bluuebunny/crossref_metadata_2025 huggingface dataset:
Form of dietary selenium affects mRNA encoding interferon-stimulated and progesterone-induced genes in the bovine endometrium and conceptus length at maternal recognition of pregnancy
Authors: Crites Benjamin R , Carr Sarah N , Anderson Leslie H , Matthews James C , Bridges Phillip J
Published: July 2022

Widespread regions of the southeast United States have soils, and hence forages, deficient in selenium (Se), necessitating Se supplementation to grazing cattle for optimal immune function, growth, and fertility. We have reported that supplementation with an isomolar 1:1 mix (MIX) of inorganic (ISe) and organic (OSe) forms of Se increases early luteal phase (LP) concentrations of progesterone (P4) above that in cows on ISe or OSe alone. Increased early LP P4 advances embryonic development. Our objective was to determine the effects of the form of Se on the development of the bovine conceptus and the endometrium using targeted real-time PCR (qPCR) on day 17 of gestation, the time of maternal recognition of pregnancy (MRP). Angus-cross yearling heifers underwent 45-d Se-depletion then repletion periods, then at least 90 d of supplementation (TRT) with 35 ppm Se per day as either ISe (n = 10) or MIX (n = 10). Heifers were inseminated to a single sire after detected estrus (day 0). On day 17 of gestation, caruncular (CAR) and intercaruncular (ICAR) endometrial samples and the developing conceptus were recovered from pregnant heifers (ISe, n = 6 and MIX, n = 6). qPCR was performed to determine the relative abundance of targeted transcripts in CAR and ICAR samples, with the expression data subjected to one-way ANOVA to determine TRT effects. The effect of TRT on conceptus development was analyzed using a one-tailed Student’s t-test. When compared with ISe-treated heifers, MIX heifers had decreased (P < 0.05) abundance of several P4-induced and interferon-stimulated mRNA transcripts, including IFIT3, ISG15, MX1, OAS2, RSAD2, DGAT2, FGF2 in CAR and DKK1 in ICAR samples and tended (P ≤ 0.10) to have decreased mRNA abundance of IRF1, IRF2, FOXL2, and PGR in CAR samples, and HOXA10 and PAQR7 in ICAR samples. In contrast, MIX-supplemented heifers had increased (P < 0.05) mRNA abundance of MSTN in ICAR samples and an increase in conceptus length (ISe: 17.45 ± 3.08 cm vs. MIX: 25.96 ± 3.95 cm; P = 0.05). Notably, myostatin increases glucose secretion into histotroph and contributes to advanced conceptus development. This advancement in conceptus development occurred in the presence of similar concentrations of serum P4 (P = 0.88) and whole blood Se (P = 0.07) at MRP.
First predicted cosmic ray spectra, primary-to-secondary ratios, and ionization rates from MHD galaxy formation simulations
Authors: Hopkins Philip F , Butsky Iryna S , Panopoulou Georgia V , Ji Suoqing , Quataert Eliot , Faucher-Giguère Claude-André , Kereš Dušan
Published: July 2022

We present the first simulations evolving resolved spectra of cosmic rays (CRs) from MeV–TeV energies (including electrons, positrons, (anti)protons, and heavier nuclei), in live kinetic-magnetohydrodynamics galaxy simulations with star formation and feedback. We utilize new numerical methods including terms often neglected in historical models, comparing Milky Way analogues with phenomenological scattering coefficients ν to Solar-neighbourhood [Local interstellar medium (LISM)] observations (spectra, B/C, e+/e−, $\mathrm{\bar{p}}/\mathrm{p}$, 10Be/9Be, ionization, and γ-rays). We show it is possible to reproduce observations with simple single-power-law injection and scattering coefficients (scaling with rigidity R), similar to previous (non-dynamical) calculations. We also find: (1) The circumgalactic medium in realistic galaxies necessarily imposes an $\sim 10\,$ kpc CR scattering halo, influencing the required ν(R). (2) Increasing the normalization of ν(R) re-normalizes CR secondary spectra but also changes primary spectral slopes, owing to source distribution and loss effects. (3) Diffusive/turbulent reacceleration is unimportant and generally sub-dominant to gyroresonant/streaming losses, which are sub-dominant to adiabatic/convective terms dominated by $\sim 0.1-1\,$ kpc turbulent/fountain motions. (4) CR spectra vary considerably across galaxies; certain features can arise from local structure rather than transport physics. (5) Systematic variation in CR ionization rates between LISM and molecular clouds (or Galactic position) arises naturally without invoking alternative sources. (6) Abundances of CNO nuclei require most CR acceleration occurs around when reverse shocks form in SNe, not in OB wind bubbles or later Sedov–Taylor stages of SNe remnants.
GRMHD simulations of accreting neutron stars with non-dipole fields
Authors: Das Pushpita , Porth Oliver , Watts Anna L
Published: July 2022

NASA’s NICER telescope has recently provided evidence for non-dipolar magnetic field structures in rotation-powered millisecond pulsars. These stars are assumed to have gone through a prolonged accretion spin-up phase, begging the question of what accretion flows on to stars with complex magnetic fields would look like. We present results from a suite of general relativistic magnetohydrodynamic simulations of accreting neutron stars for dipole, quadrupole, and quadrudipolar stellar field geometries. This is a first step towards simulating realistic hotspot shapes in a general relativistic framework to understand hotspot variability in accreting millisecond pulsars. We find that the location and size of the accretion columns resulting in hotspots changes significantly depending on initial stellar field strength and geometry. We also find that the strongest contributions to the stellar torque are from disc-connected field lines and the pulsar wind, leading to spin-down in almost the entire parameter regime explored here. We further analyse angular momentum transport in the accretion disc due to large-scale magnetic stresses, turbulent stresses, and wind and compressible effects which we identify with convective motions. The disc collimates the initial open stellar flux forming jets. For dipoles, the disc–magnetosphere interaction can either enhance or reduce jet power compared to the isolated case. However for quadrupoles, the disc always leads to an enhanced net open flux making the jet power comparable to the dipolar case. We discuss our results in the context of observed neutron star jets and provide a viable mechanism to explain radio power both in the low- and high-magnetic field case.
Probing the inner circumgalactic medium and quasar illumination around the reddest ‘extremely red quasar’
Authors: Lau Marie Wingyee , Hamann Fred , Gillette Jarred , Perrotta Serena , Rupke David S N , Wylezalek Dominika , Zakamska Nadia L
Published: July 2022

Dusty quasars might be in a young stage of galaxy evolution with prominent quasar feedback. A recently discovered population of luminous, extremely red quasars at z ∼ 2–4 has extreme spectral properties related to exceptionally powerful quasar-driven outflows. We present Keck/KCWI observations of the reddest known ERQ, at z = 2.3184, with extremely fast [O iii] λ5007 outflow at ∼6000 km s−1. The Lyα halo spans ∼100 kpc. The halo is kinematically quiet, with velocity dispersion ∼300 km s−1 and no broadening above the dark matter circular velocity down to the spatial resolution ∼6 kpc from the quasar. We detect spatially resolved He ii λ1640 and C iv λ1549 emissions with kinematics similar to the Lyα halo and a narrow component in the [O iii] λ5007. Quasar reddening acts as a coronagraph, allowing views of the innermost halo. A narrow Lyα spike in the quasar spectrum is inner halo emission, confirming the broad C iv λ1549 in the unresolved quasar is blueshifted by 2240 km s−1 relative to the halo frame. We propose the inner halo is dominated by moderate-speed outflow driven in the past and the outer halo dominated by inflow. The high central concentration of the halo and the symmetric morphology of the inner region are consistent with the ERQ being in earlier evolutionary stage than blue quasars. The He ii λ1640/Lyα ratio of the inner halo and the asymmetry level of the overall halo are dissimilar to Type II quasars, suggesting unique physical conditions for this ERQ that are beyond orientation differences from other quasar populations. We find no evidence of mechanical quasar feedback in the Lyα-emitting halo.
Insights into the origin of halo mass profiles from machine learning
Authors: Lucie-Smith Luisa , Adhikari Susmita , Wechsler Risa H
Published: July 2022

The mass distribution of dark matter haloes is the result of the hierarchical growth of initial density perturbations through mass accretion and mergers. We use an interpretable machine-learning framework to provide physical insights into the origin of the spherically-averaged mass profile of dark matter haloes. We train a gradient-boosted-trees algorithm to predict the final mass profiles of cluster-sized haloes, and measure the importance of the different inputs provided to the algorithm. We find two primary scales in the initial conditions (ICs) that impact the final mass profile: the density at approximately the scale of the haloes’ Lagrangian patch RL ($R\sim 0.7\, R_L$) and that in the large-scale environment (R ∼ 1.7 RL). The model also identifies three primary time-scales in the halo assembly history that affect the final profile: (i) the formation time of the virialized, collapsed material inside the halo, (ii) the dynamical time, which captures the dynamically unrelaxed, infalling component of the halo over its first orbit, (iii) a third, most recent time-scale, which captures the impact on the outer profile of recent massive merger events. While the inner profile retains memory of the ICs, this information alone is insufficient to yield accurate predictions for the outer profile. As we add information about the haloes’ mass accretion history, we find a significant improvement in the predicted profiles at all radii. Our machine-learning framework provides novel insights into the role of the ICs and the mass assembly history in determining the final mass profile of cluster-sized haloes.
Regulation of both transcription and RNA turnover contribute to germline specification
Authors: Tan Kun , Wilkinson Miles F
Published: July 2022

The nuanced mechanisms driving primordial germ cells (PGC) specification remain incompletely understood since genome-wide transcriptional regulation in developing PGCs has previously only been defined indirectly. Here, using SLAMseq analysis, we determined genome-wide transcription rates during the differentiation of embryonic stem cells (ESCs) to form epiblast-like (EpiLC) cells and ultimately PGC-like cells (PGCLCs). This revealed thousands of genes undergoing bursts of transcriptional induction and rapid shut-off not detectable by RNAseq analysis. Our SLAMseq datasets also allowed us to infer RNA turnover rates, which revealed thousands of mRNAs stabilized and destabilized during PGCLC specification. mRNAs tend to be unstable in ESCs and then are progressively stabilized as they differentiate. For some classes of genes, mRNA turnover regulation collaborates with transcriptional regulation, but these processes oppose each other in a surprisingly high frequency of genes. To test whether regulated mRNA turnover has a physiological role in PGC development, we examined three genes that we found were regulated by RNA turnover: Sox2, Klf2 and Ccne1. Circumvention of their regulated RNA turnover severely impaired the ESC-to-EpiLC and EpiLC-to-PGCLC transitions. Our study demonstrates the functional importance of regulated RNA stability in germline development and provides a roadmap of transcriptional and post-transcriptional regulation during germline specification.
A super-Earth orbiting near the inner edge of the habitable zone around the M4.5 dwarf Ross 508
Authors: Harakawa Hiroki , Takarada Takuya , Kasagi Yui , Hirano Teruyuki , Kotani Takayuki , Kuzuhara Masayuki , Omiya Masashi , Kawahara Hajime , Fukui Akihiko , Hori Yasunori , Ishikawa Hiroyuki Tako , Ogihara Masahiro , Livingston John , Brandt Timothy D , Currie Thayne , Aoki Wako , Beichman Charles A , Henning Thomas , Hodapp Klaus , Ishizuka Masato , Izumiura Hideyuki , Jacobson Shane , Janson Markus , Kambe Eiji , Kodama Takanori , Kokubo Eiichiro , Konishi Mihoko , Krishnamurthy Vigneshwaran , Kudo Tomoyuki , Kurokawa Takashi , Kusakabe Nobuhiko , Kwon Jungmi , Matsumoto Yuji , McElwain Michael W , Mitsui Koyu , Nakagawa Takao , Narita Norio , Nishikawa Jun , Nugroho Stevanus K , Serabyn Eugene , Serizawa Takuma , Takahashi Aoi , Ueda Akitoshi , Uyama Taichi , Vievard Sébastien , Wang Ji , Wisniewski John , Tamura Motohide , Sato Bun’ei
Published: July 2022

We report the near-infrared radial velocity (RV) discovery of a super-Earth planet on a 10.77 d orbit around the M4.5 dwarf Ross 508 (Jmag = 9.1). Using precision RVs from the Subaru Telescope IRD (InfraRed Doppler) instrument, we derive a semi-amplitude of $3.92^{+0.60}_{-0.58}\:\mbox{m}\:{\mbox{s}^{-1}}$, corresponding to a planet with a minimum mass $m \sin i = 4.00^{+0.53}_{-0.55}\, M_{\oplus }$. We find no evidence of significant signals at the detected period in spectroscopic stellar activity indicators or MEarth photometry. The planet, Ross 508 b, has a semi-major axis of $0.05366^{+0.00056}_{-0.00049}\:$au. This gives an orbit-averaged insolation of ≈1.4 times the Earth’s value, placing Ross 508 b near the inner edge of its star’s habitable zone. We have explored the possibility that the planet has a high eccentricity and its host is accompanied by an additional unconfirmed companion on a wide orbit. Our discovery demonstrates that the near-infrared RV search can play a crucial role in finding a low-mass planet around cool M dwarfs like Ross 508.
A diRNA–protein scaffold module mediates SMC5/6 recruitment in plant DNA repair
Authors: Jiang Jieming , Ou Xiaolin , Han Danlu , He Zhipeng , Liu Song , Mao Ning , Zhang Zhonghui , Peng Chang-Lian , Lai Jianbin , Yang Chengwei
Published: July 2022

In eukaryotes, the STRUCTURAL MAINTENANCE OF CHROMOSOME 5/6 (SMC5/6) complex is critical to maintaining chromosomal structures around double-strand breaks (DSBs) in DNA damage repair. However, the recruitment mechanism of this conserved complex at DSBs remains unclear. In this study, using Arabidopsis thaliana as a model, we found that SMC5/6 localization at DSBs is dependent on the protein scaffold containing INVOLVED IN DE NOVO 2 (IDN2), CELL DIVISION CYCLE 5 (CDC5), and ALTERATION/DEFICIENCY IN ACTIVATION 2B (ADA2b), whose recruitment is further mediated by DNA-damage-induced RNAs (diRNAs) generated from DNA regions around DSBs. The physical interactions of protein components including SMC5–ADA2b, ADA2b–CDC5, and CDC5–IDN2 result in formation of the protein scaffold. Further analysis indicated that the DSB localization of IDN2 requires its RNA-binding activity and ARGONAUTE 2 (AGO2), indicating a role for the AGO2–diRNA complex in this process. Given that most of the components in the scaffold are conserved, the mechanism presented here, which connects SMC5/6 recruitment and small RNAs, will improve our understanding of DNA repair mechanisms in eukaryotes.
The maize genematernal derepression of r1encodes a DNA glycosylase that demethylates DNA and reduces siRNA expression in the endosperm
Authors: Gent Jonathan I , Higgins Kaitlin M , Swentowsky Kyle W , Fu Fang-Fang , Zeng Yibing , Kim Dong won , Dawe R Kelly , Springer Nathan M , Anderson Sarah N
Published: July 2022

Demethylation of transposons can activate the expression of nearby genes and cause imprinted gene expression in the endosperm; this demethylation is hypothesized to lead to expression of transposon small interfering RNAs (siRNAs) that reinforce silencing in the next generation through transfer either into egg or embryo. Here we describe maize (Zea mays) maternal derepression of r1 (mdr1), which encodes a DNA glycosylase with homology to Arabidopsis thaliana DEMETER and which is partially responsible for demethylation of thousands of regions in endosperm. Instead of promoting siRNA expression in endosperm, MDR1 activity inhibits it. Methylation of most repetitive DNA elements in endosperm is not significantly affected by MDR1, with an exception of Helitrons. While maternally-expressed imprinted genes preferentially overlap with MDR1 demethylated regions, the majority of genes that overlap demethylated regions are not imprinted. Double mutant megagametophytes lacking both MDR1 and its close homolog DNG102 result in early seed failure, and double mutant microgametophytes fail pre-fertilization. These data establish DNA demethylation by glycosylases as essential in maize endosperm and pollen and suggest that neither transposon repression nor genomic imprinting is its main function in endosperm.
Health Coaching for Low Back Pain and Hip and Knee Osteoarthritis: A Systematic Review with Meta-Analysis
Authors: Prior Joanna Louise , Vesentini Giovana , Michell De Gregorio Jose Antonio , Ferreira Paulo H , Hunter David J , Ferreira Manuela L
Published: July 2022

Background

Health coaching aims to empower people to reach their goals and is increasingly used in health care settings. Whether health coaching improves pain and disability for people with hip or knee osteoarthritis (OA) or low back pain (LBP) is unknown.

Methods

Six databases were searched for randomized controlled trials assessing health coaching or motivational programs in adults with hip or knee OA or LBP, with each condition investigated independently. Meta-analyses were performed with random-effects models in the Cochrane Collaboration Review Manager 5.3 program.

Results

Seventeen eligible studies were found. No studies analyzing hip OA alone were found. Pooled analyses found statistically significant decreases in mid-term pain (mean difference [MD]: –7.57; 95% confidence interval [CI]: –10.08 to –5.07; P < 0.001, I2 = 0%), short-term disability (standard mean difference [SMD]: –0.22; 95% CI: –0.41 to –0.03; P = 0.02, z = 2.32, I2 = 0%), and mid-term disability (SMD: –0.42; 95% CI: –0.75 to –0.09; P = 0.01, z = 2.49, I2 = 60%), favoring the intervention for chronic LBP. There were significant improvements in knee OA long-term functional disability (MD: –3.04; 95% CI: –5.70 to –0.38; P = 0.03; z = 2.24; I2 = 0%).

Conclusion

Meta-analyses provide evidence that health coaching reduces both disability and pain in people with chronic LBP and reduces disability in people with knee OA, though the clinical significance is unknown. There is currently no evidence supporting or refuting the use of health coaching for hip OA.
Techniques for advanced glycation end product measurements for diabetic bone disease: pitfalls and future directions
Authors: Sroga Grażyna E. , Stephen Samuel J. , Wang Bowen , Vashishth Deepak
Published: July 2022

Purpose of review

Multiple biochemical and biophysical approaches have been broadly used for detection and quantitation of posttranslational protein modifications associated with diabetic bone, yet these techniques present a variety of challenges. In this review, we discuss recent advancements and complementary roles of analytical (UPLC/UPLC-MS/MS and ELISA) and biophysical (Raman and FTIR) techniques used for characterization of glycation products, measured from bone matrix and serum, and provide recommendations regarding the selection of a technique for specific study of diabetic bone.

Recent findings

Hyperglycemia and oxidative stress in diabetes contribute to the formation of a large subgroup of advanced glycation end products (AGEs) known as glycoxidation end products (AGOEs). AGEs/AGOEs have various adverse effects on bone health. Commonly, accumulation of AGEs/AGOEs leads to increased bone fragility. For example, recent studies show that carboxymethyllysine (CML) and pentosidine (PEN) are formed in bone at higher levels in certain diseases and metabolic conditions, in particular, in diabetes and aging. Detection and quantitation of AGEs/AGOEs in rare and/or precious samples is feasible because of a number of technological advancements of the past decade.

Recent technological advancements have led to a significant improvement of several key analytical biochemistry and biophysics techniques used for detection and characterization of AGEs/AGOEs in bone and serum. Their principles and applications to skeletal tissue studies as well as limitations are discussed in this review.
The future of telehealth in type 1 diabetes
Authors: Cobry Erin C. , Wadwa R. Paul
Published: July 2022

Purpose of review

Although telemedicine and telehealth services have been a part of type 1 diabetes (T1D) clinical care for several decades, the expansion of in-home telemedicine during the COVID-19 pandemic significantly increased interest in long-term use as part of routine care. This review highlights the current literature regarding telemedicine in T1D care as well as the benefits and barriers to use in a postpandemic world.

Recent findings

Telemedicine has increased patient contact with healthcare providers, allowing for more frequent insulin dose adjustments and improvements in glycemic outcomes. In addition to routine clinical care, T1D device training and mental healthcare have been successful through telemedicine. Significant barriers to continued telemedicine care exist, including patient access and technology knowledge, language, and loss of face-to-face interaction. Healthcare providers additionally face unpredictable reimbursement and loss of continuity across state lines, and lack of resources and training for device downloads and telemedicine software.

Telemedicine can be successfully used in T1D care and has the potential to significantly impact glycemic and long-term outcomes. Due to continued interest for in-person visits by people with T1D and providers, it is likely that long-term telemedicine use will include a hybrid format.
Glutamic acid decarboxylase immunotherapy for type 1 diabetes
Authors: Ludvigsson Johnny
Published: July 2022

Purpose of review

To describe recent development of an autoantigen (GAD) treatment towards well tolerated and efficacious precision medicine in type 1 diabetes.

Recent findings

Although subcutaneous GAD-alum treatment failed to reach primary endpoint in a phase III trial, metanalyses showed a 97% probability of efficacy, and clear efficacy in patients carrying Hyman Leucoycte Antigen (HLA) DR3DQ2. Efforts have been made to improve efficacy by trying combination therapies with vitamin D + Ibuprofen resp vitamin D + Etanercept (TNF-α inhibition), without any breakthrough until the administration of GAD-alum was changed from subcutaneous to intralymphatic. With a very small dose of GAD-alum (4 μg) given into an inguinal lymph three times with 1 month interval, the efficacy in patients with HLADR3DQ2 has been impressive, with significantly better beta cell preservation than patients who got placebo in a double-blind randomized trial, and clinical efficacy with more patients in partial remission (IDAA1c < 9) and larger proportion of patients with CGM-measured blood glucose Time In Range (TIR), significantly correlated to the C-peptide values. The treatment has been easy for patients and healthcare without treatment-related risk or adverse events.

Intralymphatic GAD-alum treatment in type 1 diabetes patients carrying HLA DR3DQ2 seems to be an attractive immune intervention.
Association of Fear of Falling With Cognition and Physical Function in Community-Dwelling Older Adults
Authors: Wang Qian X. , Ye Zhu M. , Wu Wei J. , Zhang Yu , Wang Cong L. , Zheng Hua G.
Published: July 2022

Background

Fear of falling (FOF) might be associated with physical and cognitive function, but there is a lack of understanding of the specific relationship between the three variables.

Objectives

The aim of this study was to accurately investigate the association of FOF with cognitive and physical function in community-dwelling older adults.

Methods

Six hundred sixty-nine older adults (>60 years old) participated in this study. A self-report questionnaire collected information about demographic characteristics, lifestyle, and behavioral habits. FOF was evaluated through the Shortened Version of the Falls Efficacy Scale International. Global cognitive function and the subdomains of cognitive function (including memory, visual–spatial, language, attention, and executive function) were assessed using the Montreal Cognitive Assessment scale, the Auditory Verbal Learning Test, the Clock Drawing Test (CDT), the Verbal Fluency Test, and the Trail Making Test. Subjective memory complaints were assessed using the Subjective Memory Complaints Questionnaire. Physical function was evaluated by measuring muscle strength and balance ability, and muscle strength was indicated by hand grip strength. In contrast, balance was assessed using the Timed Up and Go (TUG) Test.

Results

After adjustment for potential confounding factors, the linear or ordinal regression analysis showed that the values of hand grip strength, Montreal Cognitive Assessment, Auditory Verbal Learning Test, and CDT were significantly and negatively correlated with the score of FOF. On the other hand, Subjective Memory Complaints Questionnaire and TUG Test values showed significant positive correlations with FOF scores. Moreover, compared with other cognitive or physical measures, the CDT and TUG Test values showed a greater association with the FOF scores.

Discussion

Low subjective or objective cognitive ability and low physical function, especially low visuospatial and balance ability, were positively associated with the risk of FOF in a community-dwelling older population.
Recovery in Stroke Patients Treated With Fluoxetine Versus Placebo
Authors: Elsnhory Ahmed , Hasan Mohammed T. , Hagrass Abdulrahman I. , Hanbal Ahmed , Fathy Anas , Ahmed Eslam , Ouerdane Yassamine , Ragab Khaled M. , Elfil Mohamed , Doheim Mohamed F.
Published: July 2022

Background:

Stroke is a major cause of disability and death. Stroke recovery outcomes range from functional impairment to disability. This study was designed to compare the recovery results of stroke patients treated with fluoxetine to those treated with placebo.

Review Summary:

Seventeen randomized clinical trials were identified by searching PubMed, Cochrane, Scopus, and Web of Science until June 2021. Fluoxetine enhances the National Institutes of Health Stroke Scale (NIHSS) score [mean difference (MD)=−0.67, 95% confidence interval (CI) (−1.19 to −0.15)] and the Fugl-Meyer Motor Scale (FMMS) score [MD=17.36, 95% CI (12.12-22.61)] at the 3-month follow up. However, the NIHSS score showed no significant difference between the 2 groups at 2 weeks [MD=−0.32, 95% CI (−0.72 to 0.07)] or at 6 months [MD=−0.17, 95% CI (−0.47 to 0.14)]. Fluoxetine-treated and placebo-treated patients had the same overall impact on FMMS scores at 1 month (P=0.41). Barthel index showed no significant difference between the 2 arms at 3 months (P=0.21) or 6 months (P=0.68). Fluoxetine-treated patients were at a higher risk of broken bone [risk ratios (RR)=2.30, 95% CI (1.59-3.32)] and hyponatremia [RR=2.12, 95% CI (1.19-3.76)], and at lower risk of new depression [RR=0.72, 95% CI (0.61-0.84)] in comparison with placebo.

Conclusion:

The efficacy of fluoxetine on the NIHSS and FMMS is likely to take time to emerge and is expected to be transient. The Barthel index score did not differ between the fluoxetine and placebo groups. The use of fluoxetine increased the incidence of hyponatremia and bone fractures while decreasing the risk of new-onset depression.
Immunohistochemical Expression of LHRH Receptor in Different Compartments of Female Genital Tract in Patients With Endometrial Cancer
Authors: Barczyński Bartłomiej , Frąszczak Karolina , Wertel Iwona , Zakrzewska Ewelina , Zdunek Małgorzata , Szumiło Justyna , Kotarski Jan
Published: July 2022

Luteinizing hormone–releasing hormone receptor (LHRHR) expression has been reported in various cancers, including endometrial neoplasms. Thus, LHRHR provides a potential point for therapeutic approach using LHRH analogs as carrier molecules for chemotherapeutic agents in this cancer population. However, clinical data did not prove any potential benefits for patients. We decided to assess LHRHR expression in patients with endometrial cancer to explain possible lack of efficacy in previous clinical reports. LHRHR expression was assessed immunohistochemically in different anatomic and histogenetic compartments of female genital tract of patients with endometrial cancer. The study sample consisted of paraffin tissue blocks obtained from patients who has undergone primary surgery owing to endometrial cancer. Strong LHRHR expression was found in endometrial cancer, fallopian tube, and concurrent atypical hyperplasia. Interestingly, LHRHR expression showed significant differences depending on the respective compartment of the ovary analyzed. Level of LHRHR expression in patients with primary advanced and unresectable disease, particularly in certain ovarian compartments may be substantially lower, which may influence the use of new targeted therapy regimens. The studies on secondary Müllerian system compartment and its hormonal receptor status may be crucial to understand mechanisms of lack of efficacy of LHRH hybrid molecules anti-cancer treatment.
Hepatic Cysts
Authors: Armutlu Ayse , Quigley Brian , Choi Hegyong , Basturk Olca , Akkas Gizem , Pehlivanoglu Burcin , Memis Bahar , Jang Kee-Taek , Erkan Mert , Erkan Burcu , Balci Serdar , Saka Burcu , Bagci Pelin , Farris Alton B. , Kooby David A. , Martin Diego , Kalb Bobby , Maithel Shishir K. , Sarmiento Juan , Reid Michelle D. , Adsay N. Volkan
Published: July 2022

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight ≥1 cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10 cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as “hepatobiliary cystadenoma.” II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11 cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (<3 cm); choledochal cyst (5%), foregut cyst (2%). V. Miscellaneous (4%). In conclusion, hepatic cysts occur predominantly in women (3/1), are mostly (90%) non-neoplastic, and seldom (<2%) malignant. Cystic bile duct hamartomas and their relative not otherwise specified-type benign biliary cysts are frequently multifocal and often misdiagnosed as “cystadenoma/carcinoma.” Defined by OTS, MCNs (the true “hepatobiliary cystadenoma/carcinoma”) are solitary, constitute only 10.5% of hepatic cysts, and have a significantly different profile than the impression in the literature in that essentially all are perimenopausal females, and rarely associated with carcinoma (7%). Since MCNs can only be diagnosed by demonstration of OTS through complete microscopic examination, it is advisable to avoid the term “cystadenoma/cystadenocarcinoma” solely based on radiologic examination, and the following simplified terminology would be preferable in preoperative evaluation to avoid conflicts with the final pathologic diagnosis: (1) noncomplex (favor benign), (2) complex (in 3 subsets, as favor benign, cannot rule out malignancy, or favor malignancy), (3) malignant features.
Metastatic Giant Cell Tumor Causing Small Bowel Intussusception on 18F-FDG PET/CT
Authors: Walcutt Julie E. , Johnson Craig M. , Ly Quan P. , Downey Ryan T.
Published: July 2022

An 89-year-old man with a history of a malignant giant cell tumor of soft parts in the right thigh with recurrent/metastatic tumor in the right pelvis was found to have pulmonary nodules concerning for metastatic disease. Subsequent PET/CT unexpectedly demonstrated a right lower quadrant intussusception with a hypermetabolic mass serving as a lead point. Pathology of the resected mass causing the intussusception was compatible with a metastasis from the patient's malignant giant cell tumor of soft parts.
Evaluation of five commercial DNA extraction kits using Salmonella as a model for implementation of rapid Nanopore sequencing in routine diagnostic laboratories
Authors: Eagle Shannon H.C. , Robertson James , Bastedo D. Patrick , Liu Kira , Nash John H.E.
Published: July 2022

Oxford Nanopore long-read sequencing offers advantages over Illumina short-reads for the identification and characterization of bacterial pathogens for outbreak detection and surveillance activities within a diagnostic public health laboratory context. Compared to Illumina, Nanopore is more cost-effective for small batches, has a lower capital costs, and has a faster turnaround times, in addition to the ability to assemble complete bacterial genomes. The quantity and quality of DNA required for Nanopore sequencing is higher than Illumina, and DNA extraction methods recommended for obtaining high molecular weight DNA are different from those typically used in diagnostic laboratories. Using a Salmonella isolate with a previously closed PacBio genome as a model Enterobacteriaceae organism, we evaluated the quantity, quality, and fragmentation of five commercial DNA extraction kits. Nanopore sequencing performance was evaluated for the top three methods: Qiagen EZ1 DNA Tissue, Qiagen DNeasy Blood and Tissue, and a modified, in-house version of the MasterPure Complete DNA and RNA purification. To evaluate the effect of post-extraction DNA purification methods, we subjected extracted DNA from the three selected methods to purification by AMPure beads or ethanol precipitation and compared these outputs with untreated DNA as a control. All methods are suitable for routine WGS, since all 60 replicates had very high genome recovery rates, with ≥ 98% of the reference genome covered by mapped Nanopore reads. For 85% of the replicates assembly was able to produce a complete, circular chromosome using either Flye or Canu. In most cases, it is recommended to move directly from extraction to sequencing as untreated DNA had the highest rates of genome closure regardless of extraction method. Using our evaluation criteria, the Qiagen DNeasy Blood and Tissue kit was found to be the best overall method due to its low-cost, ability to scale from single tube to 96-well plates, and high consistency in yield and sequencing performance.
Chromosome level reference genome for European flat oyster (Ostrea edulis L.)
Authors: Gundappa Manu Kumar , Peñaloza Carolina , Regan Tim , Boutet Isabelle , Tanguy Arnaud , Houston Ross D. , Bean Tim P. , Macqueen Daniel J.
Published: July 2022

The European flat oyster (Ostrea edulis L.) is a bivalve naturally distributed across Europe that was an integral part of human diets for centuries, until anthropogenic activities and disease outbreaks severely reduced wild populations. Despite a growing interest in genetic applications to support population management and aquaculture, a reference genome for this species is lacking to date. Here we report a chromosome-level assembly and annotation for the European Flat oyster genome, generated using Oxford Nanopore, Illumina, Dovetail OmniC™ proximity ligation and RNA sequencing. A contig assembly (N50: 2.38Mb) was scaffolded into the expected karyotype of 10 pseudo-chromosomes. The final assembly is 935.13 Mb, with a scaffold-N50 of 95.56 Mb, with a predicted repeat landscape dominated by unclassified elements specific to O. edulis. The assembly was verified for accuracy and completeness using multiple approaches, including a novel linkage map built with ddRAD-Seq technology, comprising 4,016 SNPs from four full-sib families (8 parents and 163 F1 offspring). Annotation of the genome integrating multi-tissue transcriptome data, comparative protein evidence and ab-initio gene prediction identified 35,699 protein-coding genes. Chromosome level synteny was demonstrated against multiple high-quality bivalve genome assemblies, including an O. edulis genome generated independently for a French O. edulis individual. Comparative genomics was used to characterize gene family expansions during Ostrea evolution that potentially facilitated adaptation. This new reference genome for European flat oyster will enable high-resolution genomics in support of conservation and aquaculture initiatives, and improves our understanding of bivalve genome evolution.
The influence of selection, drift and immigration on the diversity of a tropical tree community
Authors: Cid Jeronimo , Lambert Ben , Leroi Armand M.
Published: July 2022

Ecology is rich in theories that aim to explain why natural communities have as many species as they do. Neutral theory, for example, supposes that a community’s diversity depends on the rate at which it gains species by immigration or speciation and loses them to ecological drift [1–5]. Classical niche theory, by contrast, supposes that diversity is regulated by the complexity of the environment: how many dimensions of resources it has and how finely species can subdivide them [6–10]. These theories are about levels of diversity at equilibrium. But non-equilibrium theory supposes that communities are perpetually buffeted by environmental change so that communities rarely contain all the individuals and species they might [11, 12]. When that happens, some species may profit from their immediate circumstances, but their gains are short lived as the environment changes again, favouring others. Such theories are often seen as competing visions of nature (e.g., [1, 2, 13–20]), but they can also be viewed as collectively describing a set of forces, any of which may be at work at a given time and place (cf. [21]). The relative importance of these forces in shaping the evolution of a community’s diversity can be captured by a small set of parameters: the community’s effective size,Ne, the rate at which it gains new species,μ, and the magnitude and form of species-specific selection coefficients,s[22]. Here we present a way of estimating these parameters using time series data and apply it to the famous Barro Colorado Island Neotropical forest dataset. We show that, for the last thirty years, this community has been dominated by directional selection. We then simulate the evolution of this community in order to disentangle how these forces have shaped the species diversity that we see today. We show that, while species richness can be maintained by a neutral force, immigration, species evenness cannot and argue that it is likely maintained by temporally varying selection driven by environmental change [23–25].
Time-resolved transcriptomic profiling of senescence-associated secretory phenotype (SASP) in multiple senescent cell subtypes
Authors: Razali Nurhanani , Moriyama Yohsuke , Chiu Yatzu , Suda Kojiro , Kono Keiko
Published: July 2022

Cellular senescence, irreversible cell cycle arrest, is induced by various triggers including telomere shortening, oncogene activation, and DNA damage. Senescent cells exhibit the senescence-associated secretory phenotype (SASP), a pathological feature that contributes to organismal aging. We previously showed that transient plasma membrane damage (PMD) induces a novel subtype of cellular senescence (PMDS) accompanied by SASP, but the overall expression profiles of SASP during PMDS induction was unknown. Here, using mRNA-seq, qPCR, and bioinformatics, we revealed the time-resolved SASP transcriptomic profile in PMDS in comparison with calcium influx-induced senescence, DNA damage response-induced senescence, and replicative senescence. Although the expression of SASP factors was postulated to increase steadily during senescence, we counterintuitively found that the variety of SASP peaks in early PMDS. The pathway comparison analyses and Ingenuity Pathway Analysis suggest that, in early PMDS, wound-healing SASP factors, namelyIl-6,Mmp1, andMmp3,inhibit the GPVI collagen signaling pathway, which in turn further upregulates the same SASP factors, forming a feedback loop. At late senescence, common SASP factors includingIl-6andCcl2 are upregulated in all senescent cell subtypes. Thus, SASP is diverse at early senescence and becomes relatively uniform at late senescence. Diverse SASP may contribute to senescent cell subtype-specific paracrine/autocrine functions in vivo.
A model-based analysis reveals three-dimensional genome organization heterogeneity and functional sub-compartments in cell populations
Authors: Zheng Xiaobin , Tran Joseph R. , Zheng Yixian
Published: July 2022

The computational inference of genome organization based on Hi-C sequencing has greatly aided the understanding of chromatin and nuclear organization in three dimensions (3D). However, existing computational methods used to infer sub-compartments from Hi-C data fail to address the cell population heterogeneity. Here we describe a model-based method, called CscoreTool-M, which uses probabilistic modeling to build multiple 3D genome sub-compartments from Hi-C data. The compartment scores inferred using CscoreTool-M directly represents the probability of a genomic region locating in a specific sub-compartment. Compared to published methods, CscoreTool-M is more accurate in inferring local sub-compartment containing heterochromatin marked by Histone lysine trimethylation (H3K27me3) surrounded by the actively transcribed euchromatic regions. The compartment scores calculated by CscoreTool-M also help to quantify the levels of heterogeneity in sub-compartment localization within cell populations for different genomic regions. By comparing proliferating cells and terminally differentiated non-proliferating cells, we show that the proliferating cells have higher genome organization heterogeneity, which is likely caused by cells at different cell-cycle stages. By analyzing 10 sub-compartments, we found a sub-compartment containing chromatin potentially related to the early-G1 chromatin regions proximal to the nuclear lamina in HCT116 cells, suggesting the method can deconvolve cell cycle stage-specific genome organization among asynchronously dividing cells. Finally, we show that CscoreTool-M can further identify sub-compartments that contain genes enriched in housekeeping or cell-type-specific functions.
The Interictal Suppression Hypothesis in Focal Epilepsy: Electrographic and Structural Evaluation
Authors: Johnson Graham W. , Doss Derek J. , Morgan Victoria L. , Shless Jared S. , Paulo Danika L. , Kang Hakmook , Bick Sarah K. , Roberson Shawniqua Williams , Wallace Mark T. , Englot Dario J.
Published: July 2022

Why are people with focal epilepsy not constantly seizing? Previous molecular work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is the high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure onset zones have an increased inward connectivity. Accordingly, we hypothesize that seizure onset zones are actively suppressed by the rest of the brain network during interictal states.

We tested this hypothesis on 81 subjects with drug resistant focal epilepsy undergoing presurgical evaluation. We utilized intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, propagative, and non-involved regions. We then utilized diffusion imaging to acquire estimates of white matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, using our observations, we generated a resting-state classification model to assist clinicians in detecting seizure onset and propagative zones without the need for multiple ictal recordings.

Our findings indicate that seizure onset and propagative zones demonstrate markedly increased inward connectivity and decreased outward connectivity on both resting-state and neurostimulation analyses. When controlling for distance between regions, the difference between inward vs. outward connectivity remained stable up to 80 mm between brain connections. Structure-function coupling analyses revealed that seizure onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue. Using these observations, our classification models achieved a maximum held-out testing set accuracy of 92.0±2.2%.

These results indicate that seizure onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure onset zones. These findings have implications for the identification of seizure onset zones using only brief resting-sate recordings to reduce patient morbidity and augment the presurgical evaluation of drug resistant epilepsy. Furthermore, testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative, and neuromodulation approaches to improve surgical success rates in those suffering from drug resistant focal epilepsy.
Involvement of CaV2.2 channels and α2δ-1 in hippocampal homeostatic synaptic plasticity
Authors: Pilch Kjara S , Ramgoolam Krishma H , Dolphin Annette C
Published: July 2022

In the mammalian brain, presynaptic CaV2 channels play a pivotal role for synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the active zone of presynaptic terminals. However, the distribution and modulation of CaV2.2 channels at highly plastic hippocampal synapses remains to be elucidated. Here, we assess CaV2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. We show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+ transients, mediated by increased levels of CaV2.2 channels at the presynaptic site. This work focussed further on the role of α2δ-1 subunits, important regulators of synaptic transmission and CaV2.2 channel abundance at the presynaptic membrane. We find that α2δ-1-overexpression reduces the contribution of CaV2.2 channels to total Ca2+ flux without altering the amplitude of the Ca2+ transients. Levels of endogenous α2δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α2δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV2.2 channels and novel roles for α2δ-1 during synaptic plastic adaptation.