bluuebunny/crossref_metadata_2025 huggingface dataset:
Only the NAD precursor nicotinamide riboside maintains cardioprotection under clinically relevant conditions, possibly through activation of glycolysis
Authors: Xiao Y , Phelp P , Bakker D , Nederlof R , Hollmann M W , Weber N C , Zuurbier C J
Published: October 2021

Purpose

Cardioprotective strategies against ischaemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Here, we examined the efficacy of the cardioprotective compounds fingolimod (Fingo), empagliflozin (Empa), melatonin (Mela) and nicotinamide riboside (NR) in the presence of drugs routinely used clinically in IRI conditions such as cardiac by-pass surgery and PCI procedures (opiates, benzodiazepines, P2Y12 antagonist, propofol). Furthermore, we examine the mechanism of protection of effective compound(s).

Methods

Following pilot dose-response curves of each compound, cardioprotective efficacy of Fingo, Empa, Mela and NR in an in vivo rat model employing a clinically relevant anaesthetic background therapy (fentanyl-midazolam) were examined alone or in combination. Drugs were administered 30 min before 25 min left ascending coronary (LAD) ischaemia. Infarct size (IS) was determined following 2 h of reperfusion. Effective treatments were then tested in the presence of a P2Y12 antagonist (cangrelor) or propofol anaesthesia. Finally, the underlying metabolic mechanism of the efficient compound(s) was explored in an ex vivo Langendorff-perfused mouse heart model of cardiac IRI.

Results

We found that among these four compounds, only singular NR was able to reduce IS (30±14% vs 60±16%, P=0.009 vs control, Fig.1A) in vivo in the presence of clinically relevant background anaesthesia. NR still reduced IS in the presence of cangrelor (51±18% vs 71±4%, P=0.016 vs control, Fig.1B), but lost protection in the presence of propofol anaesthesia (62±16% vs 60±14%, P=0.839 vs control, Fig.1C). Furthermore, NR showed protection in the ex vivo model of IRI, where isolated hearts were perfused with glucose (G) and free fatty acid (FFA) palmitate (G+FFA): (IS%: 40±14% vs 64±12%, P=0.003 vs control; LDH release: 28.3±7.2 U/min/GWW vs 37.8±3.7 U/min/GWW, P=0.005 vs control; Rate-Pressure-Product (RPP) recovery (43±12% vs 31±8%, P=0.031 vs control, Fig.2A-C). However, NR's protection was lost when 1) glycolysis was by-passed, by replacing glucose in the perfusate with lactate (L) and pyruvate (P) (LP+FFA) or 2) glycolysis was overly activated by adding insulin to the perfusate (G+FFA+insulin) (Fig.2).

Conclusion

Our data suggests that NR is a promising cardioprotective agent to target cardiac ischaemia-reperfusion injury in clinical conditions employing opioid agonists, benzodiazepines and platelet P2Y12 inhibitors. This protection may, at least partly, be due to NR stimulation of cardiac glycolysis.

Funding Acknowledgement

Type of funding sources: None.
ADAR Editing in Viruses: An Evolutionary Force to Reckon with
Authors: Piontkivska Helen , Wales-McGrath Benjamin , Miyamoto Michael , Wayne Marta L
Published: October 2021

Adenosine Deaminases that Act on RNA (ADARs) are RNA editing enzymes that play a dynamic and nuanced role in regulating transcriptome and proteome diversity. This editing can be highly selective, affecting a specific site within a transcript, or nonselective, resulting in hyperediting. ADAR editing is important for regulating neural functions and autoimmunity, and has a key role in the innate immune response to viral infections, where editing can have a range of pro- or antiviral effects and can contribute to viral evolution. Here we examine the role of ADAR editing across a broad range of viral groups. We propose that the effect of ADAR editing on viral replication, whether pro- or antiviral, is better viewed as an axis rather than a binary, and that the specific position of a given virus on this axis is highly dependent on virus- and host-specific factors, and can change over the course of infection. However, more research needs to be devoted to understanding these dynamic factors and how they affect virus–ADAR interactions and viral evolution. Another area that warrants significant attention is the effect of virus–ADAR interactions on host–ADAR interactions, particularly in light of the crucial role of ADAR in regulating neural functions. Answering these questions will be essential to developing our understanding of the relationship between ADAR editing and viral infection. In turn, this will further our understanding of the effects of viruses such as SARS-CoV-2, as well as many others, and thereby influence our approach to treating these deadly diseases.
The Effect of Delay Duration on Delay Discounting Across Adulthood
Authors: Leverett Shelby , Garza Christopher , Seaman Kendra
Published: October 2021

Objectives

Literature about the relationship between age and delay discounting, or the willingness to wait for delayed rewards, is mixed. We posit that some of this heterogeneity may be attributable to inconsistent delay durations across studies. Here we investigate how delay duration influences discounting across adulthood by systematically varying the duration of the delay between the smaller, sooner and the larger, later option.

Methods

288 healthy participants (age range: 25–84 years) completed an online delay discounting task that probed 12 different time delays across 3 discount rates. Discounting was analyzed in 2 statistical models that treated delay duration as either a categorical or a continuous predictor.

Results

Longer delays were generally associated with decreased discounting. However, this was dependent on both age of the participant and delay duration. Both models revealed that, at short to moderate time delays, older adults discounted less than younger adults. However, at very long delays (5 and 10 years), older adults discounted at similar rates to younger adults.

Discussion

Results suggest that delay length can moderate the relationship between age and discounting. Using delays longer than those tested here (>10 years) could reveal yet another trend (i.e., a reversal) to those found here. Future research should investigate whether this reversal in discounting exists, why it exists, and where the inflection point lies.
An Extension of the Three Gap Theorem to Interval Exchange Transformations
Authors: Taha Diaaeldin
Published: October 2021

The three gap theorem asserts that for any real $\alpha $ and any positive integer $N$, the fractional parts of the sequence $0, \alpha , 2\alpha , \cdots , (N-1)\alpha $ have at most three distinct gap lengths. In this note, we extend the three gap theorem to arbitrary orbits of interval exchange transformations, and in the process, we generalize the three gap theorem and a result by Boshernitzan.
Ceding Control and Taking it Back: The Origins of Free Movement in EU Law
Authors: Barnard Catherine , Fraser Butlin Sarah
Published: October 2021

Given the emphasis, at the time of the 2016 referendum, on the need to take back control of UK immigration policy, the article raises the question as to why the founding EU States decided not only to cede control in this sensitive field but also to allow such a generous approach to economic migration (to include not just workers but also their family members and to include equal access to benefits, including to housing) (the ‘why’ question). We also wanted to know whether any of the concerns which so resonated in the 2016 referendum campaign, especially about benefit tourism and pressure on public services, were ventilated at the time (the ‘risks’ question). Given that the contemporaneous academic literature did not offer much insight, we went to the archives and traced the evolution of the debates on economic migration in the period leading up to the signing of the Treaty of Rome, and again in the run up to the adoption of the key Regulation on workers, Regulation 1612/68 (now Regulation 492/11). We suggest that in respect of the ‘why’ question there was no single—or simple—explanation as to why the founding states agreed to the introduction of free movement but various justifications were offered. In respect of the ‘risks’ question, our research revealed little contemporaneous discussion of the concerns that subsequently took hold, primarily in the UK but also elsewhere. More striking were the extensive debates on adequate housing for migrant workers and their families. This was less couched in terms of risk but in terms of the paucity of provision of adequate housing for all families. The article concludes by considering the question as to why there was so little attention paid to the radical nature of free movement.
Modern Slavery and Directors’ Disqualification: A Convergence of Opportunity and Challenge
Authors: Mamutse Blanca
Published: October 2021

Prevention and elimination of modern slavery is a priority of this era, eliciting responses at an international level and in domestic laws. The duty of organisations to ensure transparency in their supply chains is the strongest representation of corporate responsibility in this field. Less attention has been given to the current/potential role of insolvency mechanisms, in relation to companies’ commission of modern slavery offences, and in relation to their failure to comply with their supply-chain obligations. This paper engages with this novel question by examining the proposition to incorporate a directors’ disqualification sanction into the United Kingdom framework governing companies’ modern slavery supply chain obligations. This represents an opportunity, insofar as the disqualification regime is ostensibly well-placed to address weaknesses in companies’ compliance with their responsibilities. However, it represents a challenge in that adoption and implementation would have to navigate drawbacks such as the limitations of existing grounds for disqualification and potential weaknesses in the design and enforcement of a bespoke sanction. Moreover, it should confront uncertainty as to whether disqualification is an effective tool for preventing misconduct by the professional/executive class of managers at the helm of large companies. Increased emphasis on regulating the human rights obligations of companies makes it imperative that this question is addressed.
GIST case turned out to be a perforated peptic ulcer: a case report
Authors: Miratashi Yazdi Seyed Amir , Habibi Pedram , Eftekhar Javadi Arezoo , Hajebi Reza
Published: October 2021

Gastrointestinal stromal tumors (GISTs) are tumors arising from the fourth layer of the stomach. They are the most common form of mesenchymal neoplasms in the gastrointestinal tract. The diagnosis for the aforementioned tumors is made through endoscopic ultrasonography (EUS) with no further inspection through biopsies and aspirations. Regarding the fact that biopsies are not made in these cases, pathological misdiagnoses, however rare and effectless in the final outcome of the surgery, do occur. Here, we present a case of a 35-year-old male diagnosed with GIST through the means of EUS however, the post-op pathology report showed something very interesting. This patient was reported to be a case of perforated peptic ulcer and we found vegetable fiber component in the tissue of this patient. Bearing in mind the finding, misdiagnoses of GIST patients are probable, and careful planning prior to the surgery is recommended.
Spontaneous resolution of gastric perforation caused by an ingested foreign body: a case report
Authors: Williams Taylor Raines , Okoli Joel
Published: October 2021

Foreign body ingestions are commonly seen and are usually uneventful. Very rarely, ingested foreign bodies will cause perforation of the gastrointestinal tract, which can lead to peritonitis, abscesses or fistulation. This is the case of a patient with vague abdominal pain after voluntary ingestion of bleach and an ink pen. The ink pen was found lodged in the gastric antral wall on esophagogastroduodenoscopy. The foreign body spontaneously migrated into the gastric lumen and was successfully removed with endoscopy.
A Case Report of External Cardiac Pads Used for Internal Cardiac Defibrillation During Resuscitative Thoracotomy
Authors: Brown Samuel , Mool Jason L , Young William E , Hollensteiner Kourtney M , Cyr Ashley , Yi Fia , Gausepohl Andrew J
Published: October 2021

This is a case report regarding the use of non-conventional methods to perform internal cardiac defibrillation on a trauma patient in an austere environment. The patient was a polytrauma causality of an improvised explosive device who arrived to a far forward resuscitative surgical team during a recent armed conflict. After arrival, the patient lost pulses. An emergency resuscitative thoracotomy was performed, and the patient was noted to have ventricular fibrillation on direct cardiac visualization. In the absence of standard surgical defibrillation paddles, the team applied external defibrillator stickers directly to the patient’s myocardium to deliver an electrical shock. The procedure successfully led to the return of spontaneous circulation. This report highlights a novel approach to resuscitation in resource-limited environments by a military surgical team.
Chest Pain and Fever in a Healthcare Provider During the Global Coronavirus Pandemic
Authors: Zavala Armando , Stark Christopher M
Published: October 2021

The coronavirus disease 2019 (COVID-19) global pandemic has posed unique challenges to healthcare providers that work in austere environments. Military healthcare providers advise commanders on endemic disease risk, prevention, and management during field training exercises. Healthcare workers are at increased risk of exposure to infectious pathogens. We present a case of a military healthcare provider who presented with fever, cough, and fatigue during the COVID-19 global pandemic that was diagnosed with a primary pulmonary coccidioidal infection. Treatment after appropriate diagnosis consisted of supportive care. Respiratory and pain symptoms resolved by 2 months post-diagnosis. Although COVID-19 must be closely monitored in the field training environment, it is important to maintain a high index of suspicion of endemic infectious diseases as a potential etiology for respiratory illnesses.
Overweight BMI (25–29) in Active Duty Military: Excess Fat or More Lean Mass? A Look at the Evidence
Authors: Clerc Philip G , Mayer Stéphanie B , Graybill Sky
Published: October 2021

Many active duty service members and their health care providers feel that the current body mass index (BMI) standard for diagnosing obesity, BMI ≥30 kg/m2, may unfairly overclassify as obese those with higher muscle mass. Unfortunately, a closer look at the data available for service members repeatedly demonstrates the exact opposite: we are actually underestimating the rates of obesity in service members using current BMI cutoffs when compared with body fat mass as measured by either dual-energy X-ray absorptiometry or bioelectrical impedance analysis as the gold standard. Using a lower BMI threshold and refining positive results via history, exam, labs, and/or more specific measurements of body composition would more accurately estimate body fat percentage in active duty service members while remaining convenient and scalable. Given the current obesity epidemic in our nation, this suggests the critical need for new approaches to screening, as well as treatment, of overweight and obesity in our military to improve service readiness.
Complications of Nonpermanent Facial Fillers: A Systematic Review
Authors: Oranges Carlo M. , Brucato Davide , Schaefer Dirk J. , Kalbermatten Daniel F. , Harder Yves
Published: October 2021

Background:

A variety of complications after injection of nonpermanent fillers for facial rejuvenation have been reported so far. However, to date, the overall complication rate is still a matter of debate. The aim of this study was to perform a systematic review of literature to assess the type and severity of associated complications following injections in different anatomical regions of the face.

Methods:

The entire PubMed/Medline database was screened to identify case reports and clinical studies describing complications that have occurred after injection of nonpermanent fillers in the face. These complications have been reviewed and analyzed according to their occurrence in different anatomical regions of the face.

Results:

Forty-six articles including a total of 164 patients reported on a total of 436 complications during the time period between January 2003 and February 2020. The majority of the complications were reported after injections to the nose and the nasolabial fold (n = 230), the forehead and the eyebrows (n = 53), and the glabellar region (n = 36). Out of 436 complications, 163 have been classified as severe or permanent including skin necrosis (n = 46), loss of vision (n = 35), or encephalitis (n = 1), whereas 273 complications were classified as mild or transient, such as local edema (n = 74), skin erythema (n = 69), and filler migration (n = 2). The most severe complications were observed in treatments of nose, glabella, and forehead.

Conclusions:

Nonpermanent facial fillers are associated with rare but potentially severe complications. Severity and impact of complications depend on the anatomical region of the face and eventually require profound knowledge of facial anatomy.
Nuclear cataract, moderate oblique corneal astigmatism, and glaucoma in a highly myopic eye implanted with a foldable iris-fixated phakic IOL
Authors: Menapace Rupert
Published: October 2021

A 65-year-old woman had undergone bilateral foldable iris-fixated phakic intraocular lens (pIOL) implantation in 2008 to correct for high myopia of −10 diopters (D). 12 years later, she presented with nuclear and subcortical cataract in her right eye. The Artiflex pIOL (Figure 1

JOURNAL/jcrs/04.03/02158034-202111000-00021/figure1/v/2023-08-19T002621Z/r/image-tiff

) was well centered and fixed to the iris. Endothelial cell count (ECC) was 2159 per mm2 and corneal thickness 515 µm. Residual correction in her distance glass was −1.75 + 1.5 × 60. Topography showed a symmetric bowtie with a mean simulated keratometry of 1.3 D at an axis of 67 degrees (Figure 2

JOURNAL/jcrs/04.03/02158034-202111000-00021/figure2/v/2023-08-19T002621Z/r/image-tiff

). Keratometry was 1.5 @ 65. Left eye refraction was −1.5 + 1.0 × 175. The patient had also developed chronic open-angle glaucoma with intraocular pressure measurements exceeding 30 mm Hg, which was currently regulated with topical medication.

What would be your surgical approach for cataract surgery with IOL removal and replacement when also considering the possible later need for superior glaucoma filtering surgery?
Mouse Model of Critical Persistent Inflammation, Immunosuppression, and Catabolism Syndrome
Authors: Chen Xiancheng , Li Xiaojing , Lu Huimin , Xu Yali , Wei Yu , Cao Ke , Zhu Zhanghua , Chen Ming , Yu Wenkui
Published: October 2021

Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a growing challenge in intensive care units (ICUs). PIICS causes a severe illness with high mortality. Currently, treatment is expensive, and the outcomes are dismal. Herein, we established a PIICS model to study the disease pathophysiology and its potential treatment. Using a modified sublethal cecal ligation and puncture (CLP) to induce sepsis (day 1) and the injection of lipopolysaccharide (LPS) to induce an aggravated inflammation response (day 11), CLP + LPS mice recapitulating PIICS features were successfully generated (day 14). Adult male mice were divided into CLP + LPS, CLP + daily chronic stress (DCS), CLP, DCS, LPS, and sham control groups. A survival curve was generated, and phenotypes were analyzed using markers for catabolism, inflammation, and immunosuppression. The CLP + LPS model showed two mortality peaks (after CLP and after LPS), whereas the CLP + DCS and CLP groups showed one peak. Surviving CLP + LPS mice exhibited significantly increased catabolism and inflammatory cytokine levels and aggravated inflammation, including organ inflammation. CLP + LPS mice exhibited strong immune suppression as evidenced by decreased splenic cluster of differentiation (CD)8+ and interferon-γ+CD8+ T cell counts and a concomitant and significant increase in the myeloid-derived suppressor cell population. This CLP+LPS-induced PIICS model differs from acute sepsis models, showing two mortality peaks and a protracted course of 14 days. Compared to previous PIICS models, ours shows a re-aggravated status and higher catabolism, inflammation, and immunosuppression levels. Our aim was to use the PIICS model to simulate PIICS pathophysiology and course in the ICU, enabling investigation of its mechanism and treatment.
Early Graft Loss Following Transplantation From Expanded Criteria Donors
Authors: Larkins Nicholas G. , Wong Germaine , Johnson David W. , Hawley Carmel , Teixeira-Pinto Armando , Pleass Henry , Pilmore Helen , Lim Wai H.
Published: October 2021

Background.

Expanded criteria donor (ECD) kidneys are associated with higher graft loss rates than standard criteria donor kidneys. We sought to determine factors associated with early graft loss and their discrimination ability for this outcome compared with kidney donor risk index.

Methods.

Data were extracted from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) for ECD transplants between 1997 and 2014. The primary outcome was early graft loss (all-cause graft loss within 3 y of transplantation). Death-censored graft loss was substituted as a sensitivity analysis. Era-adjusted odds ratios were calculated by multivariable logistic regression for donor, recipient, and transplant factors available at transplantation. Discrimination was assessed by c-statistic, with 95% confidence intervals (CIs) calculated by bootstrapping.

Results.

Of 2152 ECD kidney transplants, early graft loss occurred in 406 (19%) and was associated with recipient diabetes, smoking, First Nations recipients, and oliguria. Of factors defining ECD (age, elevated terminal creatinine, hypertension, death from cerebrovascular accident), all but mode of death were associated with early graft loss. The multivariable model, including known donor, recipient, and transplant factors, was moderately good at predicting early graft loss (c-statistic 0.65; 95% CI, 0.62-0.68). Recipient factors (c-statistic 0.62; 95% CI, 0.59-0.65) performed equally well compared with donor factors (c-statistic 0.60; 95% CI, 0.57-0.64) or the kidney donor risk index (c-statistic 0.60; 95% CI, 0.56-0.63).

Conclusions.

Early graft loss occurs in approximately one-fifth of ECD kidney transplants. The discriminatory value of commonly used recipient, donor, and transplant factors are approximately comparable and limited.
Can the Rapid Antigen Test for COVID-19 Replace RT-PCR: A Meta-analysis of Test Agreement
Authors: Elmakaty Ibrahim , Elsayed Abdelrahman , Hommos Rama Ghassan , Abdo Ruba , Mohamed Amira , Yousif Zahra , Fakhroo Maryam , Alansari Abdulrahman , Coyle Peter V. , Doi Suhail A. R.
Published: October 2021

Background

Several studies have compared the performance of reverse transcription-polymerase chain reaction (RT-PCR) and antigen rapid diagnostic tests (Ag-RDTs) as tools to diagnose SARS-CoV-2 disease (COVID-19). As the performance of Ag-RDT may vary among different products and viral load scenarios, the clinical utility of the Ag-RDT remains unclear. Our aim is to assess the diagnostic agreement between Ag-RDTs and RT-PCR in testing for COVID-19 across different products and cycle threshold (Ct) values.

Methods

An evidence synthesis and meta-analysis of Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) was conducted after an exhaustive search of five databases to locate published studies that compared Ag-RDT to RT-PCR and reported quantitative comparison results. After the screening, quality assessment, and data extraction, the synthesis of pooled estimates was carried out utilizing the quality-effects (QE) model and Freeman-Tukey double arcsine transformation (FTT) for variance stabilization. Subgroup analysis was also conducted to evaluate the tests’ diagnostic agreement across distinctive products and Ct-value thresholds.

Findings

A total of 420 studies were screened by title and abstract, of which 39 were eventually included in the analysis. The overall NPA was 99.4% (95%CI 98.8-99.8, I2=91.40%). The PPA was higher in lower Ct groups such as groups with Ct <20 and Ct <25, which had an overall PPA of 95.9% (95%CI 92.7-98.2, I2=0%) and 96.8% (95%CI 95.2-98.0, I2=50.1%) respectively. This is in contrast to groups with higher Ct values, which had relatively lower PPA. Panbio and Roche Ag-RDTs had the best consistent overall PPA across different Ct groups especially in groups with Ct <20 and Ct <25.

Interpretation

The findings of our meta-analysis support the use of Ag-RDTs in lieu of RT-PCR for decision making regarding COVID-19 control measures, since the enhanced capacity of RT-PCR to detect disease in those that are Ag-RDT negative will be unlikely to have much public health utility. This step will drastically reduce the cost and time in testing for COVID-19.

Funding

This research did not receive any specific funding.
Antennapedia and optix regulate metallic silver wing scale development and cell shape in Bicyclus anynana butterflies
Authors: Prakash Anupama , Finet Cédric , Banerjee Tirtha Das , Saranathan Vinodkumar , Monteiro Antónia
Published: October 2021

Butterfly wing scale cells can develop very intricate cuticular nanostructures that interact with light to produce structural colors including silvery hues, but the genetic basis of such nanostructures is mostly unexplored. Here, we first identified that optix is necessary for metallic scale development in the butterfly Bicyclus anynana. We then characterized different subtypes of wildtype metallic silver scales and addressed the function of five genes – apterous A, Ultrabithorax, doublesex, Antennapedia, and optix – in the differentiation of silver scales, at a single-cell resolution, by leveraging crispants that exhibited either ectopic gains or losses of silver scales. Wildtype silver scales were generally rounded and had low amounts of pigmentation, exhibiting a common ultrastructural modification for metallic broadband reflectance, i.e., an undulatory air layer enclosed by an upper and lower lamina. Our results indicated that the varying air layer thickness was the important parameter of the bilaminate scale for producing a broadband reflectance across visible wavelengths. While a single lamina of the appropriate thickness could also produce broadband colors, the bilaminate structure is advantageous as it increases the overall reflectivity. Crispant brown scales differed from wildtype silver scales via the loss of the continuous upper lamina, increased lower lamina thickness, and increased pigmentation. The reverse was seen when brown scales became silver. We identified Antennapedia and optix as high-level regulators in the network differentiating different silver scale subtypes and determining overall cell shape in both sexes. In addition, Antp exhibits a novel, post-embryonic role in the determination of ridge and crossrib orientation.
Cables1 links Slit/Robo and Wnt/Frizzled signaling in commissural axon guidance
Authors: Zuñiga Nikole , Stoeckli Esther T.
Published: October 2021

During neural circuit formation, axons navigate from one intermediate target to the next, until they find their final target. At intermediate targets, axons switch from being attracted to being repelled by changing the guidance receptors on the growth cone surface. For smooth navigation of the intermediate target and the continuation of their journey, the switch in receptor expression has to be orchestrated in a precisely timed manner. As an alternative to changes in expression, receptor function could be regulated by phosphorylation of receptors or components of signaling pathways. We identifed Cables1 as a linker between floor-plate exit of commissural axons regulated by Slit/Robo signaling and the rostral turn of post-crossing axons regulated by Wnt/Frizzled signaling. Cables1 localizes β-Catenin phosphorylated at tyrosine 489 by Abelson kinase to the distal axon, which in turn is necessary for the correct navigation of post-crossing commissural axons in the developing chicken spinal cord.
Encapsulated actomyosin patterns drive cell-like membrane shape changes
Authors: Bashirzadeh Yashar , Moghimianavval Hossein , Liu Allen P.
Published: October 2021

Cell shape changes from locomotion to cytokinesis are, to a large extent, driven by myosin-driven remodeling of cortical actin patterns. Passive crosslinkers such as α-actinin and fascin as well actin nucleator Arp2/3 complex largely determine the architecture and connectivity of actin network patterns; consequently, they regulate network remodeling and membrane shape changes. Membrane constriction in animal cell cytokinesis proceeds by assembly and contraction of a contractile ring pattern rich in α-actinin and myosin at the equator of the cell cortex, with which the ring is contiguous. Here we reconstitute actomyosin networks inside cell-sized lipid bilayer vesicles and show that, depending on vesicle size and concentrations of α-actinin and fascin, actomyosin networks assemble into ring and aster-like patterns. Anchoring actin to the membrane enhances the interaction of the contractile networks with lipid membrane but does not change the architecture of the patterns. A membrane-bound actomyosin ring exerts force and constricts the membrane. An Arp2/3 complex-mediated actomyosin cortex is shown to assemble a ring-like pattern at the equatorial cortex and contribute to myosin-driven clustering of the cortex and consequently membrane deformation. An active gel theory unifies a model for the observed membrane constriction and protrusion induced by the membrane-bound actomyosin networks.
A Recombinant Multivalent Vaccine (rCpa1) Induces Protection for C57BL/6 and HLA Transgenic Mice Against Pulmonary Infection with Both Species of Coccidioides
Authors: Campuzano Althea , Pentakota Komali Devi , Liao Yu-Rou , Zhang Hao , Wiederhold Nathan , Ostroff Gary , Hung Chiung-Yu
Published: October 2021

Coccidioidomycosis is caused by Coccidioides posadasii (Cp) and Coccidioides immitis (Ci) that have 4-5% differences in their genomic sequences. There is an urgent need to develop a human vaccine against both species. A previously created recombinant antigen (rCpa1) that contains multiple peptides derived from Cp isolate C735 is protective against the autologous isolate. The focus of this study is to evaluate cross-protective efficacy and immune correlates by the rCpa1- based vaccine against both species of Coccidioides. DNA sequence analyses of the homologous genes for the rCpa1 antigen were conducted for 39 and 17 clinical isolates of Cp and Ci, respectively. Protective efficacy and vaccine-induced immunity were evaluated for both C57BL/6 and human HLA-DR4 transgenic mice against 5 highly virulent isolates of Cp and Ci. There are a total of 7 amino acid substitutions in the rCpa1 antigen between Cp and Ci. Both C57BL/6 and HLA-DR4 mice that were vaccinated with a rCpa1 vaccine resulted in significant reduction of fungal burden and increased numbers of IFN-γ- and IL-17-producing CD4+ T cells in the first 2 weeks post-challenge. These data support that rCpa1 has cross-protection activity against Cp and Ci pulmonary infection through activation of early Th1 and Th17 responses.
Assessment of Tuberculosis Prevention and Care Measures in Mining Industries of Malawi, 2019
Authors: Dimba Andrew , Ng’ambi Wingston Felix , Banda Knox , Soundappan Kathirvel , Chongwe Gershom , Banda Pilirani , Rambiki Ethel , Mpunga James , Chanda- Kapata Pascalina , Lwanda Levi , Matu Martin , Girma Belaineh , Gowelo Happy , Kapokosa Mphatso , Kathyola Damson
Published: October 2021

Setting

Karonga, Rumphi, Kasungu and Lilongwe districts of Malawi in 2019.

Objectives

To determine the availability and utilization of TB preventive and care services in fifteen licensed mining industries in four selected districts in Malawi in 2019.

Design

We conducted a cross-sectional study using mixed-methods. Qualitative data were analysed using content analysis and thematic approach. We calculated the frequencies, proportions, median and interquartile range in STATA v16.0. Qualitative data was analysed using content analysis. We triangulated the qualitative and quantitative results.

Results

Of the 373 miners, 215 (58%) indicated that they were provided with annual TB screening while 43 (12%) had TB screened before being recruited in the mine, 171 (46%) were provided with masks, and 25 (7%) were aware of compensation after being sick while working in a mine. Of the 171 miners that indicated that masks were provided, 110 (64%) cited N95, 55 (32%) cited surgical mask, and 6 (4%) cited cotton wasters. The common OHS measures at the mines were banning of smoking within the mining site, sensitization of the miners on TB and adequate ventilation. The key challenges were the absence of the national Occupational Health and Safety Policy (OHSP), limited financial resources to consistently procure the PPE, and poor coordination between the mines, labour and health offices at district level.

Conclusion

The mining industries of Malawi have implemented an array of the expected measures however most of these are available at a sub-optimal level. The absence of the national OHSP has provided a loophole for non-adherence of the mining industries to providing OHS to the miners. Therefore, Malawi should put in place OHSP to safeguard the health and social protection as well as compensation of the miners and ex-miners.
Hydraulic synchrony of spawning sites amongst Earth’s riverine fishes
Authors: O’Sullivan Antóin M. , Morgan Alexander M. , Newbury Robert , Linnansaari Tommi , Kurylyk Barret L. , Helminen Jani , Wegscheider Bernhard , Johns Robert C. , Samways Kurt , Alex Kari I. , Curry R. Allen , Cunjak Richard A.
Published: October 2021

Earth’s riverine fishes utilize a suite of reproductive guilds, broadly following four guilds: nest guarders, broadcast pelagic spawners, broadcast benthic spawners and nest non-guarders 1,2, and these guilds utilize different mechanisms to aerate eggs 3,4. Globally, river fishes populations are declining5, and spawning habitat rehabilitation has become a popular tool to counter these declines6. However, there is a lack of understanding as to what classifies suitable spawning habitats for riverine fishes, thereby limiting the efficacy of these efforts and thus the restoration of the target species. Using data from n = 220 peer-reviewed papers and examining n = 128 unique species, we show the existence of a hydraulic pattern (defined by Froude number (Fr), a non-dimensional hydraulic parameter) that characterizes the reproductive guilds of riverine fishes. We found nest guarders, broadcast pelagic spawners, benthic spawners, and nest non-guarders selected sites with mean Fr = 0.05, 0.11, 0.22, and 0.28, respectively. Some of the fishes in this study are living fossils, suggesting that that these hydraulic preference patterns may be consistent across time. Our results suggest this hydraulic pattern can guide spawning habitat rehabilitation for all riverine fish species globally in absence of specific spawning habitat information for a species, where resource managers can establish the reproductive guild of the species of interest, and then apply the specific hydraulic requirements (Fr range) of that reproductive guild, as presented herein, in the rehabilitation of the target species.
A patatin-like phospholipase mediatesRickettsia parkeriescape from host membranes
Authors: Borgo Gina M. , Burke Thomas P. , Tran Cuong J. , Lo Nicholas T. N. , Engström Patrik , Welch Matthew D.
Published: October 2021

Spotted fever groupRickettsiaspecies are arthropod-borne obligate intracellular bacteria that can cause mild to severe human disease. These bacteria invade host cells, replicate in the cell cytosol, and then spread from cell to cell. To access the host cytosol and avoid detection by immune surveillance mechanisms, these pathogens must have evolved efficient ways to escape membrane-bound vacuoles. AlthoughRickettsiaare predicted to express factors that disrupt host membranes, little is known about how and when these proteins function during infection. Here, we investigated the role of aRickettsiapatatin-like phospholipase A2 enzyme (Pat1) during host cell infection by characterizing aRickettsia parkerimutant with a transposon insertion in thepat1gene. We show that Pat1 is important for infection in a mouse model and in host cells. We further show that Pat1 is critical for efficiently escaping from the single and double membrane-bound vacuoles into the host cytosol, and for avoiding host galectins that mark damaged membranes. In the host cytosol, Pat1 is important for avoiding host polyubiquitin, preventing recruitment of autophagy receptor p62, and promoting actin-based motility and cell-cell spread. Our results show that Pat1 plays critical roles in escaping host membranes and promoting cell-cell spread duringR. parkeriinfection and suggest diverse roles for patatin-like phospholipases in facilitating microbial infection.

Importance

Spotted fever groupRickettsiaare bacteria that reside in ticks and can be transmitted to mammalian hosts, including humans. Severe disease is characterized by high fever, headache, and rash, and results in occasional mortality despite available treatment.Rickettsiainteract with host cell membranes while invading cells, escaping into the cytosol, and evading cellular defenses. Bacterial phospholipase enzymes have been proposed as critical factors for targeting host cell membranes, however the specific roles of rickettsial phospholipases are not well defined. We investigated the contribution of one conserved patatin-like phospholipase, Pat1, inRickettsia parkeri. We observed that Pat1 is important for virulence in an animal model. Moreover, Pat1 plays critical roles in host cells by facilitating access to the cell cytosol, inhibiting detection by host defense pathways, and promoting cell-cell spread. Our study indicates that Pat1 performs several critical functions, suggesting a broad role for phospholipases throughout theRickettsialifecycle.
Use-dependent biases primarily originate from a contaminated motor plan
Authors: Tsay Jonathan S , Kim Hyosub E , Saxena Arohi , Parvin Darius E , Verstynen Timothy , Ivry Richard B
Published: October 2021

Repetition of a specific movement biases subsequent actions towards the recently practiced movement, a phenomenon referred to as use-dependent learning (UDL). UDL has been attributed to shifts in the tuning of neurons in the motor cortex. However, recent studies employing a forced reaction time task, including the eLife article by Marinovic et al (2017), indicate that these biases may also arise from a contaminated motor plan, one that is biased towards the practiced direction. We advanced this line of inquiry, seeking to establish the relative contribution of execution and planning processes to UDL in a center-out reaching task in which participants were able to initiate movements of their own volition. On most trials, the target appeared at a designated “frequent” location; on other trials, the target appeared at one of six “rare” locations. In Experiment 1, participants exhibited a robust movement bias towards the frequent target when movements were self-initiated quickly, but a small movement bias when movements were self-initiated slowly – the signature of a contaminated motor plan. Strikingly, the heading angles were bimodally distributed, with one peak at the frequent target location and the other at the rare target location – a finding reinforced by a re-analysis of two widely cited studies on UDL. Notably, the latter peak was shifted in the frequently practiced direction, a signature of a motor execution bias. To eliminate the contribution of planning-related UDL, we imposed a delay between target onset and movement initiation in Experiment 2. As predicted, the heading angles became unimodally distributed around the rare target. The peak of this distribution was again shifted towards the location of the frequent target, indicative of a persistent bias in motor execution. Taken together, these results highlight two distinct components of UDL even when movements are self-initiated: First, the temporal dynamics underlying movement planning, in which a default plan is progressively overridden by a new plan, produces a pronounced motor planning bias. Second, there is a small, temporally stable bias that may reflect shifts in motor unit tuning.
Spatially-resolved transcriptomics analyses of invasive fronts in solid tumors
Authors: Wu Liang , Yan Jiayan , Bai Yinqi , Chen Feiyu , Xu JiangShan , Zou Xuanxuan , Huang Ao , Hou Liangzhen , Zhong Yu , Jing Zehua , Zhou Xiaorui , Sun Haixiang , Cheng Mengnan , Ji Yuan , Luo Rongkui , Li Qinqin , Wu Liang , Wang Pengxiang , Guo Dezhen , Huang Waidong , Lei Junjie , Liao Sha , Li Yuxiang , Jiang Zhifeng , Yao Na , Yu Yang , Li Yao , Liu Fengming , Zhang Mingyuan , Yang Huanming , Yang Shuang , Xu Xun , Liu Longqi , Wang Xiangdong , Wang Jian , Fan Jia , Liu Shiping , Yang Xinrong , Chen Ao , Zhou Jian
Published: October 2021

Solid tumors are complex ecosystems, and heterogeneity is the major challenge for overcoming tumor relapse and metastasis. Uncovering the spatial heterogeneity of cell types and functional states in tumors is essential for developing effective treatment, especially in invasive fronts of tumor, the most active region for tumor cells infiltration and invasion. We firstly used SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq) with a nanoscale resolution to characterize the tumor microenvironment of intrahepatic cholangiocarcinoma (ICC). Enrichment of distinctive immune cells, suppressive immune microenvironment and metabolic reprogramming of tumor cells were identified in the 500µm-wide zone centered bilaterally on the tumor boundary, namely invasive fronts of tumor. Furthermore, we found the damaged states of hepatocytes with overexpression of Serum Amyloid A (SAA) in invasive fronts, recruiting macrophages for facilitating further tumor invasion, and thus resulting in a worse prognosis. We also confirmed these findings in hepatocellular carcinoma and other liver metastatic cancers. Our work highlights the remarkable potential of high-resolution-spatially resolved transcriptomic approaches to provide meaningful biological insights for comprehensively dissecting the tumor ecosystem and guiding the development of novel therapeutic strategies for solid tumors.
Microbial stowaways – waterbirds as dispersal vectors of aquatic pro- and microeukaryotic communities
Authors: Szabó Beáta , Szabó Attila , Vad Csaba F. , Boros Emil , Lukić Dunja , Ptacnik Robert , Márton Zsuzsanna , Horváth Zsófia
Published: October 2021

Aim

Waterbirds are important dispersal vectors of multicellular organisms such as macrophytes, aquatic macroinvertebrates, and zooplankton. However, no study to date has focused on their potential role in dispersing aquatic microbial communities (i.a., bacteria, algae, protozoa). Here, we explicitly studied passive transport (endozoochory) of prokaryotes and unicellular microeukaryotes by waterbirds based on DNA metabarcoding approaches. By directly comparing the dispersed set of organisms to the source pool of a natural metacommunity, we aimed for a realistic estimate of the overall importance of waterbird zoochory for natural microbial communities.

Location

Shallow saline temporary ponds (soda pans) in the cross-border region of Austria and Hungary.

Taxon

Prokaryotes and unicellular microeukaryotes.

Methods

In 2017 and 2018, water samples from 25 natural aquatic habitats along with fresh droppings of the dominant greylag goose (Anser anser) and four other waterbird species were collected in a habitat network of temporary ponds. Their prokaryotic and microeukaryotic communities were identified via 16S and 18S rRNA gene amplicon sequencing. Sequence reads were analysed using mothur. After quality filtering of the reads, pro- and microeukaryotic amplicon sequencing variant (ASV) compositions were compared between the aquatic and dropping samples, across years and waterbird species.

Results

We found that 28% of the dominant aquatic prokaryotic and 19% of the microeukaryotic ASVs were transported byA. anser. ASV richness inA. anserdroppings was lower, but compositional variation was higher compared to the aquatic communities, probably resulting from stochastic pick-up of microbes from multiple aquatic habitats. We furthermore found that the composition of prokaryotic ASVs in bird droppings were different among the two years and reflected the actual aquatic communities. The dispersed set of microbes were largely similar among the different waterbird species except for the planktivore filter-feeder northern shoveler (Spatula clypeata) which was outstanding by dispersing a more species-rich subset of microeukaryotes than shorebirds or geese.

Main conclusions

By using a combined amplicon-sequencing approach to characterize microorganisms in waterbird droppings and in the associated environment, our study provides strong evidence for endozoochory of natural aquatic microorganism communities. These results imply that waterbirds may be crucial in maintaining ecological connectivity between discrete aquatic habitats at the level of microbial communities.
Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome
Authors: Martinez-Ara Miguel , Comoglio Federico , van Arensbergen Joris , van Steensel Bas
Published: October 2021

Gene expression is in part controlled by cis-regulatory elements (CREs) such as enhancers and repressive elements. Anecdotal evidence has indicated that a CRE and a promoter need to be biochemically compatible for promoter regulation to occur, but this compatibility has remained poorly characterised in mammalian cells. We used high-throughput combinatorial reporter assays to test thousands of CRE – promoter pairs from three Mb-sized genomic regions in mouse cells. This revealed that CREs vary substantially in their promoter compatibility, ranging from striking specificity for a single promoter to quantitative differences in activation across a broad set of promoters. More than half of the tested CREs exhibit significant promoter selectivity. Housekeeping promoters tend to have similar CRE preferences, but other promoters exhibit a wide diversity of compatibilities. Higher-order TF motif combinations may account for compatibility. CRE–promoter selectivity does not correlate with looping interactions in the native genomic context, suggesting that chromatin folding and compatibility are two orthogonal mechanisms that confer specificity to gene regulation.
Sex differences in the strength of selection under facultative sex
Authors: Haaland Thomas R. , Ebert Dieter , Kokko Hanna
Published: October 2021

Facultative sex, the ability to reproduce both sexually and asexually, is widespread across the tree of life. In anisogamous species, the frequency of sex modulates selection on traits with sex-specific expression. Current theory on conditional gene expression posits that the strength of selection on loci only expressed by a subset of individuals, and/or in a subset of environments, is proportional to the frequency of expressers in the population. We show here that this assumption does not hold when the subsets in question are males or females (because of the Fisher condition) and is most important in facultatively sexual populations. In this case, the proportion of sexually produced offspring is not determined by male frequency (sex ratio), but on relative female investment in sexual versus asexual reproduction. This breaks the link between the frequency of expressers and selection for loci with sex-specific expression. However, certain conditions can re-establish this link, for example male traits that predict mating success better under strong male-male competition, and sex ratio affecting the relative fecundity of sexual versus asexual females. Our work highlights the importance of the Fisher condition for understanding the efficiency of selection and has implications for differences in the genetic load among sexes.