bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes
Authors: Pathak Ankit K , Mishra Gyan Prakash , Uppili Bharathram , Walia Safal , Fatihi Saman , Abbas Tahseen , Banu Sofia , Ghosh Arup , Kanampalliwar Amol , Jha Atimukta , Fatma Sana , Aggarwal Shifu , Dhar Mahesh Shanker , Marwal Robin , Radhakrishnan Venkatraman Srinivasan , Ponnusamy Kalaiarasan , Kabra Sandhya , Rakshit Partha , Bhoyar Rahul C , Jain Abhinav , Divakar Mohit Kumar , Imran Mohamed , Faruq Mohammed , Sowpati Divya Tej , Thukral Lipi , Raghav Sunil K , Mukerji Mitali
Published: January 2022

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying variants of concern (VOC). Viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host single nucleotide variations (iSNVs). Analysing 1347 samples collected till June 2020, we recorded 16 410 iSNV sites throughout the SARS-CoV-2 genome. We found ∼42% of the iSNV sites to be reported as SNVs by 30 September 2020 in consensus sequences submitted to GISAID, which increased to ∼80% by 30th June 2021. Following this, analysis of another set of 1774 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) lineage-defining variations appeared as iSNVs before getting fixed in the population. Besides, mutations in RdRp as well as RNA-editing by APOBEC and ADAR deaminases seem to contribute to the differential prevalence of iSNVs in hosts. We also observe hyper-variability at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions.
Mechanistic decoupling of exonuclease III multifunctionality into AP endonuclease and exonuclease activities at the single-residue level
Authors: Lee Donghun , Oh Sanghoon , Cho HyeokJin , Yoo Jungmin , Lee Gwangrog
Published: January 2022

Bacterial exonuclease III (ExoIII) is a multifunctional enzyme that uses a single active site to perform two conspicuous activities: (i) apurinic/apyrimidinic (AP)-endonuclease and (ii) 3′→5′ exonuclease activities. The AP endonuclease activity results in AP site incision, while the exonuclease activity results in the continuous excision of 3′ terminal nucleobases to generate a partial duplex for recruiting the downstream DNA polymerase during the base excision repair process (BER). The key determinants of functional selection between the two activities are poorly understood. Here, we use a series of mutational analyses and single-molecule imaging to unravel the pivotal rules governing these endo- and exonuclease activities at the single amino acid level. An aromatic residue, either W212 or F213, recognizes AP sites to allow for the AP endonuclease activity, and the F213 residue also participates in the stabilization of the melted state of the 3′ terminal nucleobases, leading to the catalytically competent state that activates the 3′→5′ exonuclease activity. During exonucleolytic cleavage, the DNA substrate must be maintained as a B-form helix through a series of phosphate-stabilizing residues (R90, Y109, K121 and N153). Our work decouples the AP endonuclease and exonuclease activities of ExoIII and provides insights into how this multifunctional enzyme controls each function at the amino acid level.
Higher-dimensional polytopal universe in Regge calculus
Authors: Tsuda Ren , Fujiwara Takanori
Published: January 2022

The higher-dimensional closed Friedmann–Lemaître–Robertson–Walker (FLRW) universe with a positive cosmological constant is investigated by Regge calculus. A Cauchy surface of the discretized FLRW universe is replaced by a regular polytope in accordance with the Collins–Williams formalism. Polytopes in arbitrary dimensions can be systematically dealt with by a set of five integers integrating the Schläfli symbol of the polytope. The Regge action in the continuum time limit is given. It possesses reparameterization invariance of the time variable. The variational principle for edge lengths and struts yields a Hamiltonian constraint and an evolution equation. They describe an oscillating universe in dimensions larger than three. To go beyond the approximation by regular polytopes, we propose pseudo-regular polytopes with fractional Schläfli symbols as a substitute for geodesic domes in higher dimensions. We examine the pseudo-regular polytope model as an effective theory of Regge calculus for the geodesic domes. In the infinite frequency limit, the pseudo-regular polytope model reduces to the continuum FLRW universe.
Can Environmental Policy Encourage Technical Change? Emissions Taxes and R&D Investment in Polluting Firms
Authors: Brown James R , Martinsson Gustav , Thomann Christian
Published: January 2022

Higher country taxes on noxious manufacturing emissions lead to substantial increases in firms’ R&D spending. The R&D response is entirely driven by those high-pollution firms most affected by emissions taxes. Pollution taxes increase the marginal value of R&D spending in polluting firms, even when this spending does not lead to new innovation. Pollution taxes have the strongest effect on R&D investment in sectors in which new invention is difficult to appropriate and outside knowledge is easier to acquire, suggesting an important reason dirty firms invest in R&D is to expand their capacity to absorb external knowledge and technical know-how.
Sleep deficiency in spaceflight is associated with degraded neurobehavioral functions and elevated stress in astronauts on six-month missions aboard the International Space Station
Authors: Jones Christopher W , Basner Mathias , Mollicone Daniel J , Mott Christopher M , Dinges David F
Published: January 2022

Astronauts are required to maintain optimal neurobehavioral functioning despite chronic exposure to the stressors and challenges of spaceflight. Sleep of adequate quality and duration is fundamental to neurobehavioral functioning, however astronauts commonly experience short sleep durations in spaceflight (<6 h). As humans embark on long-duration space exploration missions, there is an outstanding need to identify the consequences of sleep deficiency in spaceflight on neurobehavioral functions. Therefore, we conducted a longitudinal study that examined the sleep-wake behaviors, neurobehavioral functions, and ratings of stress and workload of N = 24 astronauts before, during, and after 6-month missions aboard the International Space Station (ISS). The computerized, Reaction SelfTest (RST), gathered astronaut report of sleep–wake behaviors, stress, workload, and somatic behavioral states; the RST also objectively assessed vigilant attention (i.e. Psychomotor Vigilance Test-Brief). Data collection began 180 days before launch, continued every 4 days in-flight aboard the ISS, and up to 90 days post-landing, which produced N = 2,856 RSTs. Consistent with previous ISS studies, astronauts reported sleeping ~6.5 h in-flight. The adverse consequences of short sleep were observed across neurobehavioral functions, where sleep durations <6 h were associated with significant reductions in psychomotor response speed, elevated stress, and higher workload. Sleep durations <5 h were associated with elevated negative somatic behavioral states. Furthermore, longer sleep durations had beneficial effects on astronaut neurobehavioral functions. Taken together, our findings highlight the importance of sleep for the maintenance of neurobehavioral functioning and as with humans on Earth, astronauts would likely benefit from interventions that promote sleep duration and quality.
A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women
Authors: Rahman Shadab A , Nathan Margo D , Wiley Aleta , Crawford Sybil , Cohn Aviva Y , Harder Jessica A , Grant Leilah K , Erickson Athena , Srivastava Akanksha , McCormick Kathleen , Bertisch Suzanne M , Winkelman John W , Joffe Hadine
Published: January 2022

Study Objectives

The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for the vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS.

Methods

In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 min of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10–20 mg (n = 27) or placebo (n = 29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race.

Results

Mean baseline ISI scores were 18.1 (95% CI, 16.8 to 19.4) and 18.3 (95% CI, 17.2 to 19.5) in the suvorexant and placebo groups, respectively (p = .81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant (−8.1 [95% CI, −10.2 to −6.0]) compared to placebo (−5.6 [95% CI, −7.4 to −3.9], p = .04). Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p < .01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparisons. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated.

Conclusion

These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia.

Clinical Trial Information

Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia, https://clinicaltrials.gov/ct2/show/NCT03034018, ClinicalTrials.gov Identifier: NCT03034018.
Dyscoordination of non-rapid eye movement sleep oscillations in autism spectrum disorder
Authors: Mylonas Dimitrios , Machado Sasha , Larson Olivia , Patel Rudra , Cox Roy , Vangel Mark , Maski Kiran , Stickgold Robert , Manoach Dara S
Published: January 2022

Study Objectives

Converging evidence from neuroimaging, sleep, and genetic studies suggest that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD.

Methods

Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9–17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep.

Results

ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but their relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite.

Conclusions

The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.
Effect of zinc sources and experimental conditions on zinc balance in growing wethers
Authors: Lee Chanhee , Copelin Jacob E , Socha Mike T
Published: January 2022

Three experiments were conducted with growing wethers to evaluate apparent excretion and retention of Zn from various sources. In experiments 1 and 2, Zn-ethylene diamine (ZE), Zn hydroxychloride (ZHYD), Zn-lysine/glutamate (ZAA), and Zn-glycinate (ZG) were used and ZnSO4 (ZS), ZHYD, ZAA, and ZG were used in experiment 3. In experiment 1, eight wethers were used in a replicated 4 × 4 Latin square design. In experiments 2 and 3, 40 wethers were used in a randomized block design. In experiment 1, each period (total four periods) consisted of 14-d diet adaptation and 4 d of total collection of feces and urine. In experiments 2 and 3, wethers received a basal diet for 14 d and received experimental diets for 9 d (diet adaptation), followed by 4 d of total collection of feces and urine. Total collection was conducted in wooden metabolic cages. All data were analyzed using the MIXED procedure of SAS as a Latin square design for experiment 1 and a completed randomized block design for experiments 2 and 3. In all experiments, dry matter intake did not differ among treatments except that it tended to be different in experiment 2. In experiment 1, no difference in Zn excretion (88%) and retention (11%) as proportion of Zn intake was observed among Zn sources. In experiment 2, total tract digestibility of crude protein was greater (P < 0.01) for ZAA than ZE and ZG (82.0% vs. 79.1% and 77.8%, respectively) and greater (P < 0.01) for ZHYD than ZG (80.2% vs. 77.8%). However, total tract digestibility of neutral detergent fiber was low (on average 16%) for all treatments with no difference among treatments in experiment 2. Apparent excretion and retention of Zn as proportion of Zn intake did not differ among treatments, and Zn retention (~1.4% of Zn intake) was very low for all treatments. In experiment 3, ZHYD and ZAA had greater retention of Zn (17.8% vs. 1.5%; P = 0.01) than ZG. Fecal Zn excretion was greater (97.3% vs. 81.2%; P = 0.01) for ZG vs. ZHYD and ZAA, and Zn retention for ZG was only 1.5% of Zn intake. In conclusion, potential increases in Zn absorption and retention were observed for ZHYD and ZAA compared with ZS and ZG in experiment 3 and these differences were not found in experiments 1 and 2. Experiment 1 used a Latin square design and experiment 2 used a diet containing largely undigestible fiber. These experimental conditions may have affected Zn metabolism in wethers. Inconsistent results on Zn balance for ZG among the experiments warrant further studies regarding its bioavailability.
Minimum Esophageal Resection Length to Ensure Negative Proximal Margin in Total Gastrectomy for Gastric Cancer
Authors: Koterazawa Yasufumi , Ohashi Manabu , Hayami Satoshi , Kumagai Koshi , Sano Takeshi , Nunobe Souya
Published: January 2022

Objective:

To identify the minimum length of esophageal resection to ensure a pathologically negative proximal margin (PM) in total gastrectomy for gastric cancer.

Background:

In total gastrectomy, a certain esophageal length is resected to obtain a pathologically negative PM because of the possibility of unexpected pathological esophageal invasion. However, a recommendation regarding the esophageal transection site in total gastrectomy has not been established.

Methods:

The data of patients who underwent total gastrectomy for gastric cancer from 2005 to 2018 were collected. We evaluated the length of unexpected pathological esophageal invasion (esophageal ΔPM) in each type of disease and each location of the gross proximal tumor boundary (PB) using the length between the PB and the esophagogastric junction (PB-EGJ length).

Results:

Of the 1005 patients eligible for this study, 277, 196, and 532 had cT1, cT2–4 expansive (Exp), and cT2–4 infiltrative (Inf) growth patterns, respectively. In cT1 and Exp, no unexpected pathological esophageal invasion occurred when the PB-EGJ length was >1 cm, whereas pathological esophageal invasion occurred in 20.0% of cT1 and 32.7% of Exp when the PB-EGJ length was ≤1 cm. The esophageal ΔPM was <1 cm. In Inf, no unexpected pathological esophageal invasion occurred when the PB-EGJ length was >3 cm, whereas pathological esophageal invasion occurred in 17.4% of patients when the PB-EGJ length was ≤3 cm. The esophageal ΔPM was <2 cm.

Conclusions:

New recommendations regarding the esophageal resection length required to ensure a pathologically negative PM in total gastrectomy are herein proposed.
Quantifying Skin Removal During a Face-lift: Does the Approach Matter?
Authors: Fezza John P. , Woodward Julie
Published: January 2022

BACKGROUND

The purpose of this study was to measure the amount of skin removed around the ears during a face-lift procedure. The secondary metric assessed skin removal comparing different face-lift techniques of SMASectomy versus deep plane approach and lastly comparing with and without midline corset platysmaplasty (MCP).

METHODS

One hundred fifty consecutive face-lift patients were measured for skin removal at 3 cardinal locations in the postauricular, preauricular, and temple regions. Measurements were quantitated and compared statistically with different face-lift techniques.

RESULTS

The average skin removal in the postauricular area was 4 cm, the preauricular area was 2.4 cm, and the temple 1.9 cm. There was no difference in skin removal comparing SMASectomy and deep plane face-lift. There was a small but significant difference when MCP was performed, with more skin removal with MCP.

CONCLUSION

Quantifying the amount of skin removal during a face-lift procedure provides surgeons and patients important information. There was no difference when comparing the simpler SMASectomy technique with the more invasive deep plane technique.
Intensive Daily Symptom and Function Monitoring Is Feasible and Acceptable to Women Undergoing First-Line Chemotherapy for Gynecologic Cancer
Authors: Campbell Grace B. , Belcher Sarah M. , Lee Young Ji , Courtney-Brooks Madeleine , Bovbjerg Dana H. , Bizhanova Zhadyra , Donovan Heidi S.
Published: January 2022

Background

Women receiving chemotherapy for gynecologic cancer (GC) experience severe symptoms with associated functional changes. Understanding day-to-day symptom and function variation within and across chemotherapy treatment cycles could inform improved symptom management, but such studies are rare and may be infeasible in clinical care.

Objective

The aim of this study was to evaluate feasibility and acceptability of daily symptom monitoring combined with objective and self-reported functional assessments every 21 days during active chemotherapy for GC.

Methods

Thirty women enrolled in a prospective observational study during first-line chemotherapy completed a daily symptom and falls diary during their entire chemotherapy treatment period. Patient-reported outcomes and objective symptom and function testing were assessed before each chemotherapy appointment. Study outcomes included accrual and attrition rates, completion of study assessments, and qualitative perceptions of study participation.

Results

Participants were 92% White, 60% had high school or higher education, 68% were married/partnered, and 62% had stage III or IV cancer at diagnosis. The study had an 83% accrual rate, 6.6% early withdrawal rate, and 17% total attrition rate. Missing assessments for prechemotherapy patient-reported outcomes and objective assessments ranged from 27% to 35% and 35% to 47% respectively, with a general decrease across cycles. Daily diary completion rate was 83% overall. Participants rated study participation positively.

Conclusions

Intensive daily symptom and function monitoring was feasible and acceptable to GC patients and may provide a sense of symptom controllability.

Implications for Practice

Daily symptom and function monitoring in research studies may provide patients with information to support symptom discussions with the clinical team. Future work should develop proactive symptom management interventions using personalized symptom trajectories.
Identifying Potentially Preventable Reasons Nurses Intend to Leave a Job
Authors: Taylor-Clark Tanekkia M. , Swiger Pauline A. , Anusiewicz Colleen V. , Loan Lori A. , Olds Danielle M. , Breckenridge-Sproat Sara T. , Raju Dheeraj , Patrician Patricia A.
Published: January 2022

OBJECTIVE

The aim of this study was to describe the relationships between intent to leave, reasons nurses intend to leave, and the nursing work environment in military hospitals.

BACKGROUND

Intention to leave is a precursor of nurse turnover. The reasons nurses intend to leave may be influenced by leader interventions and potentially preventable.

METHODS

This descriptive, correlational secondary analysis included 724 nurse survey responses from 23 US Army hospitals. Bivariate correlations and predictive modeling techniques were used.

RESULTS

Forty-nine percent of nurses indicated they intended to leave, 44% for potentially preventable reasons. Dissatisfaction with management and the nursing work environment were the top potentially preventable reasons to leave. Nurses who intended to leave for potentially preventable reasons scored aspects of the nursing work environment significantly lower than those intending to leave for nonpreventable reasons.

CONCLUSIONS

Identifying potentially preventable reasons in conjunction with intent to leave can provide leaders opportunities to intervene and influence turnover intention.
False-Positive Radioiodine Uptake From an Intracranial Surgical Clip
Authors: Walsh James P. , Sims Justin B. , Iranpour Pooya
Published: January 2022

A 73-year-old man with papillary thyroid cancer underwent total thyroidectomy and bilateral neck dissections. He was subsequently treated with 131I. The posttherapy scan showed radioiodine uptake at the left supraorbital region, which localized to a metallic surgical clip. There was no evidence of metastasis in this area. This is not a commonly reported finding. Knowledge of this false-positive finding can help avoid unnecessary workup and treatment.
Mickey Mouse Sign on Bone Scan
Authors: Khan Fiza M. , Chen Bo , Takalkar Amol M.
Published: January 2022

An 81-year-old man with prostate adenocarcinoma demonstrated interval progression of the osteoblastic metastatic disease on surveillant bone scan with a new lumbar lesion resembling the configuration of Mickey's head (Mickey Mouse sign), a sign considered to be specific for Paget disease, even in the presence of malignancy. However, our case demonstrates that this appearance can be caused by other etiologies. In the era of SPECT/CT and MRI, it is prudent to obtain further cross-sectional correlation at the time of radionuclide bone scintigraphy to clarify the underlying cause for “Mickey Mouse sign” to prevent misinterpretation, allowing for efficient and accurate patientcare.
Incidental Spinal Meningioma on an 18F-Fluciclovine PET/CT
Authors: Marcus Charles , Baugnon Kristen , Schuster David M.
Published: January 2022

Incidental PET radiotracer uptake is not infrequently encountered in PET/CT imaging. We present the 18F-fluciclovine PET/CT of a 60-year-old man undergoing evaluation of biochemically recurrent prostate cancer with incidental radiotracer uptake in the thoracic spinal canal, which was proven to be a World Health Organization grade I spinal meningioma on surgical pathology. 18F-fluciclovine and 18F-FDG PET/CT images of a 60-year-old man with biochemically recurrent prostate cancer prostate cancer with a prostate-specific antigen of 14.4 ng/mL, 7 years after primary external beam radiation followed by a prostate-specific antigen nadir of 1.6 ng/mL, are presented.
18FDG PET–Positive Congenital Pulmonary Airway Malformation Mimicking Lung Cancer
Authors: Morizumi Shun , Hino Hiroyuki , Miyatake Kana , Naruse Keishi , Shinohara Tsutomu
Published: January 2022

Adult cases of type 2 congenital pulmonary airway malformation (CPAM) are extremely rare, and no PET/CT findings have been reported for CPAM. We encountered a case of 18FDG PET–positive CPAM mimicking lung cancer in a 45-year-old asymptomatic man. CT revealed a large cavitary mass in the left lower lobe. SUVmax measured by 18FDG PET was 3.5. The patient underwent video-assisted thoracoscopic lobectomy on suspicion of CPAM with/or lung cancer. Histologically, no neoplastic cells were present, and the lesion was consistent with type 2 CPAM. An adenomatoid proliferative pattern and granulomatous lesions may have contributed to a PET/CT false-positive result.
The Spike–Wave Index of the First 100 Seconds of Sleep Can Be a Reliable Scoring Method for Electrographic Status Epilepticus in Sleep
Authors: Kulkarni Neil , Albert Dara V. F. , Klamer Brett , Drees Michael , Twanow Jaime D.
Published: January 2022

Introduction:

Electrical status epilepticus in sleep (ESES) is an electrographic pattern in which interictal epileptiform activity is augmented by the transition to sleep, with non-rapid eye movement sleep state characterized by near-continuous lateralized or bilateral epileptiform discharges. The aim of this study was to measure the reliability of the spike–wave index (SWI) of the first 100 seconds of sleep as a tool for the diagnosis of ESES.

Methods:

One hundred forty studies from 60 unique patients met the inclusion. Two neurophysiologists calculated the SWI of the first 100 seconds of spontaneous stage II non-rapid eye movement sleep. This was compared with the SWI of the first 5 minutes of non-rapid eye movement sleep and the cumulative SWI of three 5-minute bins of sleep. Agreement between the three SWI methods were analyzed using several statistical tools and methods.

Results:

Using an SWI of 50% as a diagnostic cutoff, 57% of records had a diagnosis of ESES based on the first 100 seconds of sleep. Fifty-four percent of records had a diagnosis of ESES based on the method of using the SWI of three bins. This resulted in a diagnostic accuracy of 92%, sensitivity of 96%, and specificity of 88%. Positive predictive values of children diagnosed with ESES using the first 100 seconds of sleep, compared with 3 combined bins, was determined to be 90% and a negative predictive value was determined to be 95%.

Conclusions:

This analysis confirmed the diagnostic accuracy of using the SWI of the first 100 seconds of sleep and the cumulative total of three 5-minute bins.
The heritability of BMI varies across the range of BMI – a heritability curve analysis in a twin cohort
Authors: Azzolini Francesca , Berentsen Geir D. , Skaug Hans J. , Hjelmborg Jacob v.B. , Kaprio Jaakko A.
Published: January 2022

The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family, twin, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. Thus, we demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritabilities and major differences in mean values between countries or over time.
Detection of bifenthrin, bifenazate, etoxazole resistance inTetranychus urticaecollected from mint fields and hop yards using targeted sequencing and TaqMan approaches
Authors: Shumate Silas , Haylett Maggie , Nelson Brenda , Young Nicole , Lamour Kurt , Walsh Doug , Bradford Benjamin , Clements Justin
Published: January 2022

Tetranychus urticae(Koch) is an economically important pest of many agricultural commodities in the Pacific Northwest. Multiple miticides are currently registered for control including abamectin, bifenazate, bifenthrin, and extoxazole. However, populations ofTetranychus urticaehave developed miticide resistance through multiple mechanisms, in many different growing regions. Producers of agricultural commodities whereTetranychus urticaeinfestations are problematic rely on integrated pest management tools to determine optimal control methods. Within this species multiple single nucleotide polymorphisms have been documented in different genes which are associated with miticide resistance phenotypes. The detection of these mutations through TaqMan qPCR has been suggested as a practical, quick, and reliable tool to inform agricultural producers of miticide resistance phenotypes present within their fields and have potential utility for making appropriate miticide application and integrated pest management decisions. Within this investigation we examined the use of a TaqMan qPCR-based approach to determine miticide resistance genotypes in field-collected populations ofTetranychus urticaefrom mint fields and hop yards in the Pacific Northwest of the United States and confirmed the results with a multiplex targeted sequencing. The results suggest the TaqMan approach accurately genotypesTetranychus urticaepopulations collected from agricultural fields. The interpretation of the results, however, provide additional challenges for integrated pest management practitioners, including making miticide application recommendations where populations ofTetranychus urticaeare a mix of resistant and wildtype individuals.
RICTOR Drives ZFX-mediated Ganglioside Biosynthesis to Promote Breast Cancer Progression
Authors: Rajput Kajal , Ansari Mohd. Nafees , Jha Somesh K. , Medatwal Nihal , Sharma Pankaj , Datta Sudeshna , Kar Animesh , Pani Trishna , Cholke Kaushavi , Rana Kajal , Khan Ali , Mukherjee Geetashree , Deo SVS , Prabhu Jyothi S , Mukhopadhyay Arnab , Bajaj Avinash , Dasgupta Ujjaini
Published: January 2022

Sphingolipid and ganglioside metabolic pathways are crucial components of cell signalling, having established roles in tumor cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside biosynthesis in mammalian cells is less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in luminal breast cancer-specific MCF-7 and BT-474 cells through transcriptional and epigenetic mechanisms. RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA methyltransferases and histone demethylase (KDM5A) that are known AKT substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of EGFR signalling pathway, thereby promoting tumor growth. In line with our findings in cell culture and mice models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian luminal breast cancer tissues, and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast cancer progression.
A method for partitioning trends in genetic mean and variance to understand breeding practices
Authors: Oliveira T. P. , Obšteter J. , Pocrnic I. , Heslot N. , Gorjanc G.
Published: January 2022

Background

In breeding programmes, the observed genetic change is a sum of the contributions of different groups of individuals. Quantifying these sources of genetic change is essential for identifying the key breeding actions and optimizing breeding programmes. However, it is difficult to disentangle the contribution of individual groups due to the inherent complexity of breeding programmes. Here we extend the previously developed method for partitioning genetic mean by paths of selection to work both with the mean and variance of breeding values.

Methods

We first extended the partitioning method to quantify the contribution of different groups to genetic variance assuming breeding values are known. Second, we combined the partitioning method with the Markov Chain Monte Carlo approach to draw samples from the posterior distribution of breeding values and use these samples for computing the point and interval estimates of partitions for the genetic mean and variance. We implemented the method in theRpackageAlphaPart. We demonstrated the method with a simulated cattle breeding programme.

Results

We showed how to quantify the contribution of different groups of individuals to genetic mean and variance. We showed that the contributions of different selection paths to genetic variance are not necessarily independent. Finally, we observed some limitations of the partitioning method under a misspecified model, suggesting the need for a genomic partitioning method.

Conclusion

We presented a partitioning method to quantify sources of change in genetic mean and variance in breeding programmes. The method can help breeders and researchers understand the dynamics in genetic mean and variance in a breeding programme. The developed method for partitioning genetic mean and variance is a powerful method for understanding how different paths of selection interact within a breeding programme and how they can be optimised.
Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis
Authors: Kihara Yasuyuki , Zhu Yunjiao , Jonnalagadda Deepa , Romanow William , Palmer Carter , Siddoway Benjamin , Rivera Richard , Dutta Ranjan , Trapp Bruce D. , Chun Jerold
Published: January 2022

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2) – the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.
Regenerating aggregates of hydra display unique cytoskeletal organisation that is absent in a regeneration-deficient strain
Authors: Bhagavan Hemalatha , Prabhu Sujana , Govindasamy Niraimathi , Ghanekar Yashoda
Published: January 2022

Hydra has the unique ability to regenerate from aggregates of dissociated single cells that lack positional information. We compared two strains of hydra, a strain of hydra that was capable of regenerating from aggregates and a strain of hydra that was deficient in this type of regeneration. We observed unique actin cytoskeletal arrangements that were present in the regenerates of regeneration-competent strain but not in the regeneration-deficient strain. Concomitantly, the regeneration-deficient strain failed to organise the extracellular cytoskeleton of laminin and collagen between ectodermal and endodermal epithelial cells. These interesting preliminary observations highlight the importance of the cytoskeletal organisation in regeneration of hydra and suggest that regeneration from the aggregates of dissociated cells through de novo patterning requires correct structural organisation of cytoskeletal elements.
Ablation of SAMD1 in Mice Causes Failure of Angiogenesis, Embryonic Lethality
Authors: Campbell Bruce , Engle Sandra , Ozolins Terence , Bourassa Patricia , Aiello Robert
Published: January 2022

Pathological retention of LDL in the intima is involved in atherosclerosis, although the retention mechanisms are not well-understood. Previously, we reported Sterile Alpha Motif Domain Containing 1 (SAMD1), a protein secreted by intimal smooth muscle cells in atherosclerotic lesions, appears to bind LDL in extracellular matrix around intimal cells. Fab-fragment inhibitors of apparently irreversible SAMD1/LDL binding reduced LDL retention in carotid injury models, but did not have a significant effect on early spontaneous lesion development. Our histology of mouse atherosclerosis models revealed extensive SAMD1 expression, possibly related to cell phenotype modulation and antigen presentation. Although the normal function of SAMD1 is unknown, it may have multiple epigenetic roles. For this report, we generated SAMD1−/−, SAMD1−/+, and SAMD1−/+ apoE−/− mice to further explore SAMD1’s role in atherosclerosis. SAMD1 was found in tissues throughout the SAMD1+/+ and SAMD1−/+ embryos. Homozygous loss of SAMD1 was embryonic lethal: at embryonic day 14, organs were partially developed and/or degraded; heads and brains were malformed; no blood vessels were observed; red blood cells were scattered and pooled, primarily near the embryo surface; and cell death was occurring. Development appeared normal in heterozygous SAMD1 embryos, but postnatal genotyping showed a reduced ability to thrive. Growth of atherosclerotic lesions in SAMD1−/+ apoE−/− after 35 weeks was not significantly less than in mice SAMD1+/+ apoE−/− mice.
rescomp: An R package for defining, simulating and visualizing ODE models of consumer-resource interactions
Authors: Letten Andrew D.
Published: January 2022

Mechanistic models of resource competition underpin numerous foundational concepts and theories in ecology, and continue to be employed widely to address diverse research questions. Nevertheless, current software tools present a comparatively steep barrier to entry.

I introduce the R package rescomp to support the specification, simulation and visualisaton of a broad spectrum of consumer-resource interactions. rescomp is compatible with diverse model specifications, including an unlimited number of consumers and resources, different consumer functional responses (type I, II and III), different resource types (essential or substitutable) and supply dynamics (chemostats, logistic and/or pulsed), delayed consumer introductions, time dependent growth and consumption parameters, and instantaneous changes to consumer and/or resource densities.

Several examples on implementing rescomp are provided. In addition, a wide variety of additional examples can be found in the package vignettes, including using rescomp to reproduce the results of several well known studies from the literature.

rescomp provides users with an accessible tool to reproduce classic models in ecology, to specify models resembling a wide range of experimental designs, and to explore diverse novel model formulations.
Aedes aegypti and Aedes albopictus abundance, landscape coverage and spectral indices effects in a subtropical city of Argentina
Authors: Martín Mía Elisa , Alonso Ana Carolina , Faraone Janinna , Stein Marina , Estallo Elizabet Lilia
Published: January 2022

The presence, abundance and distribution of Aedes (Stegomyia) aegypti (Linnaeus 1762) and Aedes (Stegomyia) albopictus (Skuse 1894) could be conditioned by different data obtained from satellite remote sensors. In this paper, we aim to estimate the effect of landscape coverage and spectral indices on the abundance of Ae. aegypti and Ae. albopictus from the use of satellite remote sensors in Eldorado, Misiones, Argentina. Larvae of Aedes aegypti and Ae. albopictus were collected monthly from June 2016 to April 2018, in four outdoor environments: tire repair shops, cemeteries, family dwellings, and an urban natural park. The proportion of each land cover class was determined by Sentinel-2 image classification. Furthermore spectral indices were calculated. Generalized Linear Mixed Models were developed to analyze the possible effects of landscape coverage and vegetation indices on the abundance of mosquitoes. The model’s results showed the abundance of Ae. aegypti was better modeled by the minimum values of the NDVI index, the maximum values of the NDBI index and the interaction between both variables. In contrast, the abundance of Ae. albopictus has to be better explained by the model that includes the variables bare soil, low vegetation and the interaction between both variables.
Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome
Authors: Unda Brianna K. , Chalil Leon , Yoon Sehyoun , Kilpatrick Savannah , Xing Sansi , Murtaza Nadeem , Cheng Anran , Afonso Alexandria , McCready Elizabeth , Ronen Gabriel , Howe Jennifer , Caye-Eude Aurélie , Verloes Alain , Doble Brad W. , Faivre Laurence , Vitobello Antonio , Scherer Stephen W , Lu Yu , Penzes Peter , Singh Karun K.
Published: January 2022

Copy number variations (CNV) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase (DUB) function. The OTUD7A protein-protein interaction (PPI) network revealed interactions with synaptic, axonal, and cytoskeletal proteins and was enriched for known ASD and epilepsy risk genes. The interactions between OTUD7A and the NDD risk genes Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment (AIS), while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Further, our study highlights the utility of targeting CNV genes using cell-type specific proteomics to identify shared and unexplored disease mechanisms across NDDs.
A comparative study of cellular diversity between the Xenopus pronephric and mouse metanephric nephron
Authors: Corkins Mark E. , Achieng MaryAnne , DeLay Bridget D. , Krneta-Stankic Vanja , Cain Margo P. , Walker Brandy L. , Chen Jichao , Lindström Nils O. , Miller Rachel K.
Published: January 2022

The kidney is an essential organ that ensures bodily fluid homeostasis and removes soluble waste products from the organism. The functional units within the kidneys are epithelial tubules called nephrons. These tubules take in filtrate from the blood or coelom and selectively reabsorb nutrients through evolutionarily conserved nephron segments, leaving waste product to be eliminated in the urine. Genes coding for functional transporters are segmentally expressed, enabling nephrons to function as selective filters. The developmental patterning program that generates these segments is of great interest. The Xenopus embryonic kidney, the pronephros, has served as a valuable model to identify genes involved in nephron formation and patterning. Prior work has defined the gene expression profiles of Xenopus epithelial nephron segments via in situ hybridization strategies, but our understanding of the cellular makeup of the Xenopus pronephric kidney remains incomplete. Here, we scrutinize the cellular composition of the Xenopus pronephric nephron through comparative analyses with previous Xenopus studies and single-cell mRNA sequencing of the adult mouse kidney, this study reconstructs the cellular makeup of the pronephric kidney and identifies conserved cells, segments, and expression profiles. The data highlight significant conservation in podocytes, proximal and distal tubule cells and divergence in cellular composition underlying the evolution of the corticomedullary axis, while emphasizing the Xenopus pronephros as a model for physiology and disease.

Summary Statement

Assessment of the conservation of gene expression between functional Xenopus laevis pronephric and mouse metanephric nephrons through single-cell RNA sequencing.
Impact of Ghost Introgression on Coalescent-based Species Tree Inference and Estimation of Divergence Time
Authors: Pang Xiao-Xu , Zhang Da-Yong
Published: January 2022

Abstract

The species studied in any evolutionary investigation generally constitute a very small proportion of all the species currently existing or that have gone extinct. It is therefore likely that introgression, which is widespread across the tree of life, involves “ghosts,” i.e., unsampled, unknown, or extinct lineages. However, the impact of ghost introgression on estimations of species trees has been rarely studied and is thus poorly understood. In this study, we use mathematical analysis and simulations to examine the robustness of species tree methods based on a multispecies coalescent model under gene flow sourcing from an extant or ghost lineage. We found that very low levels of extant or ghost introgression can result in anomalous gene trees (AGTs) on three-taxon rooted trees if accompanied by strong incomplete lineage sorting (ILS). In contrast, even massive introgression, with more than half of the recipient genome descending from the donor lineage, may not necessarily lead to AGTs. In cases involving an ingroup lineage (defined as one that diverged no earlier than the most basal species under investigation) acting as the donor of introgression, the time of root divergence among the investigated species was either underestimated or remained unaffected, but for the cases of outgroup ghost lineages acting as donors, the divergence time was generally overestimated. Under many conditions of ingroup introgression, the stronger the ILS was, the higher was the accuracy of estimating the time of root divergence, although the topology of the species tree is more prone to be biased by the effect of introgression.