bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matching into Plastic Surgery: Insights into the Data
Authors: Sarac Benjamin A. , Janis Jeffrey E. 
Published: May 2022

Summary
Matching into plastic and reconstructive surgery residency, whether integrated or independent, is a competitive process. This article serves to examine, review, and summarize data published on both residency application processes. Through the results summarized, applicants should carefully review the objective and subjective factors used in evaluation to strategize how to make themselves as competitive as possible. Specifically, though, early review of the data presented may allow applicants time to focus on what modifiable factors still remain before their respective application seasons.
Single Center Oncoplastic Experience and Patient Satisfaction Reported via Patient Reported Outcomes
Authors: Wang Xuanji , Mathews Alexandra , Erickson Anne , Veselack Teresa , Bucholz Eleanor , Vandevender Darl , Godellas Constantine , Vaince Faaiza 
Published: May 2022

Background:
Oncoplastic breast surgery (OPS) is gaining in popularity compared with traditional breast conserving surgery due to wider resections and better satisfaction with cosmetic outcomes. This study analyzed OPS versus traditional breast conserving surgery outcomes: wound complications, reoperations for margins or fat necrosis, and ipsilateral recurrence.

Methods:
This retrospective review compared 191 OPS and traditional breast conserving surgery patients on patient-related factors, primary outcomes, and patient reported outcome measures results. A propensity score method analysis using 1:1 to nearest neighbor was also performed.

Results:
OPS patients were younger, less likely to be smokers, more likely to be ER+ and PR+, and had larger specimen volumes than did traditional breast conserving surgery patients (P < 0.05). There were also differences in distribution of invasive ductal carcinoma and noninvasive disease (P < 0.05). After the propensity score method, the differences observed between the cohorts disappeared. No differences were observed between groups for wound complication, reoperation for positive margins or fat necrosis, or ipsilateral recurrence. Results of patient reported outcome measures showed greater satisfaction with breast surgery in OPS patients (P < 0.01).

Conclusions:
We showed that OPS is a noninferior technique that should be discussed with appropriate patients. Operative planning should involve patient preferences in optimizing long-term cosmetic outcomes.
A Retrospective Study of Puncture and Drainage for Primary Brainstem Hemorrhage With the Assistance of a Surgical Robot
Authors: Zhang Shuai , Chen Tao , Han Bing , Zhu Weisheng 
Published: May 2022

Background:
Whether primary brainstem hemorrhage (PBH) should be treated with a conservative treatment or with surgical intervention (such as craniotomy, puncture, and drainage) is still controversial. The aim of this study was to assess the feasibility and safety of puncture and drainage for PBH with the assistance of a surgical robot.

Patients and Methods:
A total of 53 patients diagnosed with PBH were included in this study. They were divided into surgical and nonsurgical groups. All patients in the surgical group underwent puncture and drainage of PBH assisted with surgical robots at Beijing Jingmei General Hospital from June 2017 to January 2021. We evaluated this technology with radiographic and clinical results.

Results:
Postoperative computed tomography showed that all the drainage catheters had been pushed to the target point, which had been designated before the operation. After the operation, the hematoma was reduced by an average of 3.7 mL. None of the patients experienced serious surgery-related complications. Clinical follow-up revealed that 2 patients could not be followed-up, 8 died, and the rest were in disability or in a vegetative state.

Conclusions:
It may be safe, feasible, and effective to complete the puncture and drainage of PBH with the assistance of a surgical robot. This technique has fewer complications than the traditional puncture method and has high accuracy. It may be more suitable for patients with a hematoma volume of 5 to 10 mL in PBH. The amount of hematoma volume >10 mL may be associated with poor postoperative prognosis. However, high-quality cohorts or case-control studies are needed to verify the effect in this study.
Concerns About Compounded Bioidentical Menopausal Hormone Therapy
Authors: Pinkerton JoAnn V. 
Published: May 2022

Abstract
Following the release of the Women's Health Initiative data, women began to use compounded bioidentical hormone therapy (cBHT) in the misguided belief of greater safety and efficacy than traditional hormone therapy. New guidelines recommend government-approved hormone therapy for symptomatic healthy menopausal women younger than 60 years or within 10 years of menopause at the time of initiation. For women requesting bioidentical hormones, those similar to the hormones present before menopause, there are many government-approved hormone therapies with extensive pharmacokinetic, safety, and efficacy data provided with package inserts delineating efficacy, safety, and potential risks. For women requesting non–Food and Drug Administration–approved (cBHT), these cBHTs lack data on pharmacokinetics, safety, and efficacy and are not provided a label detailing risk. Their use should be restricted to women with allergies or dosing or formulations not available in government-approved therapies. Pellet therapy providing women with supraphysiologic hormone dosing raises even more safety concerns.
Menopausal Hormone Therapy and Breast Cancer
Authors: Chlebowski Rowan T. , Manson JoAnn E. 
Published: May 2022

Abstract
Associations of estrogen-alone and estrogen plus progestin with breast cancer incidence and related mortality are reviewed from observational studies (The Collaborative Group on Hormonal Factors in Breast Cancer and The Million Women Study, 2019) and the Women’s Health Initiative’s (2020) two randomized trials evaluating conjugated equine estrogen alone, for women with prior hysterectomy or with medroxyprogesterone acetate. Findings are generally concordant for estrogen plus progestin use with both observational and randomized studies reporting higher breast cancer incidence. Findings are discordant for estrogen-alone use where, in the WHI randomized trial, a lower incidence and lower breast cancer mortality was seen. In contrast, in the observational studies, estrogen-alone use was associated with higher breast cancer incidence and higher breast cancer mortality. Although these discordant findings are difficult to fully reconcile, we conclude with a discussion of public health implications of the available evidence on menopausal hormone therapy and breast cancer.
Magnetic resonance spectroscopy shows associations between neurometabolite levels and perivascular space volume in Parkinson’s disease: a pilot and feasibility study
Authors: Donahue Erin K. , Bui Vy , Foreman Ryan P. , Duran Jared J. , Venkadesh Siva , Choupan Jeiran , Van Horn John D. , Alger Jeffry R. , Jakowec Michael W. , Petzinger Giselle M. , O’Neill Joseph 
Published: May 2022

Objective
Higher volume fraction of perivascular space (PVS) has recently been reported in Parkinson’s disease (PD) and related disorders. Both elevated PVS and altered levels of neurometabolites, assayed by proton magnetic resonance spectroscopy (MRS), are suspected indicators of neuroinflammation, but no published reports have concurrently examined PVS and MRS neurometabolites.

Methods
In an exploratory pilot study, we acquired multivoxel 3-T MRS using a semi-Localization by Adiabatic SElective Refocusing (sLASER) pulse-sequence (repetition time/echo time = 2810/60 ms, voxels 10 × 10 × 10 mm3) from a 2D slab sampling bilateral frontal white matter (FWM) and anterior middle cingulate cortex (aMCC). PVS maps obtained from high-resolution (0.8 × 0.8 × 0.8 mm3) T1-weighted MRI were co-registered with MRS. In each MRS voxel, PVS volume and neurometabolite levels were measured.

Results
Linear regression accounting for age, sex, and BMI found greater PVS volume for higher levels of choline-containing compounds (Cho; P = 0.047) in FWM and lower PVS volume for higher levels of N-acetyl compounds (NAA; P = 0.012) in aMCC. Since (putatively) higher Cho is associated with inflammation while NAA has anti-inflammatory properties, these observations add to evidence that higher PVS load is a sign of inflammation. Additionally, lower Montreal Cognitive Assessment scores were associated with lower NAA in aMCC (P = 0.002), suggesting that local neuronal dysfunction and inflammation contribute to cognitive impairment in PD.

Conclusion
These exploratory findings indicate that co-analysis of PVS and MRS is feasible and may help elucidate the cellular and metabolic substrates of glymphatic and inflammatory processes in PD.
Acupuncture improves the structure of spastic muscle and decreases spasticity by enhancing GABA, KCC2, and GABAAγ2 in the brainstem in rats after ischemic stroke
Authors: Sun Tian-Yi , Ma Liang-Xiao , Mu Jie-Dan , Zhang Zhou , Yu Wen-Yan , Qian Xu , Tian Yuan , Zhang Yi-Dan , Wang Jun-Xiang 
Published: May 2022

Background
Increasing data show that structural changes of spastic muscle and hyperexcitability of reticulospinal tract (RST) are involved in the pathogenesis of spasticity after stroke (SAS). Our previous study has indicated that the anti-spastic effect of acupuncture, especially waggle needling (WN, a multiple directional needling method with joint movement), on SAS rats was related to the KCC2-GABAA pathway in cerebral cortex. Furthermore, as a peripheral stimulation to treat upper motor neuron injury-related spasticity, acupuncture’s effect on peripheral spastic muscles and inhibitory neurotransmitters in the brainstem, the origin of the RST, should be further clarified. This study aimed to examine the effect of acupuncture on the structure of spastic muscle and on the KCC2-GABAA pathway in the brainstem of SAS rats.

Methods
Middle cerebral artery occlusion (MCAO) or a sham operation were conducted in SD rats to establish SAS and control models. Behavioral assays, muscle myosin ATPase staining, and molecular biology technologies were used to compare different groups.

Results
In SAS models, hindlimb motor ability was decreased, neurologic deficits and spasticity were induced, the proportion of type I muscle fibers in spastic muscle was increased, and the expressions of γ-aminobutyric acid (GABA), KCC2, and the GABAAγ2 subunit of the pentameric GABAA receptor in the brainstem were decreased. Acupuncture including WN and perpendicular needling (PN) reversed these effects of MCAO. Furthermore, the therapeutic effect of WN was better than that of PN.

Conclusions
Acupuncture after MCAO improves the structure of spastic muscle and decreases spasticity probably at least partly by enhancing GABA, KCC2, and GABAAγ2 in the brainstem in SAS rats.
In silico modelling demonstrates that user variability during tumor measurement can affect in vivo therapeutic efficacy outcomes
Authors: Murkin Jake T. , Amos Hope E. , Brough Daniel W. , Turley Karl D. 
Published: May 2022

AbstractUser measurement bias during subcutaneous tumor measurement is a source of variation in preclinical in vivo studies. We investigated whether this user variability could impact efficacy study outcomes, in the form of the false negative result rate when comparing treated and control groups.Two tumor measurement methods were compared; calipers which rely on manual measurement, and an automatic 3D and thermal imaging device. Tumor growth curve data were used to create an in silico efficacy study with control and treated groups. Before applying user variability, treatment group tumor volumes were statistically different to the control group. Utilizing data collected from 15 different users across 9 in vivo studies, user measurement variability was computed for both methods and simulation was used to investigate its impact on the in silico study outcome.User variability produced a false negative result in 3.5% to 19.5% of simulated studies when using calipers, depending on treatment efficacy. When using an imaging device with lower user variability this was reduced to 0.0% to 2.4%, demonstrating that user variability impacts study outcomes and the ability to detect treatment effect.Reducing variability in efficacy studies can increase confidence in efficacy study outcomes without altering group sizes. By using a measurement device with lower user variability, the chance of missing a therapeutic effect can be reduced and time and resources spent pursuing false results could be saved. This improvement in data quality is of particular interest in discovery and dosing studies, where being able to detect small differences between groups is crucial.
Lola-I is a developmentally regulated promoter pioneer factor
Authors: Ramalingam Vivekanandan , Yu Xinyang , Slaughter Brian D. , Unruh Jay R. , Brennan Kaelan J. , Onyshchenko Anastasiia , Lange Jeffrey J. , Natarajan Malini , Buck Michael , Zeitlinger Julia 
Published: May 2022

AbstractWhile enhancers are often regulated at the level of accessibility by pioneer factors, promoters tend to be constitutively accessible and poised for activation by paused Pol II — thus are often not considered as sites of developmental regulation. Here we show that the accessibility of promoters and the acquisition of paused Pol II can be subject to developmental regulation by pioneer factors. We show that Lola-I, aDrosophilazinc finger transcription factor, is ubiquitously expressed at the end of embryogenesis and causes its target promoters to become accessible and acquire paused Pol II throughout the embryo. This promoter transition is required but not sufficient for tissue-specific target gene expression. Lola-I mediates this function by binding to the edges of the promoter nucleosomes, which leads to their depletion, similar to the action of pioneer factors at enhancers. These results uncover a level of regulation for promoters that is normally found at enhancers, providing further evidence that promoters and enhancers display unexpectedly similar characteristics.
Optimizing Oscillators for Specific Tasks Predicts Preferred Biochemical Implementations
Authors: Agrahar Chaitra , Rust Michael J 
Published: May 2022

Oscillatory processes are used throughout cell biology to control time-varying physiology including the cell cycle, circadian rhythms, and developmental patterning. It has long been understood that free-running oscillations require feedback loops where the activity of one component depends on the concentration of another. Oscillator motifs have been classified by the positive or negative net logic of these loops. However, each feedback loop can be implemented by regulation of either the production step or the removal step. These possibilities are not equivalent because of the underlying structure of biochemical kinetics. By computationally searching over these possibilities, we find that certain molecular implementations are much more likely to produce stable oscillations. These preferred molecular implementations are found in many natural systems, but not typically in artificial oscillators, suggesting a design principle for future synthetic biology. Finally, we develop an approach to oscillator function across different reaction networks by evaluating the biosynthetic cost needed to achieve a given phase coherence. This analysis predicts that phase drift is most efficiently suppressed by delayed negative feedback loop architectures that operate without positive feedback.PACS numbers47.15.-x
satmut_utils: a simulation and variant calling package for multiplexed assays of variant effect
Authors: Hoskins Ian , Sun Song , Cote Atina , Roth Frederick P. , Cenik Can 
Published: May 2022

AbstractBackgroundThe impact of thousands of individual genetic variants on molecular phenotypes for disease-relevant genes remains unknown. Multiplexed assays for variant effect (MAVEs) are highly scalable methods to annotate the relevant variants. However, current software methods for analyzing MAVEs lack standardized annotation, can require cumbersome configuration, and do not easily scale to large target regions.ResultsHere, we present satmut_utils as a flexible solution for 1) simulation of saturation mutagenesis data; and 2) quantification of variants across four orders of magnitude from multiplexed assay data. Improvements of satmut_utils over existing solutions include support for multiple experimental strategies, unique molecular identifier-based consensus deduplication, and machine learning-based error correction. We developed a rigorous simulation workflow to validate the performance of satmut_utils and carried out the first benchmarking of existing software for variant calling. Finally, we used satmut_utils to determine the mRNA abundance of thousands of coding variants in cystathionine beta-synthase (CBS) by two library preparation methods. We identified an association between variants near chemical cofactor binding sites and decreased mRNA abundance. We also found a correlation between codon optimality and the magnitude of variant effects, emphasizing the potential of single-nucleotide variants to alter mRNA abundance.Conclusionssatmut_utils enables high-performance analysis of saturation mutagenesis data, achieves unprecedented specificity through novel error correction approaches, and reveals the capability of single-codon variants to alter mRNA abundance in native coding sequences.
Conditional covalent lethality driven by oncometabolite accumulation
Authors: Perez Minervo , Nance Kellie D. , Bak Daniel W. , Gamage Supuni Thalalla , Najera Susana S. , Conte Amy N. , Linehan W. Marston , Weerapana Eranthie , Meier Jordan L. 
Published: May 2022

AbstractHereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase (FH). Inactivation of FH causes accumulation of the electrophilic oncometabolite fumarate. In the absence of methods for reactivation, tumor suppressors can be targeted via identification of synthetic lethal interactions using genetic screens. Inspired by recent advances in chemoproteomic target identification, here we test the hypothesis that the electrophilicity of the HLRCC metabolome may produce unique susceptibilities to covalent small molecules, a phenomenon we term conditional covalent lethality. Screening a panel of chemically diverse electrophiles we identified a covalent ligand, MP-1, that exhibits FH-dependent cytotoxicity. Synthesis and structure-activity profiling identified key molecular determinants underlying the molecule’s effects. Chemoproteomic profiling of cysteine reactivity together with clickable probes validated the ability of MP-1 to engage an array of functional cysteines, including one lying in the Zn-finger domain of the tRNA methyltransferase enzyme TRMT1. TRMT1 overexpression rescues tRNA methylation from inhibition by MP-1 and partially attenuates the covalent ligand’s cytotoxicity. Our studies highlight the potential for covalent metabolites and small molecules to synergistically produce novel synthetic lethal interactions and raise the possibility of applying phenotypic screening with chemoproteomic target identification to identify new functional oncometabolite targets.
Isolated BAP1 loss in malignant pleural mesothelioma predicts immunogenicity with implications for immunotherapeutic response
Authors: Osmanbeyoglu Hatice Ulku , Palmer Drake , Sagan April , Sementino Eleonora , Testa Joseph R 
Published: May 2022

AbstractMalignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are associated with MPM. The impact of single versus multiple losses of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B loss consistently contributed to an adverse clinical outcome. Since the loss of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it is a candidate for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing MPM therapies.
Fixation Can Change the Appearance of Phase Separation in Living Cells
Authors: Irgen-Gioro Shawn , Yoshida Shawn , Walling Victoria , Chong Shasha 
Published: May 2022

AbstractFixing cells with paraformaldehyde (PFA) is an essential step in numerous biological techniques as it is thought to preserve a snapshot of biomolecular transactions in living cells. Fixed cell imaging techniques such as immunofluorescence have been widely used to detect liquid-liquid phase separation (LLPS)in vivo. Here, we compared images, before and after fixation, of cells expressing intrinsically disordered proteins that are able to undergo LLPS. Surprisingly, we found that PFA fixation can both enhance and diminish putative LLPS behaviors. For specific proteins, fixation can even cause their droplet-like puncta to artificially appear in cells that do not have any detectable puncta in the live condition. Fixing cells in the presence of glycine, a molecule that modulates fixation rates, can reverse the fixation effect from enhancing to diminishing LLPS appearance. We further established a kinetic model of fixation in the context of dynamic protein-protein interactions. Simulations based on the model suggest that protein localization in fixed cells depends on an intricate balance of protein-protein interaction dynamics, the overall rate of fixation, and notably, the difference between fixation rates of different proteins. Consistent with simulations, live-cell single-molecule imaging experiments showed that a fast overall rate of fixation relative to protein-protein interaction dynamics can minimize fixation artifacts. Our work reveals that PFA fixation changes the appearance of LLPS from living cells, presents a caveat in studying LLPS using fixation-based methods, and suggests a mechanism underlying the fixation artifact.
The first glimpse of Homo sapiens hereditary fusion genes
Authors: Zhuo Degen 
Published: May 2022

ABSTRACTFamily-inherited fusion genes have been known to be associated with human disease for decades. However, only a small number of them have been discovered so far. In this report, monozygotic (MZ) twins are used as a genetic model to investigate hereditary fusion genes (HFG). We have analyzed RNA-Seq from 37 MZ twins and discovered 1,180 HFGs, the maximum of which is 608 per haploid genome. Eight HFGs associated with MZ twin inheritance range from 52.7% to 67.6%, some of which are previously-studied cancer fusion genes and indicate hereditary cancer genes. These data suggest that HFGs are major genetic factors for human diseases and complex traits. This study gives us the first glimpse of human HFGs and lays theoretical and technological foundations for future genetic and medical studies.