bluuebunny/crossref_metadata_2025 huggingface dataset:
P030 The effects of continuous positive airway pressure (CPAP) therapy in moderate to severe obstructive sleep apnea (OSA): A high-density electroencephalography (EEG) study
Authors: D’Rozario A , Kao C , Mullins A , Memarian N , Yee B , Duffy S , Banerjee D , Cho G , Wong K , Kremerskothen K , Chapman J , Haroutonian C , Bartlett D , Naismith S , Grunstein R
Published: October 2021

Introduction

A previous high-density EEG investigation in OSA showed regional sleep EEG deficits particularly slow wave activity (SWA) in the parietal region. It is unclear whether CPAP treatment can reverse local sleep EEG abnormalities, and whether any recovery is related to improved cognitive function.

Methods

Fifteen males with moderate-severe OSA (age 50.4±6.5yrs, AHI 51.7±23.5/h) underwent polysomnography with 256-channel high-density EEG at baseline and following 3 months of CPAP. Tasks assessing cognitive performance and sleep-dependent memory were administered. Topographical spectral power maps were calculated for standard frequency ranges for sleep stages. Differences in normalized power between baseline and treatment were determined by statistical nonparametric mapping.

Results

In 11 CPAP compliant patients (data loss: intolerant of CPAP[n=3]/high-density EEG [n=1]), total sleep time did not change after CPAP but N1 (baseline vs. treatment: 66.9 vs. 39.5 mins, p=0.008) and N2 (195.0 vs. 150.6 mins, p=0.002) sleep was lower and N3 (89.8 vs. 128.7 mins, p=0.003) was higher. Topographic high-density EEG analysis revealed a regional increase in SWA (1–4.5Hz) during N3 sleep in a cluster of 22 electrodes overlying the parietal cortex (paired t-test, t(10)=-3.9, p=0.0029). The change in N3 SWA in the parietal cluster after CPAP was correlated with improved overnight procedural memory on the motor sequence task (rho=0.79, p=0.03) and better executive functioning (Stroop accuracy, rho=0.73, p=0.01).

Conclusion

CPAP treatment reduces localised deficits in sleep EEG, and specific regional recovery relates to short-term improvements in memory and executive function. These data also highlight the potential for long-term therapeutic effects on cognitive outcomes.
P052 Mental health predictors for shift work disorder in paramedics during their early career
Authors: Harris R , Drummond S , Meadley B , Rajaratnam S , Williams B , Smith K , Bowles K , Nguyen E , Dobbie M , Wolkow A
Published: October 2021

Introduction

Shift work disorder (SWD) involves excessive sleepiness and/or insomnia and is associated with poor health outcomes in those affected. This study assessed the prevalence of and risk factors for SWD during the first six-months of paramedics’ careers. Furthermore, the study explored potential mediators in the relationship between mental health and SWD risk.

Methods

Recruit paramedics’ (n=101) SWD risk (SWD-Screening Questionnaire) was assessed at baseline (i.e., before shift work) and at six-months after engaging in shift work as a graduate paramedic. Logistic regression models assessed whether baseline depression (Patient Health Questionnaire-9) and baseline anxiety (Generalised Anxiety Disorder Questionnaire-7) predicted a high risk for SWD at six-months. Lavaan path analysis was used to assess whether shift and sleep variables, created from participants’ sleep and work diaries, mediated the relationship between mental health and SWD risk.

Results

After six-months of emergency work 21.5% of paramedics were high risk for SWD. Baseline depression predicted 1.28-times greater odds for SWD at six-months. Shift and sleep variables were not mediators in the relationship between baseline mental health and subsequent SWD risk. Baseline depression was independently associated with increased sleepiness levels following paramedics’ major sleep periods across all work conditions (nightshift, workdays, and non-workdays) at six-months. Depression levels before shift work also predicted a greater perceived workload on nightshifts.

Conclusions

Depression symptoms before starting shift work are a modifiable risk factor for SWD. Moreover, the first six-months of paramedics’ careers is a critical period for implementing preventative measures for SWD, including interventions to decrease depression symptoms.
P099 Physiological phenotypes of obstructive sleep apnoea (OSA) in Pacific Islanders and equally obese Caucasians
Authors: Naidoo C , Landry S , Edwards B , O’Driscoll D , Johnson P , Wheatley J , Lambert S , Kairaitis K
Published: October 2021

Background

Pacific islanders (PI) have a high prevalence of severe OSA, attributed to obesity. Ethnic differences in mechanisms contributing to OSA have been reported. We compared physiological polysomnography characteristics in obese PI and Caucasian (C) patients with OSA.

Methods

Retrospective polysomnography (PSG) studies from a tertiary hospital sleep laboratory were identified for PI and age, gender and BMI matched C patients (BMI>30 kgm²). All PSGs were rescored by a single scorer, and pharyngeal collapsibility (Vpassive), upper airway muscle compensation (Vcomp), arousal threshold (AT), [all expressed as percentage of steady-state breathing (Veupnea)], and loop gain (LG) were determined non-invasively via established/validated techniques.

Progress to date

14 PI [8 female] and 29 C [15 female] were identified. There were no differences in age [52.2±17.0 PI; 52.5±13.3 C years], BMI [46.9±7.7 PI; 48.2±10.1 C kgm²] or AHI (35.6 [17.9–77.5] PI; 41.2 [20.9–83.6] C events/hour) (mean±SD or median[IQR]; all p>0.4; paired t-test or Wilcoxon signed rank). There were no significant differences in Vpassive (88.8 [88.4–97.1] PI; 91.8 [44.4–95.8]C %Veupnea; p=0.38), Vcomp (1.2 [-12.0–9.2] PI; 5.8 [-1.9–9.6] C %Veupnea; p=0.30), AT (131.4 [110.5–140.8] PI; 126.1 [110.4–180.7] C %Veupnea; p=0.67) or LG (0.6±0.1 PI; 0.7±0.3 C; p=0.23).

Intended outcome and impact

In a small cohort of PI and age, gender and BMI matched C with OSA, upper airway obstructive event frequency was the same and there were no differences in physiological phenotypes, suggesting similar mechanisms contribute to OSA severity in both groups. Confirmation of these findings in a larger cohort is ongoing.
P109 The association between sleep microarchitecture and cognitive function in middle-aged and older men: A community-based study
Authors: Parker J , Melaku Y , D’Rozario A , Wittert G , Martin S , Toson B , Catcheside P , Lechat B , Teare A , Appleton S , Adams R , Vakulin A
Published: October 2021

Introduction

Sleep microarchitecture metrics determined by quantitative power spectral analysis (PSA) of the electroencephalogram (EEG) have been proposed as potential biomarkers of cognitive function. However, there remain no data from community-based samples. This study examined cross-sectional associations between sleep microarchitecture metrics determined by PSA and cognitive function outcomes in community-dwelling men.

Methods

Men, Androgen, Inflammation, Lifestyle, Environment, and Stress (MAILES) study participants (n=477) underwent home-based polysomnography between 2010–2011. All-night EEG recordings were processed using PSA following exclusion of artefacts. MAILES participants also completed the inspection time task, Fuld object memory evaluation, and trail-making test A (TMT-A) and B (TMT-B). Multivariable linear regression models were used to determine the associations of sleep microarchitecture (relative spectral power) with cognitive function in the complete and age-stratified samples.

Results

Power spectral densities in theta-alpha ranges during NREM and REM sleep were associated with worse TMT-A performance, whereas higher delta density was associated with better TMT-A performance in the complete sample and men ≥65 years (all p<0.05). Similar associations were observed with TMT-B performance in men ≥65 years. Furthermore, in men <65 years, higher sigma density during NREM sleep was associated with faster inspection time (B= -3.14, 95% CI [-6.00, -0.27], p=0.032), whereas in men ≥65 years, higher theta density during NREM sleep was associated with faster inspection time (B = -3.33, 95% CI [-6.65, -0.02], p=0.049).

Discussion

PSA markers of sleep microarchitecture are independently associated with cognitive function. Longitudinal studies are needed to determine whether sleep microarchitecture metrics predict future cognitive dysfunction and decline.
P149 The role of OSA pathophysiological traits on mandibular advancement treatment response and efficacy of a novel mandibular advancement device
Authors: Tong B , Osman A , Bull C , Chiang A , Donegan M , Pinczel A , Rawson G , Pitcher G , Brown E , Kwan B , Mukherjee S , Adams R , Eckert D
Published: October 2021

Mandibular advancement devices (MAD) are an effective therapy for OSA. However, treatment response is difficult to predict. Recent studies have investigated the influence of OSA endotypes on MAD outcomes albeit using simplified endotyping methods. We aimed to prospectively quantify and compare OSA pathophysiological traits between responders and non-responders to a novel MAD using gold-standard endotyping methodology.

Data from 30 OSA patients (AHI>10events/h) are analysed to date. OSA was confirmed via in-laboratory polysomnography. Next, a detailed physiology night was conducted before MAD therapy. Participants were instrumented with EEG, nasal mask, pneumotachograph, epiglottic pressure catheter and intramuscular genioglossus electrodes to quantify baseline OSA pathophysiological traits. Pcrit was quantified via CPAP drops and non-anatomical traits from naturally occurring respiratory events. Participants were fitted with a novel MAD with a built-in oral airway (Oventus O2Vent Optima™) and titrated to ≥75% of maximum mandibular advancement. A treatment efficacy PSG followed therapy acclimatisation.

OSA severity decreased by 41±30% (25.1[16.3,39.2] vs. 12.1[7.3,20.0] events/h P<0.001) with MAD therapy. Similar reductions occurred in participants with high nasal resistance. OSA pathophysiological traits measured by gold-standard methodology were similar between responders and non-responders to MAD (residual AHI>10events/h). MAD responders had less collapsible airways at baseline when measured using simple estimates (Vpassive: 92.5[86.3,97.0] vs. 72.5[43.0,91.3] %Veupnea, P=0.022).

The novel MAD reduced OSA severity by ~40% including in those with nasal obstruction. The upper airway was less collapsible in responders to MAD when estimated but not when directly measured. Simple estimates of OSA pathophysiological traits may be used to predict responses to MAD.
Targeted and Nontargeted Detection and Characterization of Trace Organic Chemicals in Human Serum and Plasma Using QuEChERS Extraction
Authors: Manz Katherine E , Yamada Kyle , Scheidl Lukas , La Merrill Michele A , Lind Lars , Pennell Kurt D
Published: October 2021

Humans are exposed to a broad range of organic chemicals. Although targeted gas chromatography mass spectrometry techniques are used to quantify a limited number of persistent organic pollutants and trace organic contaminants in biological samples, nontargeted, high-resolution mass spectrometry (HRMS) methods assess the human exposome more extensively. We present a QuEChERS extraction for targeted and nontargeted analysis of trace organic contaminants using HRMS and compare this method to a traditional, cartridge-based solid-phase extraction (SPE). Following validation using reference and spiked serum samples, the method was applied to plasma samples (n = 75) from the Prospective investigation of Obesity, Energy, and Metabolism (POEM) study. We quantified 44 analytes using targeted analysis and 6247 peaks were detected using the nontargeted approach. Over 90% of targeted analytes were at least 90% recovered using the QuEChERS method in spiked serum samples. In nontargeted analysis, 84% of the peaks were above the method detection limit with area counts up to 3.0 × 105 times greater using the QuEChERS method. Of the targeted compounds, 88% were also identified in the nontargeted analysis. We categorized the 4212 chemicals assigned an identity in using EPA’s CompTox Dashboard and 1076 chemicals were found in at least one list. The category with the highest number of chemicals was “androgen or estrogen receptor activity.” The findings demonstrate that a QuEChERS technique is suitable for both targeted and nontargeted analysis of trace organic contaminants in biological samples.
‘Bumps down under:’ hemorrhoids, skin tags and all things perianal
Authors: Alvarez-Downing Melissa M. , da Silva Giovanna
Published: October 2021

Purpose of review

There continues to be a concentrated effort to improve treatment options readily available for some of the most common perianal diseases: hemorrhoids, anal fissure and anal fistula. The emphasis remains on therapies that definitively address the underlying pathology yet minimize pain and risk of incontinence, have a short recovery period, and are cost-effective. In this analysis, recent developments in the literature are reviewed.

Recent findings

Treatment of early stage hemorrhoidal disease remains the same. For grades II–IV disease, hemorrhoidal vessel ligation/obliteration with laser or bipolar energy are reported. For more advanced diseases, modifying the technique for hemorrhoidectomy to improve postoperative complications and pain is described. For anal fissure, a stepwise method continues to be the mainstay of treatment (initiating with vasodilators, followed by botox, and ultimately sphincterotomy), which decreases the risk of incontinence with proper patient selection and technique. Management of anal fistula continues to be challenging, balancing cure vs. risk of harm. Recent developments include modifications to ligation of intersphincteric fistula tract procedure and use of laser to obliterate the tract.

Advancements in managing benign anorectal disease are ongoing. Several reports are novel, whereas others involve enhancing well-established treatment options by either operative technique or patient selection.
Patient-Focused Websites Related to Postpartum Pelvic Floor Health: A DISCERN Quality Analysis
Authors: Maheshwari Deepali , Kunycky Christina , Jia Xibei , Tangada Abhilasha , Leung Katherine , Solomon Ellen R.
Published: October 2021

Objective

The aim of the study was to evaluate the quality of patient-focused websites addressing postpartum pelvic floor health.

Methods

The Google search engine was used to perform a search of the following 3 terms: (1) “postpartum pelvic floor (PPF),” (2) “postpartum leaking urine (PLU),” and (3) “postpartum leaking stool (PLS).” The top 20 results from each search term were evaluated using the DISCERN quality appraisal tool and Journal of the American Medical Association (JAMA) benchmark criteria by 2 independent researchers. Websites were also categorized by type. Cohen κ was performed to determine interrater reliability between reviewers. The Kruskal-Wallis test was used to evaluate the differences in DISCERN and JAMA criteria scores.

Results

The weighted mean κ between the investigators for each search term was κ = 0.47 (range = 0.163 [PPF] to 0.759 [PLU]), suggesting moderate agreement between reviewers. There was a significant difference in mean DISCERN scores between the terms, with “postpartum leaking urine” yielding the highest mean score. When comparing DISCERN scores by category, society- and government-sponsored websites (mean = 55 ± 13) scored significantly higher than other categories. Using JAMA criteria, mean scores ranged between 1.83 and 2.83/4, but there were no significant differences between websites.

Conclusions

The overall quality of health information available on the internet regarding postpartum pelvic health is low. Higher-quality search results are found within society- and government-sponsored websites as well as under the search term “postpartum leaking urine.” It is important for health care providers to guide their patients to websites with reliable information about postpartum pelvic floor recovery.
Development and retinal remodeling in the brown anole lizard (Anolis sagrei)
Authors: Rasys Ashley M. , Pau Shana H. , Irwin Katherine E. , Luo Sherry , Kim Hannah Q. , Wahle M. Austin , Menke Douglas B. , Lauderdale James D.
Published: October 2021

Background

The fovea, a pit in the retina, is believed to be important for high-acuity vision and is a feature found in the eyes of humans and a limited number of vertebrate species that include certain primates, birds, lizards, and fish. At present, model systems currently used for ocular research lack a foveated retina and studies investigating fovea development have largely been limited to histological and molecular studies in primates. As a result, progress towards understanding the mechanisms involved in regulating fovea development in humans is limited and is completely lacking in other, non-primate, vertebrates. To address this knowledge gap, we provide here a detailed histological atlas of retina and fovea development in the bifoveated Anolis sagrei lizard, a novel reptile model for fovea research. We also further test the hypothesis that retinal remodeling, which leads to fovea formation and photoreceptor cell packing, is related to asymmetric changes in eye shape.

Results

Anole retina development follows the conventional spatiotemporal patterning observed in most vertebrates, where retina neurogenesis begins within the central retina, progresses throughout the temporal retina, and concludes in the nasal retina. One exception to this general rule is that areas that give rise to the fovea undergo retina differentiation prior to the rest of the retina. We find that retina thickness changes dynamically during periods of ocular elongation and retraction. During periods of ocular elongation, the retina thins, while during retraction it becomes thicker. Ganglion cell layer mounding is also observed in the temporal fovea region just prior to pit formation.

Conclusions

Anole retina development parallels that of humans, including the onset and progression of retinal neurogenesis followed by changes in ocular shape and retinal remodeling that leads to pit formation in the retina. We propose that anoles are an excellent model system for fovea development research.

Key Findings

Retina mounding that occurs in foveal areas prior to retinal differentiation progressively disappear as foveal regions of the eye elongate.

The central and temporal foveal areas undergo retina differentiation before the rest of the retina.

GCL mounding prior to pit formation occurs in the area of the temporal fovea but not the central fovea.

When the eye is experiencing ocular retraction, photoreceptor cell packing, and pit formation are observed within foveal regions.
Novel Real-Time Library Search driven data acquisition strategy for identification and characterization of metabolites
Authors: Bills Brandon , Barshop William D. , Sharma Seema , Canterbury Jesse , Robitaille Aaron M. , Senko Michael W. , Zabrouskov Vlad
Published: October 2021

Identification and structural characterization of novel metabolites in drug discovery or metabolomics experiments is one of the most challenging tasks. Multi-level fragmentation (MSn) based approaches combined with various dissociation modes are frequently utilized for facilitating structure assignment of the unknown compounds. As each of the MS precursors undergoes MSn, the instrument cycle time can limit the total number of precursors analyzed in a single run for complex samples. This necessitates splitting data acquisition into several LC/MS analyses where the results obtained in one acquisition inform the experimental design for the successive experiment.

Here we present a new LC/MS data acquisition strategy, termed Met-IQ, where the decision to perform an MSn acquisition is automatically made in real time based on the similarity between an acquired experimental MS2 spectrum and a spectrum in a reference spectral library. Each MS2 spectrum is searched in real time against the spectra for the known compounds of interest. If a similarity to a spectrum in the library is found, the instrument performs a decision-dependent event, such as an MS3 scan. Compared to an intensity-based, data-dependent MSn experiment, only a selective number of MS3 are triggered using Met-IQ, increasing the overall MS2 instrument sampling rate. We applied this strategy to an Amprenavir sample incubated with human liver microsomes. The number of MS2 scan events increased nearly 3.5-fold compared to the standard data dependent experiment where MS3 was triggered for each precursor ion, resulting in identification and structural characterization of 55% more unique metabolites. Furthermore, the MS3 precursor fragments were selected intelligently, focusing on higher mass fragments of sufficient intensity to maximize acquisition of MS3 data relevant for structure assignment. The described Met-IQ strategy is not limited to metabolism experiments, and can be applied to analytical samples where the detection of unknown compounds structurally related to a known compound(s) is sought.
Retrograde adenosine/A2Areceptor signaling facilitates excitatory synaptic transmission and seizures
Authors: Nasrallah Kaoutsar , Berthoux Coralie , Hashimotodani Yuki , Chávez Andrés E. , Gulfo Michelle , Luján Rafael , Castillo Pablo E.
Published: October 2021

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2Areceptor (A2AR) as a novel retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity.

Highlights

Postsynaptic firing induces presynaptic LTP at mossy cell to granule cell synapses

Postsynaptic TrkB activation induces adenosine release from granule cells

Presynaptic adenosine A2Areceptors are necessary and sufficient to induce LTP

Adenosine/A2AR signaling within the dentate gyrus is pro-convulsant

In Brief

Nasrallah et al. report a novel retrograde signaling pathway at hippocampal synapses that involves postsynaptic TrkB-dependent release of adenosine and the activation of presynaptic A2Areceptors. This pathway mediates presynaptic long-term potentiation at a key hippocampal excitatory synapse and can also promote epileptic seizures.
Hearing Ability of Prairie Voles (Microtus ochrogaster)
Authors: New Emily M. , Li Ben-Zheng , Lei Tim C. , McCullagh Elizabeth A.
Published: October 2021

Hearing ability of mammals can be impacted by many factors including social cues, environment, and physical properties of animal morphology. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been fully characterized. In this study, we measure morphological head and pinna features and use auditory brainstem responses to measure auditory capabilities of prairie voles characterizing monaural and binaural hearing and hearing range. Additionally, we measured unbonded male and female voles to characterize differences due to sex. We found that prairie voles show a hearing range with greatest sensitivity between 8 – 32 kHz, robust binaural hearing, and characteristic monaural ABRs. We show no differences between the sexes for binaural hearing or hearing range, however female voles have increased amplitude of peripheral ABR waves I and II and increased latency of wave IV. Our results confirm that prairie voles have both low and high frequency hearing, binaural hearing, and despite biparental care and monogamy, differences in processing of sound information between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in behavioral responses between sexes.

Highlights

Monogamous prairie voles hear across both low and high frequencies.

Female prairie voles show differences in monaural hearing compared to males.

There is no difference in binaural hearing or pinna/head size morphology between the sexes.
The mechanical and morphological properties of systemic and pulmonary arteries differ in the earth boa, a snake without ventricular pressure separation
Authors: van Soldt Benjamin J. , Wang Tobias , Filogonio Renato , Danielsen Carl Christian
Published: October 2021

The walls of the mammalian aorta and pulmonary artery are characterized by diverging morphologies and mechanical properties, which has been correlated with high systemic and low pulmonary blood pressures, as a result of intraventricular pressure separation in the mammalian ventricle. However, the relation between intraventricular pressure separation and diverging aortic and pulmonary artery wall morphologies and mechanical characteristics is not understood. The snake cardiovascular system poses a unique model for the study of this question, since representatives both with and without intraventricular pressure separation exist. In this study we perform uniaxial tensile testing on vessel samples taken from the aortas and pulmonary arteries of the earth boa, Acrantophis madagascariensis, a species without intraventricular pressure separation. We then compare these morphological and mechanical characteristics with samples from the ball python, Python regius, and the yellow anaconda, Eunectes notaeus, species with and without intraventricular pressure separation, respectively. Strikingly, we find that although the aortas and pulmonary arteries of A. madagascariensis respond similarly to the same intramural blood pressures, they diverge strongly in morphology, and that this is a common attribute among species without intraventricular pressure separation in this study. In contrast, P. regius aortas and pulmonary arteries diverge both morphologically and in terms of their mechanical properties. Altogether our data indicate that intraventricular pressure separation does not explain diverging aortic and pulmonary artery morphologies. Following the Law of Laplace, we propose that thin pulmonary arteries represent a mechanism to protect the fragile pulmonary vascular bed by reducing the blood volume that passes through, to which genetic factors may contribute more strongly than physiological parameters.
Low-dimensional encoding of decisions in parietal cortex reflects long-term training history
Authors: Latimer Kenneth W. , Freedman David J.
Published: October 2021

Neurons in parietal cortex exhibit task-related activity during decision-making tasks. However, it remains unclear how long-term training to perform different tasks over months or even years shapes neural computations and representations. We examine lateral intraparietal area (LIP) responses during a visual motion delayed-match-to-category (DMC) task. We consider two pairs of monkeys with different training histories: one trained only on the DMC task, and another first trained to perform fine motion-direction discrimination. We introduce generalized multilinear models to quantify low-dimensional, task-relevant components in population activity. During the DMC task, we found stronger cosine-like motion-direction tuning in the pretrained monkeys than in the DMC-only monkeys, and that the pretrained monkeys’ performance depended more heavily on sample-test stimulus similarity. These results suggest that sensory representations in LIP depend on the sequence of tasks that the animals have learned, underscoring the importance of training history in studies with complex behavioral tasks.
General structure-free energy relationships of hERG blocker binding under native cellular conditions
Authors: Wan Hongbin , Spiru Kristina , Williams Sarah , Pearlstein Robert A.
Published: October 2021

We proposed previously that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water (“the solvation field”) relative to bulk solvent, where the association barrier equates to enthalpic losses incurred from incomplete replacement of the H-bonds of expelled H-bond enriched solvation by inter-partner H-bonds, and the dissociation barrier equates to enthalpic + entropic losses incurred during dissociation-induced resolvation of H-bond depleted positions of the free partners (where dynamic occupancy is powered largely by the expulsion of such solvation to bulk solvent during association). We went on to analyze blockade of the human ether-a-go-go-related gene potassium channel (hERG) based on these principles, the results of which suggest that blockers: 1) project a single rod-shaped R-group (denoted as “BP”) into the pore at a rate proportional to the desolvation cost of BP, with the largely solvated remainder (denoted as “BC”) occupying the cytoplasmic “antechamber” of hERG; and 2) undergo second-order entry to the antechamber, followed byfirst-orderassociation of BP to the pore. In this work, we used WATMD to qualitatively survey the solvation fields of the pore and a representative set of 16 blockers sampled from the Redfern dataset of marketed drugs spanning a range of pro-arrhythmicity. We show that the highly non-polarporeis solvated principally by H-bond depleted and bulk-like water (incurring zero desolvation cost), whereasblocker BP moietiesare solvated by variable combinations of H-bond enriched and depleted water. With a few explainable exceptions, theblockersolvation fields (and implied desolvation/resolvation costs) are qualitatively well-correlated with both blocker potency and Redfern safety classification.
CCR5 closes the temporal window for memory linking
Authors: Shen Yang , Zhou Miou , Cai Denise , Filho Daniel Almeida , Fernandes Giselle , Cai Ying , Kim Nury , Necula Deanna , Zhou Chengbin , Liu Andy , Kang Xiaoman , Kamata Masakazu , Lavi Ayal , Huang Shan , Silva Tawnie , Heo Won Do , Silva Alcino J.
Published: October 2021

Real world memories are formed in a particular context and are not acquired or recalled in isolation 1-5. Time is a key variable in the organization of memories, since events experienced close in time are more likely to be meaningfully associated, while those experienced with a longer interval are not1-4. How does the brain segregate events that are temporally distinct? Here, we report that a delayed (12-24h) increase in the expression of the C-C chemokine receptor type 5 (CCR5), an immune receptor well known as a co-receptor for HIV infection6,7, following the formation of a contextual memory, determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed CCR5 expression in mouse dorsal CA1 (dCA1) neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dCA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, thus closing the temporal window for memory linking. Remarkably, our findings also show that an age-related increase in CCL5/CCR5 expression leads to impairments in memory linking in aged mice, which could be reversed with a CCR5 knockout and an FDA approved drug that inhibits this receptor, a result with significant clinical implications. All together the findings reported here provide the first insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.
Persistent Immunogenicity of Integrase Defective Lentiviral Vectors delivering membrane tethered Native-Like HIV-1 Envelope Trimers
Authors: Gallinaro Alessandra , Pirillo Maria Franca , Aldon Yoann , Cecchetti Serena , Michelini Zuleika , Tinari Antonella , Borghi Martina , Canitano Andrea , McKay Paul F. , Bona Roberta , Vescio Maria Fenicia , Grasso Felicia , Blasi Maria , Baroncelli Silvia , Scarlatti Gabriella , LaBranche Celia , Montefiori David , Klotman Mary E. , Sanders Rogier W. , Shattock Robin J. , Negri Donatella , Cara Andrea
Published: October 2021

Integrase Defective Lentiviral Vectors (IDLVs) represent an attractive vaccine platform for delivering HIV-1 antigens, given their ability to induce specific and persistent immune responses in both mice and non-human primates (NHPs). Recent advances in HIV-1 immunogen design demonstrated that native-like HIV-1 Envelope (Env) trimers that mimic the structure of virion-associated Env induce neutralization breadth in rabbits and macaques. Here, we describe the development of an IDLV-based HIV-1 vaccine expressing either soluble ConSOSL.UFO.664 or membrane-tethered ConSOSL.UFO.750 native-like Env immunogens with enhanced bNAb epitopes exposure. We show that IDLV can be pseudotyped with properly folded membrane-tethered native-like UFO.750 trimers. After a single IDLV injection in BALB/c mice, IDLV-UFO.750 induced a faster humoral kinetic as well as higher levels of anti-Env IgG compared to IDLV-UFO.664. IDLV-UFO.750 vaccinated cynomolgus macaques developed unusually long-lasting anti-Env IgG antibodies, as underlined by their remarkable half-life both after priming and boost with IDLV. After boosting with recombinant ConM SOSIP.v7 protein, two animals developed neutralization activity against the autologous tier 1B ConS virus mediated by V1/V2 and V3 glycan sites responses. By combining the possibility to display stabilized trimeric Env on the vector particles with the ability to induce sustained humoral responses, IDLVs represent an appropriate strategy for delivering rationally designed antigens to progress towards an effective HIV-1 vaccine.
Live cell imaging of metabolic heterogeneity by quantitative fluorescent ATP indicator protein, QUEEN-37C
Authors: Yaginuma Hideyuki , Okada Yasushi
Published: October 2021

Adenosine triphosphate (ATP) is often referred as the energy currency of the cell. Yet, non-invasive, real-time, and quantitative measurement of its concentration in living mammalian cells has been difficult. Here we report an improved fluorescent ATP indicator protein, QUEEN-37C, which is optimized for measuring ATP concentration in living mammalian cells. Absolute value of the ATP concentration can be estimated from the ratiometric fluorescence imaging, and its accuracy was verified by the luciferase assay. Since QUEEN-37C enables the single-cell measurement of ATP concentration, we can not only measure its mean but its distribution in the cell population, which revealed that the ATP concentration is tightly regulated in most cells. We also noted the positive correlations in the ATP concentration among adjacent cells in epithelial cell sheet and mouse embryonic stem cell colonies. Thus, QUEEN-37C would serve as a new tool for the investigation of the single cell heterogeneity of metabolic states.
Nanchangmycin regulates FYN, FAK and ERK to control the fibrotic activity of hepatic stellate cells
Authors: Li Wenyang , Chen Jennifer Y. , Sun Cheng , Sparks Robert P. , Pantano Lorena , Rahman Raza-Ur , Moran Sean P. , Pondick Joshua V. , Kirchner Rory , Wrobel David , Bieler Michael , Ho Sui Shannan J. , Doerner Julia F. , Rippmann Jörg F. , Mullen Alan C.
Published: October 2021

Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic drugs, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca2+ and reduces the phosphorylated protein levels of FYN, FAK, ERK1/2, HSP27 and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. The identification of the antifibrotic effects of NCMC and the pathways by which NCMC inhibits fibrosis provides new tools and therapeutic targets to combat the development and progression of liver fibrosis.
Can floral nectars reduce transmission ofLeishmania?
Authors: Palmer-Young Evan C , Schwarz Ryan S , Chen Yanping , Evans Jay D
Published: October 2021

Insect-vectoredLeishmaniaare the second-most debilitating of human parasites worldwide. Elucidation of the environmental factors that affect parasite transmission by vectors is essential to develop sustainable methods of parasite control that do not have off-target effects on beneficial insects or environmental health. Many phytochemicals that inhibit growth of sand fly-vectoredLeishmania—which have been exhaustively studied in the search for phytochemical-based drugs—are abundant in nectar, which provide sugar-based meals to infected sand flies. In a quantitative meta-analysis, we compare inhibitory phytochemical concentrations forLeishmaniato concentrations present in floral nectar and pollen. We show that nectar concentrations of several flowering plant species exceed those that inhibit growth ofLeishmaniacell cultures, suggesting an unexplored, landscape ecology-based approach to reduceLeishmaniatransmission. Strategic planting of antiparasitic phytochemical-rich floral resources or phytochemically enriched baits could reduceLeishmanialoads in vectors, providing an environmentally friendly complement to existing means of disease control.
Targeting a central feature of asthma using a cell type-selective IL-13-responsive enhancer
Authors: Koh Kyung Duk , Bonser Luke R. , Eckalbar Walter L. , Shen Jiangshan , Yizhar-Barnea Ofer , Zeng Xiaoning , Sun Dingyuan I. , Zlock Lorna T. , Finkbeiner Walter E. , Ahituv Nadav , Erle David J.
Published: October 2021

IL-13 is a central mediator of asthma1–3. Here, we used genome-wide approaches to characterize genes and regulatory elements modulated by IL-13 and other asthma-associated cytokines in airway epithelial cells and showed how they can be used for therapeutic purposes. Using bulk and single cell RNA-seq, we found distinctive responses to IL-13, IL-17, and interferons in human bronchial epithelial basal, ciliated, and secretory cells. H3K27ac ChIP-seq revealed that IL-13 had widespread effects on regulatory elements. Detailed characterization of an enhancer of SPDEF, a transcription factor required for pathologic mucin production, revealed that STAT6 and KLF5 binding sites cooperate to drive IL-13-dependent transcription selectively in secretory cells. Using this enhancer to drive CRISPRi and knockdown either SPDEF or the mucin MUC5AC showed the potential use of this approach for asthma therapeutics. This work identifies numerous genes and regulatory elements involved in cell type-selective cytokine responses and showcases their use for therapeutic purposes.
Molecular dynamics simulations of hydrophobic peptides that form β-hairpin structures in solution
Authors: Moharana Tushar Ranjan , Nagaraj Ramakrishnan
Published: October 2021

Peptides designed with residues that have high propensity to occur in β-turns, form β-hairpin structures in apolar solvents as well in polar organic solvents such as dimethyl sulfoxide (DMSO), methanol and varying percentages of DMSO in chloroform (CHCl3). Presumably due to limited solubility, their conformations have not been investigated by experimental methods in water. We have examined the conformations of such designed peptides that fold into well-defined β-hairpin structures facilitated by β-turns, in the crystalline state and in solution, by Molecular Dynamics Simulations (MDS). The peptides fold into β-hairpin structures in water, starting from extended conformation. In DMSO, folding into β-hairpin structures was not observed, starting from extended conformation. However, when the starting structure is in β-hairpin conformation, unfolding is not observed during MDS in DMSO. Water clearly favours folding of short, hydrophobic peptides into β-turn and β-hairpin conformations from extended structures. DMSO does not have a denaturing effect on short, hydrophobic peptides.
Genomic architecture of three newly isolated unclassified Butyrivibrio species elucidate their potential role in the rumen ecosystem
Authors: Sengupta Kriti , Hivarkar Sai Suresh , Palevich Nikola , Chaudhary Prem Prashant , Dhakephalkar Prashant K. , Dagar Sumit Singh
Published: October 2021

One cellulose-degrading strain CB08 and two xylan-degrading strains XB500-5 and X503 were isolated from buffalo rumen. All the strains were designated as putative novel species of Butyrivibrio based on phylogeny, phylogenomy, digital DNA-DNA hybridization, and average nucleotide identity with their closest type strains. The draft genome length of CB08 was ∼3.54 Mb, while X503 and XB500-5 genome sizes were ∼3.24 Mb and ∼3.27 Mb, respectively. Only 68.28% of total orthologous clusters were shared among three genomes, and 40-44% of genes were identified as hypothetical proteins. The presence of genes encoding diverse carbohydrate-active enzymes (CAZymes) exhibited the lignocellulolytic potential of these strains. Further, the genome annotations revealed the metabolic pathways for monosaccharide fermentation to acetate, butyrate, lactate, ethanol, and hydrogen. The presence of genes for chemotaxis, antibiotic resistance, antimicrobial activity, synthesis of vitamins, and essential fatty acid suggested the versatile metabolic nature of these Butyrivibrio strains in the rumen environment.
Self-organized tissue mechanics underlie embryonic regulation
Authors: Caldarelli Paolo , Chamolly Alexander , Alegria-Prévot Olinda , Gros Jerome , Corson Francis
Published: October 2021

Early amniote development is a highly regulative and self-organized process, capable to adapt to interference through cell-cell interactions, which are widely believed to be mediated by molecules. Analyzing intact and mechanically perturbed avian embryos, we show that the mechanical forces that drive embryogenesis self-organize in an analog of Turing’s molecular reaction-diffusion model, with contractility locally self-activating and the ensuing tension acting as a long-range inhibitor. This mechanical feedback governs the persistent pattern of tissue flows that shape the embryo and steers the concomitant emergence of embryonic territories by modulating gene expression, ensuring the formation of a single embryo under normal conditions, yet allowing the emergence of multiple, well-proportioned embryos upon perturbations. Thus, mechanical forces are a central signal in embryonic self-organization, feeding back onto gene expression to canalize both patterning and morphogenesis.
NOD1 is super-activated through spatially-selective ubiquitination by the Salmonella effector SspH2
Authors: Delyea Cole , Luo Shu Y. , Dubrule Bradley E. , Julien Olivier , Bhavsar Amit P.
Published: October 2021

As part of its pathogenesis, Salmonella enterica serovar Typhimurium delivers effector proteins into host cells. One effector is SspH2, a member of the novel E3 ubiquitin ligase family, interacts with, and enhances, NOD1 pro-inflammatory signaling, though the underlying mechanisms are unclear. Here, we report the novel discovery that SspH2 interacts with multiple members of the NLRC family to enhance pro-inflammatory signaling that results from targeted ubiquitination. We show that SspH2 modulates host innate immunity by interacting with both NOD1 and NOD2 in mammalian epithelial cell culture. We also show that SspH2 specifically interacts with the NBD and LRR domains of NOD1 and super-activates NOD1- and NOD2-mediated cytokine secretion via the NF-κB pathway. Mass spectrometry analyses identified lysine residues in NOD1 that were ubiquitinated after interaction with SspH2. Through NOD1 mutational analyses, we identified four key lysine residues that are required for NOD1 super-activation by SspH2, but not its basal activity. These critical lysine residues are positioned in the same region of NOD1 and define a surface on NOD1 that is targeted by SspH2. Overall, this work provides evidence for post-translational modification of NOD1 by ubiquitin, and uncovers a unique mechanism of spatially-selective ubiquitination to enhance the activation of an archetypal NLR.

SYNOPSIS

SspH2 is an E3 ubiquitin ligase injected by Salmonella Typhimurium into host cells that induces pro-inflammatory signaling. The immune receptor, NOD1, is ubiquitinated in the presence of SspH2, resulting in increased pro-inflammatory cytokine secretion.

SspH2 super-activates NOD1 and NOD2 to increase pro-inflammatory cytokine secretion, in part, through the NF-κB pathway

Ubiquitin modification of NOD1 were identified by mass spectrometry

A specific region of NOD1 is targeted by SspH2 to enhance NOD1 activity.
Stimulus-specific processing of the plasma membrane receptor-like kinase FERONIA inArabidopsis thaliana
Authors: Cornblatt Cassidy S. , Shih Han-Wei , Monshausen Gabriele B.
Published: October 2021

FERONIA (FER), a receptor-like kinase involved in plant immunity, cell expansion, and mechanical signal transduction, is known to be endocytosed and degraded in response to treatment with its peptide ligand RAPID ALKALINIZATION FACTOR 1 (RALF1). Using confocal fluorescence microscopy and biochemical assays, we have found that full length FER-eGFP abundance at the plasma membrane is also regulated by mechanical stimulation, but through a separate, cysteine protease-dependent pathway. Like RALF1 treatment, both mechanical bending and mechanical wounding trigger a reduction in plasma membrane-localized, native promoter-driven FER-eGFP in Arabidopsis roots, hypocotyls, and cotyledons. However, pharmacological inhibition of protein trafficking and degradation suggests that while RALF1 induces clathrin-mediated endocytosis and subsequent degradation of FER-eGFP, mechanical stimulation triggers cleavage and/or degradation of FER-eGFP in a cysteine protease-dependent, clathrin-independent manner. Despite the stimulus-dependent differences in these two pathways, we found that both require early FER signaling components, including Ca2+signaling, FER kinase activity, and the presence of LLG1, a FER-interacting protein with an essential role in FER-dependent signal transduction.
TSCDA: A novel greedy approach for community discovery in networks
Authors: Ferdowsi Arman , Khanteymoori Alireza , Chenary Maryam Dehghan
Published: October 2021

In this paper, we introduce a new approach for detecting community structures in networks. The approach is subject to modifying one of the connectivity-based community quality functions based on considering the impact that each community’s most influential node has on the other vertices. Utilizing the proposed quality measure, we devise an algorithm that aims to detect high-quality communities of a given network based on two stages: finding a promising initial solution using greedy methods and then refining the solutions in a local search manner.

The performance of our algorithm has been evaluated on some standard real-world networks as well as on some artificial networks. The experimental results of the algorithm are reported and compared with several state-of-the-art algorithms. The experiments show that our approach is competitive with the other well-known techniques in the literature and even outperforms them. This approach can be used as a new community detection method in network analysis.