bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal Clinically Important Difference in AIMS Score Based on CGIC and PGIC in Patients With Tardive Dyskinesia Treated With Deutetrabenazine
Authors: Barkay Hadas , Hauser Robert A. , Wilhelm Amanda , Wieman Maria , Gordon Mark Forrest , Savola Juha-Matti
Published: May 2021

Background

Deutetrabenazine is FDA approved for tardive dyskinesia (TD) based on two 12-week, placebo-controlled studies evaluating safety and efficacy in patients with baseline Abnormal Involuntary Movement Scale (AIMS) score ≥6. Deutetrabenazine reduced overall AIMS scores compared with placebo in ARM-TD (–3.0 vs –1.6, P=0.019) and AIM-TD (24 mg/day, –3.2 vs –1.4, P=0.003; 36 mg/day, –3.3 vs –1.4, P=0.001). This analysis assessed Minimal Clinically Important Difference (MCID) in AIMS score in patients with TD treated with deutetrabenazine.

Methods

MCID is the smallest change from baseline in AIMS score that is meaningful for patients. MCID analyses were performed based on Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors described by Hauser et al., where MCID is the difference between patients treated with deutetrabenazine who were minimally improved and patients treated with placebo who were unchanged. Additional MCID definitions were explored: difference between patients who demonstrated treatment improvement versus those who did not (Method 2); difference between patients who demonstrated treatment success versus those who did not (Method 3).

Results

295 patients were analyzed. Based on PGIC, the suggested MCID was –2.8. Results were similar for Method 2 (75% of patients had treatment improvement; MCID = –2.8) and Method 3 (38% of patients had treatment success; MCID = –2.6). Based on CGIC, the suggested MCID was –2.6. Results were similar for Method 2 (76% of patients had treatment improvement; MCID = –2.8) and Method 3 (41% of patients had treatment success; MCID = –3.0). Therefore, the suggested MCID for deutetrabenazine is –3.

Conclusions

The MCID for change in AIMS score based on PGIC and CGIC for deutetrabenazine was –3 regardless of the analytical method. Findings suggest an AIMS score reduction of ~3 is associated with clinically meaningful improvement in TD symptoms.

Funding

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Comparative Bioavailability of Amphetamine Extended-Release Oral Suspension and Extended-Release Mixed Amphetamine Salts
Authors: Pardo Antonio , Bouhajib Mohammed , Rafla Eman , King Thomas R. , Kando Judith C.
Published: May 2021

Purpose

This open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension (treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.

Methods

The crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%–125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.

Results

Thirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80–125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.

Conclusions

The bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.

Funding

Tris Pharma, Inc.
The Effectiveness of De-Escalation Techniques as Compared to Physical Restraint/Seclusion on Inpatient Psychiatric Units: A Quantitative Systematic Review
Authors: Chase Shavar
Published: May 2021

Background

Restraint and seclusion were considered a form of treatment but consistently has led to physical and mental injuries to staff and patients. De-escalation has been viewed as a safer option. Understanding which intervention yields decreased injuries, aggression and violence will guide policy and inform practice.

Objectives

To identify which intervention leads to decreased physical and psychological injury to patients and staff.

Methods

The frequency of physical injuries to patients and staff from aggressive patients; frequency of psychological injuries to patients and staff from violent, aggressive incidents; frequency of violence, agitation and aggression; competence of staff at managing aggression and violence were evaluated.

Results

Fourteen studies were included in this review. There are many forms of de-escalation. Studies where techniques were taught to staff, the intervention was effective in decreasing injury in approximately half the studies. De-escalation techniques taught to patients decreased injury in 100% of the studies included in this review.

Conclusion

Consensus on which intervention works best could not be reached, nor is there overwhelming evidence for a particular type of de-escalation better suited for decreasing aggression and violence. Caution should be exercised when choosing a de-escalation technique for implementation in institutions due to lack of regulating agencies that inform practice and standards. In addition, the literature lacks best practices for de-escalation techniques backed by evidence. Restraint and seclusion should be used as a last resort due to inherent risk associated with the intervention.
Methylphenidate-Induced Chorea Due to Possible Cytochrome P450 Metabolism Heterogeneity - A Rare Case
Authors: Jadapalle Sree Latha Krishna , McCray Edwin , Masoud John Azat , Kortz Michael W.
Published: May 2021

Background

Chorea is defined as a hyperactive movement disorder associated with involuntary, quick, and unpredictable muscle contractions of the limbs, face, and trunk. The unpredictable nature of these movements includes variation in speed, timing, and direction of movement. A wide variety of medications, medical conditions and illicit drugs have been associated with movement disorders. Examples include a multitude of antipsychotic induced movement disorders and dyskinesia related to dopaminergic agents, like levodopa and metoclopramide. Dyskinesias have been associated with psycho-stimulant use, such as methylphenidate. However, most cases reported were associated with large doses or chronic use. Aside from dyskinesia, methylphenidate is known to be associated with tic disorder, tremor, and muscle spasm. However, this case reported is unlike any of the above described and involved the development of chorea after only 2 days of moderate doses of methylphenidate, in a patient on chronic methadone maintenance treatment, with successful arrest of symptoms following discontinuation of the methylphenidate.

Case Presentation

A 47-year-old female was admitted to our hospital after presenting to the emergency department with 1 week of violent flailing movements. The ballistic flailing movements started acutely after 2 days of initiating methylphenidate in addition to her chronic methadone treatment and 2-week period of initiation of paroxetine. Lab work showed normal CBC, CMP, CRP, CK, and TSH. Urine drug screen, CT angiography of the head, and Huntington’s disease testing were all unremarkable, suggesting a decreased likelihood of illicit drugs, traumatic brain injury, or Huntington’s disease etiologies. Confirmation of the diagnosis was made as the chorea symptoms abruptly resolved upon discontinuation of methylphenidate and administration of intravenous Benadryl. The patient has been on methadone alone for 11 months and methylphenidate alone 2 years back with no involuntary movements or any similar presentation that shows the possibility of drug interaction through cytochrome P450 metabolism between Methylphenidate and methadone.

Conclusion

We are presenting a rare case report that adds on to the scarce literature on methylphenidate-induced chorea. It also challenges the consulting psychiatrists to broaden their differential diagnosis for acute onset of choreiform movement disorders. This unique case intrigues the thought process to consider the interaction of methylphenidate in the presence of cytochrome P450 2D6 and 3A4 inhibitors like methadone.
The barriers, benefits and training needs of clinicians delivering psychological therapy via video
Authors: Buckman Joshua E. J. , Saunders Rob , Leibowitz Judy , Minton Rebecca
Published: May 2021

Background:

Due to the COVID-19 pandemic, mental health services have had to offer psychological therapy via video with little time to prepare or mitigate potential problems. Identifying the barriers, benefits and training needs highlighted by clinicians may support the effective delivery of care.

Method:

Changes in the mode therapy sessions were delivered in during 2020 were assessed in two high-volume psychological therapies services. Sixty-six therapists completed a survey about their experiences of delivering therapy via video.

Results:

The lockdown in March 2020 precipitated a dramatic shift from face-to-face to telephone and video-delivered sessions. Most clinicians (89%) found video-based sessions acceptable. Barriers to effective delivery included technological issues, problems with online platforms, and feeling more tired after sessions. Benefits included generalised learning from behavioural work, improvements in efficiency and in the therapeutic relationship, particularly in comparison with telephone-based sessions. Tutorials and support guides were recommended to maximise use of sessions via video.

Conclusions:

Video-delivered therapy was liked by clinicians and preferred to telephone-based sessions. Issues with platforms, internet connections and access for patients need addressing, local troubleshooting guides, video-based tutorials and greater support for low-intensity therapists to maximise uptake of video sessions where appropriate, may be beneficial.
Skewness in the literature on infectious livestock diseases in an emerging economy – the case of Vietnam
Authors: Rajala Elisabeth , Lee Hu Suk , Nam Nguyen Hoai , Huong Chu Thị Thanh , Son Hoang Minh , Wieland Barbara , Magnusson Ulf
Published: May 2021

Livestock production has increased in many emerging economies, but productivity is often substantially impaired by infectious diseases. The first step towards improved livestock health and productivity is to map the presence of livestock diseases. The objective of this review was to summarize studies conducted on such diseases in an emerging economy, Vietnam, and thereby identifying knowledge gaps that may inform the design of surveillance and control programs. Few studies were found to evaluate the distribution of infectious livestock diseases other than avian influenza. Also, many regions with dense livestock populations had received little attention in terms of disease investigation. A large proportion of the studies dealt with zoonoses and food-borne infections which might be due to funding agencies priorities. On the contrary, studies targeting infections that affect livestock and their productivity were few. We think that this limitation in scientific reports on infectious diseases that only affect livestock productivity is a common phenomenon in low and lower middle income countries. More science-based data on such diseases would help policymakers to prioritize which livestock diseases should be subject to animal health programs aimed to support rural livelihoods and economic development.
Dynamics of a Solidifying Icy Satellite Shell
Authors: Buffo J. J. , Meyer C. R. , Parkinson J. R. G.
Published: May 2021

Ocean worlds have been identified as high‐priority astrobiology targets due to the link between life and liquid water. Young surface terrain on many icy bodies indicates that they support active geophysical cycles that may facilitate ocean‐surface transport that could provide observables for upcoming missions. Accurately interpreting spacecraft observations requires constraining the relationship between ice shell characteristics and interior dynamics. On Earth, the composition, physical characteristics, and bioburden of ocean‐derived ices are related to their formation history and parent fluid composition. In such systems, the ice–ocean interface, which exists as a multiphase mushy layer, dictates the overlying ice’s properties and evolution. Inclusion of the physics governing these boundaries is a novel strategy in modeling planetary ices and thus far has been limited to 1D approaches. Here, we present results from 2D simulations of an archetypal ice–ocean world. We track the evolution of temperature, salinity, porosity, and brine velocity within a thickening ice shell enabling us to place improved constraints on ice–ocean world properties, including the composition of planetary ice shells, the thickness and hydraulic connectivity of ice–ocean interfaces, and heterogeneous dynamics/structures in the interfacial mushy layer. We show that stable eutectic horizons are likely a common feature of ice–ocean worlds and that ocean composition plays an important role in governing the structure and dynamics of the interface, including the formation of chemical gradient‐rich regions within the mushy layer. We discuss the geophysical and astrobiological implications of our results and highlight how they can be validated by instrument‐specific measurements.
Lake Outflow and Hillslope Lateral Inflows Dictate Thermal Regimes of Forested Streams Draining Small Lakes
Authors: Leach Jason A. , Neilson Bethany T. , Buahin Caleb A. , Moore R. Dan , Laudon Hjalmar
Published: May 2021

Empirical studies have highlighted the important influence of lakes on stream temperature at landscape scales, even when lakes comprise just a small fraction of the catchment area. However, only a few studies have focused on the hydrologic and thermal processes underpinning these landscape patterns. We collected detailed field measurements at a boreal stream that drains a headwater lake and used these data within a process‐based stream temperature model to, (a) document the downstream extent of lake influences at both seasonal and event‐based timescales, (b) assess the hydrologic and thermal processes that control the observed downstream variability, and (c) compare downstream temperature for streams with and without a headwater lake. Summer and autumn lake outlet temperatures were elevated compared to hillslope lateral inflow temperatures. During periods of low lake outflow, stream temperatures decreased rapidly downstream as local energy fluxes, primarily lateral inflows from the hillslopes and hyporheic exchange, overwhelmed the lake effects. The lake influence on downstream temperature was the greatest during periods of high lake outflow and persisted at least 1.4 km downstream. Since lakes can moderate and delay upstream rainfall runoff response, periods of high lake outflow and high hillslope inflow rates were generally out‐of‐phase. This difference in timing of warm lake outlet and cool hillslope water creates a dynamic thermal environment downstream of the small lake. Such lakes are ubiquitous in northern landscapes, and accounting for the competing influence of lake and hillslope contributions on downstream water temperature is critical for predicting how network‐scale thermal regimes will respond to environmental change.
Two Distinct Modes of Tropical Convection Structure and Associated Climate Variability Over East Asia/Korea in January
Authors: Yeo Sae‐Rim , Kim WonMoo , Kim Baek‐Min
Published: May 2021

Two distinct modes of convection variability over the tropical Indo‐Pacific during January and the associated climate variability over East Asia, especially in Korea, are identified. The first mode (empirical orthogonal functions [EOF1]) exhibits a zonal dipole structure of suppressed convection over the Maritime Continent and enhanced convection over the tropical central Pacific, which represents a typical El Niño response. The second mode (EOF2) is a tripole pattern showing suppressed convection over the eastern Indian Ocean and east of the dateline, and enhanced convection over the tropical western Pacific. The temporal variation of EOF2 exhibits a distinctive positive trend and stronger amplitude after the early 2000s. During the positive phase of EOF2, the sea surface temperature (SST) anomaly pattern displays central Pacific (CP) El Niño, and the associated atmospheric circulation pattern is characterized by a high‐pressure anomaly that directly affects Korea and induces warm and dry conditions. Of the winter months, these distinctive features of EOF2 are particularly evident in January. This study attempts to identify a possible mechanism for the relatively unfamiliar convection structure of EOF2. Enhanced Madden‐Julian Oscillation (MJO) activity over the tropical western Pacific, namely, phases 5, 6, and 7, plays a crucial role in driving the positive phase of the EOF2 convection structure. The recent CP type El Niño, which does not accompany the cold SST anomaly and suppressed convection over the Maritime Continent, may provide favorable conditions for the frequent occurrence of MJO phases 5, 6, and 7.
Serotonin transporter availability increases in patients recovering from a depressive episode
Authors: Svensson Jonas E. , Svanborg Cecilia , Plavén-Sigray Pontus , Kaldo Viktor , Halldin Christer , Schain Martin , Lundberg Johan
Published: May 2021

Molecular imaging studies have shown low cerebral concentration of serotonin transporter in patients suffering from depression, compared to healthy control subjects. Whether or not this difference also is present before disease onset and after remission (i.e. a trait), or only at the time of the depressive episode (i.e. a state) remains to be explored. We examined 17 patients with major depressive disorder with positron emission tomography using [11C]MADAM, a radioligand that binds to the serotonin transporter, before and after treatment with internet-based cognitive behavioral therapy. In all, 17 matched healthy control subjects were examined once. Cerebellum was used as reference to calculate the binding potential. Differences before and after treatment, as well as between patients and controls, were assessed in a composite cerebral region and in the median raphe nuclei. All image analyses and confirmatory statistical tests were preregistered. Depression severity decreased following treatment (p < 0.001). [11C]MADAM binding in patients increased in the composite region after treatment (p = 0.01), while no change was observed in the median raphe (p = 0.51). No significant difference between patients at baseline and healthy controls were observed in the composite region (p = 0.97) or the median raphe (p = 0.95). Our main finding was that patients suffering from a depressive episode show an overall increase in cerebral serotonin transporter availability as symptoms are alleviated. Our results suggest that previously reported cross-sectional molecular imaging findings of the serotonin transporter in depression most likely reflect the depressive state, rather than a permanent trait. The finding adds new information on the pathophysiology of major depressive disorder.
Distinct immune signatures in chronic lymphocytic leukemia and Richter syndrome
Authors: Wang Yucai , Sinha Sutapa , Wellik Linda E. , Secreto Charla R. , Rech Karen L. , Call Timothy G. , Parikh Sameer A. , Kenderian Saad S. , Muchtar Eli , Hayman Suzanne R. , Koehler Amber B. , Van Dyke Daniel L. , Leis Jose F. , Slager Susan L. , Dong Haidong , Kay Neil E. , He Rong , Ding Wei
Published: May 2021

Richter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such asTP53andNOTCH1mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%,P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%,P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%,P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%,P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th–75th], 0.107 [0.070–0.209] vs. 0.233 [0.111–0.406],P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS.
3D mechanical characterization of single cells and small organisms using acoustic manipulation and force microscopy
Authors: Läubli Nino F. , Burri Jan T. , Marquard Julian , Vogler Hannes , Mosca Gabriella , Vertti-Quintero Nadia , Shamsudhin Naveen , deMello Andrew , Grossniklaus Ueli , Ahmed Daniel , Nelson Bradley J.
Published: May 2021

Quantitative micromechanical characterization of single cells and multicellular tissues or organisms is of fundamental importance to the study of cellular growth, morphogenesis, and cell-cell interactions. However, due to limited manipulation capabilities at the microscale, systems used for mechanical characterizations struggle to provide complete three-dimensional coverage of individual specimens. Here, we combine an acoustically driven manipulation device with a micro-force sensor to freely rotate biological samples and quantify mechanical properties at multiple regions of interest within a specimen. The versatility of this tool is demonstrated through the analysis of single Lilium longiflorum pollen grains, in combination with numerical simulations, and individual Caenorhabditis elegans nematodes. It reveals local variations in apparent stiffness for single specimens, providing previously inaccessible information and datasets on mechanical properties that serve as the basis for biophysical modelling and allow deeper insights into the biomechanics of these living systems.
Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration of laboratory and spiny mice
Authors: Harn Hans I-Chen , Wang Sheng-Pei , Lai Yung-Chih , Van Handel Ben , Liang Ya-Chen , Tsai Stephanie , Schiessl Ina Maria , Sarkar Arijita , Xi Haibin , Hughes Michael , Kaemmer Stefan , Tang Ming-Jer , Peti-Peterdi Janos , Pyle April D. , Woolley Thomas E. , Evseenko Denis , Jiang Ting-Xin , Chuong Cheng-Ming
Published: May 2021

Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice (Mus), the regeneration is limited to the center of the wound unlike those observed in African spiny (Acomys) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (μm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine.
Expanding the chemistry of borates with functional [BO2]− anions
Authors: Huang Chunmei , Mutailipu Miriding , Zhang Fangfang , Griffith Kent J. , Hu Cong , Yang Zhihua , Griffin John M. , Poeppelmeier Kenneth R. , Pan Shilie
Published: May 2021

More than 3900 crystalline borates, including borate minerals and synthetic inorganic borates, in addition to a wealth of industrially-important boron-containing glasses, have been discovered and characterized. Of these compounds, 99.9 % contain only the traditional triangular BO3 and tetrahedral BO4 units, which polymerize into superstructural motifs. Herein, a mixed metal K5Ba2(B10O17)2(BO2) with linear BO2 structural units was obtained, pushing the boundaries of structural diversity and providing a direct strategy toward the maximum thresholds of birefringence for optical materials design. 11B solid-state nuclear magnetic resonance (NMR) is a ubiquitous tool in the study of glasses and optical materials; here, density functional theory-based NMR crystallography guided the direct characterization of BO2 structural units. The full anisotropic shift and quadrupolar tensors of linear BO2 were extracted from K5Ba2(B10O17)2(BO2) containing BO2, BO3, and BO4 and serve as guides to the identification of this powerful moiety in future and, potentially, previously-characterized borate minerals, ceramics, and glasses.
Spin-polarized oxygen evolution reaction under magnetic field
Authors: Ren Xiao , Wu Tianze , Sun Yuanmiao , Li Yan , Xian Guoyu , Liu Xianhu , Shen Chengmin , Gracia Jose , Gao Hong-Jun , Yang Haitao , Xu Zhichuan J.
Published: May 2021

The oxygen evolution reaction (OER) is the bottleneck that limits the energy efficiency of water-splitting. The process involves four electrons’ transfer and the generation of triplet state O2 from singlet state species (OH- or H2O). Recently, explicit spin selection was described as a possible way to promote OER in alkaline conditions, but the specific spin-polarized kinetics remains unclear. Here, we report that by using ferromagnetic ordered catalysts as the spin polarizer for spin selection under a constant magnetic field, the OER can be enhanced. However, it does not applicable to non-ferromagnetic catalysts. We found that the spin polarization occurs at the first electron transfer step in OER, where coherent spin exchange happens between the ferromagnetic catalyst and the adsorbed oxygen species with fast kinetics, under the principle of spin angular momentum conservation. In the next three electron transfer steps, as the adsorbed O species adopt fixed spin direction, the OER electrons need to follow the Hund rule and Pauling exclusion principle, thus to carry out spin polarization spontaneously and finally lead to the generation of triplet state O2. Here, we showcase spin-polarized kinetics of oxygen evolution reaction, which gives references in the understanding and design of spin-dependent catalysts.
A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis
Authors: Malinova Tsveta S. , Angulo-Urarte Ana , Nüchel Julian , Tauber Marina , van der Stoel Miesje M. , Janssen Vera , de Haan Annett , Groenen Anouk G. , Tebbens Merel , Graupera Mariona , Plomann Markus , Huveneers Stephan
Published: May 2021

Angiogenic sprouting relies on collective migration and coordinated rearrangements of endothelial leader and follower cells. VE-cadherin-based adherens junctions have emerged as key cell-cell contacts that transmit forces between cells and trigger signals during collective cell migration in angiogenesis. However, the underlying molecular mechanisms that govern these processes and their functional importance for vascular development still remain unknown. We previously showed that the F-BAR protein PACSIN2 is recruited to tensile asymmetric adherens junctions between leader and follower cells. Here we report that PACSIN2 mediates the formation of endothelial sprouts during angiogenesis by coordinating collective migration. We show that PACSIN2 recruits the trafficking regulators EHD4 and MICAL-L1 to the rear end of asymmetric adherens junctions to form a recycling endosome-like tubular structure. The junctional PACSIN2/EHD4/MICAL-L1 complex controls local VE-cadherin trafficking and thereby coordinates polarized endothelial migration and angiogenesis. Our findings reveal a molecular event at force-dependent asymmetric adherens junctions that occurs during the tug-of-war between endothelial leader and follower cells, and allows for junction-based guidance during collective migration in angiogenesis.
Semi-conducting 2D rectangles with tunable length via uniaxial living crystallization-driven self-assembly of homopolymer
Authors: Yang Sanghee , Kang Sung-Yun , Choi Tae-Lim
Published: May 2021

Semi-conducting two-dimensional (2D) nanoobjects, prepared by self-assembly of conjugated polymers, are promising materials for optoelectronic applications. However, no examples of self-assembled semi-conducting 2D nanosheets whose lengths and aspect ratios are controlled at the same time have been reported. Herein, we successfully prepared uniform semi-conducting 2D sheets using a conjugated poly(cyclopentenylene vinylene) homopolymer and its block copolymer by blending and heating. Using these as 2D seeds, living crystallization-driven self-assembly (CDSA) was achieved by adding the homopolymer as a unimer. Interestingly, unlike typical 2D CDSA examples showing radial growth, this homopolymer assembled only in one direction. Owing to this uniaxial growth, the lengths of the 2D nanosheets could be precisely tuned from 1.5 to 8.8 μm with narrow dispersity according to the unimer-to-seed ratio. We also studied the growth kinetics of the living 2D CDSA and confirmed first-order kinetics. Subsequently, we prepared several 2D block comicelles (BCMs), including penta-BCMs in a one-shot method.
Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions
Authors: Tsutsui Ko , Machida Hiroki , Nakagawa Asako , Ahn Kyungmin , Morita Ritsuko , Sekiguchi Kiyotoshi , Miner Jeffrey H. , Fujiwara Hironobu
Published: May 2021

Inter-tissue interaction is fundamental to multicellularity. Although the basement membrane (BM) is located at tissue interfaces, its mode of action in inter-tissue interactions remains poorly understood, mainly because the molecular and structural details of the BM at distinct inter-tissue interfaces remain unclear. By combining quantitative transcriptomics and immunohistochemistry, we systematically identify the cellular origin, molecular identity and tissue distribution of extracellular matrix molecules in mouse hair follicles, and reveal that BM composition and architecture are exquisitely specialized for distinct inter-tissue interactions, including epithelial–fibroblast, epithelial–muscle and epithelial–nerve interactions. The epithelial–fibroblast interface, namely, hair germ–dermal papilla interface, makes asymmetrically organized side-specific heterogeneity in the BM, defined by the newly characterized interface, hook and mesh BMs. One component of these BMs, laminin α5, is required for hair cycle regulation and hair germ–dermal papilla anchoring. Our study highlights the significance of BM heterogeneity in distinct inter-tissue interactions.
Constrained crystals deep convolutional generative adversarial network for the inverse design of crystal structures
Authors: Long Teng , Fortunato Nuno M. , Opahle Ingo , Zhang Yixuan , Samathrakis Ilias , Shen Chen , Gutfleisch Oliver , Zhang Hongbin
Published: May 2021

Autonomous materials discovery with desired properties is one of the ultimate goals for materials science, and the current studies have been focusing mostly on high-throughput screening based on density functional theory calculations and forward modeling of physical properties using machine learning. Applying the deep learning techniques, we have developed a generative model, which can predict distinct stable crystal structures by optimizing the formation energy in the latent space. It is demonstrated that the optimization of physical properties can be integrated into the generative model as on-top screening or backward propagator, both with their own advantages. Applying the generative models on the binary Bi-Se system reveals that distinct crystal structures can be obtained covering the whole composition range, and the phases on the convex hull can be reproduced after the generated structures are fully relaxed to the equilibrium. The method can be extended to multicomponent systems for multi-objective optimization, which paves the way to achieve the inverse design of materials with optimal properties.
Cutting through complexity: the Breathing, Thinking, Functioning clinical model is an educational tool that facilitates chronic breathlessness management
Authors: Spathis Anna , Burkin Julie , Moffat Catherine , Tuffnell Rachel , Barclay Stephen , Mant Jonathan , Booth Sara
Published: May 2021

Chronic breathlessness is a distressing symptom that is challenging to manage. The Breathing, Thinking, Functioning clinical model is an educational tool developed to support breathlessness management. Health professionals report that the model increases clinician and patient understanding of this complex symptom, and provides a simple and structured approach to personalised self-management.
Error suppression in adiabatic quantum computing with qubit ensembles
Authors: Mohseni Naeimeh , Narozniak Marek , Pyrkov Alexey N. , Ivannikov Valentin , Dowling Jonathan P. , Byrnes Tim
Published: May 2021

Incorporating protection against quantum errors into adiabatic quantum computing (AQC) is an important task due to the inevitable presence of decoherence. Here, we investigate an error-protected encoding of the AQC Hamiltonian, where qubit ensembles are used in place of qubits. Our Hamiltonian only involves total spin operators of the ensembles, offering a simpler route towards error-corrected quantum computing. Our scheme is particularly suited to neutral atomic gases where it is possible to realize large ensemble sizes and produce ensemble-ensemble entanglement. We identify a critical ensemble size Nc where the nature of the first excited state becomes a single particle perturbation of the ground state, and the gap energy is predictable by mean-field theory. For ensemble sizes larger than Nc, the ground state becomes protected due to the presence of logically equivalent states and the AQC performance improves with N, as long as the decoherence rate is sufficiently low.
New freshwater mussels from two Southeast Asian genera Bineurus and Thaiconcha (Pseudodontini, Gonideinae, Unionidae)
Authors: Konopleva Ekaterina S. , Bolotov Ivan N. , Pfeiffer John M. , Vikhrev Ilya V. , Kondakov Alexander V. , Gofarov Mikhail Yu. , Tomilova Alena A. , Tanmuangpak Kitti , Tumpeesuwan Sakboworn
Published: May 2021

The Mekong and Chao Phraya rivers harbor a species-rich freshwater mussel assemblage containing a large radiation of the Pseudodontini species. Members of the genera Bineurus Simpson 1900 and Thaiconcha Bolotov et al., 2020 primarily inhabit small and medium-sized tributaries of these rivers. Here, we present an integrative taxonomic review of these genus-level clades. We show that Bineurus contains four species: B. mouhotii (Lea, 1863), B. exilis (Morelet, 1866) stat. rev., B. anodontinum (Rochebrune, 1882) stat. rev., and B. loeiensis sp. nov. In its turn, Thaiconcha comprises three species: T. callifera (Martens, 1860), T. munelliptica sp. nov., and T. thaiensis sp. nov. Two species, Pseudodon ovalis Morlet, 1889 and P. thomsoni Morlet, 1884, are considered here as questionable taxa. These findings further highlight that Southeast Asia represents a significant evolutionary hotspot of freshwater mussels, which requires further international collaborative research and conservation efforts.
The cytochrome P450 (CYP) superfamily in cnidarians
Authors: Pankov Kirill V. , McArthur Andrew G. , Gold David A. , Nelson David R. , Goldstone Jared V. , Wilson Joanna Y.
Published: May 2021

The cytochrome P450 (CYP) superfamily is a diverse and important enzyme family, playing a central role in chemical defense and in synthesis and metabolism of major biological signaling molecules. The CYPomes of four cnidarian genomes (Hydra vulgaris, Acropora digitifera, Aurelia aurita, Nematostella vectensis) were annotated; phylogenetic analyses determined the evolutionary relationships amongst the sequences and with existing metazoan CYPs. 155 functional CYPs were identified and 90 fragments. Genes were from 24 new CYP families and several new subfamilies; genes were in 9 of the 12 established metazoan CYP clans. All species had large expansions of clan 2 diversity, with H. vulgaris having reduced diversity for both clan 3 and mitochondrial clan. We identified potential candidates for xenobiotic metabolism and steroidogenesis. That each genome contained multiple, novel CYP families may reflect the large evolutionary distance within the cnidarians, unique physiology in the cnidarian classes, and/or different ecology of the individual species.
Distinctive in-planta acclimation responses to basal growth and acute heat stress were induced in Arabidopsis by cattle manure biochar
Authors: Kumar Abhay , Friedman Haya , Tsechansky Ludmila , Graber Ellen R.
Published: May 2021

In-planta mechanisms of biochar (BC)-mediated improved growth were evaluated by examining oxidative stress, metabolic, and hormonal changes of Arabidopsis wild-type plants under basal or acute heat stress (–HS/ + HS) conditions with or without BC (+ BC/–BC). The oxidative stress was evaluated by using Arabidopsis expressing redox-sensitive green fluorescent protein in the plastids (pla-roGFP2). Fresh biomass and inflorescence height were greater in + BC(‒HS) plants than in the –BC(‒HS) plants, despite similar leaf nutrient levels, photosystem II (PSII) maximal efficiencies and similar oxidative poise. Endogenous levels of jasmonic and abscisic acids were higher in the + BC(‒HS) treatment, suggesting their role in growth improvement. HS in ‒BC plants caused reductions in inflorescence height and PSII maximum quantum yield, as well as significant oxidative stress symptoms manifested by increased lipid peroxidation, greater chloroplast redox poise (oxidized form of roGFP), increased expression of DNAJ heat shock proteins and Zn-finger genes, and reduced expression of glutathione-S-transferase gene in addition to higher abscisic acid and salicylic acid levels. Oxidative stress symptoms were significantly reduced by BC. Results suggest that growth improvements by BC occurring under basal and HS conditions are induced by acclimation mechanisms to ‘microstresses’ associated with basal growth and to oxidative stress of HS, respectively.
Validation of a DKK1 RNAscope chromogenic in situ hybridization assay for gastric and gastroesophageal junction adenocarcinoma tumors
Authors: Caldwell Charles , Rottman James B. , Paces Will , Bueche Elizabeth , Reitsma Sofia , Gibb Joseph , Adisetiyo Vitria , Haas Michael S. , Heath Heidi , Newman Walter , Baum Jason , Gianani Roberto , Kagey Michael H.
Published: May 2021

Dickkopf-1 (DKK1) is a secreted modulator of Wnt signaling that is frequently overexpressed in tumors and associated with poor clinical outcomes. DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and has demonstrated clinical activity in gastric/gastroesophageal junction (G/GEJ) patients with elevated tumoral expression of DKK1. Here we report on the validation of a DKK1 RNAscope chromogenic in situ hybridization assay to assess DKK1 expression in G/GEJ tumor tissue. To reduce pathologist time, potential pathologist variability from manual scoring and support pathologist decision making, a digital image analysis algorithm that identifies tumor cells and quantifies the DKK1 signal was developed. Following CLIA guidelines the DKK1 RNAscope chromogenic in situ hybridization assay and digital image analysis algorithm were successfully validated for sensitivity, specificity, accuracy, and precision. The DKK1 RNAscope assay in conjunction with the digital image analysis solution is acceptable for prospective screening of G/GEJ adenocarcinoma patients. The work described here will further advance the companion diagnostic development of our DKK1 RNAscope assay and could generally be used as a guide for the validation of RNAscope assays with digital image quantification.
Peering inside a cough or sneeze to explain enhanced airborne transmission under dry weather
Authors: Liu Kai , Allahyari Majid , Salinas Jorge S. , Zgheib Nadim , Balachandar S.
Published: May 2021

High-fidelity simulations of coughs and sneezes that serve as virtual experiments are presented, and they offer an unprecedented opportunity to peer into the chaotic evolution of the resulting airborne droplet clouds. While larger droplets quickly fall-out of the cloud, smaller droplets evaporate rapidly. The non-volatiles remain airborne as droplet nuclei for a long time to be transported over long distances. The substantial variation observed between the different realizations has important social distancing implications, since probabilistic outlier-events do occur and may need to be taken into account when assessing the risk of contagion. Contrary to common expectations, we observe dry ambient conditions to increase by more than four times the number of airborne potentially virus-laden nuclei, as a result of reduced droplet fall-out through rapid evaporation. The simulation results are used to validate and calibrate a comprehensive multiphase theory, which is then used to predict the spread of airborne nuclei under a wide variety of ambient conditions.
Influence of survival, promotion, and growth on pattern formation in zebrafish skin
Authors: Konow Christopher , Li Ziyao , Shepherd Samantha , Bullara Domenico , Epstein Irving R.
Published: May 2021

The coloring of zebrafish skin is often used as a model system to study biological pattern formation. However, the small number and lack of movement of chromatophores defies traditional Turing-type pattern generating mechanisms. Recent models invoke discrete short-range competition and long-range promotion between different pigment cells as an alternative to a reaction-diffusion scheme. In this work, we propose a lattice-based “Survival model,” which is inspired by recent experimental findings on the nature of long-range chromatophore interactions. The Survival model produces stationary patterns with diffuse stripes and undergoes a Turing instability. We also examine the effect that domain growth, ubiquitous in biological systems, has on the patterns in both the Survival model and an earlier “Promotion” model. In both cases, domain growth alone is capable of orienting Turing patterns above a threshold wavelength and can reorient the stripes in ablated cells, though the wavelength for which the patterns orient is much larger for the Survival model. While the Survival model is a simplified representation of the multifaceted interactions between pigment cells, it reveals complex organizational behavior and may help to guide future studies.
Impact of histological response after neoadjuvant therapy on podocalyxin as a prognostic marker in pancreatic cancer
Authors: Eurola Annika , Ristimäki Ari , Mustonen Harri , Nurmi Anna-Maria , Hagström Jaana , Haglund Caj , Seppänen Hanna
Published: May 2021

Podocalyxin overexpression associates with poor survival in pancreatic cancer (PDAC). We investigated whether podocalyxin expression correlates with treatment response or survival in neoadjuvant-treated PDAC. Through immunohistochemistry, we evaluated podocalyxin expression in 88 neoadjuvant and 143 upfront surgery patients using two antibodies. We developed a six-tier grading scheme for neoadjuvant responses evaluating the remaining tumor cells in surgical specimens. Strong podocalyxin immunopositivity associated with poor survival in the patients responding poorly to the neoadjuvant treatment (HR 4.16, 95% CI 1.56–11.01, p = 0.004), although neoadjuvant patients exhibited generally low podocalyxin expression (p = 0.017). Strong podocalyxin expression associated with perineural invasion (p = 0.003) and lack of radiation (p = 0.036). Two patients exhibited a complete neoadjuvant response, while a strong neoadjuvant response (≤ 5% of residual tumor cells) significantly associated with lower stage, pT-class and grade, less spread to the regional lymph nodes, less perineural invasion, and podocalyxin negativity (p < 0.05, respectively). A strong response predicted better survival (HR 0.28, 95% CI 0.09–0.94, p = 0.039). In conclusion, strong podocalyxin expression associates with poor survival among poorly responding neoadjuvant patients. A good response associates with podocalyxin negativity. A strong response associates with better outcome.
Single-cell transcriptome profiling of buffelgrass (Cenchrus ciliaris) eggs unveils apomictic parthenogenesis signatures
Authors: Ke Yuji , Podio Maricel , Conner Joann , Ozias-Akins Peggy
Published: May 2021

Apomixis, a type of asexual reproduction in angiosperms, results in progenies that are genetically identical to the mother plant. It is a highly desirable trait in agriculture due to its potential to preserve heterosis of F1 hybrids through subsequent generations. However, no major crops are apomictic. Deciphering mechanisms underlying apomixis becomes one of the alternatives to engineer self-reproducing capability into major crops. Parthenogenesis, a major component of apomixis, commonly described as the ability to initiate embryo formation from the egg cell without fertilization, also can be valuable in plant breeding for doubled haploid production. A deeper understanding of transcriptional differences between parthenogenetic and sexual or non-parthenogenetic eggs can assist with pathway engineering. By conducting laser capture microdissection-based RNA-seq on sexual and parthenogenetic egg cells on the day of anthesis, a de novo transcriptome for the Cenchrus ciliaris egg cells was created, transcriptional profiles that distinguish the parthenogenetic egg from its sexual counterpart were identified, and functional roles for a few transcription factors in promoting natural parthenogenesis were suggested. These transcriptome data expand upon previous gene expression studies and will be a resource for future research on the transcriptome of egg cells in parthenogenetic and sexual genotypes.