bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Ventricular Hypertrophy Increases Susceptibility to Bupivacaine-induced Cardiotoxicity through Overexpression of Transient Receptor Potential Canonical Channels in Rats
Authors: Hino Hideki , Matsuura Tadashi , Kuno Miyuki , Hori Kotaro , Tsujikawa Shogo , Mori Takashi , Nishikawa Kiyonobu
Published: October 2020

Background

Local anesthetics, particularly potent long acting ones such as bupivacaine, can cause cardiotoxicity by inhibiting sodium ion channels; however, the impact of left ventricular hypertrophy on the cardiotoxicity and the underlying mechanisms remain undetermined. Transient receptor potential canonical (TRPC) channels are upregulated in left ventricular hypertrophy. Some transient receptor potential channel subtypes have been reported to pass relatively large cations, including protonated local anesthetics; this is known as the “pore phenomenon.” The authors hypothesized that bupivacaine-induced cardiotoxicity is more severe in left ventricular hypertrophy due to upregulated TRPC channels.

Methods

The authors used a modified transverse aortic constriction model as a left ventricular hypertrophy. Cardiotoxicity caused by bupivacaine was compared between sham and aortic constriction male rats, and the underlying mechanisms were investigated by recording sodium ion channel currents and immunocytochemistry of TRPC protein in cardiomyocytes.

Results

The time to cardiac arrest by bupivacaine was shorter in aortic constriction rats (n =11) than in sham rats (n = 12) (mean ± SD, 1,302 ± 324 s vs. 1,034 ± 211 s; P = 0.030), regardless of its lower plasma concentration. The half-maximal inhibitory concentrations of bupivacaine toward sodium ion currents were 4.5 and 4.3 μM, which decreased to 3.9 and 2.6 μM in sham and aortic constriction rats, respectively, upon coapplication of 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3 channel activator. In both groups, sodium ion currents were unaffected by QX-314, a positively charged lidocaine derivative, that hardly permeates the cell membrane, but was significantly decreased with QX-314 and 1-oleoyl-2-acetyl-sn-glycerol coapplication (sham: 79 ± 10% of control; P = 0.004; aortic constriction: 47± 27% of control; P = 0.020; n = 5 cells per group). Effects of 1-oleoyl-2-acetyl-sn-glycerol were antagonized by a specific TRPC3 channel inhibitor.

Conclusions

Left ventricular hypertrophy exacerbated bupivacaine-induced cardiotoxicity, which could be a consequence of the “pore phenomenon” of TRPC3 channels upregulated in left ventricular hypertrophy.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That New
The POSITIONED Study: Prone Positioning in Nonventilated Coronavirus Disease 2019 Patients—A Retrospective Analysis
Authors: Jagan Nikhil , Morrow Lee E. , Walters Ryan W. , Klein Lauren P. , Wallen Tanner J. , Chung Jacqueline , Plambeck Robert W.
Published: October 2020

Objectives:

Given perceived similarities between coronavirus disease 2019 pneumonia and the acute respiratory distress syndrome, we explored whether awake self-proning improved outcomes in coronavirus disease 2019-infected patients treated in a rural medical center with limited resources during a significant local coronavirus disease 2019 outbreak.

Design:

Retrospective analysis of prospectively collected clinical data.

Setting:

Single-center rural community-based medical center in Grand Island, NE.

Patients:

One hundred five nonintubated, coronavirus disease-infected patients.

Interventions:

None.

Measurements and Main Results:

After patients were educated on the benefits of awake self-proning, compliance was voluntary. The primary outcome was need for intubation during the hospital stay; secondary outcomes included serial peripheral capillary oxygen saturation measured by pulse oximetry to the Fio2 ratios, in-hospital mortality, and discharge disposition. Of 105 nonintubated, coronavirus disease-infected patients, 40 tolerated awake self-proning. Patients who were able to prone were younger and had lower disease severity. The risk of intubation was lower in proned patients after adjusting for disease severity using Sequential Organ Failure Assessment scores (adjusted hazard ratio, 0.30; 95% CI, 0.09–0.96; p = 0.043) or Acute Physiology and Chronic Health Evaluation II scores (adjusted hazard ratio, 0.30; 95% CI, 0.10–0.91; p = 0.034). No prone patient died compared with 24.6% of patients who were not prone (p < 0.001; number needed to treat = 5; 95% CI, 3–8). The probability of being discharged alive and peripheral capillary oxygen saturation measured by pulse oximetry to the Fio2 ratios were statistically similar for both groups.

Conclusions:

Awake self-proning was associated with lower mortality and intubation rates in coronavirus disease 2019-infected patients. Prone positioning appears to be a safe and inexpensive strategy to improve outcomes and spare limited resources. Prospective efforts are needed to better delineate the effect of awake proning on oxygenation and to improve patients’ ability to tolerate this intervention.
Delayed Development of Coronary Artery Dilitation in Suspected Severe Acute Respiratory Syndrome Coronavirus 2 Multisystem Inflammatory Syndrome: More Research Needed
Authors: Orr William B. , Elward Alexis M. , Lin John C. , Reich Patrick J. , Scheel Janet N. , Hayes Ericka V. , Remy Kenneth E.
Published: October 2020

Background:

Although significant disease burden in the severe acute respiratory syndrome coronavirus 2 pandemic has been relatively uncommon in children, worldwide cases of a postinfectious multisystem inflammatory syndrome in children and possible atypical Kawasaki-like disease attributing to severe acute respiratory syndrome coronavirus 2 infection have arisen. Original thinking for coronavirus disease-19 disease was that an overwhelming proinflammatory response drove disease pathogenesis. Emerging reports suggest that a robust immune suppression may be more relevant and predominant. Recently reported data on children with multisystem inflammatory syndrome in children have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial proinflammatory state; however, data are lacking to support this. Likewise, understanding development of certain clinical findings to changes in the immune system is lacking.

Case Summary:

We report a 12-year-old multiracial male with negative coronavirus disease-19 nasopharyngeal RNA polymerase chain reaction testing but positive severe acute respiratory syndrome coronavirus 2 serology, subsequent development of vasodilatory shock with myocardial depression, and subsequent delayed development of coronary artery dilatation after resolution of myocardial depression. Unlike previous reported cases of multisystem inflammatory syndrome in children, he exhibited profound lymphopenia without specific inflammatory cytokines elevations, whereas nonspecific markers (ferritin and C-reactive protein) were increased. He subsequently was discharged on day 12 of hospitalization with complete recovery.

Conclusion:

Our representative case of a patient with coronavirus disease-19-associated multisystem inflammatory syndrome in children without robust hyperinflammation and a delayed finding of coronary artery dilatation compared with reported case series highlights the need for further mechanistic understanding of coronavirus disease-19 disease and subsequent multisystem inflammatory syndrome in children or Kawasaki disease development. This report offers a number of disease mechanisms and clinical evolution considerations for further elucidation to guide development of potential therapies.
External Evaluation of Population Pharmacokinetics and Pharmacodynamics in Linezolid-Induced Thrombocytopenia: The Transferability of Published Models to Different Hospitalized Patients
Authors: Ogami Chika , Tsuji Yasuhiro , Nishi Yoshifumi , Kawasuji Hitoshi , To Hideto , Yamamoto Yoshihiro
Published: October 2020

Background:

The objective of this study was to perform an external evaluation of published linezolid population pharmacokinetic and pharmacodynamic models, to evaluate the predictive performance using an independent data set. Another aim was to offer an elegant environment for display and simulation of both the concentration and platelet count after linezolid administration.

Methods:

We performed a systematic literature search in PubMed for all studies evaluating the population pharmacokinetic and pharmacodynamic parameters of linezolid in patients and selected the models to be used for the external validation. The bias of predictions was visually evaluated by plotting prediction errors (PEs) and relative PEs. The precision of prediction was evaluated by calculating the mean absolute error (MAE), root mean squared error (RMSE), and mean relative error (MRE).

Results:

Three articles (models A, B, and C) provided linezolid-induced platelet dynamic models using population pharmacokinetic and pharmacodynamic modeling approaches. The PE and relative PE of both linezolid concentrations and platelet counts for models A and C showed similar predictive distributions. With respect to the prediction accuracy of total linezolid concentration, the MAE, RMSE, and MRE of population prediction values for model C was the smallest. The comparison of the MAE, RMSE, and MRE of patient-individual prediction values for the 3 pharmacodynamic models revealed no large differences.

Conclusions:

We confirmed the transferability of published population pharmacokinetic and pharmacodynamic models and showed that they were suitable for extrapolation to other hospitals and/or patients. This study also introduced application software based on model C for the therapeutic drug monitoring of linezolid.
The Impact of Air Pollution on Neurodegenerative Diseases
Authors: Wang Jian , Ma Tengfei , Ma Ding , Li Huimin , Hua Li , He Qing , Deng Xiaobei
Published: October 2020

Background:

With the development of industrialization in human society, ambient pollutants are becoming more harmful to human health. Epidemiological and toxicological studies indicate that a close relationship exists between particulate matter with a diameter ≤2.5 µm (PM2.5) and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). To further confirm the relationship, we focus on possible relevant mechanisms of oxidative stress and neuroinflammation underlying the association between PM2.5 and neurodegenerative diseases in the review.

Methods:

A literature search was performed on the studies about PM2.5 and neurodegenerative diseases via PubMed. A total of 113 articles published were selected, and 31 studies were included.

Results:

PM2.5 can enter the central nervous system through 2 main pathways, the blood–brain barrier and olfactory neurons. The inflammatory response and oxidative stress are 2 primary mechanisms via which PM2.5 leads to toxicity in the brain. PM2.5 abnormally activates microglia, inducing the neuroinflammatory process. Inflammatory markers such as IL-1β play an essential role in neurodegenerative diseases such as AD and PD. Moreover, the association between lipid mechanism disorders related to PM2.5 and neurodegenerative diseases has been gaining momentum.

Conclusions:

In conclusion, PM2.5 could significantly increase the risk of neurological disorders, such as AD and PD. Furthermore, any policy aimed at reducing air-polluting emissions and increasing air quality would be protective in human beings.
Encapsulated Gamma Source Contact Dose Conversion Factors: Updating NCRP-40 Guidance
Authors: Waller Edward , Heritage Eric
Published: October 2020

Secondary electron generation on the surface of encapsulated gamma sources can play a large role in the dose measured near the surface of the encapsulation. The National Council on Radiation Protection and Measurements Report No. 40 contains contact dose rate conversion factors for encapsulated gamma sources, along with recommended secondary electron correction factors. However, secondary electron correction factors were based on experiments performed in the 1930s and 1940s with encapsulated radium sources, and the correction factors for the other sources listed in the report were estimated based on these radium source measurements. Monte Carlo simulations were performed using the Particle and Heavy Ion Transport code System (PHITS) to calculate the contact dose rate conversion factors for each encapsulated gamma source presented in NCRP-40, taking into account the dose from both gamma rays and secondary electrons. These simulations showed that the contact dose rate conversion factors are much lower than those presented in NCRP-40, and the secondary electron contribution was much greater than the values proposed by NCRP-40. The original research used results from encapsulated 226Ra experiments to determine the secondary electron correction factors for NCRP-40. To support the current Monte Carlo calculations, experiments were conducted using an encapsulated 137Cs source, rare earth magnet, and ion chamber detector to show that the secondary electron correction factors presented in NCRP-40 were not applicable to the geometry of tissue in direct contact with the encapsulation. In this work, contact dose conversion factors for common encapsulated radionuclide sources are presented.
COMPARISON OF 25- AND 27-GAUGE SUTURELESS CANNULA-BASED INTRAOCULAR LENS SCLERAL FIXATION VISUAL ACUITY OUTCOMES AND COMPLICATION RATES
Authors: Kadakia Ankit B. , Wong Tien P. , Wykoff Charlie C. , Shah Ankoor R.
Published: October 2020

Purpose:

To compare the visual outcomes and complication rates of sutureless cannula-based intraocular lens scleral (SCILS) fixation performed with 25-gauge (25 G) versus 27-gauge (27 G) instrumentation.

Methods:

A retrospective chart review of consecutive cases of eyes without capsular support that underwent SCILS fixation of a three-piece intraocular lens. Sutureless cannula-based intraocular lens scleral fixation was performed by transconjunctival use of either 25-G or 27-G trocar cannulas. During postoperative follow-up evaluations, visual acuity and intraocular pressure were measured, and slit-lamp and indirect ophthalmoscopy examinations were performed to assess for development of known complications.

Results:

A total of 69 eyes underwent 25 G (27 eyes) or 27 G (42 eyes) SCILS fixation. The mean preoperative logarithm of the minimum angle of resolution visual acuity trended toward improvement from 0.95 ± 0.68 (20/178 Snellen equivalent) to 0.67 ± 0.64 (20/94 Snellen equivalent) for 25 G group at 1 year. Similar trend toward visual acuity improvement was seen in 27 G group with a mean preoperative logarithm of the minimum angle of resolution visual acuity of 1.43 ± 0.94 (20/538 Snellen equivalent) improving to 0.86 ± 1.00 (20/145 Snellen equivalent) at 1 year. Statistically significant improvement was seen as early as postoperative week one for 27 G group (P < 0.01), whereas statistically significant worsening was noted at the same time in 25 G group (P = 0.01). There was a statistically significant reduction in intraocular lens displacement (P = 0.01) and need for reoperation (P = 0.01) in 27 G group.

Conclusion:

Compared with 25 G SCILS fixation, eyes managed with 27 G SCILS fixation experienced more rapid visual acuity improvement. In addition, there was a lower rate of complications including intraocular lens displacement and need for reoperation.
Effect of ethanolic extract of Zataria multiflora Boiss (Shiraz thyme extract) on the kidney and spleen tissues of mice infected with visceral candidiasis and the stimulation of Th1, Th17, and Treg immune cells
Authors: Bayat Mansour , Hassannejad Niloofar , Ghazanfari Hadi
Published: October 2020

Background and aims:

Candidiasis is one of the most important fungal infections, which has been associated with antimicrobial resistance.

Materials and Methods:

Candida albicans ATCC10231 strain were isolated from the patient's body. To prepare the desired yeast number in a specific size, the serial dilution was performed. Doses of 2 × 107–108 were used and four mice were selected for each dose. The PAS staining was performed on the sections of the kidney and spleen prepared in paraffin blocks. The chloroform fraction of Zataria multiflora Boiss ethanolic extract was obtained and standardized by HPLC. Forty-two female BALB/C mice were randomly included with ages of 6–8 weeks. The administration of drugs into mice in each group was performed 24 h of C. albicans injection (the onset of the visceral candidiasis appearance in mice), and a single dose of 0.1 ml of the extract was injected to each group for every 6 days. Mononuclear cells of spleen and kidney were prepared from buffy coat layer and culture in 50 ml of 1640 RPMI medium. Th1, Th17, and Treg cells were measured in MNCs.

Results:

In mice that had medication intervention (including chloroform fraction of Shiraz thyme, thymol, carvacrol, or fluconazole), the fungal purification rate in the spleen was higher than the kidney (groups 1–5). In mice with no medication (group 6), the fungal purification rate in the kidney was higher than the spleen. All groups having medication intervention had a significant difference in terms of fungal elimination with group 7 and their fungal load was significantly decreased. In this regard, the amounts of fungal load reduction in spleen and kidney tissues in relation to extracts were the most. After extract, the highest rate of tissue cleansing was related to fluconazole followed by thymol and carvacrol. Thymol and carvacrol had no significant difference in terms of the effect on reducing the fungal load in the studied tissues. The percentage of TH1 cells in the culture of these cells was higher than that of the kidney cells. The highest percentage of TH17 cells was observed in group 1. The percentage of Treg cells in the kidney and spleen in the extract-receiving group had a significant decrease compared with the nondrug-receiving group.

Conclusion:

The Z. multiflora Boiss fraction can be considered as a powerful alternative to other drug treatments for achieving proper outcomes. Therefore, the use of this compound as a therapeutic agent in visceral candidiasis is possibly a new turning point in treatment, which can postpone the progress of the disease among patients.
Frequent Detection of Undiagnosed HIV Within Emergency Departments in Botswana
Authors: Pintye Jillian , Ortblad Katrina F. , Mawandia Shreshth , Bakae Odirile , Tau Lenna , Grande Matias , Mogomotsi Goabaone Panky , Mmatli Esther , Ngombo Modise , Norman Tebogo , Seckel Laura , Ledikwe Jenny
Published: October 2020

Among 130,161 HIV testing records from unique individuals at 149 programmatic sites in Botswana, frequency of detecting undiagnosed HIV infection within emergency departments (EDs) was 4.7% (455/9695), 2-fold higher than other clinic-based HIV counseling and testing. Men and noncitizens less frequently initiated same-day antiretroviral therapy after testing HIV positive within emergency departments.
The Effect of Surgical Timing on 30-Day Outcomes in Cleft Palate Repair
Authors: Peck Connor J. , Gowda Arvind U. , Shultz Blake N. , Wu Robin T. , Bourdillon Alexandra , Singh Anusha , Steinbacher Derek M.
Published: October 2020

Background:

The optimal age for cleft palate repair continues to be debated, with little discussion of surgical risk related to operative timing. This study of 3088 cleft palate patients analyzed the impact of surgical timing on perioperative and 30-day postoperative outcomes.

Methods:

Primary cleft palate repairs were identified in the National Surgical Quality Improvement Program database from 2012 to 2015. Data were combed for total postoperative complications, rates of readmission and reoperation, operating room time, and length of stay. Bivariate analyses were performed comparing 3-month periods from months 6 to 18, and months 0 to 5, 18 to 23, 24 to 29, and 30 to 59.

Results:

Despite a higher proportion of isolated soft palate closure, children operated on before 6 months had a higher complication rate than children at other ages (7.1 percent versus 3.2 percent; OR, 2.4; p = 0.04), and higher rates of both readmission (3.6 percent versus 1.4 percent; OR, 3.6; p = 0.02) and reoperation (2.4 percent versus 0.5 percent; OR, 4.7; p = 0.04). There were no differences in short-term outcomes for any other age group younger than 5 years, and no differences in hospital length of stay among any age groups.

Conclusions:

The authors’ findings suggest a relative contraindication to operation before 6 months. As there were no differences between any other age groups, long-term speech optimization should continue to be the primary consideration for operative planning. These findings improve the current rationale for palatoplasty timing, and can aid surgeons and parents in the surgical decision-making process.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
New insights on how and where to measure muscle mass
Authors: Fayh Ana Paula Trussardi , de Sousa Iasmin Matias , Gonzalez Maria Cristina
Published: October 2020

Purpose of review

This article will discuss different muscle mass assessment methods and emphasize their highlights.

Recent findings

Several measurement techniques can be used to evaluate muscle mass, recognized as important prognostic markers for adverse functional and clinical outcomes. Choosing the best method depends on the knowledge regarding their theoretical and practical limitations and the purpose of the assessment. Image techniques are considered the gold standards, with good accuracy and precision, but not always available in clinical settings. A new biological technique, the D3-creatinine dilution, can provide not only direct information about muscle mass but also shows a strong association with physical function. With the advancement of the use of the computed tomography (CT) images to assess skeletal muscle mass, mainly in patients with cancer, the assessment of skeletal muscle radiodensity (SMD), as a marker of muscle quality, may provide additional information regarding the association between muscle composition, muscle function and prognosis. Additional muscle function assessment can improve the risk prediction in several clinical situations.

The use of the best tool for the muscle mass assessment should be performed carefully among the various methodologies, according to their characteristics and clinical situation.
Impact of a Web-Based Decisional Aid on Satisfaction in Women Undergoing Prolapse Surgery
Authors: Collins Sarah A. , Mueller Margaret G. , Geynisman-Tan Julia , Lewicky-Gaupp Christina , Kenton Kimberly
Published: October 2020

Objectives

The objective of this study was to determine whether a computerized, condition-specific Decision Analysis Tool (DAT) for the surgical treatment of pelvic organ prolapse (POP) improves patient satisfaction and alters decision making.

Methods

Together with a health care startup company, we created a computerized DAT using the best evidence available on success rates and risks associated with sacrocolpopexy, native tissue apical suspension, and colpocleisis. Consecutively scheduled women before and after implementation of the DAT in an academic practice of 4 fellowship-trained, board-certified urogynecologists were included. The primary outcome was patient satisfaction using the Satisfaction with Decision Scale (SDS). Secondary outcomes included the Decision Regret Scale (DRS) questionnaire, differences in surgical choice, patient-reported outcomes, and individual SDS and DRS items. The SDS and DRS were administered at the 3-month postoperative visit.

Results

Forty-seven women before DAT implementation and 54 women after DAT implementation were included. There were no differences in SDS or DRS total scores (4.62 ± 0.66 vs 4.52 ± 0.72, P = 0.10 and 1.48 ± 0.79 vs 1.52 ± 0.82, P = 0.77) or individual question responses between groups. Women using the DAT were more likely to choose sacrocolpopexy than those who did not (76% vs 51%, P = 0.01). All 3 procedures led to similarly improved POP symptoms (P = 0.98), but those who underwent sacrocolpopexy had higher SDS scores compared with native tissue or colpocleisis patients (P = 0.01). Several individual SDS and DRS items were more favorable after sacrocolpopexy.

Conclusions

Women choosing surgery for POP are satisfied with their decision-making experiences with and without the assistance of a DAT. More women using a DAT, however, undergo sacrocolpopexy, which is associated with improved satisfaction.
Is Pisum sativum a good model species for the study of root responses to neighbours and barriers in soil? A bayesian hierarchical meta-analysis
Authors: Mobley Mariah L , Kruse Audrey S , McNickle Gordon G
Published: October 2020

Plant-plant competition is ubiquitous in nature. However, studying below ground behaviour of roots has always posed certain difficulties. Pea (Pisum sativum L.) has become a sort of model species for ecological studies about how plant roots respond to neighbouring plant roots and barriers in soil. However, published results point in several different directions. This has sometimes been interpreted as pea having sophisticated context dependent responses that can change in complex ways depending on its surroundings. To explore this further, here, we combine the result of five new experiments with published results to examine 18 unique experiments from 7 different studies for a total of 254 replicates. We used a Bayesian hierarchical meta-analysis approach to estimating the likely effect size from the available data, as well as quantify heterogeneity among different experiments, studies and cultivars. The posterior distributions show that, at the coarsest possible scale of total root production, it is unlikely that P. sativum root growth is influenced by either neighbours or barriers to root growth imposed by the walls of pots that vary in volume. We suggest that further work should consider repeating experiments that reported finer scale root plasticity in pea at the rhizosphere scale, and also consider alternative model species for the study of plant root responses to external cues.
Multisensory Configural Learning of a Home Refuge in the Whip SpiderPhrynus marginemaculatus
Authors: Flanigan Kaylyn AS , Wiegmann Daniel D , Hebets Eileen A , Bingman Verner P
Published: October 2020

Whip spiders (Amblypygi) reside in structurally complex habitats and are nocturnally active yet display notable navigational abilities. From the theory that uncertainty in sensory inputs should promote multisensory representations to guide behavior, we hypothesized that their navigation is supported by a configural, multisensory representation of navigational inputs, an ability documented in a few insects and never reported in arachnids. We trainedPhrynus marginemaculatusto recognize a home shelter characterized by both discriminative olfactory and tactile stimuli. In tests, subjects readily discriminated between shelters based on the paired stimuli. However, subjects failed to recognize the shelter in tests with either of the component stimuli alone. This result is consistent with the hypothesis that the terminal phase of their navigational behavior, shelter recognition, can be supported by the integration of multisensory stimuli as a configural representation. We hypothesize that multisensory configural learning occurs in the whip spiders’ extraordinarily large mushroom bodies, which may functionally resemble the hippocampus of vertebrates.
Determination of Bacterial Surface Charge Density Via Saturation of Adsorbed Ions
Authors: Wilhelm M.J. , Sharifian Gh. M. , Chang C.M. , Wu T. , Li Y. , Ma J. , Dai H.L.
Published: October 2020

Bacterial surface charge is a critical characteristic of the cell’s interfacial physiology that influences how the cell interacts with the local environment. A direct, sensitive, and accurate experimental technique capable of quantifying bacterial surface charge is needed to better understand molecular adaptations in interfacial physiology in response to environmental changes. We introduce here the method of second harmonic light scattering (SHS) which is capable of detecting the number of molecular ions adsorbed as counter charges on the exterior bacterial surface, thereby providing a measure of the surface charge. In this first demonstration, we detect the small molecular cation, malachite green, electrostatically adsorbed on the surface of representative strains of Gram-positive and Gram-negative bacteria. Surprisingly, the SHS deduced molecular transport rates through the different cellular ultra-structures are revealed to be nearly identical. However, the adsorption saturation densities on the exterior surfaces of the two bacteria were shown to be characteristically distinct. The negative charge density of the lipopolysaccharide coated outer surface of Gram-negativeE. coli(8.7±1.7 nm−2) was deduced to be seven times larger than that of the protein surface layer of Gram-positiveL. rhamnosus(1.2±0.2 nm−2). The feasibility of SHS deduced bacterial surface charge density for Gram-type differentiation is presented.

STATEMENT of SIGNIFICANCE

Bacterial surface charge density is an important physiological characteristic which determines how the cell interacts with its local environment. Directly measuring the surface charge density, however, is experimentally non-trivial. In this work, we report an experimental method, second harmonic light scattering, that can directly and accurately quantify the surface charge density of individual living bacteria. This is achieved by measuring the number of molecular ions electrostatically adsorbed on the exterior cellular surface as counter charges. It is found that the negative charge density of a representative Gram-negative bacterium is 7 times larger than a representative Gram-positive bacterium. It is suggested that this disparity of surface charge density can be exploited as a basis for Gram-classification of bacteria.
WITHDRAWN: ToxVec: Deep Language Model-Based Representation Learning for Venom Peptide Classification
Authors: Ahmadi Meisam , Jahed-Motlagh Mohammad Reza , Asgari Ehsaneddin , Torkaman Rahmani Adel , McHardy Alice C.
Published: October 2020

WITHDRAWAL STATEMENT

bioRxiv has withdrawn this manuscript as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Transcriptional regulation ofSLIT2expression in pancreatic cancer cell lines
Authors: Rheinheimer Brenna A. , Vrba Lukas , Futscher Bernard W , Heimark Ronald L
Published: October 2020

Background

SLIT2 has been shown to serve as a tumor suppressor in breast, lung, colon, and liver cancers. Additionally, expression of SLIT2 has been shown to be epigenetically regulated in prostate cancer. Therefore, we sought to determine transcriptional regulation of SLIT2 in pancreatic ductal adenocarcinoma.

Methods

RNA expression of SLIT2, SLIT3, and ROBO1 was examined in a panel of pancreatic ductal adenocarcinoma cell lines while protein expression of ROBO1 and SLIT2 was examined in tumor tissue. Methylation of the SLIT2 promoter was determined using Sequenom while histone modifications were queried by chromatin immunoprecipitation. Reexpression of SLIT2 was tested by treatment with 5-aza-2’deoxycytidine and Trichostatin A.

Results

Pancreatic cancer cell lines fall into three distinct groups based on SLIT2 and ROBO1 expression. The SLIT2 promoter is methylated in pancreatic ductal adenocarcinoma and SLIT2 expression is dependent on the level of methylation at specific CpG sites. Treatment with 5-aza-2’deoxycytidine (but not Trichostatin A) led to SLIT2 reexpression. The SLIT2 promoter is bivalent in pancreatic ductal adenocarcinoma and histone marks around the transcriptional start site are responsible for transcription.

Conclusions

Loss of SLIT2 expression modulated by epigenetic silencing may play a role in pancreatic ductal adenocarcinoma progression.
Deep-fUS: Functional ultrasound imaging of the brain using deep learning and sparse data
Authors: Di Ianni Tommaso , Airan Raag D.
Published: October 2020

Functional ultrasound (fUS) is a rapidly emerging modality that enables whole-brain imaging of neural activity in awake and mobile rodents. To achieve sufficient blood flow sensitivity in the brain microvasculature, fUS relies on long ultrasound data acquisitions at high frame rates, posing high demands on the sampling and processing hardware. Here we develop an end-to-end image reconstruction approach based on deep learning that significantly reduces the amount of data necessary while retaining the imaging performance. We trained a convolutional neural network to learn the power Doppler reconstruction function from sparse sequences of ultrasound data with a compression factor up to 95%, using high-quality images fromin vivoacquisitions in rats. We tested the imaging performance in a functional neuroimaging application. We demonstrate that time series of power Doppler images can be reconstructed with sufficient accuracy to detect the small changes in cerebral blood volume (~10%) characteristic of task-evoked cortical activation, even though the network was not formally trained to reconstruct such image series. The proposed platform may facilitate the development of this neuroimaging modality in any setting where dedicated hardware is not available or in clinical scanners.
A Diaphanous and Enabled dependent asymmetric actin cable array repositions nuclei during Drosophila oogenesis
Authors: Logan Gregory , McCartney Brooke M.
Published: October 2020

Cells reposition their nuclei for a diversity of specialized functions through a wide variety of cytoskeletal mechanisms. To complete oogenesis, Drosophila nurse cells employ novel actin cable arrays to reposition their nuclei. During oogenesis, 15 nurse cells connected by ring canals contract to “dump” their cytoplasmic contents into the oocyte. Just prior to dumping, actin cables initiate from the nurse cell cortex and elongate toward their nuclei, pushing them away from the ring canals to prevent obstruction. How the actin cable arrays generate directional nuclear movement is not known. We found regional differences in the actin cable growth rate that are dependent on the differential localization of the actin assembly factors Enabled (Ena) and Diaphanous (Dia). Mislocalization of Ena resulted in actin cable arrays with a uniform growth rate. In the absence of growth rate asymmetry, nuclear relocation was significantly altered and cytoplasmic dumping was incomplete. This novel mechanism for nuclear repositioning relies on the regulated cortical localization of Dia and Ena producing asymmetric actin cable arrays that push the nuclei away from the ring canals, enabling successful oogenesis.

Summary statement

This work demonstrates that an asymmetric actin cable array regulated by the differential localization of Diaphanous and Enabled is necessary to reposition nurse cell nuclei and complete oogenesis in Drosophila.
Exhaled aerosol increases with COVID-19 infection, and risk factors of disease symptom severity
Authors: Edwards David A. , Ausiello Dennis , Langer Robert , Salzman Jonathan , Devlin Tom , Beddingfield Brandon J. , Fears Alyssa C. , Doyle-Meyers Lara A. , Redmann Rachel K. , Killeen Stephanie Z. , Maness Nicholas J. , Roy Chad J.
Published: October 2020

Coronavirus disease-19 (COVID-19) transmits by droplets generated from surfaces of airway mucus during processes of respiration within hosts infected by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus. We studied respiratory droplet generation and exhalation in human and nonhuman primate subjects with and without COVID-19 infection to explore whether SARS-CoV-2 infection, and other changes in physiological state, translates into observable evolution of numbers and sizes of exhaled respiratory droplets in healthy and diseased subjects. In our observational cohort study of the exhaled breath particles of 74 healthy human subjects, and in our experimental infection study of eight nonhuman primates infected by aerosol with SARS-CoV-2, we found that exhaled aerosol particles increase one to three orders of magnitude with aging, high BMI, and COVID-19 infection. These variances appear to be related to changes in airway mucus surface composition and the propensity for mucus surfaces to breakup into small droplets during acts of breathing. We also observed that 20% of those participating in our human study accounted for 80% of the overall exhaled bioaerosol, reflecting a bioaerosol distribution analogous to a classical 20:80 super spreader distribution.
Lineage-specific protection and immune imprinting shape the age distributions of influenza B cases
Authors: Vieira Marcos C. , Donato Celeste M. , Arevalo Philip , Rimmelzwaan Guus F. , Wood Timothy , Lopez Liza , Huang Q. Sue , Dhanasekaran Vijaykrishna , Koelle Katia , Cobey Sarah
Published: October 2020

How a history of influenza virus infections contributes to protection is not fully understood, but such protection might explain the contrasting age distributions of cases of the two lineages of influenza B, B/Victoria and B/Yamagata. Fitting a statistical model to those distributions using surveillance data from New Zealand, we found they could be explained by historical changes in lineage frequencies combined with cross-protection between strains of the same lineage. We found additional protection against B/Yamagata in people for whom it was their first influenza B infection, similar to the immune imprinting observed in influenza A. While the data were not informative about B/Victoria imprinting, B/Yamagata imprinting could explain the fewer B/Yamagata than B/Victoria cases in cohorts born in the 1990s and the bimodal age distribution of B/Yamagata cases. Longitudinal studies can test if these forms of protection inferred from historical data extend to more recent strains and other populations.
Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway
Authors: Marroqui Laura , Martinez-Pinna Juan , Castellano-Muñoz Manuel , dos Santos Reinaldo S. , Medina-Gali Regla M. , Soriano Sergi , Quesada Ivan , Gustafsson Jan-Ake , Encinar José A. , Nadal Angel
Published: October 2020

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic β-cells from wild type (WT) and estrogen receptor β (ERβ) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in β-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+(KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in β-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERβ pathways. Molecular dynamics simulations indicated differences in ERβ ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERβ whose activation alters three key cellular events in β-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.
Immunization by exposure to live virus (SIVmne/HIV-2287) during antiretroviral drug prophylaxis reduces risk of subsequent viral challenge
Authors: Frenkel LM , Kuller L , Beck IA , Tsai C-C , Joy JP , Mulvania TM , Montefiori DC , Anderson DM
Published: October 2020

Rationale/Study Design

A major challenge in the development of HIV vaccines is finding immunogens that elicit protection against a broad range of viral strains. Immunity to a narrow range of viral strains may protect infants of HIV-infected women or partners discordant for HIV. We hypothesized that immunization to the relevant viral variants could be achieved by exposure to infectious virus during prophylaxis with antiretroviral drugs. To explore this approach in an animal model, macaques were exposed to live virus (SIVmneor HIV-2287) during prophylaxis with parenteral tenofovir. The humoral and cellular immune responses were quantified. Subsequently, experimental animals were challenged with homologous virus to evaluate protection from infection, and if infection occurred, the course of disease was compared to control animals. Experimental animals uninfected with SIVmnewere challenged with heterologous HIV-2287to assess resistance to retroviral infection.

Methodology/Principal Findings

JuvenileMacaca nemestrina(N=8) were given ten weekly intravaginal exposures with either moderately (SIVmne) or highly (HIV-2287) pathogenic virus during tenofovir prophylaxis. Tenofovir protected all 8 experimental animals from infection, while all untreated control animals became infected. Specific non-neutralizing antibodies were elicited in blood and vaginal secretions of experimental animals, but no ELISPOT responses were detected. Six weeks following the cessation of tenofovir, intravaginal challenge with homologous virus infected 2/4 (50%) of the SIVmne-immunized animals and 4/4 (100%) of the HIV-2287-immunized animals. The two SIVmne-infected and 3 (75%) HIV-2287-infected had attenuated disease, suggesting partial protection.

Conclusions/Significance

Repeated exposure to SIVmneor HIV-2287during antiretroviral prophylaxis blocked infection induced binding antibodies in the blood and mucosa, but not neutralizing antibodies or specific cellular immune responses. Studies to determine whether antibodies are similarly induced in breastfeeding infants and sexual partners discordant for HIV infection and receiving pre-exposure antiretroviral prophylaxis are warranted, including whether these antibodies appear to confer partial or complete protection from infection.
A deep learning framework for characterization of genotype data
Authors: Ausmees Kristiina , Nettelblad Carl
Published: October 2020

Dimensionality reduction is a data transformation technique widely used in various fields of genomics research. The application of dimensionality reduction to genotype data is known to capture genetic similarity between individuals, and is used for visualization of genetic variation, identification of population structure as well as ancestry mapping. Among frequently used methods are PCA, which is a linear transform that often misses more fine-scale structures, and neighbor-graph based methods which focus on local relationships rather than large-scale patterns.

Deep learning models are a type of nonlinear machine learning method in which the features used in data transformation are decided by the model in a data-driven manner, rather than by the researcher, and have been shown to present a promising alternative to traditional statistical methods for various applications in omics research. In this paper, we propose a deep learning model based on a convolutional autoencoder architecture for dimensionality reduction of genotype data.

Using a highly diverse cohort of human samples, we demonstrate that the model can identify population clusters and provide richer visual information in comparison to PCA, while preserving global geometry to a higher extent than t-SNE and UMAP. We also discuss the use of the methodology for more general characterization of genotype data, showing that models of a similar architecture can be used as a genetic clustering method, comparing results to the ADMIXTURE software frequently used in population genetic studies.
Cytomegaloviral determinants of CD8+T cell programming and RhCMV/SIV vaccine efficacy
Authors: Malouli Daniel , Hansen Scott G. , Hancock Meaghan H. , Hughes Colette M. , Ford Julia C. , Gilbride Roxanne M. , Ventura Abigail B. , Morrow David , Randall Kurt T. , Taher Husam , Uebelhoer Luke S. , McArdle Matthew R. , Papen Courtney R. , Trethewy Renee Espinosa , Oswald Kelli , Shoemaker Rebecca , Berkemeier Brian , Bosche William J. , Hull Michael , Greene Justin M. , Axthelm Michael K. , Shao Jason , Edlefsen Paul T. , Grey Finn , Nelson Jay A. , Lifson Jeffrey D. , Streblow Daniel , Sacha Jonah B. , Früh Klaus , Picker Louis J.
Published: October 2020

Simian immunodeficiency virus (SIV) insert-expressing, 68-1 Rhesus Cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex (MHC)-E- and -II-restricted, SIV-specific CD8+T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) has not been characterized. We demonstrate that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/.4 and Rh158-161). Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (UL128/130; UL146/147) leads to either of two distinct CD8+T cell response types – MHC-Ia-restricted-only, or a mix of MHC-II- and MHC-Ia-restricted CD8+T cells. Despite response magnitude and functional differentiation being similar to RhCMV 68-1, neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8+T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all the genes that inhibit these responses from the HCMV/HIV vector.

One-sentence summary

Eight genes in two spatially distinct RhCMV gene regions control induction of unconventionally restricted CD8+T cell responses and the efficacy of RhCMV/SIV vaccine vectors against SIV challenge.
Impact of COVID-19 lockdown on psychosocial factors, health, and lifestyle in Scottish octogenarians: the Lothian Birth Cohort 1936 Study
Authors: Taylor Adele M. , Page Danielle , Okely Judith A. , Corley Janie , Welstead Miles , Skarabela Barbora , Redmond Paul , Russ Tom C. , Cox Simon R.
Published: October 2020

Background

Little is known about effects of COVID-19 lockdown on psychosocial factors, health and lifestyle in older adults, particularly those aged over 80 years, despite the risks posed by COVID-19 to this age group.

Methods

Lothian Birth Cohort 1936 members, mean age 84 years (SD=0.3), responded to an online questionnaire in May 2020 (n=190). We examined responses (experience and knowledge of COVID-19; adherence to guidance; impact on day-to-day living; social contact; self-reported physical and mental health; loneliness; and lifestyle) and relationships between previously-measured characteristics and questionnaire outcomes.

Results

Four respondents experienced COVID-19; most had good COVID-19 knowledge (94.7%) and found guidance easy to understand (86.3%). There were modest declines in self-reported physical and mental health, and 48.2% did less physical activity. In multivariable regression models, adherence to guidance by leaving the house less often associated with less professional occupational class (OR=0.71, 95%CI 0.51– 0.98) and poorer self-rated general health (OR=0.62, 95%CI 0.42–0.92). Increased internet use associated with female sex (OR=2.32, 95%CI 1.12–4.86) and higher general cognitive ability (OR=1.53, 95%CI 1.03–2.33). Loneliness associated with living alone (OR=0.15, 95%CI 0.07–0.31) and greater anxiety symptoms (OR=1.76, 95%CI 0.45–1.24). COVID-19 related stress associated with lower emotional stability scores (OR=0.40, 95%CI 0.24–0.62). Decreased physical activity associated with less professional occupational class (OR=1.43, 95%CI 1.04–1.96), and lower general cognitive ability (OR=0.679, 95%CI 0.491–0.931).

Conclusions

Characteristics including cognitive function, occupational class, self-rated health, anxiety, and emotional stability, may be related to risk of poorer lockdown-related psychosocial and physical outcomes.