bluuebunny/crossref_metadata_2025 huggingface dataset:
Uncertainties associated with the backward integration of dwarf satellites using simple parametric potentials
Authors: D’Souza Richard , Bell Eric F
Published: February 2022

In order to backward integrate the orbits of Milky Way (MW) dwarf galaxies, much effort has been invested in recent years to constrain their initial phase-space coordinates. Yet equally important are the assumptions on the potential that the dwarf galaxies experience over time, especially given the fact that the MW is currently accreting the Large Magellanic Cloud (LMC). In this work, using a dark-matter-only zoom-in simulation, we test whether the use of common parametric forms of the potential is adequate to successfully backward integrate the orbits of the subhaloes from their present-day positions. We parametrize the recovered orbits and compare them with those from the simulations. We find that simple symmetric parametric forms of the potential fail to capture the complexities and the inhomogeneities of the true potential experienced by the subhaloes. More specifically, modelling a recent massive accretion like that of the LMC as a sum of two spherical parametric potentials leads to substantial errors in the recovered parameters of the orbits. These errors rival those caused due to (a) a 30 per cent uncertainty in the virial mass of the MW and (b) not modelling the potential of the recently accreted massive satellite. Our work suggests that (i) the uncertainties in the parameters of the recovered orbits of some MW dwarfs may be underestimated and that (ii) researchers should characterize the uncertainties inherent to their choice of integration techniques and assumptions of the potential against cosmological zoom-in simulations of the MW, which include a recently accreted LMC.
Estimating linear radiance indicators from the zenith night-sky brightness: on the Posch ratio for natural and light-polluted skies
Authors: Bará Salvador , Pérez-Couto Xabier , Falchi Fabio , Kocifaj Miroslav , Masana Eduard
Published: February 2022

Estimating the horizontal irradiance from measurements of the zenith night-sky radiance is a useful operation for basic and applied studies in observatory site assessment, atmospheric optics, and environmental sciences. The ratio between these two quantities, also known as the Posch ratio, has previously been studied for some canonical cases and reported for a few observational sites. In this work we (a) generalize the Posch ratio concept, extending it to any pair of radiance-related linear indicators, (b) describe its main algebraic properties, and (c) provide analytical expressions and numerical evaluations for its three basic night-time components (moonlight, starlight and other astrophysical light sources, and artificial light). We show that the horizontal irradiance (or any other linear radiance indicator) is generally correlated with the zenith radiance, enabling its estimation from zenith measurements if some a priori information on the atmospheric state is available.
The RecD2 helicase balances RecA activities
Authors: Ramos Cristina , Hernández-Tamayo Rogelio , López-Sanz María , Carrasco Begoña , Serrano Ester , Alonso Juan C , Graumann Peter L , Ayora Silvia
Published: February 2022

DNA helicases of the RecD2 family are ubiquitous. Bacillus subtilis RecD2 in association with the single-stranded binding protein SsbA may contribute to replication fork progression, but its detailed action remains unknown. In this work, we explore the role of RecD2 during DNA replication and its interaction with the RecA recombinase. RecD2 inhibits replication restart, but this effect is not observed in the absence of SsbA. RecD2 slightly affects replication elongation. RecA inhibits leading and lagging strand synthesis, and RecD2, which physically interacts with RecA, counteracts this negative effect. In vivo results show that recD2 inactivation promotes RecA–ssDNA accumulation at low mitomycin C levels, and that RecA threads persist for a longer time after induction of DNA damage. In vitro, RecD2 modulates RecA-mediated DNA strand-exchange and catalyzes branch migration. These findings contribute to our understanding of how RecD2 may contribute to overcome a replicative stress, removing RecA from the ssDNA and, thus, it may act as a negative modulator of RecA filament growth.
Flavodiiron proteins enhance the rate of CO2 assimilation in Arabidopsis under fluctuating light intensity
Authors: Basso Leonardo , Sakoda Kazuma , Kobayashi Ryouhei , Yamori Wataru , Shikanai Toshiharu
Published: February 2022

The proton concentration gradient (ΔpH) and membrane potential (Δψ) formed across the thylakoid membrane contribute to ATP synthesis in chloroplasts. Additionally, ΔpH downregulates photosynthetic electron transport via the acidification of the thylakoid lumen. K+ exchange antiporter 3 (KEA3) relaxes this downregulation by substituting ΔpH with Δψ in response to fluctuation of light intensity. In the Arabidopsis (Arabidopsis thaliana) line overexpressing KEA3 (KEA3ox), the rate of electron transport is elevated by accelerating the relaxation of ΔpH after a shift from high light (HL) to low light. However, the plant cannot control electron transport toward photosystem I (PSI), resulting in PSI photodamage. In this study, we crossed the KEA3ox line with the line (Flavodiiron [Flv]) expressing the Flv proteins of Physcomitrium patens. In the double transgenic line (Flv-KEA3ox), electrons overloading toward PSI were pumped out by Flv proteins. Consequently, photodamage of PSI was alleviated to the wild-type level. The rate of CO2 fixation was enhanced in Flv and Flv-KEA3ox lines during HL periods of fluctuating light, although CO2 fixation was unaffected in any transgenic lines in constant HL. Upregulation of CO2 fixation was accompanied by elevated stomatal conductance in fluctuating light. Consistent with the results of gas exchange experiments, the growth of Flv and Flv-KEA3ox plants was better than that of WT and KEA3ox plants under fluctuating light.
Intolerance of Uncertainty Moderates the Relationship between Catastrophizing, Anxiety, and Perceived Pain in People with Chronic Nononcological Pain
Authors: López-Martínez Alicia E , Ramírez-Maestre Carmen , Serrano-Ibáñez Elena R , Ruiz-Párraga Gema T , Esteve Rosa
Published: February 2022

Objective

Substantial empirical evidence has shown that intolerance of uncertainty is a central transdiagnostic feature in psychopathology and it has been suggested to be a pain-related psychological factor contributing to the experience of chronic pain. However, research in this area is virtually nonexistent. The objective of this study was to investigate associations between pain severity, catastrophizing, and anxiety in people with chronic nononcological pain, while assuming that intolerance of uncertainty moderates these relationships.

Methods

A convenience sample of 188 individuals with nononcological chronic pain (157 women and 32 men) participated in the study. We investigated the moderated mediation of intolerance of uncertainty between anxiety and catastrophizing and between catastrophizing and pain intensity.

Results

The full moderated mediation model accounted for significant variance in pain intensity (R2 = 0.148, P< .001). Intolerance of uncertainty significantly moderated the interaction between anxiety and catastrophizing (B = 0.039, SE = 0.012, 95% CI [0.015, 0.063]) and between catastrophizing and pain intensity (B = -0.034, SE = 0.010, 95% CI [−0.054, −0.014]). Anxiety and intolerance of uncertainty did not interact in predicting catastrophizing, although an interaction effect was found between intolerance of uncertainty and catastrophizing in predicting pain intensity.

Conclusion

This study is the first to address the interrelationship of intolerance of uncertainty, catastrophizing, and anxiety in relation to perceived pain intensity. The current findings support intolerance of uncertainty as a relevant psychological variable that is distinct from other relevant constructs in the setting of pain research and treatment.
Child Sexual Abuse Material Online: The Perspective of Online Investigators on Training and Support
Authors: Leclerc Benoit , Cale Jesse , Holt Thomas , Drew Jacqueline
Published: February 2022

The development of online technologies in recent decades has led to the proliferation of the distribution, consumption, and sale of child sexual abuse material (CSAM) online. This trend has arguably also contributed to the sexual abuse of children offline. In this context, many organizations, including financial institutions and police agencies, have invested human, financial, and technological resources to address this problem. Combining statistics on recent crime trends with data collected from online police investigators suggests the critical need for this phenomenon to be taken more seriously on a global scale. Using data obtained from interviews conducted with online CSAM police investigators across several Australian police agencies, this study presents a detailed view of what is needed to best support police work in this domain. The most frequent responses obtained from investigators grouped around three dimensions: (1) knowledge and skills related to the tools used during investigations, such as computers, information technology, the Internet, and legislations; (2) knowledge related to offenders, how they operate, and how investigators should interact with them virtually; and (3) mental health wellbeing of investigators.
The Dynamic Racial Structure and Disparities in Neighborhood Crime Change
Authors: Lyons Christopher J , Vélez María B , Krivo Lauren J
Published: February 2022

Cross-sectional scholarship demonstrates the importance of the U.S. racial structure in precipitating dramatic racial divisions in serious crime across neighborhoods. Yet, we know much less about the degree and sources of racial disparities in how neighborhood crime changes over time, despite considerable evolution in the components of the racial order. We articulate a dynamic racial structural perspective that centers the unfolding nature of residential segregation in producing and altering racially structured socioeconomic realities. We contend that these racialized structural inequalities, in turn, lead neighborhoods on unequal paths of crime change. We assess this perspective with new panel data (circa 2000 and 2010) from the National Neighborhood Crime Study for 7,875 census tracts across 75 cities. Despite considerable socioeconomic upheaval and demographic change during the first decade of the 2000s, we find substantial disparities in neighborhood violence and burglary change that indicate the reproduction of the ethno-racial divide. Furthermore, our dynamic racial structural model explains much of these inequalities in crime change. A dynamic racial structure perspective lays a foundation for understanding the consequences of the evolving U.S. racial structure for unequal exposure to crime across neighborhoods over time.
Characterizations of an Emerging Disease: Apple Blotch Caused by Diplocarpon coronariae (syn. Marssonina coronaria) in the Mid-Atlantic United States
Authors: Khodadadi Fatemeh , Martin Phillip L. , Donahue Daniel J. , Peter Kari A. , Aćimović Srđan G.
Published: February 2022

Apple orchards with minimal or reduced fungicide inputs in the Mid-Atlantic region of the United States have experienced outbreaks of severe premature defoliation with symptoms that matched those of apple blotch disease (ABD) caused by Diplocarpon coronariae. Fungal isolates obtained from symptomatic apple leaves and fruit produced uniform slow-growing, dark-gray colonies on peptone potato dextrose agar and had conidia. Internal transcribed spacer DNA sequences matched with D. coronariae and Koch’s postulates were fulfilled when typical ABD symptoms occurred when reinoculated onto apple leaves and fruit. Spore dispersal in nonfungicide-treated orchards detected with quantitative PCR was low in early spring and dropped to undetectable levels in late May and early June before rising exponentially to highs in July and August, which coincided with symptom development. Only low spore numbers were detected in fungicide-treated orchards and nearby forests. In preliminary fungicide tests, fluxapyroxad, thiophanate methyl, and difenoconazole effectively inhibited mycelial growth of isolates in vitro. When apple cultivars Fuji and Honeycrisp were inoculated with D. coronariae, Honeycrisp showed delayed onset of symptoms and lower disease severity, and the transcription profile of seven host defense-related genes showed that PR-2, PR-8, LYK4, and CERK1 were highly induced in Honeycrisp at 2 and 5 days postinoculation. This is the first report of ABD in the Mid-Atlantic United States, which includes studies of seasonal D. coronariae spore dispersal patterns, preliminary fungicide efficacy, and host defense-related gene expression to assist development of best ABD management practices.
Use of Vancomycin Powder in Spinal Deformity Surgery in Cerebral Palsy Patients is Associated With Proteus Surgical Site Infections
Authors: Du Jerry Y. , Dumaine Anne M. , Klyce Walter , Miyanji Firoz , Sponseller Paul D. , Glotzbecker Michael P. ,   Harms Study Group
Published: February 2022

Purpose:

Surgical site infection (SSI) rates in pediatric spinal deformity surgery for cerebral palsy (CP) patients are higher than that in idiopathic scoliosis. The use of vancomycin powder is associated with decreased risk of SSI in neuromuscular patients. Prior studies in adult and pediatric early-onset scoliosis patients have shown that vancomycin powder alters microbacterial profile in patients that develop SSI. However, the effects of topical vancomycin powder on microbiology in spinal deformity surgery for CP patients has not been studied.

Methods:

An international multicenter database of CP neuromuscular scoliosis patients was used in this retrospective cohort study. All patients that underwent posterior spinal instrumented fusion for CP neuromuscular scoliosis from 2008 to 2019 were queried, and 50 cases complicated by postoperative SSI were identified. Intraoperative antibiotic details were documented in 49 cases (98.0%). Microbiology details were documented in 45 cases (91.8%). Microbiology for patients that received topical vancomycin powder were compared with patients that did not. A multivariate regression model was used to control for potential confounders.

Results:

There were 45 patients included in this study. There were 27 males (60.0%) and 18 females (40.0%). Mean age at surgery was 14.8±2.4 years. There were 24 patients that received topical vancomycin powder (53.3%). The mean time from index surgery to SSI was 4.3±11.3 months.

On univariate analysis of microbiology cultures by vancomycin powder cohort, there were no significant differences in culture types. Proteus spp. trended on significance with association with vancomycin powder use (P=0.078). When controlling for potential confounders on multivariate analysis, intraoperative topical vancomycin powder was associated with increased risk for proteus infection (adjusted odds ratio: 262.900, 95% confidence interval: 1.806-38,267.121, P=0.028).

Discussion:

In CP patients undergoing pediatric spinal deformity surgery, the use of vancomycin powder was independently associated with increased risk for proteus infections. Further study into antibiotic regimens for spinal deformity surgery in the CP population should be performed.

Level of Evidence:

Level III—retrospective cohort study.
Yttrium-90 Radioembolization of Colorectal Cancer Liver Metastases
Authors: d’Andrea Edoardo , Russi Mariarita , Pacilio Massimiliano , Bilotta Federico
Published: February 2022

The present work aims to review the clinical evidence of survival outcome after treatment of colorectal cancer liver metastases using yttrium-90 radioembolization, existence, and relevance of clinical, imaging, and genomic predictors of treatment efficacy and the amount of administered activity. Publications listed in PubMed between July 2016 and May 2021 were screened. Predictors of overall survival were reported and distinguished in clinical, imaging, and genomic variables. Administered activity is reported as median and mean value; overall survival is presented as a median value from the treatment. Fourteen papers resulted to be eligible for this systematic review, 11 retrospective, and 3 prospective studies. Ten studies reported administered activity data, with an average mean administered activity of 1.63 GBq and an average median administered activity of 1.53 GBq. Many clinical, imaging and genomic variables have been identified or defined as predictors of efficacy, leading to the possibility of improvements in patient selection criteria. The overall survival resulted to be about 9 months. The clinical evidence on the application of radioembolization with yittrium-90 resumed in this work underlines the importance to analyze several clinical, imaging, and genomic variables to predict the outcome of the therapy. The overall survival has not improved significantly with respect to older studies. Further developments on treatment planning and patient selection could lead to better clinical outcomes.
Hypertension determinants among Ghanaians differ according to location of residence: RODAM study
Authors: van der Linden Eva L. , Meeks Karlijn A.C. , Klipstein-Grobusch Kerstin , Bahendeka Silver , Beune Erik J.A.J. , van den Born Bert-Jan H. , Agyemang Charles
Published: February 2022

Objective:

Hypertension prevalence is high among African migrants, but the determinants of hypertension in migrants in Europe in relation to the population in the country of origin still needs to be elucidated. Therefore, the aim of this study was to assess the determinants of hypertension in Ghanaians residing in Ghana and Europe.

Methods:

The current study used baseline data of 5659 participants, aged 25–70 years, of the Research on Obesity and Diabetes among African Migrants study. Multivariate logistic regression analysis was used to assess sociodemographic, lifestyle, psychosocial, anthropometric and health factors independently associated with hypertension in Ghanaians living in rural and urban Ghana, and Ghanaian migrants living in Europe.

Results:

Across all sites, older age (both sexes; odds ratio 1.07, 95% confidence interval 1.06–1.08) and diabetes (females only; 2.02, 1.54–1.67) were independently associated with hypertension. The other determinants of hypertension differed between geographical locations. Higher waist circumference (1.12, 1.05–1.20) was independently associated with hypertension in rural-Ghanaian males, as was higher body mass index (1.15, 1.03– 1.28) in urban-Ghanaian males, higher waist circumference (1.04, 1.01–1.07) and diabetes (1.75, 1.17–2.63) in European-Ghanaian males. In European-Ghanaian females, high alcohol intake (1.88, 1.01 –3.53) and waist circumference (1.04, 1.02– 1.06) were associated with hypertension, whereas in rural-Ghanaian females, a higher educational level (0.28, 0.08–0.98) was inversely associated with hypertension.

Conclusion:

The current study identified several modifiable determinants of hypertension in Ghanaians, with differences between populations residing in various geographical locations. This highlights the importance of development and implementation of context-specific interventions targeting these determinants to reduce the burden of hypertension among Ghanaian migrants and nonmigrants.
Which domains of the theoretical domains framework should be targeted in interventions to increase adherence to antihypertensives? A systematic review
Authors: Rahman Murshida , Judah Gaby , Murphy Dan , Garfield Sara F.
Published: February 2022

Nonadherence to antihypertensives is prevalent and is associated with poorer health outcomes. This study aimed to identify psychological factors associated with adherence in patients taking antihypertensives as these are potentially modifiable, and can, therefore, inform the development of effective interventions to increase adherence. PubMed, EMBASE and PsychINFO were searched to identify studies that tested for significant associations between psychological domains and adherence to antihypertensives. The domains reported were categorized according to the Theoretical Domains Framework. The quality of included studies was evaluated using the National Institute for Clinical Excellence critical appraisal of questionnaire checklist. Thirty-one studies were included. Concerns about medicines (a subdomain of ‘beliefs about consequences’) and ‘beliefs about capabilities’ consistently showed association with adherence in over five studies. Healthcare professionals should actively ask patients if they have any concerns about their antihypertensives and their belief in their ability to control their blood pressure through taking antihypertensives.
Feasibility of a “Salvage Regimen” Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis
Authors: Shah Ira , Antony Sonu , Jaiswal Akanksha , Bodhanwala Minnie , Shah Daksha , Tipre Pranita , Salve Jyoti , Parmar Malik , Sachdeva K. S.
Published: February 2022

Introduction:

The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored.

Objectives:

To study feasibility and interim outcomes of a “salvage regimen” using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18–20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India.

Design and Methods:

Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such “salvage regimen” during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described.

Results:

Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period.

Conclusions:

Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.
Nurses' and Physicians' Rationale Behind Clinical Performance and Interpretation of Routine Prefeed Gastric Aspiration in Preterm Infants
Authors: Kappel Susanne Soendergaard , Maastrup Ragnhild , Sangild Per T. , Jakobsen Kristian T. , Christensen Vibeke B. , Aunsholt Lise
Published: February 2022

This study aims at understanding the rationale behind performing prefeed gastric aspirations in preterm infants, how nurses and physicians interpret the gastric aspiration and variations between them, and illuminating potential barriers for omitting routine prefeed aspiration. Nurses and physicians from all Danish neonatal intensive care units completed a questionnaire. Of 682 participants, the majority (94%) indicated that they routinely performed prefeed aspiration, primarily to check the feeding tube placement (nurses: 88%, physicians: 46%). Nurses feared necrotizing enterocolitis when observing a large gastric residual (GR) volume (31%) and green-stained GR (63%). Fewer nurses relative to physicians had “no worries” related to large volumes (15% vs 34%) or green-stained GR (14% vs 24%, both P < .01). More nurses than physicians intended to pause enteral feeding when observing green-stained GR (31% vs 16%, P < .01) and more nurses were concerned of completely omitting routine gastric aspirations (90% vs 46%, P < .05). The rationale behind the clinical use of GR volume and color as markers of necrotizing enterocolitis and feeding intolerance differs markedly between nurses and physicians in Denmark. If routine prefeed gastric aspiration should be omitted, special focus on information about early signs of necrotizing enterocolitis and methods to check tube placement is needed.
Occipital Neuralgia May Be a Possible Limitation on the Utility of the Buffalo Treadmill Test for Concussion Assessments: 2 Case Reports
Authors: Cook Laura , Herman Daniel C.
Published: February 2022

Two female athletes presented to clinic following a head injury and exhibited signs of concussion. Both athletes experienced exacerbation of symptoms secondary to dysautonomia related to concussion injury on the Buffalo Concussion Treadmill Test (BCTT). On repeat evaluation, both athletes exhibited neck pain with symptoms immediately provoked by palpation of the occipital nerves. After a third occipital nerve block, both athletes had complete resolution of symptoms and subsequently tolerated BCTT to the maximum rate of perceived exertion with no provoked symptoms. The athletes were cleared for return to sport without issue. These cases indicate a potential limitation in the utility of the BCTT for determining the etiology and management of concussion and postconcussion syndrome.
Impact of Cirrhosis on Outcomes in Inflammatory Bowel Disease Hospitalizations
Authors: Taneja Vikas , Stein Daniel J. , Feuerstein Joseph D.
Published: February 2022

Background:

Evidence regarding outcomes in inflammatory bowel disease (IBD) hospitalizations with coexisting cirrhosis is scant. We queried the National Inpatient Sample (NIS) database to evaluate the impact of cirrhosis on hospitalization characteristics and outcomes in patients with Crohn’s disease and ulcerative colitis.

Methods:

All admissions that listed IBD as a primary diagnosis by ICD-10-CM code (K50.X for Crohn’s disease and K51.X for ulcerative colitis) in the NIS for 2016 and 2017 were included. Attributes of admissions with cirrhosis (K74.XX, 70.3, 78.81, and 71.7) were compared with noncirrhosis IBD admissions. The primary outcome was inpatient mortality. Length of stay and total hospital charges comprised secondary outcomes.

Results:

A total weighted sample of 276,430 IBD admissions were identified, including 4615 with a concomitant diagnosis of cirrhosis. In a multivariate model, after adjusting for comorbidities, age, alimentary surgery during the admission and hospital type (teaching, urban nonteaching or rural), the presence of cirrhosis was associated with a higher inpatient mortality [odds ratio: 1.57; 95% confidence interval (CI): 1.16-2.15] and increased cost of admission (mean difference $11,651; 95% CI: 3830-19,472). No difference was noted in length of stay (difference: 0.44 d; 95% CI: -0.12-1.02) among these groups. Among admission diagnoses, infectious complications were the primary cause of death in 93.3% (95% CI: 87.1%-99.5%) of all inpatient mortality in the IBD with cirrhosis cohort as compared with 80.1% (95% CI: 77.6%-82.7%) of the mortality among IBD patients without cirrhosis (P=0.01).

Conclusions:

This study demonstrates that the presence of cirrhosis has an independent negative impact on outcomes for hospitalized patients with IBD as reflected by increased in-hospital mortality and higher cost of admission. A majority of the mortality was attributable to infections.
UCsim2: two-dimensionally structured illumination microscopy using UC2
Authors: Wang Haoran , Lachmann René , Marsikova Barbora , Heintzmann Rainer , Diederich Benedict
Published: February 2022

State-of-the-art microscopy techniques enable the imaging of sub-diffraction barrier biological structures at the price of high costs or a lack of transparency. We try to reduce some of these barriers by presenting a super-resolution upgrade to our recently presented open-source optical toolbox UC2. Our new injection moulded parts allow larger builds with higher precision. The 4× lower manufacturing tolerance compared to three-dimensional printing makes assemblies more reproducible. By adding consumer-grade available open-source hardware such as digital mirror devices and laser projectors, we demonstrate a compact three-dimensional multimodal setup that combines image scanning microscopy and structured illumination microscopy. We demonstrate a gain in resolution and optical sectioning using the two different modes compared to the widefield limit by imaging Alexa Fluor ® 647- and Silicon Rhodamine-stained HeLa cells. We compare different objective lenses and by sharing the designs and manuals of our setup, we make super-resolution imaging available to everyone.

This article is part of the Theo Murphy meeting issue 'Super-resolution structured illumination microscopy (part 2)'.
A biomarker of aging, p16, predicts peripheral neuropathy in women receiving adjuvant taxanes for breast cancer
Authors: Mitin Natalia , Nyrop Kirsten A. , Strum Susan L. , Knecht Anne , Carey Lisa A , Reeder-Hayes Katherine E. , Dees E. Claire , Jolly Trevor A. , Kimmick Gretchen G. , Karuturi Meghan S. , Reinbolt Raquel E. , Speca JoEllen C. , O’Hare Erin A. , Muss Hyman B.
Published: February 2022

Importance

Identifying patients at higher risk of chemotherapy-induced peripheral neuropathy (CIPN) is a major unmet need given its high incidence, persistence, and detrimental effect on quality of life.

Objective

To determine if expression of p16, a biomarker of aging and cellular senescence, predicts CIPN.

Design

Prospective observational cohort study including one hundred fifty-two participants enrolled between January 2014 and August 2018 and followed during the course of adjuvant chemotherapy. Expression of p16 was measured prior to and at the end of chemotherapy. Side effects, including peripheral neuropathy, were assessed prior to each chemotherapy cycle.

Setting

A multi-center study including four major academic hospitals and five community oncology clinics.

Participants

Women with newly diagnosed with stage I to III breast cancer to receive chemotherapy including a taxane.

Main Outcomes and Measure

Development of grade 2+ (moderate or worse) CIPN during the course of chemotherapy. CIPN symptoms were graded by participants’ oncology clinician using the NCI-CTCAE v5 system. Expression of p16 mRNA was measured by qPCR in T-lymphocytes isolated from fresh peripheral blood.

Results

A multivariate model including taxane regimen type and p16Age Gap, a measure of discordance between chronological age and p16 expression, identified risk factors for CIPN. Participants with higher chronological age but lower p16 expression prior to chemotherapy (molecularly young) were at the highest risk. Incidence of CIPN positively correlated with chemotherapy-induced increase in p16 expression, with the largest increase seen in participants with the lowest p16 expression prior to treatment.

Conclusions and Relevance

This is the first report using a biomarker of senescence in a model to identify patients at risk for taxane-induced CIPN. Studies to confirm and validate our findings are ongoing. When validated, a p16Age Gap-based model can be used to guide chemotherapy selection in patients with early breast cancer and identify patients at high risk who may be candidates for preventive trials.

Key Points

Question

Is cellular senescence an independent risk factor for chemotherapy-induced peripheral neuropathy?

Findings

In a prospective observational cohort study of women with early-stage breast cancer undergoing treatment with taxane chemotherapy, a regression model containing a measure of cellular senescence and taxane type was a statistically significant predictor of grade 2+ CIPN incidence.

Meaning

Cellular senescence is an independent risk factor for CIPN that, if validated, could guide treatment selection and identify high-risk patients for preventive strategies.
A Robust Spike Sorting Method based on the Joint Optimization of Linear Discrimination Analysis and Density Peaks
Authors: Zhang Yiwei , Han Jiawei , Liu Tengjun , Yang Zelan , Chen Weidong , Zhang Shaomin
Published: February 2022

Objective

Spike sorting is a fundamental step in extracting single-unit activity from neural ensemble recordings, which play an important role in basic neuroscience and neurotechnologies. A few algorithms have been applied in spike sorting. However, when noise level or waveform similarity becomes relatively high, their robustness still faces a big challenge.

Approach

In this study, we propose a spike sorting method combining Linear Discriminant Analysis (LDA) and Density Peaks (DP) for feature extraction and clustering. Relying on the joint optimization of LDA and DP: DP provides more accurate classification labels for LDA, LDA extracts more discriminative features to cluster for DP, and the algorithm achieves high performance after iteration. We first compared the proposed LDA-DP algorithm with several algorithms on one publicly available simulated dataset and one real rodent neural dataset with different noise levels. We further demonstrated the performance of the LDA-DP method on a real neural dataset from non-human primates with more complex distribution characteristics.

Main results

The results show that our LDA-DP algorithm extracts a more discriminative feature subspace and achieves better cluster quality than previously established methods in both simulated and real data. Especially in the neural recordings with high noise levels or waveform similarity, the LDA-DP still yields a robust performance with automatic detection of the number of clusters.

Significance

The proposed LDA-DP algorithm achieved high sorting accuracy and robustness to noise, which offers a promising tool for spike sorting and facilitates the following analysis of neural population activity.
OncoLoop: A network-based precision cancer medicine framework
Authors: Vasciaveo Alessandro , Zou Min , Arriaga Juan Martín , de Almeida Francisca Nunes , Douglass Eugene F. , Shibata Maho , Rodriguez-Calero Antonio , de Brot Simone , Mitrofanova Antonina , Chua Chee Wai , Karan Charles , Realubit Ron , Pampou Sergey , Kim Jaime Y. , Corey Eva , Alvarez Mariano J. , Rubin Mark A. , Shen Michael M. , Califano Andrea , Abate-Shen Cory
Published: February 2022

At present, prioritizing cancer treatments at the individual patient level remains challenging, and performing co-clinical studies using patient-derived models in real-time is often not feasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework to predict and validate drug sensitivity in human tumors and their pre-existing high-fidelity (cognate) model(s) by leveraging perturbational profiles of clinically-relevant oncology drugs. As proof-of-concept, we applied OncoLoop to prostate cancer (PCa) using a series of genetically-engineered mouse models (GEMMs) that recapitulate a broad spectrum of disease states, including castration-resistant, metastatic, and neuroendocrine prostate cancer. Interrogation of published cohorts using Master Regulator (MR) conservation analysis revealed that most patients were represented by at least one cognate GEMM-derived tumor (GEMM-DT). Drugs predicted to invert MR activity in patients and their cognate GEMM-DTs were successfully validated, including in two cognate allografts and one cognate patient-derived xenograft (PDX). OncoLoop is a highly generalizable framework that can be extended to other cancers and potentially other diseases.

Significance Statement

OncoLoop is a transcriptomic-based experimental and computational framework that can support rapid-turnaround co-clinical studies to identify and validate drugs for individual patients, which can then be readily adapted to clinical practice. This framework should be applicable in many cancer contexts for which appropriate models and drug perturbation data are available.
Improved Predictions of MHC-Peptide Binding using Protein Language Models
Authors: Hashemi Nasser , Hao Boran , Ignatov Mikhail , Paschalidis Ioannis , Vakili Pirooz , Vajda Sandor , Kozakov Dima
Published: February 2022

Abstract

Major histocompatibility complex (MHC) molecules bind to peptides from exogenous antigens, and present them on the surface of cells, allowing the immune system (T cells) to detect them. Elucidating the process of this presentation is essential for regulation and potential manipulation of the cellular immune system [1]. Predicting whether a given peptide will bind to the MHC is an important step in the above process, motivating the introduction of many computational approaches. NetMHCPan [2], a pan-specific model predicting binding of peptides to any MHC molecule, is one of the most widely used methods which focuses on solving this binary classification problem using a shallow neural network. The successful results of AI methods, especially Natural Language Processing (NLP-based) pretrained models in various applications including protein structure determination, motivated us to explore their use in this problem as well. Specifically, we considered fine-tuning these large deep learning models using as dataset the peptide-MHC sequences. Using standard metrics in this area, and the same training and test sets, we show that our model outperforms NetMHCpan4.1 which has been shown to outperform all other earlier methods [2].
Spatiotemporal mapping of the neural markers of prediction error processing across multisensory and unisensory modalities
Authors: Ghosh Priyanka , Talwar Siddharth , Banerjee Arpan
Published: February 2022

Prediction errors in the brain are indexed by two event-related potentials – MMN and P300, which are elicited upon violation of regularity in the occurrence of repetitive stimuli. While MMN reflects the brain’s ability to perform automatic comparisons between consecutive stimuli and provides an electrophysiological index of sensory error detection, P300 is associated with cognitive processes such as update in working memory. Till date, there has been extensive research on the roles of MMN and P300 individually, because of their potential to be used as clinical markers of consciousness and attention, respectively. However, the relationship between these two ERPs, specifically in terms of their underlying cortical generators, in context of prediction error propagation along the hierarchical brain across multiple modalities is an open question. Our objective in this article is two-fold. First, we reconfirm previous reports regarding the generators of MMN and P300 in sensor space through source-space analysis using an accurate individual subject level co-registration of MRI and EEG data collected from healthy humans. We demonstrate that in multisensory environments, MMN and P300 markers represent “modality-specific” and “modality-independent” information processing, respectively. Advancing an earlier understanding that multisensory contexts speed upearly sensory processing, our study reveals that this temporal facilitation extends to even the later components ofprediction error processing, using custom-designed experiments that allow comparisons across different modality combinations. Such knowledge can be of immense value in clinical research for determining the stages of various treatments in aging, schizophrenia and depression, and their efficacy on cognitive function.
Alpha-Amylase increases predict a freezing-like response and cortical alpha oscillations
Authors: Luther Lisa , Jensen Ole , Hagenaars Muriel A.
Published: February 2022

Individual differences in the reactivity of the sympathetic nervous system in response to stressful situations are thought to be an important predictor for psychological well-being and the focus of current scientific investigations. Here, we explored whether increased sympathetic nervous activity (SNA) was associated with reduced alpha power and with increased freezing-like behaviour (i.e., body sway) while watching threatening stimuli, reflecting enhanced attention. Salivary alpha-amylase (sAA) was used as a proxy for sympathetic nervous activity, which is elevated in stressful situations. A passive viewing task with affective pictures (unpleasant, neutral, pleasant) was carried out, and pre- and post- task sAA samples were taken. Oscillatory brain activity in the EEG and body sway were assessed simultaneously during the task. The results point to an increase in sAA being associated with reduced alpha power decrease to the unpleasant compared to the neutral pictures as well as increased freezing-like behaviour (i.e., reduction in body sway for unpleasant versus neutral pictures). It appears that an increase in SNA is linked to less attentional valence differentiation. Furthermore, our study corroborates findings from the animal literature in that the SNA increase is linked to a freezing-like response.
pkgndep: a tool for heaviness analysis on R package dependencies
Authors: Gu Zuguang , Hübschmann Daniel
Published: February 2022

Numerous R packages have been developed for bioinformatics analysis in the last decade and dependencies among packages have become critical issues to consider. In this work, we proposed a new metric named dependency heaviness that measures the number of unique dependencies that a parent brings to a package, and we proposed possible solutions for reducing the complexity of dependencies by optimizing the use of heavy parents. We implemented the metric in a new R package pkgndep which provides an intuitive way for dependency heaviness analysis. Based on pkgndep, we additionally performed a global analysis of dependency heaviness on CRAN and Bioconductor ecosystems and we revealed top packages that have significant contributions of high dependency heaviness to their child packages.

Availability and implementation

The package pkgndep and documentations are freely available from the Comprehensive R Archive Network (CRAN) https://cran.r-project.org/package=pkgndep. The dependency heaviness analysis for all 21,741 CRAN and Bioconductor packages retrieved on 2021-10-28 are available at https://pkgndep.github.io/.
Proprioceptive and visual feedback responses in macaques exploit goal redundancy
Authors: Cross Kevin P. , Guang Hui , Scott Stephen H.
Published: February 2022

A common problem in motor control concerns how to generate patterns of muscle activity when there are redundant solutions to attain a behavioural goal. Optimal feedback control is a theory that has guided many behavioural studies exploring how the motor system incorporates task redundancy. This theory predicts that kinematic errors that deviate the limb should not be corrected if one can still attain the behavioural goal. Several studies in humans demonstrate that the motor system can flexibly integrate visual and proprioceptive feedback of the limb with goal redundancy within 90ms and 70ms, respectively. Here we show monkeys (Macaca mulatta) demonstrate similar abilities to exploit goal redundancy. We trained four male monkeys to reach for a goal that was either a narrow square or a wide, spatially redundant rectangle. Monkeys exhibited greater trial-by-trial variability when reaching to the wide goal consistent with exploiting goal redundancy. On random trials we jumped the visual feedback of the hand and found monkeys corrected for the jump when reaching to the narrow goal and largely ignored the jump when reaching for the wide goal. In a separate set of experiments, we applied mechanical loads to the monkey’s arm and found similar corrective responses based on goal shape. Muscle activity reflecting these different corrective responses were detected for the visual and mechanical perturbations starting at ∼90 and ∼70ms, respectively. Thus, rapid motor responses in macaques can exploit goal redundancy similar to humans, creating a paradigm to study the neural basis of goal-directed motor action and motor redundancy.
Navigation of Ultrasound-controlled Swarmbots under Physiological Flow Conditions
Authors: Fonseca Alexia D.C. , Kohler Tobias , Ahmed Daniel
Published: February 2022

Navigation of microrobots in living vasculatures is essential in realizing targeted drug delivery and advancing non-invasive surgeries. We developed acoustically-controlled “swarmbots” based on the self-assembly of clinically-approved microbubbles. Ultrasound is noninvasive, penetrates deeply into the human body, and is well-developed in clinical settings. Our propulsion strategy relies in two forces: the primary radiation force and secondary Bjerknes force. Upon ultrasound activation, the microbubbles self-assemble into microswarms, which migrate towards and anchor at the containing vessel’s wall. A second transducer, which produces an acoustic field parallel to the channel, propels the swarms along the wall. We demonstrated cross- and upstream navigation of the swarmbots at 3.27 mm/s and 0.53 mm/s, respectively, against physiologically-relevant flow rates of 4.2 – 16.7 cm/s. Additionally, we showed swarm controlled manipulation within mice blood and under pulsatile flow conditions of 100 beats per minute. This capability represents a much-needed pathway for advancing preclinical research.

Teaser

Navigation of ultrasound-guided microrobots inside artificial blood vessels overcoming physiological conditions, including high flow rates, pulsatile flow regimes, and high cell concentrations of blood.
Selection of Synthetic Proteins to Modulate the Human Frataxin Function
Authors: Pignataro María Florencia , Herrera María Georgina , Fernández Natalia , Aran Martín , Bataglini Fernando , Santos Javier
Published: February 2022

Frataxin is a kinetic activator of the mitochondrial supercomplex for iron–sulfur cluster assembly. Low frataxin expression or a decrease in its functionality results in Friedreich’s Ataxia (FRDA). With the aim of creating new molecular tools to study this metabolic pathway, and ultimately, to explore new therapeutic strategies, we have investigated the possibility of obtaining small proteins exhibiting a high affinity for frataxin. In this study, we applied the ribosome display approach, using human frataxin as the target. We focused on Affi_224, one of the proteins that we were able to select after five selection rounds. We have studied the interaction between both proteins and discussed some applications of this specific molecular tutor, concerning the modulation of supercomplex activity. Affi_224 and frataxin showed a KD value in the nanomolar range, as judged by surface plasmon resonance analysis. Most likely, it binds to the frataxin acidic ridge, as suggested by the analysis of chemical shift perturbations (NMR) and computational simulations. Affi_224 was able to increase Cys NFS1 desulfurase activation exerted by the FRDA frataxin variant G130V. Our results suggest quaternary addition may be a new tool to modulate frataxin function in vivo. Nevertheless, more functional experiments under physiological conditions should be carried out to evaluate Affi_224 effectiveness in FRDA cell models.