bluuebunny/crossref_metadata_2025 huggingface dataset:
Two galacturonosyltransferases function in plant growth, stomatal development, and dynamics
Authors: Guo Huimin , Xiao Chuanlei , Liu Qing , Li Ruiying , Yan Zhiqiang , Yao Xuan , Hu Honghong
Published: September 2021

The mechanical properties of guard cell (GC) walls are important for stomatal development and stomatal response to external stimuli. However, the molecular mechanisms of pectin synthesis and pectin composition controlling stomatal development and dynamics remain poorly explored. Here, we characterized the role of two Arabidopsis (Arabidopsis thaliana) galacturonosyltransferases, GAUT10 and GAUT11, in plant growth, stomatal development, and stomatal dynamics. GAUT10 and GAUT11 double mutations reduced pectin synthesis and promoted homogalacturonan (HG) demethylesterification and demethylesterified HG degradation, resulting in larger stomatal complexes and smaller pore areas, increased stomatal dynamics, and enhanced drought tolerance of plants. In contrast, increased GAUT10 or GAUT11 expression impaired stomatal dynamics and drought sensitivity. Genetic interaction analyses together with immunolabeling analyses suggest that the methylesterified HG level is important in stomatal dynamics, and pectin abundance with the demethylesterified HG level controls stomatal dimension and stomatal size. Our results provide insight into the molecular mechanism of GC wall properties in stomatal dynamics, and highlight the role of GAUT10 and GAUT11 in stomatal dimension and dynamics through modulation of pectin biosynthesis and distribution in GC walls.
The price of ‘golden’ exploitation: How money flows from the super-rich to domestic workers support inequalities
Authors: Delpierre Alizée
Published: September 2021

Wealthy people can afford full-time domestic staff at home to be served every day. Some of them spend huge amount of money in domestic service. Working for the rich, domestic workers thus receive wages, gifts and compensations in kind. They can potentially improve their standard of living. Why do super-rich pay so much for their household staff? Following the intuition of Paul Segal about inequality as entitlement over labor, I argue that money as entitlement over labor rests on what I call the ‘golden’ exploitation of the workforce. Substantial rewards do not call into question the exploitative relationship. High value gifts and high salary support exploitation even in situations where it is most likely to be undermined. The case of the ‘super-rich’ domesticity illustrates a hidden production of social inequalities: money compensates for the unlimited drudgery of the employees.
‘The Waste of Daylight’: Rhythmicity, Workers’ Health and Britain’s Edwardian Daylight Saving Time Bills
Authors: Hussey Kristin D
Published: September 2021

This article explores an interesting episode in the history of time, health, and modernity: Britain’s 1908 and 1909 Daylight Saving Time (DST) Bills. While the original DST scheme was unsuccessful, the discussions surrounding its implementation reveal tensions central to early twentieth century modernity, namely between industrial time and ‘natural’ bodily rhythms. This article argues that DST was essentially a public health measure aimed at improving the conditions of indoor workers like shop girls and clerks through government regulation of the private time of the labouring classes. Drawing on the extensive evidence provided to two House of Commons Special Committees, this article reveals how DST debates drew together contemporary discussions around sunlight therapy, night work, and the importance of regular sleeping and eating to tackle Britain's endemic urban diseases like consumption and anaemia. I suggest that the idea of bodily rhythms was increasingly important in medical thinking in this period and that the study of rhythmicity points to the potential for incorporating temporality as an analytical category in medical history.
First Draft Genome Assemblies ofPleochaeta shiraianaandPhyllactinia moricola, Two Tree-Parasitic Powdery Mildew Fungi with Hemiendophytic Mycelia
Authors: Kusch Stefan , Vaghefi Niloofar , Takamatsu Susumu , Liu Shu-Yan , Németh Márk Z. , Seress Diána , Frantzeskakis Lamprinos , Chiu Pin-En , Panstruga Ralph , Kiss Levente
Published: September 2021

Powdery mildew fungi (Erysiphaceae) are widespread obligate biotrophic plant pathogens. Thus, applying genetic and omics approaches to study these fungi remains a major challenge, particularly for species with hemiendophytic mycelium. These belong to a distinct phylogenetic lineage within the family Erysiphaceae. To date, only a single draft genome assembly is available for this clade, obtained for Leveillula taurica. Here, we generated the first draft genome assemblies of Pleochaeta shiraiana and Phyllactinia moricola, two tree-parasitic powdery mildew species with hemiendophytic mycelium, representing two genera that have not yet been investigated with genomics tools. The Pleochaeta shiraiana assembly was 96,769,103 bp in length and consisted of 14,447 scaffolds, and the Phyllactinia moricola assembly was 180,382,532 bp in length on 45,569 scaffolds. Together with the draft genome of L. taurica, these resources will be pivotal for understanding the molecular basis of the lifestyle of these fungi, which is unique within the family Erysiphaceae.
December Is Coming: A Time Trend Analysis of Monthly Variation in Adult Elective Anesthesia Caseload across Florida and Texas Locations of a Large Multistate Practice
Authors: Piersa Anastasia Pozdnyakova , Tung Avery , Dutton Richard P. , Shahul Sajid , Glick David B.
Published: September 2021

Background

Anesthesia staffing models rely on predictable surgical case volumes. Previous studies have found no relationship between month of the year and surgical volume. However, seasonal events and greater use of high-deductible health insurance plans may cause U.S. patients to schedule elective surgery later in the calendar year. The hypothesis was that elective anesthesia caseloads would be higher in December than in other months.

Methods

This review analyzed yearly adult case data in Florida and Texas locations of a multistate anesthesia practice from 2017 to 2019. To focus on elective caseload, the study excluded obstetric, weekend, and holiday cases. Time trend decomposition analysis was used with seasonal variation to assess differences between December and other months in daily caseload and their relationship to age and insurance subgroups.

Results

A total of 3,504,394 adult cases were included in the analyses. Overall, daily caseloads increased by 2.5 ± 0.1 cases per day across the 3-yr data set. After adjusting for time trends, the average daily December caseload in 2017 was 5,039 cases (95% CI, 4,900 to 5,177), a 20% increase over the January-to-November baseline (4,196 cases; 95% CI, 4,158 to 4,235; P < 0.0001). This increase was replicated in 2018: 5,567 cases in December (95% CI, 5,434 to 5,700) versus 4,589 cases at baseline (95% CI, 4,538 to 4,641), a 21.3% increase; and in 2019: 6,103 cases in December (95% CI, 5,871 to 6,334) versus 5,045 cases at baseline (95% CI, 4,984 to 5,107), a 21% increase (both P < 0.001). The proportion of commercially insured patients and those aged 18 to 64 yr was also higher in December than in other months.

Conclusions

In this 3-yr retrospective analysis, it was observed that, after accounting for time trends, elective anesthesia caseloads were higher in December than in other months of the year. Proportions of commercially insured and younger patients were also higher in December. When compared to previous studies finding no increase, this pattern suggests a recent shift in elective surgical scheduling behavior.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Persistent Postoperative Opioid Prescription Fulfillment and Peripheral Nerve Blocks for Ambulatory Shoulder Surgery: A Retrospective Cohort Study
Authors: Hamilton Gavin M. , Tierney Sarah , Ramlogan Reva , McCartney Colin J. L. , Bromley Lisa A. , McIsaac Daniel I.
Published: September 2021

Background

There is need to identify perioperative interventions that decrease chronic opioid use. The authors hypothesized that receipt of a peripheral nerve block would be associated with a lower incidence of persistent postoperative opioid prescription fulfillment.

Methods

This was a retrospective population-based cohort study examining ambulatory shoulder surgery patients in Ontario, Canada. The main outcome measure was persistent postoperative opioid prescription fulfillment. In opioid-naive patients (no opioid prescription fulfillment in 90 days preoperatively), this was present if an individual fulfilled an opioid prescription of at least a 60-day supply during postoperative days 90 to 365. In opioid-exposed (less than 60 mg oral morphine equivalent dose per day within 90 days preoperatively) or opioid-tolerant (60 mg oral morphine equivalent dose per day or above within 90 days preoperatively) patients, this was classified as present if an individual experienced any increase in opioid prescription fulfillment from postoperative day 90 to 365 relative to their baseline use before surgery. The authors’ exposure was the receipt of a peripheral nerve block.

Results

The authors identified 48,523 people who underwent elective shoulder surgery from July 1, 2012, to December 31, 2017, at one of 118 Ontario hospitals. There were 8,229 (17%) patients who had persistent postoperative opioid prescription fulfillment. Of those who received a peripheral nerve block, 5,008 (16%) went on to persistent postoperative opioid prescription fulfillment compared to 3,221 (18%) patients who did not (adjusted odds ratio, 0.90; 95% CI, 0.83 to 0.97; P = 0.007). This statistically significant observation was not reproduced in a coarsened exact matching sensitivity analysis (adjusted odds ratio, 0.85; 95% CI, 0.71 to 1.02; P = 0.087) or several other subgroup and sensitivity analyses.

Conclusions

This retrospective analysis found no association between receipt of a peripheral nerve block and a lower incidence of persistent postoperative opioid prescription fulfillment in ambulatory shoulder surgery patients.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
The clinical significance of esophagogastric varices in patients with advanced pancreatic cancer
Authors: Chen Yu-Jen , Hou Ming-Chih , Yang Tsung-Chieh , Lee Pei-Chang , Chao Yee , Li Chung-Pin , Huang Yi-Hsiang , Lee Fa-Yauh
Published: September 2021

Background:

The prevalence of esophagogastric varices (EGV) in patients with advanced pancreatic cancer is not rare. However, its clinical significance has never been investigated. This study was aimed to explore the clinical implication and outcomes of these patients.

Methods:

A retrospective analysis comprising 224 patients with advanced pancreatic cancer managed from October 2012 to December 2019 at a tertiary medical center identified 35 patients who had presented with EGV. Clinical characteristics and outcomes were analyzed with special emphasis on comparison between patients with early-onset and late-onset EGV.

Results:

Patients with EGV had lower platelet count and a higher proportion of splenomegaly but no difference in overall survival in comparison to those without EGV. Patients with early-onset EGV had a poorer bleeding survival (hazard ratio, 8.347; CI, 2.509-27.772; p = 0.001) in comparison to those with late-onset EGV. On multivariate analysis, initial serum bilirubin, γ-Glutamyltransferase, lactate dehydrogenase, cancer stage, and the response to cancer treatment determine the patient’s survival. Patients with tumor invasion to superior mesenteric and portal vein are more likely to have esophageal varices (EV) (EV: 13/15 vs gastric varices [GV]: 4/20; p < 0.001); those with splenic vein invasion are more likely to have GV (EV: 4/15 vs GV: 20/20; p < 0.001).

Conclusion:

Patients with advanced pancreatic cancer and early-onset EGV had poorer bleeding-free survival than those with late-onset EGV. Further studies are needed to clarify the benefits of the prophylactic intervention.
The Debate Between Two of the Founders of American Psychiatric Genetics, Aaron Rosanoff and Abraham Myerson, on Mendelian Models for Psychiatric Illness
Authors: Kendler Kenneth S.
Published: September 2021

In 1911, Aaron Rosanoff published among the first pedigree studies of psychiatric illness, and the first ever in the United States, claiming that the neuropathic constitution was transmitted in as a Mendelian recessive disorder. In 1917, Abraham Myerson harshly critiqued that study, focusing on the very wide phenotypic definition of neuropathic constitution. Here, I describe Rosanoff and Myerson's backgrounds, the details of Rosanoff's study, and Myerson's critique and put this controversy in the context of the history of psychiatric genetics, emphasizing four themes: a) the close interrelationship between psychiatric diagnosis and models of genetic transmission, b) the strong attraction of Mendelian models to psychiatric geneticists after their 1900 rediscovery, c) the controversy about whether familial transmission of psychiatric illness is largely homogeneous or heterogeneous, and d) the methods taken by researchers to the problems of psychiatric genetics that typically emerged as part of their broader approach to the nature of psychiatric illness.
Inpatient compliance with venous thromboembolism prophylaxis after orthopaedic trauma: results from a randomized controlled trial of aspirin versus low molecular weight heparin
Authors: Haac Bryce E. , O’Hara Nathan N. , Manson Theodore T. , Slobogean Gerard P. , Castillo Renan C. , O’Toole Robert V. , Stein Deborah M.
Published: September 2021

Objectives:

To compare inpatient compliance with venous thromboembolism prophylaxis regimens.

Design:

A secondary analysis of patients enrolled in the ADAPT (A Different Approach to Preventing Thrombosis) randomized controlled trial.

Setting:

Level I trauma center.

Patients/Participants:

Patients with operative extremity or any pelvic or acetabular fracture requiring venous thromboembolism prophylaxis.

Intervention:

We compared patients randomized to receive either low molecular weight heparin (LMWH) 30 mg or aspirin 81 mg BID during their inpatient admission.

Main Outcome Measurements:

The primary outcome measure was the number of doses missed compared with prescribed number of doses.

Results:

A total of 329 patients were randomized to receive either LMWH 30 mg BID (164 patients) or aspirin 81 mg BID (165 patients). No differences observed in percentage of patients who missed a dose (aspirin: 41.2% vs LMWH: 43.3%, P = .7) or mean number of missed doses (0.6 vs 0.7 doses, P = .4). The majority of patients (57.8%, n = 190) did not miss any doses. Missed doses were often associated with an operation.

Conclusions:

These data should reassure clinicians that inpatient compliance is similar for low molecular weight heparin and aspirin regimens.
Ricardo Miledi. 15 September 1927—18 December 2017
Authors: Parker Ian , Slater Clarke , Cull-Candy Stuart , Vincent Angela
Published: September 2021

For nearly five decades, Ricardo Miledi was among the foremost researchers in elucidating how nerves transmit signals across synapses. Born in Chihuahua, Mexico, he qualified as a medical doctor, obtained a PhD with Arturo Rosenblueth and then, while in Canberra with John Eccles FRS, was invited by Bernard Katz FRS to join the Biophysics department at University College London, where he stayed from 1958 to 1984. Both independently and with Katz, he demonstrated that influx of calcium into the presynaptic nerve terminal is the essential trigger for the release of the neurotransmitter that carries signals across to the postsynaptic cell. He found that cutting the nerve to a frog's muscle increased the number and distribution of its muscle acetylcholine (ACh) receptors, which he purified and established as membrane proteins. Together with Katz, he introduced the technique of membrane noise analysis to determine the properties of the individual ion channels opened by ACh, providing the first functional characterization of a single receptor with integral ion channel. With Eric Barnard (FRS 1981), he pioneered a new approach facilitating the study of neurotransmitter receptors and ion channels by ‘transplanting’ them from brain and other tissues into largeXenopusoocyte cells by injection of messenger RNA. After moving to the University of California, Irvine, in 1984, he helped to establish the Mexican Institute for Neurobiology at Querétaro. Working in Irvine and Mexico he extended this oocyte expression technique to incorporate transplanted brain membranes, particularly from patients with epilepsy or other neurological disorders. He received many honours for his work, including the Royal Medal (1998), but was happiest working in his lab applying his extraordinary technical skills and imagination to study synaptic transmission and inspiring a generation of neuroscientists.
Prevalence and molecular characteristics of feline coronavirus in southwest China from 2017 to 2020
Authors: Zhou Qun , Li Yan , Huang Jian , Fu Nengsheng , Song Xin , Sha Xue , Zhang Bin
Published: September 2021

Feline coronavirus (FCoV) is the causative agent of feline infectious peritonitis and diarrhoea in kittens worldwide. In this study, a total of 173 feline diarrhoeal faecal and ascetic samples were collected from 15 catteries and six veterinary hospitals in southwest China from 2017 to 2020. FCoV was detected in 80.35 % (139/173) of the samples using the RT-nPCR method; these included infections with 122 type I FCoV and 57 type II FCoV. Interestingly, 51 cases had co-infection with types I and II, the first such report in mainland China. To further analyse the genetic diversity of FCoV, we amplified 23 full-length spike (S) genes, including 18 type I and five type II FCoV. The type I FCoV and type II FCoV strains shared 85.5–98.7% and 97.4–98.9% nucleotide (nt) sequence identities between one another, respectively. The N-terminal domain (NTD) of 23 FCoV strains showed a high degree of variation (73.6–80.3 %). There was six type I FCoV strains with two amino acid insertions (159HL160) in the NTD. In addition, 18 strains of type I FCoV belonged to the Ie cluster, and five strains of type II FCoV were in the IIb cluster based on phylogenetic analysis. Notably, it was first time that two type I FCoV strains had recombination in the NTD, and the recombination regions was located 140–857 nt of the S gene. This study constitutes a systematic investigation of the current infection status and molecular characteristics of FCoV in southwest China.
Role of sleep quality in the acceleration of biological aging and its potential for preventive interaction on air pollution insults: findings from the UK Biobank cohort
Authors: Gao Xu , Huang Ninghao , Huang Tao
Published: September 2021

Background

Sleep has been associated with aging and relevant health outcomes, but their causal relationship remains inconclusive.

Methods

In this study, we investigated the associations of sleep behaviors with biological ages (BAs) among 363,886 middle and elderly-aged adults from UK Biobank. Sleep index (0 [worst]-6 [best]) of each participant was retrieved from six sleep behaviors: snoring, chronotype, daytime sleepiness, sleep duration, insomnia, and difficulties in getting up. Two BAs, the KDM-biological age and PhenoAge, were estimated by corresponding algorithms based on clinical traits, and their discrepancies with chronological age were defined as the age accelerations (AAs).

Results

We first observed negative associations between the sleep index and the two AAs, and demonstrated that the change of AAs could be the consequence of sleep quality using Mendelian randomization with genetic risk scores of sleep index and BAs. Particularly, one unit increase in sleep index was associated with 0.105- and 0.125-year decreases in KDM-biological age acceleration and PhenoAge acceleration, respectively. Furthermore, we observed significant independent and joint effects of sleep and air pollution (i.e. PM2.5 and NO2), another key driver of aging, on BAs. Sleep quality also showed modifying effect on the associations of elevated PM2.5 and NO2 levels with accelerated aging. For instance, an interquartile range increase in PM2.5 level was associated with 0.011-, 0.047-, and 0.078-year increase in PhenoAge acceleration among people with high (5-6), medium (3-4), and low (0-2) sleep index, respectively.

Conclusions

Our findings elucidate that better sleep quality could lessen accelerated biological aging resulting from exogenous exposures including air pollution.

Funding

Peking University Start-up Grant (BMU2021YJ044)
VALIDATION OF A SALIVA-BASED TEST FOR THE MOLECULAR DIAGNOSIS OF SARS-CoV-2 INFECTION
Authors: Bulfoni Michela , Sozio Emanuela , Marcon Barbara , De Martino Maria , Cesselli Daniela , De Carlo Chiara , Martinella Romina , Migotti Angelica , Vania Eleonora , Zanus-Fortes Agnese , De Piero Jessica , Nencioni Emanuele , Tascini Carlo , Isola Miriam , Curcio Francesco
Published: September 2021

Background

Since the beginning of the pandemic, clinicians and researchers have been searching for alternative tests to improve screening and diagnosis of SARS-CoV-2 infection (Y. Yang et al., medRxiv 2020; W. Wang et al., 2020.3786; A Senok et al., Infect Drug Resist 2020). Currently, the gold standard for virus identification is the nasopharyngeal (NP) swab (N. Sethuraman et al., JAMA 2020; A.J. Jamal et al Clinical Infect Disease 2021). Saliva samples, however, offer clear practical and logistical advantages (K.K.W To et al, Clinical Microb and Infect; A.L. Wylle et al. N Engl J Med 2020; N. Matic et al, Eur J Clin 2021) but due to lack of collection, transport, and storage solutions, high-throughput saliva-based laboratory tests are difficult to scale up as a screening or diagnostic tool (D. Esser et al., Biomark Insights 2008; E. Kaufman et al., Crit Rev Oral Biol Med2002). With this study, we aimed to validate an intra-laboratory molecular detection method for SARS-CoV-2 on saliva samples collected in a new storage saline solution, comparing the results to NP swabs to determine the difference in sensitivity between the two tests.

Methods

In this study, 156 patients (cases) and 1005 asymptomatic subjects (controls) were enrolled and tested simultaneously for the detection of the SARS-CoV-2 viral genome by RT-PCR on both NP swab and saliva samples. Saliva samples were collected in a preservative and inhibiting saline solution (Biofarma Srl). Internal method validation was performed to standardize the entire workflow for saliva samples.

Results

The identification of SARS-CoV-2 conducted on saliva samples showed a clinical sensitivity of 95.1% and specificity of 97.8% compared to NP swabs. The positive predictive value (PPV) was 81% while the negative predictive value (NPV) was 99.5%. Test concordance was 97.6% (Cohen’s Kappa=0.86; 95% CI 0.81-0.91). The LoD of the test was 5 viral copies for both samples.

Conclusions

RT-PCR assays conducted on a stored saliva sample achieved similar performance to those on NP swabs and this may provide a very effective tool for population screening and diagnosis. Collection of saliva in a stabilizing solution makes the test more convenient and widely available; furthermore, the denaturing properties of the solution reduce the infective risks belonging to sample manipulation.
Social-economic drivers overwhelm climate in underlying the COVID-19 early growth rate
Authors: Liu Zhenghua
Published: September 2021

Identifying the drivers underlying the spatial occurrence and spreading rate of COVID-19 can provide valuable information for their preventions and controls. Here, we examine how socio-economic and climate drivers affect the early growth rates of COVID-19 in China and the other countries, the former of which have consistently stricter quarantine during early epidemic and thus are used to enquire the influences of human interventions on trainsimissions. We find that the early growth rates of COVID-19 are higher in China than the other countries, which is consistent with previous reports. The global spread is mainly driven by the socio-economic factors such as GDP per capita, human movement and population density rather than climate. Among socio-economic factors, GDP per capita is most important showing negative relationships in China, while positive in the other countries. However, the predicability of early growth rates by socio-economic and climate variables is at least 1.6 times higher in China’s provinces than the other countries, which is further supported by metapopulation network model. These findings collectively indicate that the stochasticity of transimission processes decrease upon strict quarantine measures such as travel restrictions.

Key findings

GDP per capita is most important in driving the spread of COVID-19, which shows negative relationships within China, while positive in the other countries.

Socio-economic and climate factors are key in driving the early growth rate of COVID-19, while the former is more important.

Socio-economic and climate features explain more variations of early growth rates in China due to the decreased stochasticity of transimission processes upon strict quarantine measures.
Store-Operated Calcium Entry Controls Innate and Adaptive Immune Cell Function in Inflammatory Bowel Disease
Authors: Letizia Marilena , Kaufmann Ulrike , Wang Yin-Hu , Gerbeth Lorenz , Sand Annegret , Brunkhorst Max , Ziegler Jörn Felix , Böttcher Chotima , Schlickeiser Stephan , Fernández-Zapata Camila , Stauderman Kenneth , Kunkel Désirée ,   IBDome researchers, Siegmund Britta , Feske Stefan , Weidinger Carl
Published: September 2021

Objective

Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses and constitutes a major clinical challenge in need of new treatment modalities to improve patient care. Store-operated Ca2+entry (SOCE) is the predominant Ca2+influx pathway in T cells and other immune cells, regulating many of their functional properties. It is currently unknown whether the pharmacologic blockade of SOCE represents a suitable drug-target for IBD treatment.

Design

Using mass and flow cytometry the effects of SOCE inhibition on lamina propria (LP) immune cells of patients with ulcerative colitis (UC) and Crohn’s disease (CD) were investigated. Primary organoid cultures served to study the impact of SOCE inhibition on the function, differentiation and survival of intestinal epithelial cells (IEC). T cell transfer models of colitis were applied to examine how the genetic or pharmacologic ablation of SOCE affects the clinical course of IBD in mice.

Results

We observed that the LP of IBD patients is characterized by an enrichment of innate lymphoid cells (ILC), CD4+and CD8+effector- as well as T regulatory cells producing IL-17 and TNFα. The pharmacologic inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17, TNFα and IFNγ by human colonic T cells and ILC, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, without affecting the viability, differentiation and function of primary IEC. T cell-specific genetic deletion of the SOCE signaling componentsOrai1,Stim1orStim2revealed that the magnitude of SOCE correlates with the function of T cells and intestinal inflammation in mice. Moreover, the pharmacologic inhibition of SOCE alleviated the clinical course of colitic mice.

Conclusion

Our data suggest that SOCE inhibition may serve as a new pharmacologic strategy for treating IBD.
Critical Pressure of Intramural Delamination in Aortic Dissection
Authors: Ban Ehsan , Cavinato Cristina , Humphrey Jay D.
Published: September 2021

Computational models of aortic dissection can examine mechanisms by which this potentially lethal condition develops and propagates. We present results from phase-field finite element simulations that are motivated by a classical but seldom repeated experiment. Initial simulations agreed qualitatively and quantitatively with data, yet because of the complexity of the problem it was difficult to discern trends. Simplified analytical models were used to gain further insight. Together, simplified and phase-field models reveal power-law-based relationships between the pressure that initiates an intramural tear and key geometric and mechanical factors – insult surface area, wall stiffness, and tearing energy. The degree of axial stretch and luminal pressure similarly influence the pressure of tearing, which was ∼88 kPa for healthy and diseased human aortas having sub-millimeter-sized initial insults, but lower for larger tear sizes. Finally, simulations show that the direction a tear propagates is influenced by focal regions of weakening or strengthening, which can drive the tear towards the lumen (dissection) or adventitia (rupture). Additional data on human aortas having different predisposing disease conditions will be needed to extend these results further, but the present findings show that physiologic pressures can propagate initial medial defects into delaminations that can serve as precursors to dissection.
The extended second law of thermodynamics suggests a thermodynamic imperative driving the evolution of life systems towards increased complexity
Authors: Menendez Sergio
Published: September 2021

From a thermodynamic point of view life structures can be viewed as dissipative systems capable of self replication. Energy flowing from the external environment into the system allows growth of its self replicative components increasing the system complexity concomitantly with an increase in the entropy of the universe, thus observing the second law of thermodynamics. However, general thermodynamic models of life systems have been hampered by the lack of precise equations modelling far from equilibrium driven systems operating in non-linear response regimes. Recent theoretical advances, applying time reversal symmetry and coarse grained state transitions, have provided theoretical insights into the thermodynamic constraints that bind the behaviour of such far from equilibrium life systems. Setting additional constraints based on empirical observations allows us to apply this theoretical framework to gain a further semiquantitative insight on the thermodynamic boundaries and evolution of complex self replicative life systems. This interpretation suggests a thermodynamic hierarchical organisation based on increasing accessible levels of usable energy, which in turn drives an exponential punctuated growth of the system’s complexity. For the earth life system this growth has historically not been limited by the total energy available from the external driving field, but by the system’s internal adaptability needed to access higher levels of usable energy. Therefore, in the absence of external perturbations, the emergence of an initial self replicative dissipative structure capable of variation that enables access to higher energy levels is sufficient to drive the system’s growth irreversibly towards increased complexity across time and space in a hierarchical manner. This interpretation is consistent with current empirical observation of life systems across both time and space and explains from a thermodynamic point of view the evolutionary patterns of complex life systems on earth.
Comparative analysis of wild type accessions reveals novel determinants of Arabidopsis seed longevity
Authors: Niñoles Regina , Planes Dolores , Arjona Paloma , Ruiz-Pastor Carmen , Chazarra Rubén , Renard Joan , Bueso Eduardo , Forment Javier , Serrano Ramón , Kranner Ilse , Roach Thomas , Gadea José
Published: September 2021

Understanding the genetic factors involved in seed longevity is of paramount importance in agricultural and ecological contexts. The polygenic nature of this trait suggests that many of them remain undiscovered. Here, we exploited the contrasting seed longevity found amongst wild type Arabidopsis thaliana accessions to further understand this phenomenon. Concentrations of the antioxidant glutathione were consistently higher in longer-lived than shorter-lived accessions, supporting that redox poise plays a prominent role in seed longevity. However, high seed permeability, normally associated with shorter longevity, is also present in accessions with longer seed longevity. Transcriptome analysis indicated that the detrimental effect on longevity caused by seed coat permeability may be counterbalanced by higher levels of specific mRNAs stored in dry seed, particularly those of heat-shock proteins. Indeed, reverse genetics demonstrated that heat-shock factors HSF1A and 1B contributed to longevity. Furthermore, loss-of-function mutants of RNA-binding proteins, such as the stress-granule zinc-finger protein TZF9, or the spliceosome subunits MOS4 or MAC3A/MAC3B, extended seed longevity, positioning RNA as a novel player in the regulation of seed viability. mRNAs of proteins with putative relevance to longevity were also abundant in shorter-lived accessions, reinforcing the idea that resistance to ageing is determined by multiple factors.
A natural genetic variation screen identifies insulin signaling, neuronal communication, and innate immunity as modifiers of hyperglycemia in the absence of Sirt1
Authors: Owings Katie G. , Palu Rebecca A.S.
Published: September 2021

Variation in the onset, progression, and severity of symptoms associated with metabolic disorders such as diabetes impairs the diagnosis and treatment of at-risk patients. Diabetes symptoms, and patient variation in these symptoms, is attributed to a combination of genetic and environmental factors, but identifying the genes and pathways that modify diabetes in humans has proven difficult. A greater understanding of genetic modifiers and the ways in which they interact with metabolic pathways could improve the ability to predict a patient’s risk for severe symptoms, as well as enhance the development of individualized therapeutic approaches. In this study we use the Drosophila Genetic Reference Panel (DGRP) to identify genetic variation influencing hyperglycemia associated with loss of Sirt1 function. Through analysis of individual candidate functions, physical interaction networks, and Gene Set Enrichment Analysis (GSEA) we identify not only modifiers involved in canonical glucose metabolism and insulin signaling, but also genes important for neuronal signaling and the innate immune response. Furthermore, reducing the expression of several of these candidates suppressed hyperglycemia, making them ideal candidate therapeutic targets. These analyses showcase the diverse processes contributing to glucose homeostasis and open up several avenues of future investigation.
Emerging chikungunya virus variants at the E1-E1 inter-glycoprotein spike interface impact virus attachment and Inflammation
Authors: Rangel Margarita V. , McAllister Nicole , Dancel-Manning Kristen , Noval Maria G. , Silva Laurie A. , Stapleford Kenneth A.
Published: September 2021

Chikungunya virus (CHIKV) is a re-emerging arthropod-borne alphavirus and a serious threat to human health. Therefore, efforts toward elucidating how this virus causes disease and the molecular mechanisms underlying steps of the viral replication cycle are crucial. Using anin vivotransmission system that allows intra-host evolution, we identified an emerging CHIKV variant carrying a mutation in the E1 glycoprotein (V156A) in the serum of mice and saliva of mosquitoes. E1 V156A has since emerged in humans during an outbreak in Brazil, co-occurring with a second mutation, E1 K211T, suggesting an important role for these residues in CHIKV biology. Given the emergence of these variants, we hypothesized that they function to promote CHIKV infectivity and subsequent disease. Here, we show that E1 V156A and E1 K211T modulate virus attachment and fusion and impact binding to heparin, a homolog of heparan sulfate, a key entry factor on host cells. These variants also exhibit differential neutralization by anti-glycoprotein monoclonal antibodies, suggesting structural impacts on the particle that may be responsible for altered interactions at the host membrane. Finally, E1 V156A and E1 K211T exhibit increased titers in an adult arthritic mouse model and induce increased foot-swelling at the site of injection. Taken together, this work has revealed new roles for E1 where discrete regions of the glycoprotein are able to modulate cell attachment and swelling within the host.

IMPORTANCE

Alphaviruses represent a growing threat to human health worldwide. Chikungunya virus (CHIKV) has rapidly spread to new geographic regions in the last several decades, causing overwhelming outbreaks of disease, yet there are no approved therapeutics. The CHIKV glycoproteins are key determinants of CHIKV adaptation and virulence. In this study, we characterize the naturally emerging E1 glycoprotein variants, V156A and K211T. We demonstrate that E1 V156A and K211T function in virus attachment to cells, a role that until now has been only attributed to the CHIKV E2 glycoprotein. We also demonstrate E1 V156A and K211T to increase foot-swelling in mice. Observing that these variants and other pathogenic variants occur at the E1-E1 inter-spike interface, we highlight this structurally important region as critical for multiple steps during CHIKV infection. Together, these studies further defines the function of E1 in CHIKV infection and can inform the development of therapeutic or preventative strategies.
Associations and recovery dynamics of the nasopharyngeal microbiota during influenza-like illness in the aging population
Authors: Shetty Sudarshan A. , van Beek Josine , Bijvank Elske , Groot James , Kuiling Sjoerd , Bosch Thijs , van Baarle Debbie , Fuentes Susana
Published: September 2021

Background

Older adults are more susceptible to respiratory pathogens, several of which have been associated with an altered respiratory microbiota. Influenza-like illness (ILI), a disease caused by respiratory pathogens including but not exclusively by influenza virus, is a major health concern in this population. However, there is little information on changes in the nasopharyngeal (NP) microbiota of older adults associated with respiratory infections identified by/ reported as ILI, as well as its dynamics during recovery. Here, we compared the NP microbiota in older adults who presented with ILI (n= 240) to the NP microbiota in older adults not reporting an ILI event (n= 157) during the 2014-2015 influenza season. To investigate the dynamics of the microbiota from the acute phase to the recovery phase of the infection, participants reporting an ILI event were sampled at onset of infection (<72 hours), at 14 days and at 7-9 weeks after infection (recovery sample).

Results

Cross-sectional analysis of the microbiota at the different time-points showed no differences in alpha diversity between the groups. A small but significant effect of the ILI was observed on the microbiota community and structure when compared to controls and recovery samples. Furthermore, the NP microbiota exhibited inter-individual differences in dynamics from onset of ILI to recovery.Corynebacterium, one of the keystone species in the upper respiratory tract, was negatively associated with ILI and its abundance increased after recovery. Potential pathobionts such asHaemophilus, PorphyromonasandGemellahad higher abundances during acute-ILI. Stability and changes in the NP microbial community showed individual dynamics. Key core genera,Corynebacterium, MoraxellaandDolosigranulumexhibited higher inter-individual variability in acute-ILI, but showed comparable variability to controls after recovery. Participants in the ILI group with higher core microbiota abundances at the acute phase showed higher microbiota stability after recovery.

Conclusions

Our findings demonstrate that acute-ILI is associated with small but significant alterations in the phylogenetic structure of the NP microbiota in older adults. The observed variation in the core microbiota suggests potential imbalances in the ecosystem, which could play a role in the recovery of the NP microbiota after an ILI event.
MIMOSA2: A metabolic network-based tool for inferring mechanism-supported relationships in microbiome-metabolome data
Authors: Noecker Cecilia , Eng Alexander , Borenstein Elhanan
Published: September 2021

Motivation

Recent technological developments have facilitated an expansion of microbiome-metabolome studies, in which a set of microbiome samples are assayed using both genomic and metabolomic technologies to characterize the composition of microbial taxa and the concentrations of various metabolites. A common goal of many of these studies is to identify microbial features (species or genes) that contribute to differences in metabolite levels across samples. Previous work indicated that integrating these datasets with reference knowledge on microbial metabolic capacities may enable more precise and confident inference of such microbe-metabolite links.

Results

We present MIMOSA2, an R package and web application for model-based integrative analysis of microbiome-metabolome datasets. MIMOSA2 uses reference databases to construct a community metabolic model based on microbiome data and uses this model to predict differences in metabolite levels across samples. These predictions are compared with metabolomics data to identify putative microbiome-governed metabolites and specific taxonomic contributors to metabolite variation. MIMOSA2 supports various input data types and can be customized to incorporate user-defined metabolic pathways. We demonstrate MIMOSA2’s ability to identify ground truth microbial mechanisms in simulation datasets, and compare its results with experimentally inferred mechanisms in a dataset describing honeybee gut microbiota. Overall, MIMOSA2 combines reference databases, a validated statistical framework, and a user-friendly interface to facilitate modeling and evaluating relationships between members of the microbiota and their metabolic products.

Availability and Implementation

MIMOSA2 is implemented in R under the GNU General Public License v3.0 and is freely available as a web server and R package fromwww.borensteinlab.com/software_MIMOSA2.html.
A network approach to genetic circuit designs
Authors: Crowther Matthew , Wipat Anil , Goñi-Moreno Ángel
Published: September 2021

As genetic circuits become more sophisticated, the size and complexity of data about their designs increases. This data captured goes beyond monolithic genetic sequences and towards circuit modularity and functional details, which are beneficial for analyzing circuit performance and establishing design automation techniques. However, the accessibility, visualisation and usability of design data (and metadata) have received relatively little attention to date. Here, we present a method to turn circuit designs into networks and showcase its potential to enhance the utility of design data. Since networks are dynamic structures, initial graphs can be interactively shaped into sub-networks of relevant information based on requirements such as abstraction, hierarchy and protein interactions. Additionally, several visual changes can be applied, such as colouring or clustering nodes based on types (e.g., genes or promoters), resulting in easier comprehension from a user perspective. This approach allows circuit designs to be coupled to other networks, such as metabolic pathways or implementation protocols captured in graph-like formats. Therefore, we advocate using networks to structure, access and improve synthetic biology information.
Elevated phosphorylation of EGFR in NSCLC due to mutations in PTPRH
Authors: Swiatnicki Matthew R. , Rennhack Jonathan P. , Hollern Daniel P. , Perry Ashlee V. , Kubiak Rachel , Riveria Riveria Sarai M. , O’Reilly Sandra , Andrechek Eran R.
Published: September 2021

The role of EGFR in lung cancer is well described with numerous activating mutations that result in phosphorylation and tyrosine kinase inhibitors that target EGFR. While the role of the EGFR kinase in non-small cell lung cancer (NSCLC) is appreciated, control of EGFR signaling pathways through dephosphorylation by phosphatases is not as clear. In recent work we identified mutations in Protein Tyrosine Phosphatase Receptor Type H (Ptprh, also known as SAP-1) as being associated with elevated phosphorylation of EGFR in a mouse model of breast cancer. We have examined a series of tumors from this mouse model, revealing conserved V483MPtprhmutations within the FVB background, but a series of varied mutations in other backgrounds. Despite the variedPtprhmutations in other background strains, matched primary and metastatic tumors largely shared mutational profiles. Profiling the downstream events ofPtprhmutant tumors revealed AKT activation, suggesting a key target of PTPRH was EGFR tyrosine 1197. Given the role of EGFR in lung cancer, we explored TCGA data which revealed that a subset ofPTPRHmutant tumors shared gene expression profiles withEGFRmutant tumors, but thatEGFRmutations andPTPRHmutations were mutually exclusive. Generation of a PTPRH knockout NSCLC cell line resulted in Y1197 phosphorylation of EGFR, and a rescue with expression of wild type PTPRH returned EGFR phosphorylation to parental line values while a rescue with a D986A catalytically dead mutant PTPRH did not, demonstrating that PTPRH targets EGFR. As expected with active EGFR, the knockout of PTPRH was associated with increased growth rate. Moreover, a dose response curve illustrated that two human NSCLC lines that had naturally occurringPTPRHmutations responded to EGFR tyrosine kinase inhibition. Injection of one of the NSCLC human lines into mice resulted in tumors, and Osimertinib treatment resulted in a reduction of tumor volume relative to vehicle controls. Consistent with prior literature from breast cancer,PTPRHmutation resulted in nuclear pEGFR as seen in immunohistochemistry, suggesting that there may also be a role for EGFR as a transcriptional co-factor. Other roles for PTPRH were explored through a receptor tyrosine kinase array, noting elevated phosphorylation of FGFR1. Knockout of PTPRH in NSCLC cell lines resulted in elevated phosphorylated FGFR1 relative to controls, indicating that PTPRH has a number of targets that may be aberrantly activated in NSCLC with mutations in PTPRH. Together these data suggest that mutations in PTPRH in NSCLC may result in clinically actionable alterations using existing therapies.
Variance of allele balance calculated from low coverage sequencing data infers departure from a diploid state
Authors: Fletcher Kyle , Han Rongkui , Smilde Diederik , Michelmore Richard
Published: September 2021

Motivation

Polyploidy and heterokaryosis are common and consequential genetic phenomena that increase the number of haplotypes in an organism and complicate whole-genome sequence analysis. Allele balance has been used to infer polyploidy and heterokaryosis in diverse organisms using read sets sequenced to greater than 50x whole-genome coverage. However, Sequencing to adequate depth is costly if applied to multiple individuals or large genomes.

Results

We developed VCFvariance.pl to utilize the variance of allele balance to infer polyploidy and/or heterokaryosis at low sequence coverage. This analysis requires as little as 10x whole-genome coverage and reduces the allele balance profile down to a single value, which can be used to determine if an individual has two or more haplotypes. This approach was validated on simulated, synthetic, and authentic read sets from an oomycete, fungus, and plant. The approach was deployed to ascertain the genome status of multiple isolates of Bremia lactucae and Phytophthora infestans.

Availability and implementation

VCFvariance.pl is a Perl script available at https://github.com/kfletcher88/VCFvariance.