithm of odds [LOD] > 30) single nucleotide polymorphism (SNP)–trait associations were obtained. One SNP was developed into a highly sensitive, reliable marker for the Ms3‐associated male‐sterile phenotype. Previously described breeding strategies using DMS were updated for trait‐targeted marker‐assisted backcrossing and gene pyramiding, S1 recurrent selection, and early‐generation genomic selection. Application of DMS to association mapping, with the particular use case of the multiparent advanced generation intercross population, is also described.
Identification of the immune checkpoint signature of multiple myeloma using mass cytometry‐based single‐cell analysis
Authors: Wang Jinheng , Zheng Yongjiang , Tu Chenggong , Zhang Hui , Vanderkerken Karin , Menu Eline , Liu Jinbao
Published: April 2020

Objectives

New targets or strategies are needed to increase the success of immune checkpoint‐based immunotherapy for multiple myeloma (MM). However, immune checkpoint signals in MM microenvironment have not been fully elucidated. Here, we aimed to have a broad overview of the different immune subsets and their immune checkpoint status, within the MM microenvironment, and to provide novel immunotherapeutic targets to treat MM patients.

Methods

We performed immune checkpoint profiling of bone marrow (BM) samples from MM patients and healthy controls using mass cytometry. With high‐dimensional single‐cell analysis of 30 immune proteins containing 10 pairs of immune checkpoint axes in 0.55 million of BM cells, an immune landscape of MM was mapped.

Results

We identified an abnormality of immune cell composition by demonstrating a significant increase in activated CD4 T, CD8 T, CD8+ natural killer T‐like and NK cells in MM BM. Our data suggest a correlation between MM cells and immune checkpoint phenotypes and expand the view of MM immune signatures. Specifically, several critical immune checkpoints, such as programmed cell death 1 (PD‐1)/PD ligand 2, galectin‐9/T‐cell immunoglobulin mucin‐3, and inducible T‐cell costimulator (ICOS)/ICOS ligand, on both MM and immune effector cells and a number of activated PD‐1+ CD8 T cells lacking CD28 were distinguished in MM patients.

Conclusion

A clear interaction between MM cells and the surrounding immune cells was established, leading to immune checkpoint dysregulation. The analysis of the immune landscape enhances our understanding of the MM immunological milieu and proposes novel targets for improving immune checkpoint blockade‐based MM immunotherapy.
IgG3+ B cells are associated with the development of multiple sclerosis
Authors: Marsh‐Wakefield Felix , Ashhurst Thomas , Trend Stephanie , McGuire Helen M , Juillard Pierre , Zinger Anna , Jones Anderson P , Kermode Allan G , Hawke Simon , Grau Georges E , Hart Prue H , Byrne Scott N
Published: April 2020

Objectives

Disease‐modifying therapies (DMTs) targeting B cells are amongst the most effective for preventing multiple sclerosis (MS) progression. IgG3 antibodies and their uncharacterised B‐cell clones are predicted to play a pathogenic role in MS. Identifying subsets of IgG3+ B cells involved in MS progression could improve diagnosis, could inform timely disease intervention and may lead to new DMTs that target B cells more specifically.

Methods

We designed a 31‐parameter B‐cell‐focused mass cytometry panel to interrogate the role of peripheral blood IgG3+ B cells in MS progression of two different patient cohorts: one to investigate the B‐cell subsets involved in conversion from clinically isolated syndrome (CIS) to MS; and another to compare MS patients with inactive or active stages of disease. Each independent cohort included a group of non‐MS controls.

Results

Nine distinct CD20+IgD−IgG3+ B‐cell subsets were identified. Significant changes in the proportion of CD21+CD24+CD27−CD38− and CD27+CD38hiCD71hi memory B‐cell subsets correlated with changes in serum IgG3 levels and time to conversion from CIS to MS. The same CD38− double‐negative B‐cell subset was significantly elevated in MS patients with active forms of the disease. A third CD21+CD24+CD27+CD38− subset was elevated in patients with active MS, whilst narrowband UVB significantly reduced the proportion of this switched‐memory B‐cell subset.

Conclusion

We have identified previously uncharacterised subsets of IgG3+ B cells and shown them to correlate with autoimmune attacks on the central nervous system (CNS). These results highlight the potential for therapies that specifically target IgG3+ B cells to impact MS progression.
Quantitative determination of colistin A/B and colistin methanesulfonate in biological samples using hydrophilic interaction chromatography tandem mass spectrometry
Authors: Qi Bing , Gijsen Matthias , Van Brantegem Pieter , De Vocht Tom , Deferm Neel , Abza Getahun B. , Nauwelaerts Nina , Wauters Joost , Spriet Isabel , Annaert Pieter
Published: April 2020

Colistin (polymyxin E) is a polycation antibiotic which is increasingly used (administered as colistin methanesulfonate, CMS) as a salvage therapy in critically ill patients with multidrug resistant Gram‐negative infections. Even though colistin has been used for more than 50 years, its metabolic fate is poorly understood. One of the current challenges for studying the pharmacokinetics (PK) is the precise and accurate determination of colistin in in vitro and in vivo studies. In the present study, we developed and validated a series of sensitive and robust liquid chromatography tandem mass spectrometry (LC–MS/MS) methods for analysing biological samples obtained from in vitro and in vivo disposition assays. After a zinc acetate‐mediated precipitation, hydrophilic–lipophilic‐balanced solid phase extraction (HLB‐SPE) was used for the extraction of colistin. The compounds were retained on a hydrophilic interaction liquid chromatography (HILIC) column and were detected by MS/MS. CMS was quantified by determining the produced amount of colistin during acidic hydrolysis. The developed methods are sensitive with lower limits of quantification varying between 0.009 μg/mL and 0.071 μg/mL for colistin A, and 0.002 μg/mL to 0.013 μg/mL for colistin B. The intra‐ and inter‐day precision and accuracy were within ±15%. Calibration curves of colistin were linear (0.063 μg/mL to 8.00 μg/mL) within clinically relevant concentration ranges. Zinc acetate‐mediated precipitation and the use of a HILIC column were found to be essential. The developed methods are sensitive, accurate, precise, highly efficient and allow monitoring colistin and CMS in biological samples without the need for an internal standard.
Dry conifer forest restoration benefits Colorado Front Range avian communities
Authors: Latif Quresh S. , Truex Richard L. , Sparks Robert A. , Pavlacky, David C.
Published: April 2020

Fire suppression has increased stand density and risk of severe, stand‐replacing wildfire in lower elevation dry conifer forests of western North America, threatening ecological function. The U.S. Forest Service’s Collaborative Forest Landscape Restoration Program (CFLRP) aims to mitigate impacts to ecological function, while mandating effectiveness monitoring to verify restoration success. Expected benefits include improved conditions for biodiversity, but relatively few empirical studies evaluate restoration effects on biodiversity. We applied the Integrated Monitoring in Bird Conservation Regions program to survey birds in relation to CFLRP treatments along the Colorado Front Range in 2015–2017. We employed hierarchical models to analyze species occupancy and richness at 1972 points nested within 141 1‐km2grid cells. Our objectives were to investigate (1) species occupancy relationships with treatments at local (point) and landscape (grid) spatial scales, (2) potential mechanisms for treatment relationships considering species and treatment relationships with forest structure and composition (i.e., habitat relationships), and (3) treatment and habitat relationships with species richness. The data supported positive and negative point‐level treatment relationships, suggesting uneven species distributions between treated and untreated points. At the grid scale, however, we only found positive species relationships with percent area treated, and accordingly, grid‐level species richness increased with treatment extent. Potential mechanisms for treatment relationships included treatments generating foraging opportunities for aerial insectivores by opening the canopy, improving conditions for ground‐associated species by increasing herbaceous growth, and limiting opportunities for shrub‐nesting species by reducing shrub cover. Landscape‐scale patterns suggest CFLRP treatments can benefit avian communities by generating habitat for open‐forest species without necessarily eliminating habitat for closed‐forest species. Our results provide evidence for a commonly expected but rarely verified pattern of increased species richness with forest heterogeneity. We suggest restoration treatments will most benefit forest bird diversity by reducing canopy cover, encouraging herbaceous ground cover, limiting ladder fuel species, and encouraging shrub diversity in canopy openings, while maintaining some dense forest stands on the landscape.
Activation of the descending pain modulatory system using cuff pressure algometry: Back translation from man to rat
Authors: Cummins Tatum M. , Kucharczyk Mateusz M. , Graven‐Nielsen Thomas , Bannister Kirsty
Published: April 2020

Background

Diffuse noxious inhibitory controls (DNIC) as measured in rat and conditioned pain modulation (CPM), the supposed psychophysical paradigm of DNIC measured in humans, are unique manifestations of an endogenous descending modulatory pathway that is activated by the application of a noxious conditioning stimulus. The predictive value of the human CPM processing is crucial when deliberating the translational worth of the two phenomena.

Methods

For CPM or DNIC measurement, test and conditioning stimuli were delivered using a computer‐controlled cuff algometry system or manual inflation of neonate blood pressure cuffs, respectively. In humans (n = 20), cuff pain intensity (for pain detection and pain tolerance thresholds) was measured using an electronic visual analogue scale. In isoflurane‐anaesthetized naïve rats, nociception was measured by recording deep dorsal horn wide dynamic range (WDR) neuronal firing rates (n = 7) using in vivo electrophysiology.

Results

A painful cuff‐pressure conditioning stimulus on the leg increased pain detection and pain tolerance thresholds recorded by cuff stimulation on the contralateral leg in humans by 32% ± 3% and 24% ± 2% (mean ± SEM) of baseline responses, respectively (p < .001). This finding was back‐translated by revealing that a comparable cuff‐pressure conditioning stimulus (40 kPa) on the hind paw inhibited the responses of WDR neurons to noxious contralateral cuff test stimulation to 42% ± 9% of the baseline neuronal response (p = .003).

Conclusions

These data substantiate that the noxious cuff pressure paradigm activates the descending pain modulatory system in rodent (DNIC) and man (CPM), respectively. Future back and forward translational studies using cuff pressure algometry may reveal novel mechanisms in varied chronic pain states.

Significance

This study provides novel evidence that a comparable noxious cuff pressure paradigm activates a unique form of endogenous inhibitory control in healthy rat and man. This has important implications for the forward translation of bench and experimental pain research findings to the clinical domain. If translatable mechanisms underlying dysfunctional endogenous inhibitory descending pathway expression (previously evidenced in painful states in rat and man) were revealed using cuff pressure algometry, the identification of new analgesic targets could be expedited.
Evaluation of chiral separation based on bovine serum albumin–conjugated carbon nanotubes as stationary phase in capillary electrochromatography
Authors: Bai Qiufang , Zhang Chenning , Zhao Yanyan , Wang Chao , Maihemuti Mairewaniguli , Sun Chengpeng , Qi Yan , Peng Jinyong , Guo Xingjie , Zhang Zhen , Fang Linlin
Published: April 2020

In this work, we utilized adsorbed BSA and multiwalled carbon nanoparticles (BSA/MWCNTs) as a stationary phase in open tubular (OT) capillary for separation of chiral drugs. (3‐Aminopropyl)triethoxysilane was used to assist fabrication of BSA/MWCNTs‐coated OT column by covalent bonding. Incorporation of MWCNTs nanomaterials into a polymer matrix could increase the phase ratio and take advantage of the easy preparation of an open tubular CEC column. SEM was carried out to characterize the BSA/MWCNTs OT columns. The electrochromatographic performance of the OT columns was evaluated by separation of ketoprofen, ibuprofen, uniconazole, and hesperidin. The effects of MWCNTs concentration, background solution pH and concentration, and applied voltage on separation were investigated. Chiral separations of ketoprofen, ibuprofen, uniconazole, and hesperidin were achieved using the BSA/MWCNTs‐coated OT column with resolutions of 24.20, 12.81, 1.50, and 1.85, respectively. Their optimas were found in the 30 mM phosphate buffers at pH 5.0, 6.5, 7.0, and 6.5, respectively. In addition, the columns demonstrated good repeatability and stability with the run‐to‐run, day‐to‐day, and batch‐to‐batch RSDs of migration times less than 3.5%.