bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of IL1B (rs16944) and IL1R2 (rs4141134) polymorphisms on aggressiveness and prognosis of cutaneous melanoma
Authors: Torricelli Caroline , Carron Juliana , Carvalho Bruna Fernandes , Macedo Ligia Traldi , Rinck-Junior José Augusto , Lima Carmen Silvia Passos , Lourenço Gustavo Jacob
Published: July 2021

Cutaneous melanoma is the most aggressive skin cancer with high mortality. Proinflammatory cytokines can modulate the proliferation and survival of cutaneous melanoma cells. Higher levels of interleukin-1β (IL1B) were associated with tumor cell proliferation, invasion, and migration, and the IL-1 type II receptor (IL1R2) serves as an endogenous inhibitor of IL1B signaling. Single-nucleotide variations (SNVs) in these genes (IL1B rs16944 and IL1R2 rs4141134) can modulate cytokine production and binding; however, their role in cutaneous melanoma is still unknown. Thus, we investigated the influence of the above SNVs in clinicopathological aspects and cutaneous melanoma patients’ survival. In the present study, we analyzed 193 patients with cutaneous melanoma for IL1B c.-598T>C (rs16944) and IL1R2 c.-2009G>A (rs4141134) genotypes with TaqMan assays. Differences between groups were calculated using χ2 or Fisher’s exact test and multiple logistic regression. Progression-free survival (PFS) and melanoma-specific survival were calculated by Kaplan–Meier and Cox methods. The prognostic value of IL1R2 was also analyzed by the online consensus survival webserver for skin cutaneous melanoma (OSskcm). We found that IL1R2 rs4141134 GG genotype was more common in patients with nodular subtype (49.1% vs. 29.8%, P = 0.01) and the frequency of IL1R2 rs4141134 GG or GA was higher in patients with Clark levels III–V (87.4% vs. 75.8%, P = 0.04). Patients with IL1R2 rs4141134 GG or GA genotypes presented lower PFS (hazard ratio: 3.12, 95% confidence interval, 1.10–8.79, P = 0.03) when compared with AA genotype, supported by OSskcm results. Thus, our study presented for the first time preliminary evidence that IL1R2 rs4141134 SNV may modulate cutaneous melanoma clinicopathological aspects and survival possible by allowing IL1B signaling.
Virtual Coordinate System in Unicoronal Synostosis
Authors: Lu Xiaona , Jorge Forte Antonio , Persing John A.
Published: July 2021

Background:

We propose a landmark-based, virtual coordinate system, specifically designed for assessment of asymmetrical craniofacial anatomy associated with unicoronal synostosis.

Method:

CT scans of 33 patients with nonsyndromic unicoronal synostosis were included. Proposed mid-sagittal plane was compared with commonly used sagittal planes: (1) nasion, sella, and basion (N-S-BA); (2) midplane of bilateral frontozygomatic sutures (midFZ); and (3) the skull gravity center plane, to evaluate reliability and validity in the assessments of the anterior and posterior skull base.

Results:

The proposed midplane is similar to the midFZ plane in describing the direction of the anterior skull base. However, it has less bias than the N-S-BA (P < 0.001), and the gravity center planes (P < 0.001). The proposed midplane measures the direction of the posterior skull base plane, similar to the midFZ and gravity center planes, but it has less measurement deviation than the N-S-BA plane (P < 0.001). The most protrusive point on the frontal bone in unicoronal patients is contralateral to the fused suture and distant from the mid-sagittal plane by 13.93 ± 4.01 mm. In addition, it is more anteriorly positioned, by 5.32 mm (P < 0.001), when compared with the corresponding point on the synostotic side. The uppermost point of the supraorbital rim on the synostotic side is cephalic to that of the contralateral side by 4.09 mm (P < 0.001).

Conclusions:

Prioritized orientation of an averaged Frankfort horizontal plane, followed by the location of the mid-sagittal and coronal planes, can generate a reliable and valid coordinate framework for the assessment of asymmetric skull shape in unicoronal synostosis.
Surgical Management of Chronic Encapsulated Abdominal Wall Seroma 8 Years after Abdominoplasty
Authors: Morris Bryn E. , Thornburg Danielle A. , Teven Chad M. , Kruger Erwin A.
Published: July 2021

Seroma is a common complication of body-contouring surgery. Current literature focuses on prevention or initial management of seroma formation; however, no definitive evidence exists to guide management of chronic or recurrent seromas. We describe a case of a recurrent abdominal wall seroma following abdominoplasty. The seroma was present for 8 years despite employing multiple treatment modalities. After presentation to our clinic, the patient was taken to the operating room, where the seroma pseudocapsule was excised, progressive tension sutures were utilized, and drains were placed. To date, there has been no recurrence of the seroma. We propose that chronicity, recurrence, and persistence of seroma are indications for surgical intervention.
Attitudes of Canadian Plastic Surgeons on Temporal Artery Biopsy in Giant Cell Arteritis Management
Authors: Lafreniere Ann-Sophie , Hartley Rebecca , Ponich Brett , Nickerson Duncan , Temple-Oberle Claire F.
Published: July 2021

Background:

Temporal artery biopsies (TAB) rarely impact management of patients with suspected giant cell arteritis and carry complications. We sought plastic surgeons’ perspectives on this procedure’s risks and benefits.

Methods:

An email survey was designed, piloted, and refined to elicit Canadian Society of Plastic Surgeons (CSPS) members about TAB’s diagnostic contribution, complications, usefulness as a resident education tool, and surgeons’ insight into emerging diagnostic modalities like ultrasound. Text comments were sought at each question. A reminder was emailed one week later. Data was compared and analyzed using the chi-squared test and student t-test.

Results:

An estimated 83 responses were received from 435 surgeons (19%). Of the surgeons, 20% voiced uncertainty regarding TAB indications; 40% were unsure if TAB results changed steroid duration and dose; 83% did not see patients postoperatively. Surgeons recalled 29 cases of hematoma and three facial nerve injuries from TAB. In total, 80% felt TAB was a valuable learning opportunity for residents, although residents were involved in only 21% of cases; 65% of surgeons supported a changeover to ultrasound as primary diagnostic modality. Analysis of text comments revealed a sense of futility from TAB and disdain toward being mere technicians. Several participants wished for stakeholders to collaborate and potentially endorse noninvasive diagnostic modalities.

Conclusions:

This survey demonstrated varying attitudes to TAB. Generally, plastic surgeons were uncertain of TAB’s contribution to treatment, tended not to follow-up on results or patients, and recognized a number of complications. Conversations are desired regarding switching from scalpel to probe to evaluate the temporal artery.
Frozen Shoulder Related to Influenza Vaccine Administration
Authors: Waninger Kevin N. , Slenker Nicholas
Published: July 2021

Shoulder pain is often a transient physical finding after vaccination. We present the case of a 46-year-old woman who presented clinically with frozen shoulder that was progressively worse and temporally related to her yearly influenza vaccination. The patient failed conservative management, and 7 months postvaccination, the patient underwent shoulder manipulation under anesthesia with good results. Vaccination-related shoulder dysfunction after high-deltoid intramuscular penetration and infiltration into the subdeltoid/subacromial bursa can cause a severe local inflammatory response that clinically may present as frozen shoulder. A case report and review of the literature on suspected frozen shoulder injury related to vaccine administration is presented. A greater understanding of the shoulder anatomy and use of the correct intramuscular vaccination administration technique is important to prevent this rare postvaccination complication.
Challenging traditional carbohydrate intake recommendations for optimizing performance at high altitude
Authors: Pasiakos Stefan M. , Karl J. Philip , Margolis Lee M.
Published: July 2021

Purpose of review

To highlight emerging evidence challenging traditional recommendations to increase carbohydrate intake to optimize performance at high altitude.

Recent findings

Several studies have now clearly demonstrated that, compared with sea level, exogenous carbohydrate oxidation during aerobic exercise is blunted in lowlanders during initial exposure to high altitude. There is also no apparent ergogenic effect of ingesting carbohydrate during aerobic exercise on subsequent performance at high altitude, either initially after arriving or even after up to 22 days of acclimatization. The inability to oxidize and functionally benefit from exogenous carbohydrate intake during exercise after arriving at high altitude coincides with hyperinsulinemia, accelerated glycogenolysis, and reduced peripheral glucose uptake. Collectively, these responses are consistent with a hypoxia-mediated metabolic dysregulation reflective of insulin resistance. Parallel lines of evidence have also recently demonstrated roles for the gut microbiome in host metabolism, bioenergetics, and physiologic responses to high altitude, implicating the gut microbiome as one potential mediator of hypoxia-mediated metabolic dysregulation.

Identification of novel and well tolerated nutrition and/or pharmacological approaches for alleviating hypoxia-mediated metabolic dysregulation and enhancing exogenous carbohydrate oxidation may be more effective for optimizing performance of lowlanders newly arrived at high altitude than traditional carbohydrate recommendations.
Efficacy and safety of primary needle-knife fistulotomy in biliary cannulation: a systematic review and meta-analysis
Authors: Mutneja Hemant Raj , Bhurwal Abhishek , Attar Bashar M. , Vohra Ishaan , Tejeda Emmanuel Palomera , Verma Siddarth , Kumar Vivek , Demetria Melchor
Published: July 2021

We aimed to conduct a systematic review and meta-analysis on the efficacy and safety of primary needle-knife fistulotomy (NFK) in biliary cannulation. An electronic bibliographic search of digital dissertation databases was performed from inception till March 2020. All prospective studies, including randomized trials evaluating the use of NFK as a primary cannulation technique in biliary cannulation, were analyzed. The primary outcome was a successful cannulation rate and the secondary outcomes were post-ERCP pancreatitis rate and overall post-ERCP complication rate. A total of four prospective studies, including three randomized trials, were included for the analysis. The pooled cannulation success rate for primary NFK was 95.7% (95% CI. 83.1–99.0, P < 0.001). When compared with standard wire-guided cannulation, the analysis did not show any difference between the two techniques in terms of cannulation success (OR, 3.59, 95% CI, 0.34–37.39; P = 0.28; low certainty of evidence). The overall rate of post-ERCP pancreatitis with primary NFK was 1.5 % (95% CI, 0.6–3.9, P < 0.001). When compared with conventional wire-guided technique, the odds of developing post-ERCP pancreatitis with NFK were 0.22 (95% CI, 0.04–1.04, P = 0.06; moderate certainty of evidence). To conclude, NKF seems to be an effective means of biliary cannulation in expert hands. Although it may be associated with a lower rate of post-ERCP pancreatitis, the current strength and quality of evidence to support its use as a primary cannulation strategy is low. It may be considered in ERCPs at higher risk of pancreatitis by experienced endoscopists.
Pediatric Foreign Body Aspiration
Authors: Paap Michael K. , Leuin Shelby , Carvalho Daniela
Published: July 2021

Objectives

The goal of this study was to assess which factors could affect outcomes in pediatric patients undergoing bronchoscopy for foreign body aspiration (FBA).

Methods

This is a retrospective case series study evaluating patients who underwent bronchoscopies because of FBA at a tertiary pediatric hospital between January 1, 2010, and December 6. 2018. Data collected included demographic information, time of the aspiration event, history of developmental delay, time of the procedure, duration of the procedure, and outcome (discharged, admission to the hospital or pediatric intensive care unit [PICU], or deceased). Statistical analysis was performed using standard regression analysis and analysis of variance.

Results

There were a total of 114 patients who underwent bronchoscopy for FBA (61% male and 39% female). The mean ± SD age was 2.8 ± 3.4 years, and 16% had developmental delay. The mean age for patients with developmental delay was 3.43 years, compared with 1.69 years for patients without developmental delay. The age difference between these 2 groups was statistically significant (P = 0.0047). The most commonly aspirated object was food (57%), and patients were usually with their parents at the time of aspiration (78%). Most aspiration events (57%) happened between 4 pm to 4 am. The mean ± SD time of procedure was 38 ± 28 minutes. The probability of admission to the hospital, PICU, and death increased with the duration of the procedure (P < 0.001). Patients with procedures longer than 60 minutes had a 40% probability of admission to the PICU, and patients with cases longer than 120 minutes had 13% probability of mortality.

Conclusions

Most FBA s occurred in the evening while the children were with their parents. Education of families regarding the risk of aspiration is crucial, so they are always attentive to this issue. Although the focus on prevention tends to be with younger patients, it is essential to emphasize the risk of FBA in older patients with developmental delay. Because most episodes of aspiration occur later in the day, it is imperative that tertiary pediatric centers ensure that the evening staff is trained and have the available equipment for these complex cases.
A sensor to monitor limb depth in transtibial sockets with locking pin suspension: a technical note
Authors: Bennett Sam , Gurrey Clement , Wang Horace , Weissinger Mathew , Larsen Brian , Sanders Joan E.
Published: July 2021

Background:

Monitoring of limb depth in transtibial sockets may provide useful information toward patient education and care.

Objective:

The objective was to develop a sensor to detect the depth of a locking pin in the shuttle lock of a transtibial socket and to monitor the small motions between ratchet clicks during ambulation.

Study design:

Controlled bench testing and single-participant study.

Methods:

A copper wire coil positioned beneath the socket shuttle lock was used with an inductive sensing chip to monitor locking pin depth. A custom jig was used to calibrate the sensor and bench test the system. Repeatability, drift, and the effects of pin length, carbon fiber presence, temperature change, and pin angulation on sensor performance were tested. Testing was conducted on a participant wearing an adjustable socket, walking with the panels at four different radial positions.

Results:

The sensor demonstrated a root mean square error of 0.21% of the full-scale output. Different pins, different pin lengths, and the presence of carbon fiber affected calibration, indicating that the sensor must be calibrated to the individual user's socket and pin. Ratchet clicks and cyclic motion between clicks during walking were evident in the data. During participant testing, enlarging the socket at 1.00 mm radial increments caused significant changes in pin peak-to-peak distance (up and down motion) within a step.

Conclusions:

The sensor is sufficiently accurate to pursue studies investigating utility of the data toward clinical monitoring of socket fit.
Respiratory events after intensive care unit discharge in trauma patients: Epidemiology, outcomes, and risk factors
Authors: Rosen Joshua E. , Bulger Eileen M. , Cuschieri Joseph
Published: July 2021

BACKGROUND

Respiratory complications are associated with significant morbidity and mortality in trauma patients. The care transition from the intensive care unit (ICU) to the acute care ward is a vulnerable time for injured patients. There is a lack of knowledge about the epidemiology of respiratory events and their outcomes during this transition.

METHODS

Retrospective cohort study in a single Level I trauma center of injured patients 18 years and older initially admitted to the ICU from 2015 to 2019 who survived initial transfer to the acute care ward. The primary outcome was occurrence of a respiratory event, defined as escalation in oxygen therapy beyond nasal cannula or facemask for three or more consecutive hours. Secondary outcomes included unplanned intubation for a primary pulmonary cause, adjudicated via manual chart review, as well as in-hospital mortality and length of stay. Multivariable logistic regression was used to examine patient characteristics associated with posttransfer respiratory events.

RESULTS

There were 6,561 patients that met the inclusion criteria with a mean age of 52.3 years and median Injury Severity Score of 18 (interquartile range, 13–26). Two hundred and sixty-two patients (4.0%) experienced a respiratory event. Respiratory events occurred early after transfer (median, 2 days, interquartile range, 1–5 days), and were associated with high mortality (16% vs. 1.8%, p < 0.001), and ICU readmission rates (52.6% vs. 4.7%, p < 0.001). Increasing age, male sex, severe chest injury, and comorbidities, including preexisting alcohol use disorder, congestive heart failure, and chronic obstructive pulmonary disease, were associated with increased odds of a respiratory event. Fifty-eight patients experienced an unplanned intubation for a primary pulmonary cause, which was associated with an in-hospital mortality of 39.7%.

CONCLUSION

Respiratory events after transfer to the acute care ward occur close to the time of transfer and are associated with high mortality. Interventions targeted at this critical time are warranted to improve patient outcomes.

LEVEL OF EVIDENCE

Prognostic and Epidemiological study, level III.
Causal analysis of the temperature impact on deep-sea biodiversity
Authors: Doi Hideyuki , Yasuhara Moriaki , Ushio Masayuki
Published: July 2021

The deep sea comprises more than 90% of the ocean; therefore, understanding the controlling factors of biodiversity in the deep sea is of great importance for predicting future changes in the functioning of the ocean system. Consensus has recently been increasing on two plausible factors that have often been discussed as the drivers of deep‐sea species richness in the contexts of the species‐energy and physiological tolerance hypotheses: (i) seafloor particulate organic carbon (POC) derived from primary production in the euphotic zone and (ii) temperature. Nonetheless, factors that drive deep-sea biodiversity are still actively debated potentially owing to a mirage of correlations (sign and magnitude are generally time dependent), which are often found in nonlinear, complex ecological systems, making the characterization of causalities difficult. Here, we tested the causal influences of POC flux and temperature on species richness using long-term palaeoecological datasets derived from sediment core samples and convergent cross mapping, a numerical method for characterizing causal relationships in complex systems. The results showed that temperature, but not POC flux, influenced species richness over 10
3
–10
4
-year time scales. The temperature–richness relationship in the deep sea suggests that human-induced future climate change may, under some conditions, affect deep-sea ecosystems through deep-water circulation changes rather than surface productivity changes.
Dental wear proxy correlation in a long-term feeding experiment on sheep (
Ovis aries
)
Authors: Ackermans Nicole L. , Winkler Daniela E. , Schulz-Kornas Ellen , Kaiser Thomas M. , Martin Louise F. , Hatt Jean-Michel , Clauss Marcus
Published: July 2021

Dietary reconstruction in vertebrates often relies on dental wear-based proxies. Although these proxies are widely applied, the contributions of physical and mechanical processes leading to meso- and microwear are still unclear. We tested their correlation using sheep (
Ovis aries
,
n
= 39) fed diets of varying abrasiveness for 17 months as a model. Volumetric crown tissue loss, mesowear change and dental microwear texture analysis (DMTA) were all applied to the same teeth. We hereby correlate: (i) 46 DMTA parameters with each other, for the maxillary molars (M1, M2, M3), and the second mandibular molar (m2); (ii) 10 mesowear variables to each other and to DMTA for M1, M2, M3 and m2; and (iii) volumetric crown tissue loss to mesowear and DMTA for M2. As expected, many DMTA parameters correlated strongly with each other, supporting the application of reduced parameter sets in future studies. Correlation results showed only few DMTA parameters correlated with volumetric tissue change and even less so with mesowear variables, with no correlation between mesowear and volumetric tissue change. These findings caution against interpreting DMTA and mesowear patterns in terms of actual tissue removal until these dental wear processes can be better understood at microscopic and macroscopic levels.
Arenibaculum pallidiluteum gen. nov., sp. nov., a novel bacterium in the family Azospirillaceae, isolated from desert soil, and reclassification of Skermanella xinjiangensis to a new genus Deserticella as Deserticella xinjiangensis comb. nov., and transfer of the genera Indioceanicola and Oleisolibacter from the family Rhodospirillaceae to the family Azospirillaceae
Authors: Li Shuai , Shi Lei , Lian Wen-Hui , Lin Zhi-Liang , Lu Chun-Yan , Xu Lu , Wei Qi-Chuang , Zhang Jing-Yi , Dong Lei , Li Wen-Jun
Published: July 2021

A novel pale orange-coloured bacterium, designated strain SYSU D00532T, was isolated from sandy soil collected from the Gurbantunggut desert in Xinjiang, PR China. Cells of strain SYSU D00532Twere found to be aerobic, Gram-stain-negative, oxidase-positive, catalase-positive, motile and rod-shaped with a single polar or subpolar flagellum. Growth occurred at 15–45 °C (optimum, 28–37 °C, pH 5.0–8.0 (optimum, pH 6.0–7.0) and with 0–1.5% NaCl (w/v; optimum, 0.5 %). The major polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and phosphatidylglycerol. Unidentified aminolipids, unidentified polar lipids, an unidentified aminophospholipid and an unidentified phospholipid were also detected. The major respiratory quinone was ubiquinone-10 and the major fatty acids were summed feature 8 (C18:1ω7cand/or C18:1ω6c), C16:0and C19:0cycloω8c. The genomic DNA G+C content was 69.8 mol%. Results of phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SYSU D00532Tbelonged to the familyAzospirillaceaeand showed 93.4% (Desertibacter roseus2622T), 93.2% (Skermanella xinjiangensis10-1-101T), 93.2% (‘Skermanella rubra’ YIM 93097T) and 92.4% (Desertibacter xinjiangensisM71T) similarities. Based on the phylogenetic, phenotypic and chemotaxonomic data, strain SYSU D00532Tis proposed to represent a new species of a new genus, namedArenibaculum pallidiluteumgen. nov., sp. nov., within the familyAzospirillaceae. The type strain is SYSU D00532T(=KCTC 82269T=CGMCC 1.18631T=MCCC 1K04984T). We also propose the reclassification ofSkermanella xinjiangensisto a new genusDeserticellaasDeserticella xinjiangensiscomb. nov., and the transfer of the generaIndioceanicolaandOleisolibacterfrom the familyRhodospirillaceaeto the familyAzospirillaceaewebased on the phylogenetic results.
A quest for the origin of the uneven spread of Covid-19 cases
Authors: Bhadra Arunava , Bhattacharya Mahasweta
Published: July 2021

For more than one and a half years now the world is highly impacted by the Covid-19 pandemic. The covid-19 cases are, however, not evenly distributed across the countries; a few countries, particularly high-income countries have been hit harder than the countries of weak economic condition. The reasons for such an asymmetrical distribution are not clearly understood yet. In the present work, we have examined the unevenness of global distribution of Covid-19 incidences till 18th June 2021 in terms of the economic condition of countries. Subsequently, we have tried to identify the main underlying factors behind unequal Covid-19 cases. Our analysis suggests that the degree of Isolation, the diffusion of coronavirus (interconnectivity), and the percentage of elderly people in the population are the main causes of the different unequal spread of Covid-19 cases in different countries. We find that the Covid-19 infected and death cases are well describe by a power law in terms of the stated parameters.
Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2
Authors: Afkhami Sam , D’Agostino Michael R. , Zhang Ali , Stacey Hannah D. , Marzok Art , Kang Alisha , Singh Ramandeep , Bavananthasivam Jegarubee , Ye Gluke , Luo Xiangqian , Wang Fuan , Ang Jann C. , Zganiacz Anna , Sankar Uma , Kazhdan Natallia , Koenig Joshua F. E. , Phelps Allyssa , Jordana Manel , Wan Yonghong , Mossman Karen L. , Jeyanathan Mangalakumari , Gillgrass Amy , Medina Maria Fe C. , Smaill Fiona , Lichty Brian D. , Miller Matthew S. , Xing Zhou
Published: July 2021

The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.
Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation
Authors: Blencowe Montgomery , Chen Xuqi , Zhao Yutian , Itoh Yuichiro , McQuillen Caden , Han Yanjie , Shou Benjamin , McClusky Rebecca , Reue Karen , Arnold Arthur P. , Yang Xia
Published: July 2021

Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the Four Core Genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect and, lastly, sex chromosomal effect, along with interactions among the three factors. Tissue specificity was prominent, with a major impact of estradiol on adipose tissue gene regulation, and of testosterone on the liver transcriptome. The networks affected by the three sex-biasing factors include development, immunity and metabolism, and tissue-specific regulators were identified for these networks. Furthermore, the genes affected by individual sex-biasing factors and interactions among factors are associated with human disease traits such as coronary artery disease, diabetes, and inflammatory bowel disease. Our study offers a tissue-specific account of the individual and interactive contributions of major sex-biasing factors to gene regulation that have broad impact on systemic metabolic, endocrine, and immune functions.
The Role of Context Conditioning in the Reinstatement of Responding to an Alcohol-Predictive Conditioned Stimulus
Authors: LeCocq Mandy Rita , Sun Sophie , Chaudhri Nadia
Published: July 2021

Re-exposure to an unconditioned stimulus (US) can reinstate extinguished conditioned responding elicited by a conditioned stimulus (CS). We tested the hypothesis that the reinstatement of responding to an appetitive CS is driven by an excitatory association formed between the US and the context that the US was ingested in during US re-exposure. Male, Long-Evans rats were acclimated to drinking alcohol (15%, v/v) in the home-cage, then trained to associate an auditory CS with an alcohol-US that was delivered into a fluid port for oral intake. During subsequent extinction sessions, the CS was presented as before, but without alcohol. After extinction, rats were re-exposed to alcohol as in training, but without the CS (alcohol re-exposure). 24 h later at test, the CS was presented as in training, but without alcohol. First, we tested the effect of extinguishing the context-alcohol association, formed during alcohol re-exposure, on reinstatement. Conducting four context extinction sessions across four days (spaced extinction) after the alcohol re-exposure session did not impact reinstatement. However, four context extinction sessions conducted across two days (massed extinction) prevented reinstatement. Next, we conducted alcohol re-exposure in a context that either differed from, or was the same as, the test context. One alcohol re-exposure session in a different context did not affect reinstatement, however, three alcohol re-exposure sessions in a different context significantly reduced reinstatement during the first CS trial. These results partially support the view that a context-US association formed during US re-exposure drives the reinstatement of responding to an appetitive, alcohol-predictive CS.
The long non-coding RNAH19drives the proliferation of diffuse intrinsic pontine glioma with H3K27 mutation
Authors: Roig-Carles David , Jackson Holly , Loveson Katie , Mackay Alan , Mather Rebecca , Waters Ella , Manzo Massimiliano , Alborelli Ilaria , Golding Jon , Jones Chris , Fillmore Helen L. , Crea Francesco
Published: July 2021

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying molecular drivers of DIPG progression is of utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not been yet elucidated in DIPG. Here, we study the oncogenic role of the development-associatedH19lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression ofH19lncRNA in paediatric high-grade gliomas (pedHGG). Expression and sub-cellular location ofH19lncRNA was validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function ofH19in DIPG cells. We found thatH19expression was higher in DIPG vs normal brain tissue and other pedHGGs.H19knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically,H19bufferslet-7microRNAs, resulting in up-regulation of oncogenic let-7 target (e.gSULF2,OSMR).H19is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate to treat this incurable cancer.
Fighting cancer with oncolytic viral therapy: identifying threshold parameters for success
Authors: Jahedi Sana , Wang Lin , Watmough James
Published: July 2021

We model interactions between cancer cells and free virus during oncolytic viral therapy. One of our main goals is to identify parameter regions that yield treatment failure or success. We show that the tumor size under therapy at a particular time is less than the size without therapy. Our analysis shows there are two thresholds for the horizontal transmission rate: a “Control threshold”, the threshold above which treatment is efficient, and an “optimum threshold”, the threshold beyond which infection prevalence reaches 100% and the tumor shrinks to its smallest size. Moreover, we explain how changes in the virulence level of the free virus alter the optimum threshold and the minimum tumor size. We identify a threshold for the virulence level of the virus and show how this threshold depends on the timescale of virus dynamics. Our results suggest that when the timescale of virus dynamics is fast, the administration of a more virulent virus leads to more tumor reduction. Conversely, when the viral timescale is slow, a higher virulence will have drawbacks on the results, such as high amplitude oscillations. Furthermore, our numerical observation depicts fast and slow dynamics. Our numerical simulations indicate there exists a two-dimensional globally attracting surface that includes the unstable manifold of the interior equilibrium. All solutions with positive initial conditions rapidly approach this two-dimensional attracting surface. In contrast, the trajectories on the attracting surface slowly tend to the periodic solution.

Highlights

The assumption that the viral load is in a quasi-steady state is relaxed, and infected cells are assumed to be mitotic.

Our model strongly suggests that the tumor size is always reduced by therapy.

We identify minimum tumor size, control threshold, and optimum threshold of the therapy.

Our analysis shows optimal virulence level of oncolytic virus depends on the time scale of virus dynamics.

When virus dynamic is slow, highly virulent virus causes long remission before relapse.
Self-sensitisation of Staphylococcus aureus to the antimicrobial factors found in human blood
Authors: Douglas Edward , Brignoli Tarcisio , Recker Mario , O’Brien Eoin , McLoughlin Rachel M. , Massey Ruth C.
Published: July 2021

Introductory Paragraph

For opportunistic pathogens, the switch from a commensal to an invasive lifestyle is often considered an accidental event. But with plentiful opportunity, what leads one accidental event to result in an invasive infection, and another not to? And how much of this apparent stochasticity is driven by bacterial factors? To answer these questions, here we focussed on the major human pathogen Staphylococcus aureus, which can both reside asymptomatically as a member of our respiratory microbiome, or become invasive and cause infections as severe as bacteraemia. Survival upon exposure to the antibacterial factors found in serum is a critical aspect of their ability to cause bacteraemia, and across a collection of 300 clinical isolates we found there to be significant variability in this capability. Utilising a GWAS approach we have uncovered the genetic basis of much of this variability through the identification and functional verification of a number of new polymorphic loci that affect serum survival: tcaA, tarK, gntR, ilvC, arsB, yfhO, and pdhD. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, while simultaneously enhancing the sensitivity of S. aureus to serum through a process involving the ligation of wall teichoic acids into the cell wall. As blood-stage infections are a transmission dead-end for the bacteria, that S. aureus actively responds to serum to produce a protein which specifically limits their ability to survive in this environment demonstrates that the switch from the commensal to the invasive lifestyle is complex, and that TcaA may contribute to the long-term success of S. aureus by restricting the bacteria to their more readily transmissible commensal state.
Predicting the Conformational Variability of Oncogenic GTP-bound G12D Mutated KRas-4B Proteins at Cell Membranes
Authors: Lu Huixia , Martí Jordi
Published: July 2021

KRas proteins are the largest family of mutated Ras isoforms, participating in a wide variety of cancers. Due to their importance, large effort is being carried out on drug development by small-molecule inhibitors. However, understanding protein conformational variability remains a challenge in drug discovery. In the case of the Ras family, their multiple conformational states can affect the binding of potential drug inhibitors. To overcome this challenge, we propose a computational framework based on combined all-atom Molecular Dynamics and Metadynamics simulations able to accurately access conformational variants of the target protein. We tested the methodology using a G12D mutated GTP bound oncogenic KRas-4B protein located at the interface of a DOPC/DOPS/cholesterol model anionic cell membrane. Two main orientations of KRas-4B at the anionic membrane have been obtained and explored. The corresponding angles have been taken as reliable reaction coordinates so that free-energy landscapes have been obtained by well-tempered metadynamics simulations, revealing the local and global minima of KRas-4B binding to the cell membrane, unvealing reactive paths of the system between the two preferential orientations and highlighting opportunities for targeting the unique metastable states through the identification of druggable pockets.
MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface
Authors: Houlard Martin , Cutts Erin E. , Shamim Muhammad S. , Godwin Jonathan , Weisz David , Aiden Aviva Presser , Aiden Erez Lieberman , Schermelleh Lothar , Vannini Alessandro , Nasmyth Kim
Published: July 2021

The dramatic change in morphology of chromosomal DNAs between interphase and mitosis is one of the defining features of the eukaryotic cell cycle. Two types of enzymes, namely cohesin and condensin confer the topology of chromosomal DNA by extruding DNA loops. While condensin normally configures chromosomes exclusively during mitosis, cohesin does so during interphase. The processivity of cohesin’s LE during interphase is limited by a regulatory factor called WAPL, which induces cohesin to dissociate from chromosomes via a mechanism that requires dissociation of its kleisin from the neck of SMC3. We show here that a related mechanism may be responsible for blocking condensin II from acting during interphase. Cells from patients carrying mutations in the Mcph1 gene undergo premature chromosome condensation but it has never been established for certain whether MCPH1 regulates condensin II directly. We show that deletion of Mcph1 in mouse embryonic stem cells unleashes an activity of condensin II that triggers formation of compact chromosomes in G1 and G2 phases, which is accompanied by enhanced mixing of A and B chromatin compartments, and that this occurs even in the absence of CDK1 activity. Crucially, inhibition of condensin II by MCPH1 depends on the binding of a short linear motif within MCPH1 to condensin II’s NCAPG2 subunit. We show that the activities of both Cohesin and Condensin II may be restricted during interphase by similar types of mechanisms as MCPH1’s ability to block condensin II’s association with chromatin is abrogated by the fusion of SMC2 with NCAPH2. Remarkably, in the absence of both WAPL and MCPH1, cohesin and condensin II transform chromosomal DNAs of G2 cells into chromosomes with a solenoidal axis showing that both SMC complexes must be tightly regulated to adjust both the chromatid’s structure and their segregation.
Hexaaquadodeca-μ2-chlorido-octahedro-hexaniobium diiodide
Authors: Schröder Florian , Köckerling Martin
Published: July 2021

The title compound, [Nb6Cl12(H2O)6]I2, consists of the niobium cluster cation [Nb6Cl12(H2O)6]2+ and two non-coordinating, charge-balancing iodide ions. The edges of the Nb6 octahedron are bridged by chlorido ligands. Each Nb atom is further coordinated by a water ligand. The cluster cation has a charge of +2, which is balanced by that of two iodide anions.
Supply chain network and financing performance of small and medium enterprises in China: a survey and quasi-replication using fuzzy-set qualitative comparative analysis
Authors: Lu Qiang , Deng Yang , Yu Miao , Song Hua , Liu Beini
Published: July 2021

Purpose

This paper examines how weak ties and strong ties in the supply chain network influence the financing performance of small and medium enterprises (SMEs) through the mediation of information sharing and innovation capability.

Design/methodology/approach

Questionnaires were administered to 208 financial managers responsible for supply chain finance in SMEs in China. Data analysis techniques used included multiple regression analysis and fuzzy-set qualitative comparative analysis.

Findings

The authors found that weak ties had a more substantial impact on the financing performance of SMEs than strong ties did. Information sharing and innovation capability played a mediating role between weak and strong ties and the financing performance of SMEs. In addition, information sharing and innovation capability complement each other and jointly influence the financing performance of SMEs.

Practical implications

SMEs are suggested to actively embed themselves in the supply chain network to increase financing opportunities and reduce financing costs. The authors also recommend SMEs to enhance the level of their information sharing in the supply chain network and take advantage of their network ties to access and adopt new technology from other organisations and conduct collaborative innovation with partner institutions.

Originality/value

The paper extends the authors’ understanding of supply chain finance by exploring the intrinsic mechanism of how various constructs (weak ties, strong ties, information sharing and innovation capability) in the supply chain network have an impact on the financing performance of SMEs. In particular, the authors explore the under-researched mediating effect of information sharing and innovation capability on the relationship between network ties and the financing performance of SMEs.
International resource configuration of product-related services in the digital age – An analysis of its antecedents
Authors: Jovanovic Jelena , Morschett Dirk
Published: July 2021

Purpose

Although many manufacturers depend on international sales, and product-related services continue to increase in importance, little is known about how manufacturers should deliver their product-related services across borders. This paper examines the international configuration decision of industrial service offerings across borders by investigating the impact of different service characteristics and the servitization strategy on this decision. Additionally, the paper sheds light on how digitalization and administrative heritage impact this decision.

Design/methodology/approach

116 industrial goods manufacturers from Switzerland and Germany were surveyed.

Findings

Servitization leads companies to centralize their service resources in their home countries. However, most service characteristics do not impact decisions regarding centralization, except for knowledge intensity, which leads to more centralization of resources. This implies that the resource configuration does not depend on each service individually but on the overall service strategy. Furthermore, the digital readiness of the host country directly and positively impacts resource centralization. Notwithstanding other variables, larger companies tend to decentralize service resources more than smaller companies.

Originality/value

This paper is among the first to study the international configuration impact of servitization and of individual service characteristics, thereby adding important knowledge regarding the provision of product-related services in the international context. Additionally, different aspects of digitalization are included to analyze its impact on companies and host countries.
Reproducibility and persistence of individual marks on 3000 fired bullets from five Chinese Norinco QSZ‐92 9 × 19 mm pistols, and the search performance of Evofinder® to a 1000 firearm database of the same model firearm
Authors: Wei Zhongbo , Luo Yaping , Zhou Peng , Ji Kewei
Published: July 2021

For firearm identification, foundational validity based on the reproducibility and persistence of characteristic marks must be established. We investigate the fired bullets of five Chinese Norinco QSZ‐92 9 × 19 mm pistols over 3000 shots. The first 50 fired bullets are recovered, whereas every 50th fired bullet is recovered from the 51st to 3000th round. As such, 109 bullets are available for each pistol, and totally 545 bullets are introduced into the Evofinder® system. A large background database comprising 3000 bullets fired from 1000 registered QSZ92 9 × 19 mm pistols is used as interference. Both on‐screen analysis and automatic comparison are performed. The first fired bullets from the five pistols are separately correlated with the database. The results show that although the similarity for known match bullets changes slightly as the shot number increases, the land‐engraved area (LEA), groove‐engraved area (GEA), and slippage marks can be reproducibly transferred to the fired bullets in consecutive shots. The Evofinder system ranks all known match bullets on the top of the correlation result with the combination of LEA, GEA, and slippage marks.
Quantification of fentanyl analogs in oral fluid using LC‐QTOF‐MS
Authors: Palmquist Kaitlyn B. , Swortwood Madeleine J.
Published: July 2021

Oral fluid is a valuable alternative matrix for forensic toxicologists due to ease of observed collection, limited biohazardous exposure, and indications of recent drug use. Limited information is available for fentanyl analog prevalence, interpretation, or analysis in oral fluid. With increasing numbers of fentanyl‐related driving under the influence of drug (DUID) cases appearing in the United States, the development of detection methods is critical. The purpose of the present study was to develop and validate a quantitative method for fentanyl analogs in oral fluid (collected via Quantisal™) using liquid chromatography‐quadrupole‐time‐of‐flight‐mass spectrometry (LC‐QTOF‐MS). Validation resulted in limits of detection and quantification ranging from 0.5 to 1 ng/mL. Established linear range was 1–100 ng/mL for all analytes, except acetyl fentanyl at 0.5–100 ng/mL (R2 > 0.994). Within‐ and between‐run precision and bias were considered acceptable with maximum values of ±15.2%CV and ±14.1%, respectively. Matrix effects exhibited ionization enhancement for all analytes with intensified enhancement at a low concentration (9.3–47.4%). No interferences or carryover was observed. Fentanyl analogs were stable in processed extracts stored in the autosampler (4⁰C) for 48h. The validated method was used to quantify fentanyl analogs in authentic oral fluid samples (n=17) from probationers/parolees. Fentanyl and 4‐ANPP concentrations were 1.0–104.5 ng/mL and 1.2–5.7 ng/mL, respectively.