bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium nitrite supplementation improves motor function and skeletal muscle inflammatory profile in old mice (LB817)
Authors: Battson Micah , Gioscia‐Ryan Rachel , Johnson Lawrence , Seals Douglas , Justice Jamie
Published: June 2021

Aging is associated with motor impairments that reduce quality of life and represent a major healthcare burden, necessitating the development of potential therapies to slow or reverse age‐related functional declines. Chronic low‐grade inflammation develops with advancing age and may be a primary mediator of functional declines. We tested the hypothesis that sodium nitrite (SN) supplementation reverses age‐related motor dysfunction and reduces muscle inflammation.

Motor function was assessed using a battery of tests (grip strength [GS], open field distance [OFD] and rota‐rod endurance run [ER]) in young (Y, 3 mo, n=87), old (O, 24 mo, n=40) and old mice treated with SN (ON, n=22, 50 mg/L in drinking water, 8 wk). Function was impaired in O vs. Y (GS: 97.0 ± 18.6 vs. 130 ± 14 g; OFD: 1183 ± 453 vs. 1859 ± 265 cm; ER: 8.4 ± 6.4 vs. 14.4 ± 5.9 min; all p<0.05) and improved with SN (GS: 111 ± 17.0 g; OFD: 1486 ± 485 cm; ER: 14.9 ± 5.1 min, all p<0.05 vs. O).

Inflammatory cytokine levels were markedly increased in skeletal muscle of O vs. Y (ELISA: interleukin‐1 β [IL‐1β]: 3.86 ± 2.34 vs. 1.11 ± 0.74; interferon gamma [INFγ]: 8.31 ± 1.59 vs. 3.99 ± 2.59; tumor necrosis factor alpha [TNFα]: 1.69 ± 0.44 vs. 0.76 ± 0.30 pg/mL, all p<0.05), but returned to levels not different than Y with SN (ON: IL‐1β: 0.67 ± 0.95, INFγ: 5.22 ± 2.01, TNFα: 1.21 ± 0.39 pg/mL, all p0.05 vs. Y).

Regression models demonstrated that cytokine expression and treatment group (O vs. ON) predicted GS (R2 = 0.822, p<0.001, IL‐1β, INFγ, group), OFD (R2 = 0.574, p<0.01, IL‐1β, group) and ER (R2 = 0.477, p<0.05, INFγ).

Our results suggest that SN initiated late in life preserves motor function in old mice, possibly by reducing inflammation in skeletal muscle.

Grant Funding Source: Supported by NIH AG013038 and AG000279
Skeletal Muscle PPAR‐delta increases with 10 Weeks of Resistance Training (LB819)
Authors: Chen Vincent C.W. , Lee Chang Woock , Bui Steve , Lee Teak , Fluckey James , Riechman Steven
Published: June 2021

Purpose: PPARδ expression in skeletal muscle has been shown to increase in response to endurance exercise training. However, the effect of resistance exercise training on PPARδ expression has not been investigated in humans and is thus the purpose of this study. Methods: Seven untrained young men (N=5) and women (N=2) (Age=23.5±1.7, BMI=27.0±2.1) performed a 10‐week progressive whole body resistance training program that included leg press and leg extension for emphasis on quadriceps femoris muscles. Muscle biopsies were performed on the vastus lateralis muscles 24 hours before the first and 24 hours after the last resistance exercise sessions to study the effect of training on PPARδ. Western Blotting was conducted to detect the PPARδ content. Results: After 10 weeks of resistance exercise training, PPARδ levels increased by 97.3% (p=0.037). Conclusion: Our data suggest that resistance exercise training has positive effects on PPARδ content, which may be a key factor of lipid metabolism.
Adult dog: CT‐scan and reconstruction of an osseous cranium (LB9)
Authors: LE FLOCH‐PRIGENT Patrice , Verdeille Stéphane
Published: June 2021

The osseous cranium of a dog of unknown age and race had been systematically CT‐scanned in the frontal plane. The cranium was laid on the apparatus’ table, its longitudinal axis aligned with the table’s one and the orbito‐meatal plane parallel to the plane’s table. The length of the cranium was 18,5 cm. Several reconstructions were obtained from the native crosss‐sections with an average density. The cross‐sections in the three planes : frontal, para‐sagittal and horizontal ones were reconstructed from the frontal, native cross‐sections using an high resolution with a thickness of 0,75 mm and an interval of 0,6 mm. 308 frontal, 170 para‐sagittal, and 125 horizontal cross‐sections were analyzed. The seriated CT‐scan of an entire cranium in the dog, in the three planes of the space gave great possiblities of analysis in all the kind of bones, for the architectural rendering, their volumes and relationships. This method is now unvaluable in the morphological analysis of the complicated, osseous structures.
Using a chimera to study the role of Galectin‐1 in immunological responses and tumor progression (LB91)
Authors: Bradford Nora , Jin Cho Yong , Bailey Lily , Gustafson Jack , Huang Tianyi , Iyer Hansika , Lu Hancheng , Magliochetti‐Cammarata Tessabella , Nee William , Park Jasmin , Park Jin Young , Sherrin McLean , Sugarman Eli , Tejeda Jeanny , Zhan Bowen , Rokous Judy , Dimitroff Charles
Published: June 2021

Galectin‐1 (Gal‐1), a protein that impacts the fate and function of immune cells known to fight infection, eliminates cancer, and promotes inflammation, is found in most mammalian tissues at low levels. A small 130 amino acid “jelly‐roll” shaped ß‐galactoside‐binding lectin with a hydrophobic core, Gal‐1 plays a role in controlling intracellular processes, such as cell cycle progression and cell proliferation. Gal‐1 binds with high affinity to glycoconjugates galactose (Gal) and N‐acetylglucosamine (GlcNAc) by van der Waals forces and hydrogen bonding via a highly conserved carbohydrate recognition domain. Because native Gal‐1 oxidizes rapidly and loses its carbohydrate‐binding activity, studying the effect of Gal‐1 has been difficult. The Dimitroff laboratory engineered a Gal‐1 – human immunoglobulin Fc chimeric molecule (Gal‐1hFc), which facilitates dimerization while preventing oxidation‐induced multimerization. Experimental evidence has demonstrated that Gal‐1hFc behaves like native Gal‐1, enabling the use of the chimera to study Gal‐1’s effect on immune responses. The Governor’s Academy SMART (Students Modeling A Research Topic) Team designed a model using 3D printing technology to provide further evidence of Gal‐1hFc’s structure and binding function.

Grant Funding Source: Supported by grants from NIH‐CTSA UL1RR031973 and NIH/NCI RO1CA118124
The Silent Assassin (LB93)
Authors: Fuller J. , Kim D. , Arnhold E. , Sung R. , Borden A. , Ortega L. , Johnson R. , Albornoz‐Williams H. , Gummin C. , Martinez A. , Boldt N. , Ogunkunle O. , Ahn P. , Kasten B. , Furumo Q. , Yorke N. , McBride J. , Mullooly I. , Tripi M. , Hutt D. , Klestinski K. , Kaiser C. , Jackson William
Published: June 2021

According to World Health Organization statistics, the common cold is the most prevalent known disease of humans. The majority of colds are caused by the human rhinovirus‐‐an enterovirus genetically similar to dangerous viruses like polio and hepatitis A. Rhinovirus infection can lead to 72‐hour periods of morbidity, including symptoms like sore throat, runny nose, and muscle weakness, often causing people to miss school or work. Rhinovirus is inert until infection occurs causing the immune system to combat the virus. Rhinovirus transmission is usually via aerosolized respiratory droplets or contact with contaminated surfaces. Once in the body, the virus binds to the cell surface, allowing it to enter cells. Cells use the Intercellular Adhesion Molecule 1 (ICAM‐1) signaling protein to latch on to each other, but viruses bind to ICAM‐1 using a site on the virus surface known as the “canyon.” Since there are over 150 rhinovirus serotypes, it is impossible to put every serotype in one vaccine. Instead, scientists are developing new drugs, such as pleconaril, that bind to the canyon and prevent the virus from attaching to the host cell. This prevents the virus from replicating thus eliminating the spread of the virus and the symptoms caused by it. The Marquette University High School SMART Team modeled a portion of the human rhinovirus capsid bound to pleconaril using 3D printing technology.

Grant Funding Source: Supported by a grant from NIH‐CTSA.
Correct Splicing: The Desolation of SMA Spinal Muscular Atrophy and the Survival Motor Neuron Complex (LB94)
Authors: Daley Mary , Erickson Kayla , Griesmer Jessica , Heimermann Megan , Lewandowski Brandy , Loosen Julia , Hoffman Olivia , Rigden Gabrielle , Arnholt Mark , McNally Mark
Published: June 2021

Spinal muscular atrophy (SMA) is a genetic disorder leading to death before age two. This is caused by degeneration of motor neurons in the spine and affects one in six thousand babies yearly (Families of SMA, 2013). It is unknown why a point mutation or deletion of the SMN1 gene, which produces survival motor neuron (SMN) protein, causes degeneration. The SMN complex is made of SMN and smaller units called Gemin proteins. In a normally functioning system, the SMN1 gene codes for SMN proteins that are part of the SMN complex that forms small nuclear ribonucleoproteins (snRNPs) from SM proteins and sRNA. The SMN protein binds to Gemin‐2 which holds five of the seven SM proteins, smaller units in snRNPs, in place until the target snRNA sequence is located. The final SM proteins are added when the N‐terminus of Gemin‐2 is moved. The snRNPs have many functions in cells, and five of them are involved in RNA splicing. Knowledge available on normal interactions of SMN and Gemin‐2 allow modeling of these proteins to be completed through 3D printing by the Hartford Union SMART (Students Modeling a Research Topic) Team. In children with SMA, the SMN protein cannot to bind to Gemin‐2 because Asp44 is replaced by valine, causing a break in the ionic bond holding the helices together. While this situation still produces normally operating snRNPs, there are too few to correctly splice the pre‐mRNA, leading to SMA.

Grant Funding Source: Supported by a grant from NIH‐CTSA.
Bempedoic Acid: A New Avenue for the Treatment of Dyslipidemia
Authors: Smith William , Cheng-Lai Angela , Nawarskas James
Published: June 2021

Uncontrolled dyslipidemia, specifically elevation of low-density lipoprotein cholesterol, is a major risk factor for developing cardiovascular disease. Currently, statin therapy remains as first-line treatment for reducing both serum cholesterol levels and cardiovascular risk. However, certain patients are unable to achieve desired serum cholesterol levels despite maximally tolerated statin therapy. As a result, several nonstatin therapy avenues have been evaluated for their potential benefits in reducing cholesterol and cardiovascular risk. Bempedoic acid is one such nonstatin therapy option, which has been explored over the past few years to potentially assist patients in further reducing serum cholesterol. Bempedoic acid is a novel prodrug that inhibits cholesterol synthesis upstream of statins by inhibiting adenosine triphosphate-citrate lyase. Bempedoic acid has been studied as a single, once daily 180 mg dose. Administered as monotherapy or in combination with statin or ezetimibe, bempedoic acid significantly reduces low-density lipoprotein cholesterol. Furthermore, bempedoic acid was generally well tolerated by patients and rates of adverse events were similar to placebo with few exceptions. Despite proven reductions in cholesterol and favorable safety profile, bempedoic acid will likely remain a third- or fourth-line agent for the treatment of dyslipidemia behind other nonstatin therapies until the improvement of cardiovascular outcomes is demonstrated in future clinical trials.
Anterior Scleritis Manifesting After Coronavirus Disease 2019: A Report of Two Cases
Authors: Feizi Sepehr , Meshksar Aidin , Naderi Ali , Esfandiari Hamed
Published: June 2021

Purpose:

The purpose of this study was to report 2 patients with anterior scleritis manifesting after coronavirus disease 2019 (COVID-19).

Methods:

The patients with confirmed COVID-19 developed anterior scleritis after their systemic symptoms were markedly improved. A thorough systemic workup identified no underlying autoimmune diseases. Ocular characteristics and safety and efficacy of systemic immunosuppressive therapy were evaluated.

Results:

Case 1 was a 67-year-old woman who presented with necrotizing anterior scleritis in both eyes 3 weeks after the onset of COVID-19. One-week treatment with topical betamethasone and oral prednisolone (65 mg daily) did not result in improvement, so she was started on intravenous cyclophosphamide and subcutaneous adalimumab in addition to oral prednisolone. Necrotizing scleritis was gradually improved over 3 months. Case 2 was a 33-year-old man who presented with sectoral anterior scleritis in his right eye 2 weeks after the onset of COVID-19. He was started on topical betamethasone and oral prednisolone (85 mg daily). One week later, all signs and symptoms disappeared, and topical and oral corticosteroids were gradually tapered off over 2 weeks. There was no recurrence of respiratory symptoms or active scleritis in any cases after discontinuation of treatment.

Conclusions:

These cases suggest that COVID-19 can be associated with anterior scleritis, which responds to immunosuppressive and biologic agents. Ophthalmologists should consider anterior scleritis in patients with COVID-19 who present with ocular pain and redness during the convalescent phase of the illness.
Outcomes of cataract surgery in patients previously treated with orbital radiotherapy
Authors: Hind Jennifer , Jamison Aaron , Schipani Stefano , Connolly Julie , Cauchi Paul , Chadha Vikas
Published: June 2021

Purpose:

To quantify the risks for cataract surgery in patients who have previously undergone external beam radiotherapy (EBRT).

Setting:

Tertiary ophthalmology and oncology hospital.

Design:

Retrospective case series.

Methods:

Patients treated with orbital EBRT at the Beatson West of Scotland Cancer Centre between 2001 and 2019 were identified, and clinical records were reviewed to identify those who had subsequently undergone cataract surgery. Preoperative and postoperative case records, and operation records, were reviewed to identify demographic data and data regarding complications and surgical outcomes.

Results:

46 eyes (of 33 patients) were included. The indications for EBRT included thyroid eye disease, lymphoma, choroidal metastases, and other orbital malignancies. Mean corrected preoperative Snellen visual acuity was 20/100 (range 20/30 to 20/2000) improving to 20/25 (20/12 to 20/160, 1-way analysis of variance P < .01). Mean visual gain was 0.5 logMAR (−0.9 to 1.9). There was 1 case of posterior capsule (PC) rupture with vitreous loss (2%). Dense PC plaque was noted intraoperatively in 19.5% (n = 9). 13% (n = 6) required Nd:YAG laser posterior capsulotomy. There were 6 cases (13%) of cystoid macular edema (CME).

Conclusions:

Visual outcomes after cataract surgery in this cohort of patients were similar to those obtained in a nationwide cohort. EBRT seemed to be associated with an increased incidence of intraoperative PC plaque, postoperative CME (which in most cases settled with treatment), and need for posterior capsulotomy.
The Physiologic and Emotional Effects of 360-Degree Video Simulation on Head-Mounted Display Versus In-Person Simulation
Authors: Caruso Thomas J. , Armstrong-Carter Emma , Rama Asheen , Neiman Nicole , Taylor Katherine , Madill Martine , Lawrence Kiley , Hemphill Sydney F. , Guo Nan , Domingue Benjamin W.
Published: June 2021

Introduction

A key simulation component is its capability to elicit physiological changes, improving recall. The primary aim was to determine whether parasympathetic responses to head-mounted display simulations (HMDs) were noninferior to in-person simulations. The secondary aims explored sympathetic and affective responses and learning effectiveness.

Methods

The authors conducted a noninferiority trial. Hospital providers who did not use chronotropic medications, have motion sickness, or have seizures were included. The authors randomized participants to in-person or HMD simulation. Biometric sensors collected respiratory sinus arrhythmia and skin conductance levels to measure parasympathetic and sympathetic states at baseline, during, and after the simulation. Affect was measured using a schedule. The authors measured 3-month recall of learning points and used split-plot analysis of variance and Mann-Whitney U tests to analyze.

Results

One hundred fifteen participants qualified, and the authors analyzed 56 in each group. Both groups experienced a significant change in mean respiratory sinus arrhythmia from baseline to during and from during to afterward. The difference of change between the groups from baseline to during was 0.134 (95% confidence interval = 0.142 to 0.410, P = 0.339). The difference of change from during the simulation to after was −0.060 (95% confidence interval = −0.337 to 0.217, P = 0.670). Noninferiority was not established for either period. Sympathetic arousal did not occur in either group. Noninferiority was not established for the changes in affect that were demonstrated. The mean scores of teaching effectiveness and achievement scores were not different.

Conclusions

Although a parasympathetic and affective response to the video simulation on an HMD did occur, it was not discernibly noninferior to in-person in this study.
IMPPACT (Intravenous Monotherapy for Postoperative Perforated Appendicitis in Children Trial)
Authors: Lee Justin , Garvey Erin M. , Bundrant Nikkida , Hargis-villanueva Angela , Kang Paul , Osuchukwu Obiyo , Dekonenko Charlene , Svetanoff Wendy Jo , St. Peter Shawn D. , Padilla Benjamin , Ostlie Daniel
Published: June 2021

Background:

Perforated appendicitis is the most common cause of intraabdominal abscess (IAA) in children. The optimal postoperative antibiotic regimen to reduce IAA has evolved in the last decade from triple-drug to 2-drug therapy (CM). Recent retrospective studies show decreased infectious complications with monotherapy PT. To date prospective comparative data are lacking. Therefore, a prospective randomized trial comparing PT versus CM was conducted.

Methods:

A multi-institutional prospective randomized trial was performed in children with perforated appendicitis comparing postoperative antibiotic regimens PT or CM. The primary outcome was 30-day postoperative IAA formation. Perforation was strictly defined as a hole in the appendix or fecalith in the abdomen, documented with intraoperative photographs.

Results:

One hundred sixty-two patients were enrolled during the study period. No differences in age, weight, or duration of presenting symptoms were identified. In addition, length of stay, duration of intravenous antibiotic treatment, discharge oral antibiotic treatment, and antibiotic-related complications did not differ between groups. Compared to the CM group, the PT group had significantly lower IAA rate [6.1% vs 23.8%, odd ratio (OR) 4.80, P = 0.002], lower postoperative computed tomography imaging rate (13.9% vs 29.3%, OR 2.57, P = 0.030), and fewer emergency room visits (8.8% vs 26.4%, OR 3.73, P = 0.022). Multivariate logistic regression analysis found the use of CM versus PT (OR 9.21, P = 0.021) to be the most significant predictor for developing IAA.

Conclusions:

In children with perforated appendicitis, postoperative monotherapy with PT is superior to standard 2-drug therapy with CM and does not increase antibiotic-related complications or antibiotic exposure duration.
Florivory of Early Cretaceous flowers by functionally diverse insects: implications for early angiosperm pollination
Authors: Xiao Lifang , Labandeira Conrad , Dilcher David , Ren Dong
Published: June 2021

Florivory (flower consumption) occurs worldwide in modern angiosperms, associated with pollen and nectar consumption. However, florivory remains unrecorded from fossil flowers since their Early Cretaceous appearance. We test hypotheses that earliest angiosperms were pollinated by a diverse insect fauna by evaluating 7858 plants from eight localities of the latest Albian Dakota Formation from midcontinental North America, in which 645 specimens (8.2%) were flowers or inflorescences. Well-preserved specimens were categorized into 32 morphotypes, nine of which displayed 207 instances of damage from 11 insect damage types (DTs) by four functional-feeding groups of hole feeding, margin feeding, surface feeding and piercing-and-sucking. We assessed the same DTs inflicted by known florivores on modern flowers that also are their pollinators, and associated insect mouthpart types causing such damage. The diverse, Dakota florivore–pollinator community showed a local pattern at Braun's Ranch of flower morphotypes 4 and 5 having piercing-and-sucking as dominant and margin feeding as minor interactions, whereasDakotanthus cordiformisat Rose Creek I and II had an opposite pattern. We found no evidence for nectar robbing. These data support the rapid emergence of early angiosperms of florivore and associated pollinator guilds expressed at both the local and regional community levels.
The evolution of trait correlations constrains phenotypic adaptation to high CO2in a eukaryotic alga
Authors: Walworth Nathan G. , Hinners Jana , Argyle Phoebe A. , Leles Suzana G. , Doblin Martina A. , Collins Sinéad , Levine Naomi M.
Published: June 2021

Microbes form the base of food webs and drive biogeochemical cycling. Predicting the effects of microbial evolution on global elemental cycles remains a significant challenge due to the sheer number of interacting environmental and trait combinations. Here, we present an approach for integrating multivariate trait data into a predictive model of trait evolution. We investigated the outcome of thousands of possible adaptive walks parameterized using empirical evolution data from the algaChlamydomonasexposed to high CO2. We found that the direction of historical bias (existing trait correlations) influenced both the rate of adaptation and the evolved phenotypes (trait combinations). Critically, we use fitness landscapes derived directly from empirical trait values to capture known evolutionary phenomena. This work demonstrates that ecological models need to represent both changes in traits and changes in the correlation between traits in order to accurately capture phytoplankton evolution and predict future shifts in elemental cycling.
SARS-CoV-2 in wastewater from Mexico City used for irrigation in the Mezquital Valley: quantification and modelling of geographic dispersion
Authors: Coronado Yaxk’in , Navarro Roberto , Mosqueda Carlos , Valenzuela Valeria , Perez Juan Pablo , González-Mendoza Víctor , de la Torre Mayra , Rocha Jorge
Published: June 2021

Quantification of SARS-CoV-2 in urban wastewaters has emerged as a cheap, efficient strategy to follow trends of active COVID-19 cases in populations. Moreover, mathematical models have been developed that allow prediction of active cases following the temporal patterns of viral loads in wastewaters. In Mexico, no systematic efforts have been reported in the use of this strategies. In this work, we quantified SARS-CoV-2 in rivers and irrigation canals in the Mezquital Valley, Hidalgo, an agricultural region where wastewater from Mexico City is distributed and used for irrigation. Using quantitative RT-PCR, we detected the virus in 6 out of 8 water samples from rivers, and 5 out of 8 water samples from irrigation canals. Notably, samples showed a general consistent trend of having the highest viral loads in the sites closer to Mexico City, indicating that this is the main source that contributes to detection. Using the data for SARS-CoV-2 concentration in the river samples, we generated a simplified transport model that describes the spatial patterns of dispersion of virus in the river. We suggest that this model can be extrapolated to other wastewater systems that require knowledge of spatial patterns of viral dispersion at a geographic scale. Our work highlights the need for improved practices and policies related to the use of wastewater for irrigation in Mexico and other countries.
“You’re too young to have an eye problem”: Reasons for nonadherence to referrals for follow-up eye care for schoolchildren in Nigeria -- a descriptive qualitative study
Authors: Lohfeld Lynne , Graham Christine , Ebri Anne Effiom , Congdon Nathan , Chan Ving Fai
Published: June 2021

Study objectives

to identify reasons for non-adherence to referrals for follow-up eye care after children fail a school vision screening test.

Methods

Ten focus groups were held with parents or guardians (‘parents’) of children who had not adhered to the referral for further care in Cross River State, Nigeria, in 2019. Data from verbatim transcripts were analysed deductively using topics from the interview guide plus ‘Other’ to capture unanticipated results. Analysts followed procedures for Qualitative Content Analysis plus a modified Framework Method to identify overarching themes and barriers that are both highly salient (most frequently mentioned) and relevant (discussed in at least half of all groups).

Results

Three themes identified in the data are 1) modifiable barriers (key among them being parental beliefs and problems with the referral letter), 2) contextual factors (parents’ situation, attitudes towards children and beliefs about care) and 3) participants’ recommendations to improve the child eye care program (educate the general public and correct parents’ misconceptions). Many of the findings echoed those from previous studies conducted in both low-and-middle income countries (LMICs) and high-income countries (HICs).

Conclusion

This study went beyond identifying modifiable barriers to also identify contextual factors and what parents recommend be done to improve vision care for children in Cross River State, Nigeria. If acted on, these findings may increase acceptance and uptake of eye care services that can promote sustainability and spread of the program to other parts of Nigeria and/or Africa.
Multi-omic landscaping of human midbrains identifies neuroinflammation as major disease mechanism in advanced-stage Parkinson’s disease
Authors: Gomes Lucas Caldi , Galhoz Ana , Jain Gaurav , Roser Anna-Elisa , Maass Fabian , Carboni Eleonora , Barski Elisabeth , Lenz Christof , Lohmann Katja , Klein Christine , Bähr Mathias , Fischer André , Menden Michael P. , Lingor Paul
Published: June 2021

Parkinson’s disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The disease mechanisms of sporadic PD are not yet completely understood. Therefore, causative therapies are still lacking. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains. Tissue from 13 PD patients and 10 controls was subjected to small RNA sequencing, transcriptomics, and proteomics analysis. Differential expression analyses were performed reveal multiple deregulated molecular targets linked to known pathomechanisms of PD as well as novel processes. We found significant differential expression of miR-539-3p, miR-376a-5p, miR-218-5p, and miR-369-3p, the valid miRNA-mRNA interacting pairs of miR-218-5p/RAB6C, and miR-369-3p/GTF2H3, as well as multiple proteins relevant in the pathology of PD, including CHI3L1, SELENBP1, PRDX1, HSPA1B, and TH. Vertical integration of multiple omics analyses allowed to validate disease-mediated molecular alterations across different molecular layers and functional annotation of differentially expressed targets identified a strong enrichment of pathways related to inflammation and activation of the immune response. This suggests that neuroinflammation may significantly contribute to disease progression in PD and may be a promising therapeutic target in advanced stages of PD.
The St. Gallen 2019 Guidelines understages the Axilla in Lobular Breast Cancer – a Population-Based Study
Authors: Narbe Ulrik , Bendahl Pär-Ola , Fernö Mårten , Ingvar Christian , Dihge Looket , Rydén Lisa
Published: June 2021

Background

The St. Gallen 2019 guidelines recommend omission of completion axillary lymph node dissection (cALND) in breast cancer patients with 1-2 sentinel lymph node (SLN) metastases regardless of histopathology. Concurrently, adjuvant chemotherapy is endorsed for luminal A-like disease with ≥4 axillary lymph node (ALN) metastases. We aimed to estimate the proportion of patients with invasive lobular cancer (ILC) and invasive ductal cancer of no special type (NST) and 1-2 SLN metastases for whom cALND would indicate need of adjuvant chemotherapy.

Methods

Patients with ILC and NST histopathology undergoing primary surgery 2014-2017 were identified in the Swedish National Quality Breast Cancer register. After exclusion of patients with incongruent or missing data, 1886 patients who fulfilled the St. Gallen 2019 criteria for cALND omission were included in the study cohort.

Results

Patients with ILC (n = 329) had a higher metastatic nodal burden and more often a luminal A-like subtype compared with NST patients (n = 1507). The prevalence of ≥ 4 ALN metastases was higher in ILC (31%) than in NST (15%), corresponding to an adjusted odds of 2.26 (95% CI 1.59-3.21). Luminal A-like breast cancers with ≥4 ALN metastases were overrepresented in ILC cases (52/281 (19%)) compared to NST cases (43/1299 (3%)), P<0.001.

Conclusions

Patients with ILC more often had a luminal A-like breast cancer with ≥4 ALN metastases compared with NST patients. Abstaining cALND in patients with luminal A-like ILC with 1-2 SLN metastases warrants future attention as it risks nodal understaging and hence undertreatment in one-fifth of these patients.

Source of funding

The authors declare no conflicts of interest. The Skåne County Councils Research and Developmental Foundation, the Governmental Funding of Clinical Research within the National Health Service (ALF), the Swedish Cancer Society, the Erling Persson Family Foundation, Kronoberg County Council’s Research and Development Foundation, The Cancer Foundation Kronoberg, The Swedish Research Council and The Swedish Breast Cancer Association. The funding agencies had no role in study design or interpretation of data.

Previous communication

Preliminary findings were published as part of Ulrik Narbe’s doctoral thesis.

Trial registration

ISRCTN registry: ISRCTN14341750
GWAS on Birth Year Infant Mortality Rates Provides New Evidence of Recent Natural Selection
Authors: Wu Yuchang , Furuya Shiro , Wang Zihang , Nobles Jenna E. , Fletcher Jason M. , Lu Qiongshi
Published: June 2021

Following more than a century of phenotypic measurement of natural selection processes, much recent work explores relationships between molecular genetic measurements and realized fitness in the next generation. We take a novel approach to the study of contemporary selective pressure by examining which genetic variants are “sustained” in populations as mortality exposure declines. Specifically, we deploy a so-called “regional GWAS” that links the infant mortality rate (IMR) by place and year in the UK with common genetic variants among cohorts in the UK Biobank. These cohorts (born 1936-1970) saw a decline in IMR from above 65 per 1,000 to under 20 per 1,000, with substantial subnational variation and spikes alongside wartime exposures. Our results show several genome-wide significant loci, including LCT and TLR10/1/6, related to area-level cohort IMR exposure during gestation and infancy. Genetic correlations are found across multiple domains, including fertility, cognition, health behaviors, and health outcomes, suggesting an important role for cohort selection in modern populations.
CD56brightCD16- NATURAL KILLER CELLS ARE IN HIGHER COUNTS IN THE UMBILICAL CORD BLOOD THAN IN THE PERIPHERAL BLOOD
Authors: de Molla Vinicius Campos , Rodrigues Barbosa Míriam Cristina , Mendrone Alfredo , Gonçalves Matheus Vescovi , Kimura Eliza , Guirao Fabio , Yamamoto Mihoko , Arrais-Rodrigues Celso
Published: June 2021

Umbilical cord blood (UCB) is an alternative source for hematopoietic stem cells allogeneic hematopoietic stem cell transplantation in the absence of compatible donor. UCB transplantation has a lower incidence of chronic graft versus host disease (GvHD) but is associated with slower engraftment and slower immune reconstitution as compared to other sources. Dendritic cells (DC) and Natural Killer cells (NK) play a central role in the development of GVHD, the graft versus leukemia (GvL) effect, and in the control of infectious complications. We quantified by multiparametric flow cytometry monocytes, lymphocytes, NK cells, and DC, including their subsets, in UCB samples from 54 healthy newborns and peripheral blood (PB) from 25 healthy adult volunteers. In the UCB samples, there were higher counts of CD56brightCD16-NK cells (median 0.024×109/L), as compared to the PB samples (0.012×109/L, P<0.0001), CD56dimCD16bright NK cells (median 0.446×109/L vs. 0.259×109/L for PB samples, P= 0.001), and plasmacytoid dendritic cells (pDC, median 0.008×109/L for UCB samples vs. 0.006×109/L for PB samples, P= 0.03). Moreover, non-classical monocytes counts were lower in UCB than in PB (median 0.024×109/L vs. 0.051 x109/L, respectively, P< 0.0001). In conclusion, there were higher counts of NK cells and pDC, and lower counts of non-classical monocytes in UCB than in PB from healthy individuals. These findings might explain the lower incidence and severity of chronic GVHD although maintaining the GVL effect in UCB transplants recipients as compared to other stem cell sources.

Highlights

CD56brightCD16- NK cells are more frequent in UCB than in PB.

Plasmacytoid dendritic cells are more frequent in UCB than in PB.

Non-classical monocytes are more frequent in PB than in UCB.
Skill-level based examination of forearm muscle activation associated with efficient wrist and finger movements during typing
Authors: Ito Takanori , Matsumoto Yuka , Funakoshi Hayase , Yoshida Mio , Kanemura Naohiko , Kokubun Takanori
Published: June 2021

This study aims to elucidate the relationship between the wrist and finger movements and forearm muscle activation of people with different typing skills. It hypothesizes that skilled typists (STs) can move their wrist and finger joints faster than unskilled typists (UTs) can because they can efficiently use their muscles according to the activity characteristics of the flexors and extensors of the wrist joint. During the typing task, we measured wrist and finger movements using a 3D motion capture system and forearm muscle activation using surface electromyography. The angular velocity of the wrist and finger flexion/extension and the muscle activation of the wrist flexors was higher in the STs than that in the UTs while the muscle activation of the wrist extensors was higher in the latter than that in the former. Our results showed that STs may have used their forearm muscles to take advantage of the physical characteristics of the keys and the spring characteristics of their muscles and tendons. It was suggested that they placed less mechanical stress on their finger muscles and tendons when pressing and releasing the keys.
Cigarette Smoking-Associated Isoform Switching and 3’ UTR Lengthening Via Alternative Polyadenylation
Authors: Xu Zhonghui , Platig John , Lee Sool , Boueiz Adel , Chase Rob , Jain Dhawal , Gregory Andrew , Suryadevara Rahul , Berman Seth , Bowler Russell , Hersh Craig P. , Laederach Alain , Castaldi Peter J. ,   for the COPDGene Investigators
Published: June 2021

Background

Cigarette smoking accounts for approximately one in five deaths in the United States. Previous genomic studies have primarily focused on gene level differential expression to identify related molecular signatures and pathways, but the genome-wide effects of smoking on alternative isoform regulation and posttranscriptional modulation have not yet been described.

Results

We conducted RNA sequencing (RNA-seq) in whole-blood samples of 454 current and 767 former smokers in COPDGene Study. We assessed the association of current smoking with differential expression of genes and isoforms and differential usage of isoforms and exons. At 10% FDR, we detected 3,167 differentially expressed genes, 2,014 differentially expressed isoforms, 945 differentially used isoforms and 160 differentially used exons. Genes containing differentially used isoforms were enriched in biological pathways involving GTPase activity and innate immunity. The majority of these genes were not differentially expressed, thus not identifiable from conventional differential gene expression analysis. Isoform switch analysis revealed for the first time widespread 3′ UTR lengthening associated with cigarette smoking, where current smokers were found to have higher expression and usage of isoforms with markedly longer 3′ UTRs. The lengthening of 3′ UTRs appears to be mediated through alternative usage of distal polyadenylation sites, and these extended 3′ UTR regions are significantly enriched with functional sequence elements including adenylate-uridylate (AU)-rich elements, microRNA and RNA-protein binding sites. Expression quantitative trait locus analyses on differentially used 3′ UTRs identified 79 known GWAS variants associated with multiple smoking-related human diseases and traits.

Conclusions

Smoking elicits widespread transcriptional and posttranscriptional alterations with disease implications. It induces alternative polyadenylation (APA) events resulting in a switch towards the usage of isoforms with strikingly longer 3′ UTRs in genes related to multiple biological pathways including GTPase activity and innate immunity. The extended 3′ UTR regions are enriched with functional sequence elements facilitating post-transcriptional regulation of protein expression and mRNA stability. These findings warrant further studies on APA events as potential biomarkers and novel therapeutic targets for smoking-related diseases.
Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2
Authors: Prokopenko Dmitry , Lee Sanghun , Hecker Julian , Mullin Kristina , Morgan Sarah , Katsumata Yuriko ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Weiner Michael W. , Fardo David W. , Laird Nan , Bertram Lars , Hide Winston , Lange Christoph , Tanzi Rudolph E.
Published: June 2021

Alzheimer’s disease (AD) is a genetically complex disease for which roughly 30 genes have been identified via genome-wide association studies. We attempted to identify rare variants (minor allele frequency <0.01) associated with AD in a region-based, whole genome sequencing (WGS) association study (GSAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved p-values < 10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden test and replicated in case/control samples from the ADSP study (pmeta = 4.74×10−8). SKAT analysis revealed region-based association around the discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta =1×10−6). Here, in a region-based GSAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.
Modelling the impact of fexinidazole use on human African trypanosomiasis transmission in the Democratic Republic of Congo
Authors: Das Aatreyee M. , Chitnis Nakul , Burri Christian , Paris Daniel H. , Patel Swati , Spencer Simon E.F. , Miaka Erick M. , Castaño M. Soledad
Published: June 2021

Gambiense human African trypanosomiasis is a deadly disease that has been declining in incidence since the start of the Century, primarily due to increased screening, diagnosis and treatment of infected people. The main treatment regimen currently in use requires a lumbar puncture as part of the diagnostic process to determine disease stage and hospital admission for drug administration. Fexinidazole is a new oral treatment for stage 1 and non-severe stage 2 human African trypanosomiasis. The World Health Organization has recently incorporated fexinidazole into its treatment guidelines for human African trypanosomiasis. The treatment does not require hospital admission or a lumbar puncture for all patients, which is likely to ease access for patients; however, it does require concomitant food intake, which is likely to reduce adherence. Here, we use a mathematical model calibrated to case and screening data from Mushie territory, in the Democratic Republic of the Congo, to explore the potential negative impact of poor compliance to an oral treatment, and potential gains to be made from increases in the rate at which patients seek treatment. We find that reductions in compliance in treatment of stage 1 cases are projected to result in the largest increase in further transmission of the disease, with failing to cure stage 2 cases also posing a smaller concern. Reductions in compliance may be offset by increases in the rate at which cases are passively detected. Efforts should therefore be made to ensure good adherence for stage 1 patients to treatment with fexinidazole and to improve access to passive care.
Comprehensive characterization of COVID-19 patients with repeatedly positive SARS-CoV-2 tests using a large US electronic health record database
Authors: Dong Xiao , Zhou Yujia , Shu Xiao-ou , Bernstam Elmer V. , Stern Rebecca , Aronoff David M. , Xu Hua , Lipworth Loren
Published: June 2021

Background

In the absence of genome sequencing, two positive molecular SARS-CoV-2 tests separated by negative tests, prolonged time, and symptom resolution remain the best surrogate measure of possible re-infection.

Methods

Using a large electronic health record database, we characterized clinical and testing data for 23 patients with repeatedly positive SARS-CoV-2 PCR test results ≥60 days apart, separated by ≥2 consecutive negative test results. Prevalence of chronic medical conditions, symptoms and severe outcomes related to COVID-19 illness were ascertained.

Results

Median age was 64.5 years, 40% were Black, and 39% were female. 83% smoked within the prior year, 61% were overweight/obese, 83% had immune compromising conditions, and 96% had ≥2 comorbidities. Median interval between the two positive tests was 77 days. Among the 19 patients with 60-89 days between positive tests, 17 (89%) exhibited symptoms or clinical manifestations indicative of COVID-19 at the time of the second positive test and 14 (74%) were hospitalized at the second positive test. Of the four patients with ≥90 days between two positive tests, two had mild or no symptoms at the second positive test and one, an immune compromised patient, had a brief hospitalization at the first diagnosis, followed by ICU admission at the second diagnosis three months later.

Conclusions

Our study demonstrated a high prevalence of immune compromise, comorbidities, obesity and smoking among patients with repeatedly positive SARS-CoV-2 tests. Despite limitations, including lack of semi-quantitative estimates of viral load, these data may help prioritize suspected cases of reinfection for investigation and continued surveillance.

Importance

Comprehensive characterization of clinical and SARS-CoV-2 testing data for patients with repeatedly positive SARS-CoV-2 tests can help prioritize suspected cases of reinfection for investigation in the absence of sequencing data and for continued surveillance for potential long-term health consequences of SARS-CoV-2 infection.
Early evidence for the safety of certain COVID-19 vaccines using empirical Bayesian modeling from VAERS
Authors: von Csefalvay Chris
Published: June 2021

The advent of vaccines against SARS-CoV-2 ushered in an unprecedented global response to COVID-19, with the largest and most ambitious mass vaccination campaign in human history. The scale of this effort means that safety signals suggesting adverse effects may only be detectable using passive reporting. This paper examines reports to the CDC/FDA’s VAERS system in the first six months of 2021, using an empirical Bayesian model with a gamma Poisson shrinker to identify potential safety signals from COVID-19 vaccines currently on the U.S. market. Based on this preliminary data, it is concluded that the COVID-19 vaccine’s safety significantly exceeds that of previously marketed vaccines, and other than a known risk of thrombotic events, no safety signals of concern emerge.
Seasonal variation in SARS-CoV-2 transmission in temperate climates
Authors: Gavenčiak Tomáš , Monrad Joshua Teperowski , Leech Gavin , Sharma Mrinank , Mindermann Sören , Brauner Jan Markus , Bhatt Samir , Kulveit Jan
Published: June 2021

While seasonal variation has a known influence on the transmission of several respiratory viral infections, its role in SARS-CoV-2 transmission remains unclear. As previous analyses have not accounted for the implementation of non-pharmaceutical interventions (NPIs) in the first year of the pandemic, they may yield biased estimates of seasonal effects. Building on two state-of-the-art observational models and datasets, we adapt a fully Bayesian method for estimating the association between seasonality and transmission in 143 temperate European regions. We find strong seasonal patterns, consistent with a reduction in the time-variableRtof 42.1% (95% CI: 24.7% – 53.4%) from the peak of winter to the peak of summer. These results imply that the seasonality of SARS-CoV-2 transmission is comparable in magnitude to the most effective individual NPIs but less than the combined effect of multiple interventions.
α-ketoglutarate augments prolyl hydroxylase-2 mediated inactivation of phosphorylated-Akt to inhibit induced-thrombosis and inflammation
Authors: Shrimali Nishith M , Agarwal Sakshi , Kaur Simrandeep , Bhattacharya Sulagna , Bhattacharyya Sankar , Prchal Josef T , Guchhait Prasenjit
Published: June 2021

Phosphorylation of Akt (pAkt) regulates multiple physiological and pathological processes including thrombosis and inflammation. In an approach to inhibit the pathological signalling of pAkt by prolyl-hydroxylase-2 (PHD2) we employed α-ketoglutarate (αKG), a cofactor of PHD2. Octyl-αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG:succinate ratio and reduced aggregationin vitroby suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline alongside enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretionin vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelet and leukocyte obtained from mice supplemented with dietary-αKG, unaccompanied by alteration in their counts. Dietary-αKG significantly reduced clot formation and leukocyte accumulation in various organs including lung of mice treated with thrombosis-inducing agent carrageenan. Importantly, we observed a significant rescue effect of dietary-αKG on inflamed lung of SARS-CoV-2 infected hamsters. αKG significantly reduced leukocyte accumulation, clot formation and viral load alongside downmodulation of pAkt in lung of the infected animals. Therefore, our study suggests a safe implementation of dietary-αKG in prevention of Akt-driven anomalies including thrombosis and inflammation, highlighting a better pulmonary management in COVID-19.