bluuebunny/crossref_metadata_2025 huggingface dataset:
An Examination of Donor Factors That Impact the Results of the Glucagon Stimulation Test as an Assessment of the Pancreatic Graft Endocrine Function
Authors: Ito Taihei , Kenmochi Takashi , Aida Naohiro , Hiratsuka Izumi , Matsushima Hajime , Kurihara Kei , Suzuki Atsushi , Shibata Megumi , Kusaka Mamoru , Hasegawa Midori , Ishihara Takuma , Go Hirofumi , Yabusaki Kohei , Shintani Ayumi
Published: September 2022

Objectives

Delta C-peptide derived by the glucagon stimulation test is a reliable value for the evaluation of the pancreatic endocrine function after pancreas transplantation. We examined the associations between delta C-peptide as pancreatic graft endocrine function and donor background factors.

Methods

Sixty-five cases of pancreatic transplantation from brain-dead donors, which were performed in our facility, were enrolled in this study. Enrolled recipients underwent a glucagon stimulation test within 1 to 3 months after transplantation to evaluate the pancreatic graft endocrine function with delta C-peptide to compare donor background factors.

Results

The following factors were associated with significant deterioration of the delta C-peptide: age of 50 years or greater, death from cerebrovascular accident, hemoglobin A1c level of 5.6% or greater, creatinine level of 1.0 mg/dL or greater, C-reactive protein level of 25 mg/dL or greater, and sodium level of 150 mmol/L or greater. In addition, increased numbers of these donor factors indicated significantly greater deterioration of the posttransplant pancreatic endocrine function (P < 0.001).

Conclusions

To secure insulin independence after pancreas transplantation, which means maintaining a delta C-peptide level of 1.0 ng/mL or greater on a glucagon stimulation test, the utilization of donors, who possesses more than equal to 3 of the donor factors identified in this study, should be carefully considered.
Work Environment and Operational Failures Associated With Nurse Outcomes, Patient Safety, and Patient Satisfaction
Authors: Riman Kathryn A. , Harrison Jordan M. , Sloane Douglas M. , McHugh Matthew D.
Published: September 2022

Background

Operational failures, defined as the inability of the work system to reliably provide information, services, and supplies needed when, where, and to who, are a pervasive problem in U.S. hospitals that disrupt nurses’ ability to provide safe and effective care.

Objectives

We examined the relationship between operational failures, patient satisfaction, nurse-reported quality and safety, and nurse job outcomes (e.g., burnout and job satisfaction) and whether differences in hospital work environments explained the relationship.

Methods

We conducted a cross-sectional analysis using population-based survey data from 11,709 registered nurses in 415 hospitals who participated in the RN4CAST-US nurse survey (2015–2016) and the 2016 Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. The RN4CAST-US nurse survey focused on hospital quality and safety, job outcomes, and hospital work environments. The HCAHPS survey collected publicly reported patient data on their satisfaction with their care. Operational failures were evaluated using an eight-item composite measure that assessed missing supplies, orders, medication, missing/wrong patient diet, electronic documentation problems, insufficient staff, and time spent on workarounds and nonnursing tasks. Multilevel regression models were used to test the hypothesized relationships.

Results

Operational failures were associated with low patient satisfaction scores, poor quality and safety outcomes, and poor nurse job outcomes, and those associations were partly accounted for by hospital work environments.

Discussion

Operational failures prevent high-quality care and positive patient and nurse outcomes. Operational failures and the hospital work environment should be targeted simultaneously to maximize quality improvement efforts. Hospital leadership should work with frontline staff to identify and target the sources of operational failures in nursing units. Improvements to hospital work environments may reduce the occurrence of operational failures.
Peristomal Skin Itch
Authors: Blom Tirza , Rustemeyer Thomas
Published: September 2022

Survey data from the United Stated, the United Kingdom, and the Netherlands indicate peristomal itch is prevalant among ostomy patients. Pruritus has a significant negative impact on health-related quality of life, resulting in discomfort and interrupted sleep. In ostomy patients, peristomal skin scratching also may interfere with adherence of the ostomy pouching system. This article reviews the classification and pathophysiology of itch in the peristomal skin, along with options for its management.
Does trappability and self-selection influence cognitive performance?
Authors: Ashton Benjamin J. , Thornton Alex , Speechley Elizabeth M. , Ridley Amanda R.
Published: September 2022

Recent research has highlighted how trappability and self-selection—the processes by which individuals with particular traits may be more likely to be caught or to participate in experiments—may be sources of bias in studies of animal behaviour and cognition. It is crucial to determine whether such biases exist, and if they do, what effect they have on results. In this study, we investigated if trappability (quantified through ‘ringing status’—whether or not a bird had been trapped for ringing) and self-selection are sources of bias in a series of associative learning experiments spanning 5 years in the Western Australian magpie (
Gymnorhina tibicen dorsalis
). We found no evidence of self-selection, with no biases in task participation associated with sex, age, group size or ringing status. In addition, we found that there was no effect of trappability on cognitive performance. These findings give us confidence in the results generated in the animal cognition literature and add to a growing body of literature seeking to determine potential sources of bias in studies of animal behaviour, and how they influence the generalizability and reproducibility of findings.
Sex-specific endocrine regulation of seasonal aggression in Siberian hamsters
Authors: Munley Kathleen M. , Trinidad Jonathan C. , Demas Gregory E.
Published: September 2022

Coordinating physiological and behavioural processes across the annual cycle is essential in enabling individuals to maximize fitness. While the mechanisms underlying seasonal reproduction and its associated behaviours are well characterized, fewer studies have examined the hormonal basis of non-reproductive social behaviours (e.g. aggression) on a seasonal time scale. Our previous work suggests that the pineal hormone melatonin facilitates a ‘seasonal switch’ in neuroendocrine regulation of aggression in male and female Siberian hamsters (
Phodopus sungorus
), specifically by acting on the adrenal glands to increase the production of the androgen dehydroepiandrosterone (DHEA) during the short-day (SD) photoperiods of the non-breeding season. Here, we provide evidence that the activity of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD), a key enzyme within the steroidogenic pathway that mediates DHEA synthesis and metabolism, varies in a sex-specific and melatonin-dependent manner. Although both male and female hamsters displayed increased aggression in response to SDs and SD-like melatonin, only males showed an increase in adrenal 3β-HSD activity. Conversely, SD and melatonin-treated females exhibited reductions in both adrenal and neural 3β-HSD activity. Collectively, these results suggest a potential role for 3β-HSD in modulating non-breeding aggression and, more broadly, demonstrate how distinct neuroendocrine mechanisms may underlie the same behavioural phenotype in males and females.
Long-term effects of noise pollution on the avian dawn chorus: a natural experiment facilitated by the closure of an international airport
Authors: de Framond Léna , Brumm Henrik
Published: September 2022

The impacts of noise pollution on birdsong have been extensively investigated but potential long-term effects are neglected. Near airports, where noise levels are particularly high, birds start singing earlier in the morning, probably to gain more time of uninterrupted singing before air traffic sets in. In a previous study, we documented this phenomenon in the vicinity of Berlin Tegel airport. In 2020, Tegel airport closed down, giving us the opportunity to investigate potential long-term effects after noise removal and to gain insight into the mechanisms underlying the advancement of dawn singing. We found that several species at the airport shifted their song onset back after the closure and now had similar schedules to their conspecifics at a control site. Some species, however, still sang earlier near the closed airport. While the first suggests plastic adaptation, the latter suggests selection for early singing males in areas with long-lasting noise pollution. Our findings indicate that a uniform behavioural response to anthropogenic change in a community can be based on diverging evolutionary mechanisms. Overall, we show that noise pollution can have long-lasting effects on animal behaviour and noise removal may not lead to immediate recovery in some species.
Predator responses to prey camouflage strategies: a meta-analysis
Authors: de Alcantara Viana João Vitor , Vieira Camila , Duarte Rafael Campos , Romero Gustavo Quevedo
Published: September 2022

Although numerous studies about camouflage have been conducted in the last few decades, there is still a significant gap in our knowledge about the magnitude of protective value of different camouflage strategies in prey detection and survival. Furthermore, the functional significance of several camouflage strategies remains controversial. Here we carried out a comprehensive meta-analysis including comparisons of different camouflage strategies as well as predator and prey types, considering two response variables: mean predator search time (ST) (63 studies) and predator attack rate (AR) of camouflaged prey (28 studies). Overall, camouflage increased the predator ST by 62.56% and decreased the AR of prey by 27.34%. Masquerade was the camouflage strategy that most increased predator ST (295.43%). Background matching and disruptive coloration did not differ from each other. Motion camouflage did not increase ST but decreases AR on prey. We found no evidence that eyespot increases ST and decreases AR by predators. The different types of predators did not differ from each other, but caterpillars were the type of prey that most influenced the magnitude of camouflage's effect. We highlight the potential evolutionary mechanisms that led camouflage to be a highly effective anti-predatory adaptation, as well as potential discrepancies or redundancies among strategies, predator and prey types.
Ecological signal in the size and shape of marine amniote teeth
Authors: Fischer Valentin , Bennion Rebecca F. , Foffa Davide , MacLaren Jamie A. , McCurry Matthew R. , Melstrom Keegan M. , Bardet Nathalie
Published: September 2022

Amniotes have been a major component of marine trophic chains from the beginning of the Triassic to present day, with hundreds of species. However, inferences of their (palaeo)ecology have mostly been qualitative, making it difficult to track how dietary niches have changed through time and across clades. Here, we tackle this issue by applying a novel geometric morphometric protocol to three-dimensional models of tooth crowns across a wide range of raptorial marine amniotes. Our results highlight the phenomenon of dental simplification and widespread convergence in marine amniotes, limiting the range of tooth crown morphologies. Importantly, we quantitatively demonstrate that tooth crown shape and size are strongly associated with diet, whereas crown surface complexity is not. The maximal range of tooth shapes in both mammals and reptiles is seen in medium-sized taxa; large crowns are simple and restricted to a fraction of the morphospace. We recognize four principal raptorial guilds within toothed marine amniotes (durophages, generalists, flesh cutters and flesh piercers). Moreover, even though all these feeding guilds have been convergently colonized over the last 200 Myr, a series of dental morphologies are unique to the Mesozoic period, probably reflecting a distinct ecosystem structure.
Fitness of evolving bacterial populations is contingent on deep and shallow history but only shallow history creates predictable patterns
Authors: Smith Chelsea E. , Smith Adam N. H. , Cooper Tim F. , Moore Francisco B.-G.
Published: September 2022

Long-term evolution experiments have tested the importance of genetic and environmental factors in influencing evolutionary outcomes. Differences in phylogenetic history, recent adaptation to distinct environments and chance events, all influence the fitness of a population. However, the interplay of these factors on a population's evolutionary potential remains relatively unexplored. We tracked the outcome of 2000 generations of evolution of four natural isolates of
Escherichia coli
bacteria that were engineered to also create differences in shallow history by adding previously identified mutations selected in a separate long-term experiment. Replicate populations started from each progenitor evolved in four environments. We found that deep and shallow phylogenetic histories both contributed significantly to differences in evolved fitness, though by different amounts in different selection environments. With one exception, chance effects were not significant. Whereas the effect of deep history did not follow any detectable pattern, effects of shallow history followed a pattern of diminishing returns whereby fitter ancestors had smaller fitness increases. These results are consistent with adaptive evolution being contingent on the interaction of several evolutionary forces but demonstrate that the nature of these interactions is not fixed and may not be predictable even when the role of chance is small.
Effects of gibberellin pastes on fruit quality attributes and storability of niitaka pear
Authors: Yoo Jingi , Song Seok-Yong , Kwon Jung-Geun , Kim Dae Hyun , Win Nay Myo , Kang In-Kyu
Published: September 2022

This study evaluated the effects of four different gibberellin-pastes (GAP) on fruit quality and storability of niitaka pear in 2014 and 2015 consecutive years. Pear fruit stalks were treated with dongbu GA gold, nebaekeo, busa, and GA hyeophwa-pastes at 35 and 37 days after full bloom, respectively. After harvest time, the fruits were stored at 0°C for up to 180 days. In both years, fruit weight was 6.2-21.3% higher in GAP-treated fruits than the control fruits at harvest. In 2014 year, flesh firmness was higher in control (70.6 N) than the GAP-treated fruits (54.4-64.6 N) at harvest, but it was not different in all treatments in 2015 year. The titratable acidity (TA) at harvest was also higher in control than the GAP treated fruits in 2014 year. The soluble solids content (SSC) at harvest was slightly lower in control than the GAP treated fruits in both years. During cold storage, flesh firmness was decreased in all treatments, whereas the fruits treated with nebaekeo GAP had the lowest flesh firmness (39.4 N) after 135 days of the storage. TA was a slightly higher in control (0.19%) than the GAP-treated fruits (0.14-0.17%) after 180 days of storage. However, SSC was higher in the fruits treated with dongbu GA gold and GA hyeophwa-pastes than the control fruits during storage. Therefore, GAP-treatments increased fruit weight and SSC than control, but flesh firmness and TA of GAP-treated fruits were reduced after 180 days of the storage.
Effects of elephant garlic (Allium ampeloprasum)
extract on testosterone synthesis in TM3 Leydig cells
Authors: Park Se-Eun , Lee Hyo-Jeong , Jeong In-Seon , Kim Seung
Published: September 2022

This work investigated the effects of Allium ampeloprasum
extract (AME) on testosterone synthesis in TM3 Leydig cells under hydrogen
peroxide (H2O2)-induced oxidative stress. AME showed no
increment of cell proliferation in the oxidatively stressed cells. Testosterone
level lowered when the cells were treated with H2O2, but
increased in the presence of AME. To determine the effect of AME on the
testosterone biosynthetic pathway, we examined the expression level of the
proteins involved in the synthesis or degradation of testosterone. The protein
expression levels of CYP11A1, 3β-HSD2 and
17β-HSD3 (which are involved in testosterone
synthesis) were decreased by H2O2 but increased by the AME
treatment. Furthermore, the protein expression levels of
5α-reductase2 and aromatase (which are involved in
testosterone degradation) were increased by H2O2 but
decreased by the AME treatment. In conclusion, AME increased the testosterone
level by increasing the expression of testosterone synthetase and decreasing the
expression of the testosterone converting enzyme in TM3 Leydig cells under
H2O2-induced oxidative stress. These results indicated
that AME can alleviate andropause syndrome by restoring testosterone.
Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells
Authors: Sun Tongyu , Xu Yueyuan , Xiang Yu , Soderblom Erik J , Diao Yarui
Published: September 2022

Transposable elements (TEs) are parasitic DNA sequences accounting for over half of the human genome. Tight control of the repression and activation states of TEs is critical for genome integrity, development, immunity, and diseases, including cancer. However, precisely how this regulation is achieved remains unclear. To address this question, we develop a targeted proteomic proximity labeling approach to capture TE-associated proteins in human embryonic stem cells (hESCs). We find that the RNA N6-methyladenosine(m6A)-reader, YTHDC2, occupies genomic loci of the primate-specific TE, LTR7/HERV-H, specifically through its interaction with m6A-modified HERV-H RNAs. Unexpectedly, YTHDC2 recruits the DNA 5-methylcytosine(5mC)-demethylase, TET1, to remove 5mC from LTR7/HERV-H and prevent epigenetic silencing. Functionally, the YTHDC2/LTR7-axis inhibits neural differentiation of hESCs. Our results reveal both an underappreciated crosstalk between RNA m6A and DNA 5mC, the most abundant regulatory modifications of RNA and DNA in eukaryotes, and the fact that in hESCs this interplay controls TE activity and cell fate.
Temperature and dietary energy content influence female maturation age and egg nutritional content in Atlantic salmon
Authors: Maamela Katja S. , Åsheim Eirik R. , Debes Paul V. , House Andrew H. , Erkinaro Jaakko , Liljeström Petra , Primmer Craig R. , Mobley Kenyon B.
Published: September 2022

The environment experienced by a female influences reproductive traits in many species of fish. Environmental factors such as temperature and diet are not only important mediators of female maturation and reproduction but also of egg traits and offspring fitness through maternal provisioning. In this study, we use three-year-old, tank-reared, Atlantic salmon from two Finnish populations to investigate the effect of temperature and diet on maturation and egg traits. We show that a temperature difference of 2°C is sufficient to delay maturation in female Atlantic salmon whereas a 22% reduction in dietary energy content had no effect on maturation. Diet did not influence the body size, condition, or fecundity of the mature females or the size or protein content of the eggs. However, a higher energy diet increased egg lipid content. Neither female body size nor condition were associated with egg size or fat/protein composition. Our results indicate that female salmon that have a poorer diet in terms of energy content may have a reproductive disadvantage due to lower energy provisioning of eggs. This disadvantage has the potential to translate into fitness consequences for their offspring.
Increased conductance associated with higher photosynthesis in leaves and green stems of avocado exposed to diffuse light
Authors: Berry Z. Carter , Ávila-Lovera Eleinis , Ellertson Kendra , Goldsmith Gregory R.
Published: September 2022

Research has demonstrated that diffuse light drives changes in leaf photosynthesis, with the direction and magnitude varying across species; however, our understanding of the relationship between diffuse light and plant gas exchange, as well as the mechanisms driving these relationships remain unresolved. We studied the effects of diffuse light on plant function in potted individuals ofPersea americana(avocado). We first measured leaf gas exchange subject to varying proportions of direct and diffuse light, as well as photosynthetic response to varying CO2(A-Cicurves) in predominantly direct and predominantly diffuse light. We find that leaf photosynthetic rates increase as the proportion of diffuse light increases and that those changes are associated with stomatal conductance, rather than photosynthetic biochemistry. Given that avocados have green stems, we then measured stem gas exchange in predominantly direct compared to predominantly diffuse light. While we also observed an increase in conductance in stems subject to diffuse light, there was not an increase in photosynthetic rate, effectively decoupling gas flux from carbon gain. Finally, by scaling measurements of gas exchange to the plant, we demonstrate that stem bark conductance contributes proportionally more to whole-plant conductance under diffuse light. Our results add to our understanding of the potential mechanisms that govern how plant function varies in response to changes in light quality, the first paper to demonstrate mechanisms to explain increases under diffuse light. As diffuse light increases globally, this variable needs to be integrated into our understanding of plant carbon-water tradeoffs in response to climate change.
Transcriptional profiles of functionally distinct HLADR+CD38+ CD8 T cells subsets from acute febrile dengue patients
Authors: Singh Prabhat , Bajpai Prashant , Maheshwari Deepti , Chawla Yadya M , Gottimukkala Kamalvishnu , Reddy Elluri Seetharami , Saini Keshav , Nayak Kaustuv , Gunisetty Sivaram , Aggarwal Charu , Jain Shweta , Chaitanya  , Singla Paras , Soneja Manish , Wig Naveet , Murali-Krishna Kaja , Chandele Anmol
Published: September 2022

Previous studies showed that a discrete population of the CD8 T cells with HLADR+CD38+ phenotype expand massively during the acute febrile phase of dengue natural infection. Although about a third of these massively expanding HLADR+CD38+ CD8 T cells were of CD69high phenotype, only a small fraction of them produced IFNγ upon in vitro peptide stimulation. What other cytokines/ chemokines do these peptides stimulated HLADR+CD38+ CD8 T cells express, what transcriptional profiles distinguish the CD69+IFNγ+, CD69+IFNγ-, and CD69-IFNγ- subsets, and whether the expansion of the total HLADR+CD38+ CD8 T cells or the IFNγ producing CD8 T cells differ depending on disease severity remained unclear. This study addresses these knowledge gaps. We find that the CD69+IFNγ+ subset uniquely expressed key genes involved in protein translation, cellular metabolism, proliferation and dendritic cell cross talk. Both the CD69+IFNγ+ and CD69+IFNγ- subsets had an antigen responsive gene signature with genes involved in cytotoxic effector functions, regulation of T cell receptor signaling, signaling by MAPK, chemotaxis and T cell trafficking to inflamed tissues with the expression being more robust in the IFNγ+ CD69+ subset. On the other hand, the CD69- IFNγ- subset was biased towards expression of genes that both augment and dampen T cell responses. Lastly, the expansion of total HLADR+ CD38+ CD8 T cells and also the IFNγ producing HLADR+ CD38+ CD8 T cells was similar in patients with different grades of disease. Taken together, this study provides valuable insights into the inherent diversity of the effector CD8 T cell response during dengue.
Low precipitation due to climate change consistently reduces multifunctionality of urban grasslands in mesocosms
Authors: Rojas-Botero Sandra , Teixeira Leonardo H. , Kollmann Johannes
Published: September 2022

Urban grasslands are crucial for biodiversity and ecosystem services in cities, while little is known about their multifunctionality under climate change. Thus, we investigated the effects of simulated climate change, i.e., increased [CO2] and temperature, and reduced precipitation, on individual functions and overall multifunctionality in mesocosm grasslands sown with forbs and grasses in four different proportions aiming at mimicking road verge grassland patches. Climate change scenarios RCP 2.6 (control) and RCP 8.5 (worst-case) were simulated in walk-in climate chambers (ca. 7.7 m2), and watering was manipulated for normal vs. reduced precipitation. We measured eight indicator variables of ecosystem functions based on below- and above-ground characteristics. Recently established grassland communities responded to higher [CO2] and warmer conditions with increased vegetation cover, height, flower production, and soil respiration. Lower precipitation affected carbon cycling in the ecosystem by reducing biomass production and soil respiration. In turn, the water regulation capacity of the grasslands depended on precipitation interacting with climate change scenario, given the enhanced water efficiency resulting from increased [CO2] under RCP 8.5. Multifunctionality was negatively affected by reduced precipitation, especially under RCP 2.6. Trade-offs arose among single functions that performed best in either grass- or forb-dominated grasslands. Grasslands with an even ratio of plant functional types coped better with climate change and thus are good options for increasing the benefits of urban green infrastructure. Overall, we provide experimental evidence on the effects of climate change on the functionality of urban ecosystems. Designing the composition of urban grasslands based on ecological theory may increase their resilience to global change.
Time-scaled phylogenetic analysis of extant Lamiinae (Coleoptera, Cerambycidae) species of East of Marmara Basin, Türkiye, and their evolutionary similarity with the Eurasian congeners
Authors: Soydabaş-Ayoub Havva Kübra , Uçkan Fevzi
Published: September 2022

The subfamily Lamiinae (Cerambycidae, Coleoptera) is striking due to its morphological diversity and species richness with intricate phylogenetic relationships. We inferred the phylogeny and evolutionary history of extant species of East of Marmara Basin, Türkiye, from the tribes Acanthocinini, Acanthoderini, Agapanthiini, Batocerini, Dorcadionini, Lamiini, Mesosini, Monochamini, Phytoeciini, Phrynetini, Pogonocherini (including Exocentrini) and Saperdini using partial mitochondrial cytochromecoxidase-I (COI) and16S rRNAand nuclear28S rRNAgene regions (2257 base pair alignment length). The most recent common ancestor (MRCA) of Lamiinae members included in the analyses was dated ∼127 million years ago (Mya) in the Cretaceous. The MRCA of Dorcadionini, Lamiini and Monochamini was younger than the common ancestors of the other close tribes. There was a concurrence between resolutions of Maximum Likelihood (ML) and Bayesian analyses on the affiliations of Dorcadionini and Monochamini to Lamiini and the proximity of Batocerini to Lamiini, Acanthocinini to Acanthoderini, Phrynetini to Pogonocherini, and Phytoeciini to Saperdini. TheCOI-based Neighbor-Joining and ML gene trees suggest that the closest relatives of the extant Lamiinae species of East of Marmara Basin were the European conspecifics or congeners. Moreover,ParaleproderaandLamia(Lamiini) were sisters toImantocera(Gnomini),Oberea(Obereini) toPhytoeciaPhytoeciini), andHippopsis(Agapanthiini) toOmosarotes singularisPascoe, 1860 (Acanthomerosternoplini). Our results support Dorcadionini, Gnomini and Monochamini as synonyms of Lamiini; and Obereini and Phytoeciini of Saperdini and suggest that the emergence of the living tribes included in this study was during Paleogene, and their intrageneric diversifications occurred during Cenozoic, mostly Neogene.
Genome-wide association studies of polygenic risk score-derived phenotypes may lead to inflated false positive rates
Authors: Uffelmann Emil , Posthuma Danielle , Peyrot Wouter J.
Published: September 2022

In a recent study, a polygenic risk score (PRS) for Alzheimer’s disease was used to construct a new phenotype for a subsequent genome-wide association study (GWAS). Here we show that the applied method, in which the same genetic variants are used to construct the PRS-derived phenotype as well as to assess their effect in a GWAS of the same phenotype, leads to inflated false positive rates. We illustrate this bias by simulation. We first simulate an initial discovery cohort, and run a GWAS of a disorder like Alzheimer’s disease. We then simulate a target cohort, in which we construct a PRS based on the initial GWAS results. Following the published study, we select the bottom and top 5% of individuals in the PRS distribution and define them as controls and cases. Lastly, we run a GWAS on the new PRS-derived phenotype using all genetic variants. We show that at a significance threshold of 5 × 10−8, false positive rates are inflated up to 0.004 (an 80,000-fold increase compared to 5 × 10−8). We also show that such inflation can be prevented by excluding all variants that were used to construct the PRS (as well as all variants in linkage disequilibrium), when a GWAS on a PRS-derived phenotype is conducted.
The glutathione S-transferase Gstt1 is a robust driver of survival and dissemination in metastases
Authors: Ferrer Christina M. , Boon Ruben , Cho Hyo Min , Bernasocchi Tiziano , Wong Lai Ping , Cetinbas Murat , Haggerty Elizabeth R. , Mitsiades Irene , Wojtkiewicz Gregory R. , McLoughlin Daniel E. , Kugel Sita , Rheinbay Esther , Sadreyev Ruslan , Juric Dejan , Mostoslavsky Raul
Published: September 2022

Identifying adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (PDA), where the majority of patients present with metastatic lesions at the time of diagnosis. A loss-of-function shRNA targeted screen in metastatic-derived cells identifiedGstt1, a member of the glutathione S-transferase superfamily, as uniquely required for metastasis and dissemination however dispensable for primary tumor growth.Gstt1is expressed in early disseminated tumor cells (DTCs), is retained within a subpopulation of slow-cycling cells within established metastases and its inhibition led to a regression of macrometastatic lesions. This distinct Gstt1highpopulation is highly metastatic and retains slow-cycling phenotypes, EMT features, and DTC characteristics compared to the Gstt1lowpopulation. Mechanistic studies indicate that in this subset of cells, Gstt1 maintains metastases by binding to and modifying intracellular fibronectin, regulating Fibronectin secretion from cancer cells and deposition into the metastatic microenvironment. We identified Gstt1 as a novel mediator of metastasis, highlighting the importance of metastatic heterogeneity and its influence on the metastatic tumor microenvironment.
Discovery of a novel monoclonal PD-L1 antibody H1A that promotes T-cell mediated tumor killing activity in renal cell carcinoma
Authors: An Zesheng , Hsu Michelle A. , Gicobi Joanina K. , Xu Tianxiao , Harrington Susan M. , Zhang Henan , Pavelko Kevin D. , Hirdler Jacob B. , Lohse Christine M. , Nabavizadeh Reza , Pessoa Rodriguo R. , Sharma Vidit , Thompson R. Houston , Leibovich Bradley C. , Dong Haidong , Lucien Fabrice
Published: September 2022

In the last decade, the therapeutic landscape of renal cell carcinoma has rapidly evolved with the addition of PD-1/PD-L1 immune checkpoint inhibitors in the armamentarium of oncologists. Despite clinical evidence of improved oncological outcomes, only a minority of patients experience long-lasting antitumor immune response and complete response. The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians as no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex-vivo functional assay that measure the tumor cell killing ability of patient-derived CD8 T cells isolated from peripheral blood. Cytotoxic activity of CD8 T cells was improved at 3-month post-radical nephrectomy compared to baseline and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Pretreatment of peripheral immune cells with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CD8 T cells but differential response was observed at the individual patient level. Finally, we found a newly developed monoclonal antibody (H1A), which induces PD-L1 degradation, demonstrated superior efficacy in promoting T-cell mediated tumor killing activity compared to FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T cells in H1A-treated PBMC. To conclude, our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor. Furthermore, further work is needed to evaluate the potential of measuring T-cell cytotoxicity activity as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.
Genetic deletion and pharmacologic inhibition of FcER1 reduces renal injury in mouse models of diabetic nephropathy
Authors: Rashmi Priyanka , Silva Andrea Alice , Sigdel Tara , Damm Izabella , Gouvêa Ana Luisa Figueira , Koliwad Suneil , Walavalkar Vighnesh , Hakroush Samy , Sarwal Minnie M.
Published: September 2022

FcER1 forms a high affinity multimeric cell-surface receptor for the Fc region of immunoglobulin E (IgE) and controls the activation of mast cells and basophils. Antigen binding and cross-linking of FcER1 associated IgE induces several downstream signaling pathways that result in diverse outcomes. Canonical signaling through IgE-FcER1 has been related to allergic responses, however, recent studies have identified that their function in mast cell and basophils contribute to other pathogenic conditions such as cancer and diabetes. Previous studies have demonstrated that FcER1 protein is upregulated in advanced diabetic kidney disease (DKD) making it a targetable molecule for the treatment of DKD. This study presents evidence that loss of FcER1 signaling reduces proteinuria and renal injury in two pre-clinical mouse models of diabetes. Mice deficient for fcer1 are protected from streptozotocin mediated induction of proteinuria and display reduced fibrosis and mast cell infiltration in kidney. Furthermore, inhibition of FcER1 signaling with an antibody directed against the γ-subunit reduces proteinuria in a spontaneous model of type II diabetes. Our results show significant reduction of proteinuria and tissue damage in pre-clinical DKD models demonstrating the potential of FcER1 inhibitory approaches for developing new therapies in DKD.
HiC4D: Forecasting spatiotemporal Hi-C data with residual ConvLSTM
Authors: Liu Tong , Wang Zheng
Published: September 2022

Motivation

The Hi-C experiments have been extensively used for the studies of mammalian genomic structures. In the last few years, spatiotemporal Hi-C has significantly contributed to the study of genome dynamic reorganization. However, computationally forecasting spatiotemporal Hi-C data still has not been seen in the literature.

Results

We present HiC4D for addressing the problem of forecasting spatiotemporal Hi-C data. We designed and tested a novel network, which is a combination of residual network and convolutional long short-term memory (ConvLSTM), and named it residual ConvLSTM (ResConvLSTM). We evaluated our new method and compared it with other four methods including three outstanding video-prediction methods from the literature: ConvLSTM, spatiotemporal LSTM (ST-LSTM), and simple video prediction (SimVP), and one self-designed naïve network (NaiveNet) as a baseline. We used four different spatiotemporal Hi-C datasets for the blind test, including two from mouse embryogenesis, one from somatic cell nuclear transfer (SCNT) embryos, and one from human embryogenesis. Our evaluation results indicate that ResConvLSTM almost always outperforms the other four methods on four blind-test datasets in terms of accurately reproducing spatiotemporal Hi-C contact matrices at future time steps. Our benchmarks also indicate that all five methods can successfully recover the boundaries of topologically associating domains (TADs) called on the experimental Hi-C contact matrices.

Availability

HiC4D is publicly available athttp://dna.cs.miami.edu/HiC4D/.
Haloperidol-induced immediate early genes in striatopallidal neurons requires the converging action of cAMP/PKA/DARPP-32 and mTOR pathways
Authors: Onimus Oriane , Valjent Emmanuel , Fisone Gilberto , Gangarossa Giuseppe
Published: September 2022

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R) which is abundant in the striatum and involved in both the therapeutic and side effects of this drugs class. Pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-size spiny neurons (MSNs), leads to a plethora of molecular, cellular and behavioral adaptations which are central in the action of antipsychotics. Here, we focused on the cell type-specific (D2R-MSNs) regulation of some striatal immediate early genes (IEGs), such as cFos, Arc and Zif268. Taking advantage of transgenic mouse models, pharmacological approaches and immunofluorescence analyses, we found that haloperidol-induced IEGs in the striatum required the synergistic activation of A2a (adenosine) and NMDA (glutamate) receptors. At the intracellular signaling level, we found that the PKA/DARPP-32 and mTOR pathways synergistically cooperate to control the induction of IEGs by haloperidol. By confirming and further expanding previous observations, our results provide novel insights into the regulatory mechanisms underlying the molecular/cellular action of antipsychotics in the striatum.
Subjective assessment and taste strips testing of gustatory function, at home, and in the lab
Authors: Green Tomer , Wolf Anne , Oleszkiewicz Anna , Aronis Anna , Hummel Thomas , Pepino Marta Y , Niv Masha Y
Published: September 2022

Gustatory ability is an important marker of health status, including COVID-19 disease. We compare self-reporting with home and lab psychophysical “taste strips” tests in healthy subjects. The taste test consisted of paper strips impregnated with sweet, bitter, salty, or sour tastants, and with the trigeminal stimulus capsaicin, each in high and in low concentration. The test was carried out either in a controlled lab environment (74 participants, 47 women) with the strips being administered by the experimenter or self-administered by the participants at home (77 participants, 59 women). After self-reporting their subjective assessment of chemosensory ability, the participant identified the taste of each strip and rated intensity and pleasantness.

Identification score, intensity, and pleasantness averaged over the 8 taste strips were similar between the lab and the home-administered tests. Self-rated taste ability did not correlate with any of these scores, but strongly correlated with self-rated smell ability in the lab group (r=0.73), and moderately correlated in the home group (r=0.51). Taste identification correlated with intensity ratings (r=0.63 lab, r=0.36 home) but not with the pleasantness ratings (r=-0.14 lab, r=0.1 home).

The results of the taste strips test were similar in the lab and at home for healthy young participants and provide a baseline against which taste tests can be compared in future applications.
Design, synthesis and biological evaluation of novel quercetin derivatives as PPAR-γ partial agonists by modulating Epithelial-mesenchymal transition in lung cancer metastasis
Authors: Ballav Sangeeta , Bhosale Mrinalini , Lokhande Kiran Bharat , Paul Manash K. , Padhye Subhash , Swami K. Venkateswara , Ranjan Amit , Basu Soumya
Published: September 2022

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT, cellular differentiation, fatty acid metabolism, insulin sensitivity and adipogenesis. Several synthetic compounds act as potent full agonist for PPAR-γ. However, owing to their serious adverse effects, restricts their long-term application. Therefore, partial agonist has been greatly in demand which involves reduced and balanced PPAR-γ activity. Our previous study discerned the efficacy of quercetin and its derivatives to attain favourable stabilization with PPAR-γ. Here we extended this work by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC) and hydrazones (QUEINH, QUENH, QUE2FH and QUESH) and analysed their effects in modulating EMT of lung cancer cell lines via PPAR-γ partial activation. QDs-treated A549 cells exhibited cell death strongly in a dose and time dependent manner at nanomolar concentration along with anti-migratory effects compared to NCI-H460 cells. Of the five derivatives we screened, QUETSC, QUE2FH and QUESH exhibited the property of partial activation as compared to the over-expressive level of rosiglitazone (RSG). Consistently, with PPAR-γ partial activation, these QDs also suppressed EMT process by markedly down-regulating the levels of mesenchymal markers (Snail, Slug and Zeb-1) and concomitant up-regulation of epithelial marker (E-cadherin). In the light of these evidences; QUETSC, QUE2FH and QUESH could be used as a novel selective partial PPAR-γ modulators whose pharmacological properties is distinct from RSG and may be exploited as potential therapeutic anti-metastatic agent.
The perception of auditory motion in sighted and early blind individuals
Authors: Park Woon Ju , Fine Ione
Published: September 2022

Motion detection is a fundamental property of the visual system that plays an important role across many of the human senses. In vision, motion processing is classically described using a motion energy model which assumes spatiotemporally selective (i.e., non-separable) filters that capture the smooth continuous change in spatial position over time afforded by moving objects. However, in the case of audition, it is still not clear whether or not the primary mechanisms underlying motion sensitivity are spatiotemporally selective. We used a psychophysical reverse correlation paradigm, where participants discriminated the direction of a motion signal in the presence of spatiotemporal noise, to determine whether the filters underlying auditory motion discrimination were spatiotemporally separable or non-separable. We then examined whether these auditory motion filters were altered as a result of early blindness. We found that both sighted and early blind individuals have separable filters. However, early blind individuals show increased sensitivity to auditory motion, with reduced susceptibility to noise, with filters that were more accurate in detecting motion onsets/offsets. An ideal observer model suggested that the reliance on separable filters may be more optimal given the limited spatial resolution in auditory input.
Network controllability measures of subnetworks: implications for neurosciences
Authors: Stocker Julia Elina , Nozari Erfan , van Vugt Marieke , Jansen Andreas , Jamalabadi Hamidreza
Published: September 2022

Recent progress in network sciences has made it possible to apply key findings from control theory to the study of networks. Referred to as network control theory, this framework describes how the interactions between interconnected system elements and external energy sources, potentially constrained by different optimality criteria, result in complex network behavior. A typical example is the quantification of the functional role certain brain regions or symptoms play in shaping the temporal dynamics of brain activity or the clinical course of a disease, a property that is quantified in terms of the so-called controllability metrics. Critically though, contrary to the engineering context in which control theory was originally developed, a mathematical understanding of the network nodes and connections in neurosciences cannot be assumed. For instance, in the case of psychological systems such as those studied to understand the psychiatric disorders, a potentially large set variables are unknown. As such, while the measures offered by network control theory would be mathematically correct, in that they can be calculated with high precision, they could have little translational values with respect to their putative role suggested by controllability metrics. It is therefore critical to understand if and how the controllability metrics computer over subnetworks would deviate, if access to the complete set of variables, as in neurosciences, cannot be taken for granted. In this paper, we use a host of simulations based on synthetic as well as structural MRI data to study the potential deviation of controllability metrics in sub-compared to the full networks. Specifically, we estimate average- and modal-controllability, two of the most widely used controllability measures in neurosciences, in a large number of settings where we systematically vary network type, network size, and edge density. We find out, across all network types we test, that average and modal controllability are systematically, either over- or underestimated depending on the number of nodes in the sub- and full network and the edge density. Finally, we provide a formal theoretical proof that our observations generalize to any network type and discuss the ramifications of this systematic bias and potential solutions to alleviate the problem.