bluuebunny/crossref_metadata_2025 huggingface dataset:
The ocean pole tide loading and its effect on GPS position time-series
Authors: Niu Yujiao , Li Min , Wei Na , Shi Chuang , Chen Guo , Wang Lin
Published: June 2021

The changes in the centrifugal force induced by polar motion perturb the ocean, causing an ocean pole tide. The induced displacements due to the ocean pole tide, namely ocean pole tide loading (OPTL), previously ignored, raises the concerns in the GPS data processing with the increasing accuracy of Global Position System (GPS) technique. Though the amplitude of this effect is small, it is worth to demonstrate the magnitude and its impact on GPS solutions of the processing choices for correcting it from observations or onto estimated coordinates. For OPTL modelling, subdaily polar motion can introduce annual variations in OPTL with the small magnitudes in micrometres. The new secular pole model can cause OPTL vertical velocity difference up to 0.03 mm yr−1 compared with the mean pole model of International Earth Rotation and Reference System Service Conventions (2010). The OPTL deformation is dominated by the annual (∼365.25 d) and Chandler (∼433 d) periods, and the largest peak-to-peak variations can reach 0.70, 0.84 and 2.38 mm for East, North and Up components, respectively. We then investigate the effects of OPTL correction on GPS daily positions of 133 stations from 2014 to 2018. The root mean square of OPTL induced GPS daily displacements can reach submillimetre level. In most cases, a posteriori OPTL correction with daily averaged values applied onto the coordinates is acceptable considering the small deviation between the solution removing OPTL from coordinates and the solution correcting OPTL from observations. However, this does not hold when GPS coordinates have been aligned to a secular reference frame, as the annual/Chandler variations of OPTL would be biased. When reference frame alignment is required, either OPTL correction at observation level or a posteriori OPTL correction before reference frame alignment is recommended. Furthermore, we have demonstrated that the effects of OPTL on the annual variations of GPS position time-series can reach as much as 0.4 mm in the verticals. It has limited effect on the linear velocity and reduction of the residuals scatter (annual variations excluded), within Global Geodetic Observing System requirements for the future terrestrial reference frame at millimetre level.
The Curse of the Original: How and When Heritage Branding Reduces Consumer Evaluations of Enhanced Products
Authors: Han Minju , Newman George E , Smith Rosanna K , Dhar Ravi
Published: June 2021

Heritage branding is a common marketing strategy that has been shown to increase product appeal. Here, we find that certain forms of heritage branding can also have potentially negative consequences by leading consumers to react negatively to changes made to the brand’s original, flagship product—even if those changes objectively improve it. We demonstrate that when firms engage in heritage branding that emphasizes a brand’s longevity, consumers evaluate enhanced products less favorably than the original versions of those same products due to decreased perceptions of continuity authenticity. We demonstrate this effect across a variety of product domains (e.g., cosmetics, cookware, and food products), using online experiments as well as in-person product trials. Moreover, we provide a framework that distinguishes between types of heritage branding cues that lead to negative evaluations of enhanced products versus those that do not. Finally, beyond identifying an important boundary condition based on specific aspects of heritage branding, we further show how the negative evaluations of enhanced products can be attenuated if brands reframe product changes as continuous with the brand’s origins. Together, these studies contribute to existing theory regarding heritage branding and authenticity, while also providing a number of practical recommendations for heritage brands.
Biology and Management of Eriophyid Mites in Turfgrass
Authors: Brown Matthew S , Blubaugh Carmen K , Chong Juang Horng
Published: June 2021

Eriophyid mites (Acari: Eriophyidae) are challenging to manage in turfgrass because their small size hinders visual detection, and conventional management approaches are not consistently effective. They induce growth distortions, which lead to poor stolon and root development and eventual plant death. Aceria cynodoniensis Sayed and Aceria slykhuisi Hall live beneath leaf sheaths, and cause crowded and stunted leaves, and bunched shoot proliferation. Aceria zoysiae (Baker, Kono, & O’Neill) and Aceria cynodonis Wilson live on exposed plant surfaces and cause twisted leaf tips to get caught in folded, older leaves, producing an arched terminal leaf. Because eriophyid mites are challenging to see directly, scouting utilizes the above symptoms but not as indicators of mite abundance. Mite-induced injuries can ruin the appearance of turf on golf course fairways with high aesthetic standards. Mite infestation weakens the turf, which slows down recovery from wear on golf courses and athletic fields and leads to production losses on sod farms when the sod breaks during harvest. Available miticides are ineffective to marginally effective. For this reason, cultural control options, such as reduced fertilizer application or scalping, form the cornerstone of a management program where chemical control is complementary. Currently, incomplete ecological knowledge about turfgrass-infesting eriophyid mites hinders the development of an effective integrated management program. Better information about plant–mite interactions could provide insight that leads to developing management tactics that promote resistance and control of these enigmatic pests. This review summarizes current knowledge on life history, ecology, and management strategies for turfgrass-infesting eriophyid mites.
Harnessing translational research in wheat for climate resilience
Authors: Reynolds Matthew P , Lewis Janet M , Ammar Karim , Basnet Bhoja R , Crespo-Herrera Leonardo , Crossa José , Dhugga Kanwarpal S , Dreisigacker Susanne , Juliana Philomin , Karwat Hannes , Kishii Masahiro , Krause Margaret R , Langridge Peter , Lashkari Azam , Mondal Suchismita , Payne Thomas , Pequeno Diego , Pinto Francisco , Sansaloni Carolina , Schulthess Urs , Singh Ravi P , Sonder Kai , Sukumaran Sivakumar , Xiong Wei , Braun Hans J
Published: June 2021

Despite being the world’s most widely grown crop, research investments in wheat (Triticum aestivum and Triticum durum) fall behind those in other staple crops. Current yield gains will not meet 2050 needs, and climate stresses compound this challenge. However, there is good evidence that heat and drought resilience can be boosted through translating promising ideas into novel breeding technologies using powerful new tools in genetics and remote sensing, for example. Such technologies can also be applied to identify climate resilience traits from among the vast and largely untapped reserve of wheat genetic resources in collections worldwide. This review describes multi-pronged research opportunities at the focus of the Heat and Drought Wheat Improvement Consortium (coordinated by CIMMYT), which together create a pipeline to boost heat and drought resilience, specifically: improving crop design targets using big data approaches; developing phenomic tools for field-based screening and research; applying genomic technologies to elucidate the bases of climate resilience traits; and applying these outputs in developing next-generation breeding methods. The global impact of these outputs will be validated through the International Wheat Improvement Network, a global germplasm development and testing system that contributes key productivity traits to approximately half of the global wheat-growing area.
Synthesis of the first nitrogen-heterocycles in interstellar ice analogues containing methylamine (CH3NH2) exposed to UV radiation: formation of trimethylentriamine (TMT, c-(-CH2-NH)3) and hexamethylentetramine (HMT, (CH2)6N4)
Authors: Carrascosa H , González Díaz C , Muñoz Caro G M , Gómez P C , Sanz M L
Published: June 2021

Hexamethylentetramine has drawn a lot of attention due to its potential to produce prebiotic species. This work aims to gain a better understanding in the chemical processes concerning methylamine under astrophysically relevant conditions. In particular, this work deeps into the formation of N-heterocycles in interstellar ice analogues exposed to UV radiation, which may lead to the formation of prebiotic species. Experimental simulations of interstellar ice analogues were carried out in ISAC. ISAC is an ultrahigh vacuum chamber equipped with a cryostat, where gas and vapour species are frozen forming ice samples. Infrared and ultraviolet spectroscopy were used to monitor the solid phase, and quadrupole mass spectrometry served to measure the composition of the gas phase. The variety of species detected after UV irradiation of ices containing methylamine revealed the presence of 12 species which have been already detected in the ISM, being 4 of them typically classified as complex organic molecules: formamide (HCONH2), methyl cyanide (CH3CN), CH3NH and CH3CHNH. Warming up of the irradiated CH3NH2-bearing ice samples lead to the formation of trimethylentriamine (TMT), a N-heterocycle precursor of HMT, and the subsequent synthesis of HMT at temperatures above 230 K.
Leader Change, Time in Office and the Determinants of Voter Perceptions
Authors: Bridgewater Jack
Published: June 2021

There is a significant literature on the role of both parties and leaders in electoral politics and a broad understanding of the strength of the relationship between the two in voters’ minds. However, less has been done to determine if there is systematic variation in whether voters see a party and its leader as one and the same. I address this question by using the Comparative Study of Electoral System to measure the impact of leader changes on voter perceptions. I find that new leaders are less likely to be evaluated according to the party they represent, with some evidence that maintaining the same leader over a long period of time increases the association between leader and party.
Fluorescent biosensors illuminating plant hormone research
Authors: Balcerowicz Martin , Shetty Kartika N. , Jones Alexander M.
Published: June 2021

Phytohormones act as key regulators of plant growth that coordinate developmental and physiological processes across cells, tissues and organs. As such, their levels and distribution are highly dynamic owing to changes in their biosynthesis, transport, modification and degradation that occur over space and time. Fluorescent biosensors represent ideal tools to track these dynamics with high spatiotemporal resolution in a minimally invasive manner. Substantial progress has been made in generating a diverse set of hormone sensors with recent FRET biosensors for visualising hormone concentrations complementing information provided by transcriptional, translational and degron-based reporters. In this review, we provide an update on fluorescent biosensor designs, examine the key properties that constitute an ideal hormone biosensor, discuss the use of these sensors in conjunction with in vivo hormone perturbations and highlight the latest discoveries made using these tools.
A facile, versatile hydrogel bioink for 3D bioprinting benefits long-term subaqueous fidelity, cell viability and proliferation
Authors: Chen Hongqing , Fei Fei , Li Xinda , Nie Zhenguo , Zhou Dezhi , Liu Libiao , Zhang Jing , Zhang Haitao , Fei Zhou , Xu Tao
Published: June 2021

Both of the long-term fidelity and cell viability of three-dimensional (3D)-bioprinted constructs are essential to precise soft tissue repair. However, the shrinking/swelling behavior of hydrogels brings about inadequate long-term fidelity of constructs, and bioinks containing excessive polymer are detrimental to cell viability. Here, we obtained a facile hydrogel by introducing 1% aldehyde hyaluronic acid (AHA) and 0.375% N-carboxymethyl chitosan (CMC), two polysaccharides with strong water absorption and water retention capacity, into classic gelatin (GEL, 5%)–alginate (ALG, 1%) ink. This GEL–ALG/CMC/AHA bioink possesses weak temperature dependence due to the Schiff base linkage of CMC/AHA and electrostatic interaction of CMC/ALG. We fabricated integrated constructs through traditional printing at room temperature and in vivo simulation printing at 37°C. The printed cell-laden constructs can maintain subaqueous fidelity for 30 days after being reinforced by 3% calcium chloride for only 20 s. Flow cytometry results showed that the cell viability was 91.38 ± 1.55% on day 29, and the cells in the proliferation plateau at this time still maintained their dynamic renewal with a DNA replication rate of 6.06 ± 1.24%. This work provides a convenient and practical bioink option for 3D bioprinting in precise soft tissue repair.
A Biobehavioral Pain Hygiene Model: Narrative Review and Conceptualization
Authors: Saravanan Anitha , Reagan Louise
Published: June 2021

Objectives:

Chronic pain frequently coexists with other distressing symptoms (depressive mood, sleep disturbance, fatigue, and stress) and maladaptive beliefs (fear avoidance and pain catastrophizing) that together are linked with increased pain severity and interference, poor function, and quality of life. Although a tremendous amount of research has been conducted to identify risk factors and treatment targets for managing pain, too often the strategies are not combined in a way to make them useful for daily multimodal application. The purpose of this narrative review is to examine the existing literature on the co-occurring symptoms and maladaptive beliefs, lifestyle, and socioenvironmental factors associated with chronic pain and the current nonpharmacological treatment strategies designed to help patients manage chronic pain.

Methods:

Literature databases PubMed/Medline, CINAHL, and PsycINFO were searched to review the evidence on treatment strategies that have evidence of effectiveness in managing chronic pain and co-occurring symptoms. Conceptual models of chronic pain and nonpharmacological pain management strategies were reviewed.

Results:

Evidence was found in support of cognitive-behavioral, lifestyle, and socioenvironmental factors and treatment strategies that are effective in managing chronic pain and co-occurring symptoms. The key factors identified and proposed include lifestyle factors (physical activity, diet, maintaining body weight, keeping a routine, and sleep habits), planned phases of activities (relaxing, pacing, and meditation at regular intervals), CBT strategies (stretching, breathing, meditation, and stress reduction), socioenvironmental factors (keeping a calm, peaceful, environment), and positive support system. On the basis of this evidence, a biobehavioral pain hygiene model is proposed that combines existing strategies in managing pain to make them useful for daily multimodal application and which may be used to integrate therapeutic interventions for chronic pain management.

Discussion:

Given the dearth of research on integrative multimodal pain management, this review and the biobehavioral pain hygiene model could drive future research in the management of chronic pain. Identification of the key strategies and combining them to be a useful multimodal application will be a first step toward identifying innovative methods that could help improve pain and function in patients with chronic pain.
Long-term Clinical Outcomes of Microendoscopic Laminotomy for Cervical Spondylotic Myelopathy
Authors: Minamide Akihito , Yoshida Munehito , Nakagawa Yukihiro , Okada Motohiro , Takami Masanari , Iwasaki Hiroshi , Tsutsui Shunji , Kozaki Takuhei , Murata Shizumasa , Taiji Ryo , Murakami Kimihide , Hashizume Hiroshi , Yukawa Yasutsugu , Taneichi Hiroshi , Yamada Hiroshi , Schoenfeld Andrew J. , Simpson Andrew K.
Published: June 2021

Study Design:

This was a retrospective cohort study.

Objective:

The objective of this study was to characterize the long-term clinical and radiographic results of articular segmental decompression surgery using endoscopy [cervical microendoscopic laminotomy (CMEL)] for cervical spondylotic myelopathy (CSM) and to compare outcomes to conventional expansive laminoplasty (ELAP).

Summary of Background Data:

The spinal cord compression in CSM consists of a pincer mechanism due to bulging disk and a hypertrophied ligamentum flavum. The long-term clinical benefits of segmental decompression surgery, which removes the dorsal compressive elements of articular segment in CSM patients, have not yet been elucidated.

Materials and Methods:

Consecutive patients with CSM who required surgical treatment were enrolled. All enrolled patients (n=81) underwent CMEL or ELAP. All patients were followed postoperatively for >5 years. The preoperative and 5-year follow-up evaluation included neurological assessment [Japanese Orthopaedic Association (JOA) score], JOA recovery rates, axial neck pain (visual analog scale), and cervical sagittal alignment (C2–C7 subaxial cervical angle).

Results:

Sixty-four patients (CMEL group: 33, ELAP group: 31) were included for analysis. The preoperative JOA score was 10.1 points in the CMEL group and 11.1 points in the ELAP group (P=0.15). The JOA recovery rates were similar, 58.6% in the CMEL group and 55.2% in the ELAP group (P=0.55). The axial neck pain in the CMEL group was significantly lower than that in the ELAP group (P<0.01). At 5-year follow-up, cervical alignment was more favorable in the CMEL group, with an average 2.9 degrees gain in lordosis [vs. 2.3 degrees loss of lordosis in the ELAP group (P<0.05)] and lower incidence of postoperative kyphosis.

Conclusions:

CMEL is a novel, less invasive, technique that allows for multilevel posterior cervical decompression for treatment of CSM. Our 5-year follow-up data demonstrates that patients after CMEL have similar neurological outcomes to conventional laminoplasty, with significantly less postoperative axial pain and improved subaxial cervical lordosis when compared with their traditional laminoplasty counterparts.
Time to Lung Volume Stability After Pressure Change During High-Frequency Oscillatory Ventilation
Authors: Tingay David G. , Kiraly Nicholas , Mills John F. , Dargaville Peter A.
Published: June 2021

OBJECTIVES:

Clinicians have little guidance on the time needed before assessing the effect of a mean airway pressure change during high-frequency oscillatory ventilation. We aimed to determine: 1) time to stable lung volume after a mean airway pressure change during high-frequency oscillatory ventilation and 2) the relationship between time to volume stability and the volume state of the lung.

DESIGN:

Prospective observational study.

SETTING:

Regional quaternary teaching hospital neonatal ICU.

PATIENTS:

Thirteen term or near-term infants receiving high-frequency oscillatory ventilation and muscle relaxants.

INTERVENTIONS:

One to two cm H2O mean airway pressure changes every 10 minutes as part of an open lung strategy based on oxygen response.

MEASUREMENTS AND MAIN RESULTS:

Continuous lung volume measurements (respiratory inductive plethysmography) were made during the mean airway pressure changes. Volume signals were analyzed with a biexponential model to calculate the time to stable lung volume if the model R
2 was greater than 0.6. If volume stability did not occur within 10 minutes, the model was extrapolated to maximum 3,600 s. One-hundred ninety-six mean airway pressure changes were made, with no volume change in 33 occurrences (17%). One-hundred twenty-five volume signals met modeling criteria for inclusion; median (interquartile range) R
2, 0.96 (0.91–0.98). The time to stable lung volume was 1,131 seconds (718–1,959 s) (mean airway pressure increases) and 647 seconds (439–1,309 s) (mean airway pressure decreases), with only 17 (14%) occurring within 10 minutes and time to stability being longer when the lung was atelectatic.

CONCLUSIONS:

During high-frequency oscillatory ventilation, the time to stable lung volume after a mean airway pressure change is variable, often requires more than 10 minutes, and is dependent on the preceding volume state.
Induced Pluripotent Stem Cells Enable Disease Modeling and Drug Screening in Calreticulin del52 and ins5 Myeloproliferative Neoplasms
Authors: Secardin Lise , Gomez Limia Cintia , da Silva-Benedito Suzana , Lordier Larissa , El-Khoury Mira , Marty Caroline , Ianotto Jean-Christophe , Raslova Hana , Constantinescu Stefan N. , Bonamino Martín Hernán , Vainchenker William , Monte-Mor Barbara , Di Stefano Antonio , Plo Isabelle
Published: June 2021

Mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and primary myelofibrosis patients. To address the contribution of the human CALR mutants to the pathogenesis of myeloproliferative neoplasms (MPNs) in an endogenous context, we modeled the CALRdel52 and CALRins5 mutants by induced pluripotent stem cell (iPSC) technology using CD34+ progenitors from 4 patients. We describe here the generation of several clones of iPSC carrying heterozygous CALRdel52 or CALRins5 mutations. We showed that CALRdel52 induces a stronger increase in progenitors than CALRins5 and that both CALRdel52 and CALRins5 mutants favor an expansion of the megakaryocytic lineage. Moreover, we found that both CALRdel52 and CALRins5 mutants rendered colony forming unit–megakaryocyte (CFU-MK) independent from thrombopoietin (TPO), and promoted a mild constitutive activation level of signal transducer and activator of transcription 3 in megakaryocytes. Unexpectedly, a mild increase in the sensitivity of colony forming unit-granulocyte (CFU-G) to granulocyte-colony stimulating factor was also observed in iPSC CALRdel52 and CALRins5 compared with control iPSC. Moreover, CALRdel52-induced megakaryocytic spontaneous growth is more dependent on Janus kinase 2/phosphoinositide 3-kinase/extracellular signal-regulated kinase than TPO-mediated growth and opens a therapeutic window for treatments in CALR-mutated MPN. The iPSC models described here represent an interesting platform for testing newly developed inhibitors. Altogether, this study shows that CALR-mutated iPSC recapitulate MPN phenotypes in vitro and may be used for drug screening.
Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells
Authors: Byrgazov Konstantin , Besse Andrej , Kraus Marianne , Slipicevic Ana , Lehmann Fredrik , Driessen Christoph , Besse Lenka
Published: June 2021

Introduction of the proteasome inhibitor bortezomib has dramatically improved clinical outcomes in multiple myeloma. However, most patients become refractory to bortezomib-based therapies. On the molecular level, development of resistance to bortezomib in myeloma cells is accompanied by complex metabolic changes resulting in increased protein folding capacity, and less dependency on the proteasome. In this study, we show that aminopeptidase B, encoded by the RNPEP gene, is upregulated in bortezomib-resistant myeloma cell lines, and in a murine in vivo model. Moreover, increased RNPEP expression is associated with shorter survival in multiple myeloma patients previously treated with bortezomib-containing regimens. Additionally, expression is increased in plasma cell precursors, a B-lymphoid compartment previously associated with myeloma stem cells. We hypothesized that increased aminopeptidase B expression in aggressive myeloma clones may be used therapeutically toward elimination of the cells via the use of a novel peptide-drug conjugate, melphalan flufenamide (melflufen). Melflufen, a substrate of aminopeptidase B, efficiently eliminates bortezomib-resistant myeloma cells in vitro and in vivo, and completely suppresses clonogenic myeloma growth in vitro at subphysiological concentrations. Thus, melflufen represents a novel treatment option that is able to eradicate drug-resistant myeloma clones characterized by elevated aminopeptidase B expression.
CLASSIFYING ABCA4 MUTATION SEVERITY USING AGE-DEPENDENT ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE-DERIVED TOTAL LESION SIZE
Authors: Heath Jeffery Rachael C. , Thompson Jennifer A. , Lamey Tina M. , McLaren Terri L. , McAllister Ian L. , Constable Ian J. , Mackey David A. , De Roach John N. , Chen Fred K.
Published: June 2021

Purpose:

To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification.

Methods:

A retrospective study of patients with biallelic ABCA4 mutations that were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria, and mutation severities were classified based on the current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild, and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS.

Results:

Eighty-one patients with STGD1 (mean age = 42 ± 20 years and mean visual acuity = 20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n = 6) demonstrated an increase in TLS during their second decade reaching a mean ± SD of 796 ± 29 mm2 by age 40. Those harboring mild mutations c.5882G>A or c.5603A>T had lesions confined to the posterior pole with a mean ± SD TLS of 30 ± 39 mm2. Intermediate mutations c.6079C>T or c.[2588G>C;5603A>T] in trans with a null/severe mutation had a mean ± SD TLS of 397 ± 29 mm2. Thirty-two mutations were predicted to cause severe (n = 22), intermediate (n = 6), and mild (n = 5) impairment of ABCA4 function based on age of symptom onset and TLS.

Conclusion:

Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies to confirm its validity.
Craving Moderates the Effects of Intranasal Oxytocin on Anger in Response to Social Stress Among Veterans With Co-Occurring Posttraumatic Stress Disorder and Alcohol Use Disorder
Authors: Melkonian Alexander J. , Flanagan Julianne C. , Calhoun Casey D. , Hogan Jasara N. , Back Sudie E.
Published: June 2021

Purpose/Background

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur among US military veterans. Oxytocin may have therapeutic value in treating both conditions. The potential for oxytocin to augment affective features common to PTSD and AUD, such as anger, is relevant to inform emerging treatments.

Methods/Procedures

We examined the influence of intranasally administered oxytocin on connections between alcohol craving and stress-induced anger in a sample of 73 veterans (91.3% men) with co-occurring PTSD and AUD. Participants self-administered oxytocin (40 IU) or placebo (saline) 45 minutes before completing the Trier Social Stress Task (TSST). Self-reports of alcohol craving and anger were assessed pre- and post-TSST using a modified visual analog scale. Multiple regression analysis, including main effects for group, baseline craving, and their interaction, was used to predict post-TSST anger.

Findings/Results

A marginally significant interaction was observed, suggesting a positive association between baseline craving and anger for those in the oxytocin group (B = 0.65, P = 0.01). Among those reporting low craving, participants in the oxytocin group reported significantly lower post-TSST anger than those in the placebo group.

Implications/Conclusions

The current study is among the first to examine relevant psychosocial moderators that may influence the effects of oxytocin among veterans with comorbid PTSD and AUD. Although oxytocin attenuated ratings of anger after a stress task among those with low baseline craving, findings suggest that oxytocin may not be as effective at reducing anger, a highly salient factor in PTSD, for individuals experiencing high levels of craving. Findings are consistent with the social salience hypothesis and suggest that individual differences in alcohol craving should be considered when evaluating oxytocin as a potential treatment for individuals with comorbid PTSD and AUD.
Waldenstrom's macroglobulinemia with peripheral neuropathy and favorable long-term treatment responses
Authors: Cabacang Mary Lou Anne Y. , Rosales Raymond L.
Published: June 2021

Rationale:

Waldenstrom's Macroglobulinemia (WM), is a rare hematological disorder with an indolent course that affects about 1 in 1,000,000 people over the age of 50. The two cases presented here highlight the favorable responses to targeted therapies and that such responses may show a longer progression-free survival than the standard regimens for WM (Dexamethasone + Rituximab + Cyclophosphamide and Bendamustine + Rituximab).

Patient concerns:

We report 2 Filipino patients with WM presenting with symptoms of peripheral nerve involvement characterized by numbness, dysesthesia and weakness.

Diagnosis:

Serum immunoelectrophoresis showed distinct bands in IgM and Kappa light chain channels, indicative of IgM kappa monoclonal gammopathy. Bone marrow aspirate flow cytometry showed a B-lymphoid population, bright expression of Kappa light chain surface immunoglobulin, all consistent with a B-cell neoplasm.

Interventions:

The first case received Dexamethasone + Rituximab + Cyclophosphamide. The second case was successfully treated with Rituximab + Bendamustine.

Outcomes:

The first case achieved complete remission for 9 years. However, in the 10th year of follow-up, there was recurrence of peripheral nerve symptomatology, which prompted a repeat course Rituximab monotherapy, with favorable response. The second case was successfully treated with Rituximab + Bendamustine over a 3-year course.

Lessons:

To the best of our knowledge, WM presenting with peripheral neuropathy with a long progression-free survival as described in these patients have not been reported before. The two cases highlight the potentially favorable responses to targeted therapies. Though the possibility of developing recurrence cannot be discounted, favorable outcomes with the use of the standard chemotherapies could still be expected.
Peptoniphilus faecalis sp. nov., isolated from swine faeces
Authors: Ryu Seoung Woo , Kim Ji-Sun , Oh Byeong Seob , Yu Seung Yeob , Lee Jung-Sook , Park Seung-Hwan , Kang Se Won , Lee Jiyoung , Lee Mi-Kyung , Rhee Moon-Soo , Jung Hyunjung , Hur Tai-Young , Kim Hyeun Bum , Kim Jae-Kyung , Lee Ju-Hoon , Lee Ju Huck
Published: June 2021

An obligately anaerobic, Gram-positive, non-motile, coccus-shaped bacterial strain designated AGMB00490T was isolated from swine faeces. 16S rRNA gene sequence-based phylogenetic analysis indicated that the isolate belongs to the genus

Peptoniphilus

and that the most closely related species is

Peptoniphilus gorbachii

WAL 10418T (=KCTC 5947T, 97.22 % 16S rRNA gene sequence similarity). Whole genome sequence analysis determined that the DNA G+C content of strain AGMB00490T was 31.2 mol% and moreover that the genome size and numbers of tRNA and rRNA genes were 2 129 517 bp, 34 and 10, respectively. Strain AGMB00490T was negative for oxidase and urease; positive for catalase, indole production, arginine arylamidase, leucine arylamidase, tyrosine arylamidase and histidine arylamidase; and weakly positive for phenylalanine arylamidase and glycine arylamidase. The major cellular fatty acids (>10 %) of the isolate were determined to be C16 : 0 and C18 : 1 ω9c. Strain AGMB00490T produced acetic acid as a major end product of metabolism. Accordingly, phylogenetic, physiologic and chemotaxonomic analyses revealed that strain AGMB00490T represents a novel species for which the name Peptoniphilus faecalis sp. nov. is proposed. The type strain is AGMB00490T (=KCTC 15944T=NBRC 114159T).
OFF-periods reduce the complexity of neocortical activity during sleep
Authors: González Joaquín , Cavelli Matias , Tort Adriano BL , Torterolo Pablo , Rubido Nicolás
Published: June 2021

Complexity of electroencephalographic signals decreases during slow-wave sleep (SWS), however, the neural mechanism for this decrease remains elusive. Here, we show that this complexity reduction is caused by synchronous neuronal OFF-periods. We analyse in-vivo recordings from neocortical neuronal populations, finding that OFF-periods in SWS trap cortical dynamics, making the population activity more recurrent, deterministic, and less chaotic than during REM sleep or Wakefulness. Importantly, when we exclude OFF-periods, SWS becomes indistinguishable from Wakefulness or REM sleep. In fact, we show that spiking activity for all states has a universal scaling compatible with critical phenomena. We complement these results by a critical branching model that replicates our experimental findings, where we show that forcing OFF-periods to a percentage of neurons suffices to generate a decrease in complexity that replicates SWS.
A TPR scaffold couples signal detection to OdhI phosphorylation in metabolic control by the protein kinase PknG
Authors: Lisa María-Natalia , Sogues Adrià , Barilone Nathalie , Baumgart Meike , Gil Magdalena , Graña Martín , Durán Rosario , Biondi Ricardo M. , Bellinzoni Marco , Bott Michael , Alzari Pedro M.
Published: June 2021

Signal transduction is essential for bacteria to adapt to changing environmental conditions. Among many forms of post-translational modifications, reversible protein phosphorylation has evolved as a ubiquitous molecular mechanism of protein regulation in response to specific stimuli. The Ser/Thr protein kinase PknG modulates the fate of intracellular glutamate by controlling the phosphorylation status of the 2-oxoglutarate dehydrogenase regulator OdhI, a function that is conserved among diverse actinobacteria. PknG has a modular organization characterized by the presence of regulatory domains surrounding the catalytic domain. Here we present an investigation through in vivo experiments as well as biochemical and structural methods of the molecular bases of the regulation of PknG from C. glutamicum (CgPknG), in the light of previous knowledge available for the kinase from M. tuberculosis (MtbPknG). We found that OdhI phosphorylation by CgPknG is regulated by a conserved mechanism that depends on a C-terminal domain composed of tetratricopeptide repeats (TPR) essential for metabolic homeostasis. Furthermore, we identified a conserved structural motif that physically connects the TPR domain and a flexible N-terminal extension of the kinase that is involved in docking interactions with OdhI. Based on our results and previous reports, we propose a model in which the TPR domain of PknG couples signal detection to the specific phosphorylation of OdhI. Overall, the available data indicate that conserved PknG domains in distant actinobacteria retain their roles in kinase regulation in response to nutrient availability.

IMPORTANCE

Bacteria control the metabolic processes by which they obtain nutrients and energy in order to adapt to the environment. In this way, the metabolic characteristics of a microorganism determine its ecological role and its usefulness in industrial processes. Here, we use genetic, biochemical, and structural approaches to study a key component in a system that regulates glutamate production in C. glutamicum, a species that is used for the industrial production of amino acids. We elucidated molecular mechanisms involved in metabolic control in C. glutamicum, which are conserved in related pathogenic bacteria. The findings have broader significance for diverse actinobacteria, including microorganisms that cause disease as well as environmental species used to produce billions of dollars of amino acids and antibiotics every year.
Evolution of the open-access CIViC knowledgebase is driven by the needs of the cancer variant interpretation community
Authors: Krysiak Kilannin , Danos Arpad M , Kiwala Susanna , McMichael Joshua F , Coffman Adam C , Barnell Erica K , Sheta Lana , Saliba Jason , Grisdale Cameron J , Kujan Lynzey , Pema Shahil , Lever Jake , Spies Nicholas C , Chiorean Andreea , Rieke Damian T , Clark Kaitlin A , Jani Payal , Takahashi Hideaki , Horak Peter , Ritter Deborah I , Zhou Xin , Ainscough Benjamin J , Delong Sean , Lamping Mario , Marr Alex R , Li Brian V , Lin Wan-Hsin , Terraf Panieh , Salama Yasser , Campbell Katie , Farncombe Kirsten M , Ji Jianling , Zhao Xiaonan , Xu Xinjie , Kanagal-Shamanna Rashmi , Cotto Kelsy C , Skidmore Zachary L , Walker Jason R , Zhang Jinghui , Milosavljevic Aleksandar , Patel Ronak Y , Giles Rachel H , Kim Raymond H , Schriml Lynn M , Mardis Elaine R , Jones Steven JM , Raca Gordana , Rao Shruti , Madhavan Subha , Wagner Alex H , Griffith Obi L , Griffith Malachi
Published: June 2021

CIViC (Clinical Interpretation of Variants in Cancer;civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. With nearly 300 contributors, CIViC contains peer-reviewed, published literature curated and expert-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new evidence types (predisposing, oncogenic and functional). The growing CIViC knowledgebase distributes clinically-relevant cancer variant data currently representing >2500 variants in >400 genes from >2800 publications.
Effectiveness of antifungal treatments during chytridiomycosis epizootics in populations of an endangered frog
Authors: Knapp Roland A. , Joseph Maxwell B. , Smith Thomas C. , Hegeman Ericka E. , Vredenburg Vance T. , Erdman James E. , Boiano Daniel M. , Jani Andrea J. , Briggs Cheryl J.
Published: June 2021

The recently-emerged amphibian chytrid fungusBatrachochytrium dendrobatidis(Bd) has had an unprecedented impact on global amphibian populations, and highlights the urgent need to develop effective mitigation strategies against this pathogen. We conducted field antifungal treatment experiments in populations of the endangered mountain yellow-legged frog during or immediately after Bd-caused mass die-off events. The objective of the treatments was to reduce Bd infection intensity (“load”) and in doing so alter frog-Bd dynamics and increase the probability of frog population persistence despite ongoing Bd infection. Experiments included treatment of early life stages (tadpoles and subadults) with the antifungal drug itraconazole, treatment of adults with itraconazole, and augmentation of the skin microbiome of subadults withJanthinobacterium lividum, a commensal bacterium with antifungal properties. All itraconazole treatments caused immediate reductions in Bd load, and produced longer-term effects that differed between life stages. In experiments focused on early life stages, Bd load was reduced in the two months immediately following treatment and was associated with increased survival of subadults. However, Bd load and frog survival returned to pre-treatment levels in less than one year, and treatment had no effect on population persistence. In adults, treatment reduced Bd load and increased frog survival over the three-year post-treatment period, consistent with frogs having developed an effective adaptive immune response against Bd. Despite this protracted period of reduced impacts of Bd on adults, recruitment of new individuals into the adult population was limited and the population eventually declined to near-extirpation. In the microbiome augmentation experiment, bathing frogs in aJ. lividumsolution after Bd load reduction with itraconazole increased concentrations of this bacterium on frogs, but concentrations declined to baseline levels within one month and did not have a protective effect against Bd infection. Collectively, these results suggest that Bd mitigation efforts focused on frog populations that have recently declined due to Bd emergence are ineffective in causing long-term changes in frog-Bd dynamics and increasing population persistence, due largely to the inability of early life stages to mount an effective immune response against Bd and resulting high susceptibility. This results in repeated recruitment failure and a low probability of population persistence in the face of ongoing Bd infection.
TMEM120 is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase
Authors: Xue Jing , Han Yan , Baniasadi Hamid , Zeng Weizhong , Pei Jimin , Grishin Nick , Wang Junmei , Tu Benjamin P. , Jiang Youxing
Published: June 2021

TMEM120A, also named as TACAN, is a novel membrane protein highly conserved in vertebrates and was recently proposed to be a mechanosensitive channel involved in sensing mechanical pain. Here we present the single particle cryo-EM structure of human TMEM120A which forms a tightly packed dimer with extensive interactions mediate by the N-terminal coiled coil domain (CCD), the C-terminal transmembrane domain (TMD), and the re-entrant loop between the two domains. The TMD of each TMEM120A subunit contains six transmembrane helices (TMs) and has no clear structural feature of a channel protein. Instead, the six TMs form an α-barrel with a deep pocket where a coenzyme A (CoA) molecule is bound. Intriguingly, some structural features of TMEM120A resemble those of elongase for very long-chain fatty acid (ELOVL) despite low sequence homology between them, pointing to the possibility that TEME120A may function as an enzyme for fatty acid metabolism, rather than a mechanosensitive channel.
Schizophrenia polygenic risk during typical development reflects multiscale cortical organization
Authors: Kirschner Matthias , Paquola Casey , Khundrakpam Budhachandra S. , Vainik Uku , Bhutani Neha , Hodzic-Santor Benazir , Georgiadis Foivos , Al-Sharif Noor B. , Misic Bratislav , Bernhardt Boris , Evans Alan C. , Dagher Alain
Published: June 2021

Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development may by revealed using polygenic risk scoring for schizophrenia (PRS-SCZ). We assessed PRS-SCZ and cortical morphometry in typically developing children (3–21 years) using whole genome genotyping and T1-weighted MRI (n=390) from the Pediatric Imaging, Neurocognition and Genetics (PING) cohort. We contextualise the findings using (i) age-matched transcriptomics, (ii) histologically-defined cytoarchitectural types and functionally-defined networks, (iii) case-control differences of schizophrenia and other major psychiatric disorders. Higher PRS-SCZ was associated with greater cortical thickness, which was most prominent in areas with heightened gene expression of dendrites and synapses. PRS-SCZ related increases in vertex-wise cortical thickness were especially focused in the ventral attention network, while koniocortical type cortex (i.e. primary sensory areas) was relatively conserved from PRS-SCZ related differences. The large-scale pattern of cortical thickness increases related to PRS-SCZ mirrored the pattern of cortical thinning in schizophrenia and mood-related psychiatric disorders. Age group models illustrate a possible trajectory from PRS-SCZ associated cortical thickness increases in early childhood towards thinning in late adolescence, which resembles the adult brain phenotype of schizophrenia. Collectively, combining imaging-genetics with multi-scale mapping, our work provides novel insight into how genetic risk for schizophrenia impacts the cortex early in life.
Plasmodium falciparumprotein Pfs16 is a target for transmission-blocking antimalarial drug development
Authors: Yahiya Sabrina , Saunders Charlie N. , Straschil Ursula , Fischer Oliver J. , Rueda-Zubiaurre Ainoa , Haase Silvia , Vizcay-Barrena Gema , Jordan Sarah , Hassan Sarah , Delves Michael J. , Tate Edward W. , Barnard Anna , Fuchter Matthew J. , Baum Jake
Published: June 2021

Phenotypic cell-based screens are critical to the discovery of new antimalarial lead compounds. However, identification and validation of cellular targets of lead compounds is required following discovery in a phenotypic screen. We recently discovered aPlasmodiumtransmission-blocking N-((4-hydroxychroman-4-yl)methyl)-sulfonamide (N-4HCS) compound,DDD01035881, in a phenotypic screen.DDD01035881and its potent derivatives have been shown to blockPlasmodiummale gamete formation (microgametogenesis) with nanomolar activity. Here, we synthesised a photoactivatable N-4HCS derivative, probe2, to identify the N-4HCS cellular target. Using probe2in photo-affinity labelling coupled with mass spectrometry, we identified the 16 kDaPlasmodium falciparumparasitophorous vacuole membrane protein Pfs16 as the likely cellular target of the N-4HCS series. Further validating Pfs16 as the cellular target of the N-4HCS series, the Cellular Thermal Shift Assay (CETSA) confirmed DDD01035881 stabilised Pfs16 in lysate from activated mature gametocytes. Additionally, photo-affinity labelling combined with in-gel fluorescence and immunoblot analysis confirmed the N-4HCS series interacted with Pfs16. High-resolution, widefield fluorescence and electron microscopy of N-4HCS-inhibited parasites was found to result in a cell morphology entirely consistent with targeted gene disruption ofPfs16. Taken together, these data strongly implicate Pfs16 as the target ofDDD01035881and establish the N-4HCS scaffold family as a powerful starting point from which future transmission-blocking antimalarials can be developed.