bluuebunny/crossref_metadata_2025 huggingface dataset:
Using personalized 3D printed Titanium sleeve-prosthetic composite for reconstruction of severe segmental bone loss of proximal femur in revision total hip arthroplasty
Authors: Wang Xingshan , Xu Hui , Zhang Ji
Published: January 2020

Rationale:

Allograft-prosthetic composites (APCs) and proximal femoral replacement have been applied for reconstruction of severe segmental femoral bone loss in revision total hip arthroplasty. The outcomes are encouraging but the complication rate is relatively high. Considering the high complication rates and mixed results of APCs and megaprosthesis, we presented a case using personalized 3D printed Titanium sleeve-prosthetic composite for reconstruction of segmental bone defect.

Patient concerns:

A 73-year-old woman presented to the emergency department on account of acute severe pain of the left hip without history of trauma. She had undergone a cemented total hip arthroplasty for osteonecrosis of femoral head at the left side in 2000. In 2013 she underwent a cemented revision total hip arthroplasty as a result of aseptic loosening of hip prosthesis. She denied obvious discomfort prior to this episode since the revision surgery in 2013.

Diagnosis:

According to the clinical history, imaging and physical examination, we confirmed the diagnosis of severe segmental bone loss of proximal femur and fracture of prosthetic stem. The femoral bone defect was evaluated using the Paprosky classification system and rated as Type 3B, and the acetabular bone defect was rated as Type 2C.

Interventions:

In this study, we present the first case of severe segmental bone loss of proximal femur in revision total hip arthroplasty that was successfully treated using personalized 3D printed Titanium sleeve-prosthetic composite

Outcomes:

At the 2-year follow-up, the patient was symptom free with a Harris Hip Score of 91. Radiographs showed excellent osteointegration between the interface of sleeve-prosthetic composite and the host bone, with no signs of implant loosening or subsidence.

Lessons:

Despite the absence of long term results of 3D printed Titanium sleeve-prosthetic composite reconstruction, the good clinical and radiological outcome at 2 years follow up implied its potential role for reconstruction of segmental femoral bone defect in revision THA.
Spinal epidural involvement in adult Langerhans cell histiocytosis (LCH)
Authors: Lim Cheong-Su , Cho Jae Hwan
Published: January 2020

Rationale:

Spinal involvement in adult Langerhans cell histiocytosis (LCH) is rare, and epidural involvement is unusual. LCH is mostly indistinguishable from other spinal lesions such as infection, lymphoma, and metastasis. So, it could be easily misdiagnosed without suspicion.

Patient concerns:

We report a case of a 33-year-old man who complained of gait disturbance with weakness in both legs and severe back pain.

Diagnoses:

A continuous enhancing epidural lesion with cord compression from the T7 to L1 level was detected in magnetic resonance imaging. Laboratory analysis indicated the possibility of spinal infectious disease. We assumed that the lesion could be tuberculous spondylitis.

Interventions and outcomes:

The patient underwent posterior laminectomy with marginal excision of the epidural mass to relieve cord compression. Pathological examination confirmed the diagnosis of LCH. The 12-month follow-up evaluation revealed that the patient was neurologically intact and had no gait disturbance.

Lessons:

This case report presents a patient with epidural LCH of the thoracic spinal cord, which can mimic spinal infections such as tuberculous spondylitis with abscess formation. Therefore, LCH could be considered as a possible diagnosis when a patient presents with features of infectious spondylitis with vertebral involvement.
A case report of paravertebral low-grade malignant fibrous myxoid sarcoma
Authors: Zhao Ming-Ming , Li Chen-Si , Jun-Wang  , Cheng Yuan-Pei , Zhao Dong-Xu
Published: January 2020

Rationale:

Low-grade malignant fibrous myxoid sarcoma (LGFMS) is a malignant tumor that originates from soft tissues and has specific clinical and histopathological characteristics. Paravertebral LGFMS is rarely reported.

Patient concerns:

A 60-year-old woman had pain in the lower back and right anterior thigh for more than 3 years.

Diagnosis:

Paravertebral LGFMS.

Interventions:

Tumor resection, vertebral canal decompression and pedicle screw fixation.

Outcomes:

The tumor was excised, and the vertebral arch was fixed with pedicle screws at the root. Chemoradiotherapy was not performed. Her postoperative visual analogue scale (VAS) score decreased from 7 points at admission to 2 points at follow-up. The patient was discharged at postoperative day 13, and no recurrence was observed at the 6-month follow-up.

Lessons:

Although LGFMS is rare, it should be considered in differential diagnosis of other soft tissue tumors to avoid misdiagnosis and inappropriate treatment.
Radiotherapy with apatinib for recurrence of malignant phyllodes tumor of the breast
Authors: Wu Hong , Li Lei , Yang Jing , Guo Chen , Zhang Weiming , Wang Hui
Published: January 2020

Rationale:

Malignant phyllodes tumors of the breast are rare, and there are currently no guidelines and a large number of clinical trials to guide the treatment of recurrence tumor. Here we reported a case of radiotherapy with apatinib for the treatment of recurrent malignant phyllodes tumor of the breast.

Patient concerns:

A 58-year-old patient with massive breast mass was admitted to our hospital. Two months after surgical treatment, the tumor recurred in the chest wall scar.

Diagnoses:

The histopathologic diagnoses was right breast malignant phyllodes tumor with chondrosarcomas and osteosarcomas in some areas.

Interventions:

The patient was first treated with surgery. Malignant phyllodes tumor recurred in the chest wall two months after surgery and was treated with radiotherapy and apatinib.

Outcomes:

With surgery, radiotherapy and apatinib treatment, the patient still died within several months.

Lessons:

Apatinib and radiotherapy failed to obtain good therapeutic effect in the recurrence of breast malignant phyllodes tumor in this case.
Rs10757274 gene polymorphisms in coronary artery disease
Authors: Xu Lang-Biao , Zhang Yi-Qing , Zhang Nan-Nan , Li Biao , Weng Jia-Yi , Li Xiao-Yang , Lu Wen-Chao , Yu Pei-Ran , Wang Xi , Li Yuan , Han Zhen , Chen Lu , He Hong-Tao , Zhou Ya-Feng , Ma Xue-Xing , Xu Gui-Dong
Published: January 2020

Background:

It has been reported the rs10757274 SNP (present on locus 9p21 in the gene for CDKN2BAS1) might be associated with susceptibility to coronary artery disease (CAD). Owing to mixed and inconclusive results, we conducted a meta-analysis to investigate the association between rs10757274 polymorphism and the risk of CAD.

Objectives:

The present study aimed to investigate the relationship between rs10757274 polymorphism and the risk of CAD.

Methods:

All studies of the rs10757274 SNP with CAD that were published between 2007 and 2018 were retrieved from the PubMed database. Meta-analysis was performed with Stata 14.0 software. The effect size of the rs10757274 SNP with CAD risk was assessed based on the odds ratios (ORs) with calculation of 95% confidence interval (CI).

Results:

Eleven studies including 52,209 subjects (cases: 7990, controls: 44,219) were included in the final data combination. Pooled overall analyses showed that rs10757274 (allele model: P < .001; dominant model: P < .001; recessive model: P < .001; Heterozygote codominant: P = .002; Homozygote codominant: P < .001) polymorphisms were significantly associated with the likelihood of CAD. Significant heterogeneity between individual studies appears in all 5 models. Further subgroup analyses revealed that rs10757274 polymorphisms were all significantly correlated with the likelihood of CAD and no heterogeneity were observed in West Asians.

Conclusions:

Our findings indicated that rs10757274 polymorphisms may serve as genetic biomarkers of CAD, especially in West Asians.
Efficacy and safety of platelet-rich plasma for the treatment of thin endometrium
Authors: Du Juan , Lu Hua , Yu Xujun , Lü Zili , Mi Ling , Zhang Xiaojin
Published: January 2020

Background:

Endometrial thickness has been identified as a prognostic factor for pregnancy rate for patients with female infertility. Thin endometrium is defined as <7 mm on the day of ovulation, or on the day of human chorionic gonadotrophin (HCG) injection in fresh in vitro fertilization (IVF) cycles, or the day to start progesterone in frozen-thaw embryo transfer cycles, as stated in the guideline of thin endometrium from the Canadin Fertility and Andrology Society and Chinese expert consensus from the Society of Reproductive Medicine, Chinese Medical Association. Many medicines are used for improving the endometrial thickness and embryo implantation rate of the patients with thin endometirum, but thin endometrium remains a major troublesome clinical problem with limited efficacy.

Platelet-rich plasma (PRP), as a growing and robust therapeutic option in musculoskeletal medicine, is a preparation of autologous plasma with a high concentration of platelets, and the therapeutic mechanism is based on the capacity to supply supra physiologic amounts of essential growth factors to provide a regenerative stimulus for promoting repair in tissues with low healing potential. Some randomized controlled trials have reported the application of PRP for patients with thin endometrium with satisfactory effect. However, there is no systematic review on efficacy and safety of PRP as a treatment of thin endometrium.

Methods:

The data and information will be retrieved from the databases of MEDLINE, Embase, Web of Science, Clinicaltrials.org., Cochrane Library, China Biology Medicine Database, Wan Fang Database, China National Knowledge Infrastructure Database, VIP Science Technology Periodical Database, and OpenGrey for gray literature. The randomized controlled clinical trials are going to be selected before December 20, 2019, in English or Chinese language, with the search terms including “thin endometrium,”“platelet-rich plasma,” “endometrial thickness,” “hemorheology of endometrium,” “pregnancy rate,” and “adverse reactions.” RevMan 5.3 will be used for systematic review and meta-analysis. This protocol will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, and the systematic review will be reported with the PRISMA statement.

Results and conclusion:

The efficacy and safety of PRP for the treatment of thin endometrium will be evaluated, and the conclusion will be published to provide medical evidence for a better clinical decision of patients with thin endometirum.
Comparative Study Evaluating Lumen Apposing Metal Stents Versus Double Pigtail Plastic Stents for Treatment of Walled-Off Necrosis
Authors: Ge Phillip S. , Young Joyce Y. , Jirapinyo Pichamol , Dong William , Ryou Marvin , Thompson Christopher C.
Published: January 2020

Objectives

Lumen-apposing metal stents (LAMSs) are increasingly used for direct endoscopic necrosectomy (DEN) in the management of walled-off necrosis (WON). We compared LAMS and traditional cystoenterostomy in the management of WON.

Methods

Retrospective analysis of patients who underwent DEN for management of WON was performed. Primary outcome was rate of WON resolution. Secondary outcomes included technical and clinical success, time and number of procedures until resolution, requirement for alternative therapy, recurrence, and adverse events.

Results

One hundred twelve patients underwent DEN with LAMS (n = 34) or traditional cystoenterostomy (n = 78). Mean WON size was 90.2 × 60.1 mm, and 61.8% had infected necrosis. Overall WON resolution was similar between LAMS and traditional cystoenterostomy (94.1% vs 92.1%, P = 0.510), with similar number of procedures until resolution (1.5 vs 1.5, P = 0.871). The LAMSs were associated with faster resolution (86.9 vs 133.6 days, P = 0.038), lower recurrence (6.3% vs 23.1%, P = 0.032), and decreased requirement for surgery (0% vs 12.8%, P = 0.031) compared with traditional cystoenterostomy, but higher adverse event rates (41.2% vs 7.7%, P < 0.001).

Conclusions

Despite higher adverse event rates, initial LAMS cystoenterostomy for management of WON results in faster resolution, lower recurrence, and decreased requirement for surgery.
Mismatch Repair Deficiency in Ovarian Carcinoma
Authors: Leskela Susanna , Romero Ignacio , Cristobal Eva , Pérez-Mies Belén , Rosa-Rosa Juan M. , Gutierrez-Pecharroman Ana , Caniego-Casas Tamara , Santón Almudena , Ojeda Belén , López-Reig Raquel , Palacios-Berraquero María L. , García Ángel , Ibarra Javier , Hakim Sofía , Guarch Rosa , López-Guerrero José A. , Poveda Andrés , Palacios José
Published: January 2020

Mismatch repair deficiency (MMRD) is involved in the initiation of both hereditary and sporadic tumors. MMRD has been extensively studied in colorectal cancer and endometrial cancer, but not so in other tumors, such as ovarian carcinoma. We have determined the expression of mismatch repair proteins in a large cohort of 502 early-stage epithelial ovarian carcinoma entailing all the 5 main subtypes: high-grade serous carcinoma, endometrioid ovarian carcinoma (EOC), clear cell carcinoma (CCC), mucinous carcinoma, and low-grade serous carcinoma. We studied the association of MMRD with clinicopathologic and immunohistochemical features, including tumor-infiltrating lymphocytes in EOC, the histologic type in which MMRD is most frequent. In addition, MLH1 promoter methylation status and massive parallel sequencing were used to evaluate the proportion of sporadic and Lynch syndrome–associated tumors, and the most frequently mutated genes in MMRD EOCs. MMRD occurred only in endometriosis-associated histologic types, and it was much more frequent in EOC (18%) than in CCC (2%). The most frequent immunohistochemical pattern was loss of MLH1/PMS2, and in this group, 80% of the cases were sporadic and secondary to MLH1 promoter hypermethylation. The presence of somatic mutations in mismatch repair genes was the other mechanism of MMRD in sporadic tumors. In this series, the minimum estimated frequency of Lynch syndrome was 35% and it was due to germline mutations in MLH1, MSH2, and MSH6. ARID1A, PTEN, KTM2B, and PIK3CA were the most common mutated genes in this series. Interestingly, possible actionable mutations in ERRB2 were found in 5 tumors, but no TP53 mutations were detected. MMRD was associated with younger age and increased tumor-infiltrating lymphocytes. Universal screening in EOC and mixed EOC/CCC is recommended for the high frequency of MMRD detected; however, for CCC, additional clinical and pathologic criteria should be evaluated to help select cases for analysis.
Fingertip Replantation Using Artery-Only Anastomosis With a Pulp Tissue Reduction Method
Authors: Nakajima Yuta , Iwasawa Motonao , Mishima Yoshito , Yuzuriha Shunsuke
Published: January 2020

Background

In fingertip replantation with arterial anastomosis alone, many external bleeding techniques have been described to satisfy venous outflow, and some patients require blood transfusions. We used a pulp tissue reduction method to avoid the need for external bleeding techniques and blood transfusions.

Methods

We examined 18 fingers in cases of Ishikawa's subzone II, III, and IV amputation that were replanted with artery-only anastomosis and pulp tissue reduction from April 2003 to March 2018. The method consisted of pulp tissue reduction to the level of the fingerprint core, bone fixation without gaps to promote venous drainage through bone marrow, and pinprick testing twice a day. Prostaglandin E1 and/or urokinase were administered intravenously, but no other anticoagulants were used systemically or locally. Postoperatively, only the pinprick test was performed twice a day for 5 days.

Results

The patients ranged in age from 26 to 74 years (mean, 47 years). There were 13 men and 5 women. The total success rate was 89% (16/18). Of the 2 salvage failures, one was due to venous congestion and the other was due to arterial insufficiency. The survival rates of Ishikawa's subzone II, III, and IV amputation were 100% (4/4), 71% (5/7), and 100% (7/7), respectively. No blood transfusions were required in any of the cases. The Semmes-Weinstein test was performed for 14 of 18 fingers: the result was blue in 11 fingers and purple in 3 fingers.

Conclusions

The pulp tissue reduction method resulted in a high success rate without the need for external bleeding or blood transfusions. Fingertip replantation with artery-only anastomosis, a pulp tissue reduction method, is effective for replant survival when subcutaneous venous repair is impossible because a reduced pulp volume may facilitate replant survival under conditions of irregular venous drainage, such as bone marrow drainage.
Mortality, disease progression, and disease burden of acute kidney injury in alcohol use disorder subpopulation
Authors: Le Sidney , Green-Saxena Abigail , Maharjan Jenish , Khattar Manan , Calvert Jacob , Pellegrini Emily , Hoffman Jana , Das Ritankar
Published: January 2020

Objective

The objective of this study is to quantify the relationship between acute kidney injury (AKI) and alcohol use disorder (AUD), in terms of disease burden, mortality burden and disease progression.

Methods

We used the University of California, San Francisco Medical Center in San Francisco, CA (UCSF) and Medical Information Mart for Intensive Care (MIMIC-III) databases to quantify AKI disease and mortality burden as well as AKI disease progression in the AUD and non-AUD subpopulations. We used the MIMIC-III dataset to compare two different methods of encoding AKI: ICD-9 codes, and the 2012 Kidney Disease: Improving Global Outcomes scheme (KDIGO). In addition to the AUD subpopulation (defined by AUD-related ICD-9 codes), we also present analysis for the hepatorenal syndrome (HRS) and alcohol-related cirrhosis subpopulations identified via ICD-9 coding.

Results

In both the ICD-9 and KDIGO encodings of AKI, the AUD subpopulation had a higher prevalence of AKI (ICD-9: 48.59% vs. 29.99% AKI in the non-AUD subpopulations; KDIGO: 39.84% vs. 27.99%) in the MIMIC-III dataset. In the UCSF dataset, the AUD subpopulation also had a higher prevalence of AKI than the non-AUD subpopulation (ICD-9: 48.60% vs. 8.45%). The mortality rate of the subpopulation with both AKI and an AUD-related condition (AUD, HRS, or alcohol-related cirrhosis) was consistently higher than that of the subpopulation with only AKI in both datasets after adjusting for disease severity using two methods of severity estimation in the MIMIC-III dataset. Disease progression rates were similar for AUD and non-AUD subpopulations.

Conclusions

Our work using the UCSF multi-ward academic hospital data and the MIMIC-III ICU dataset shows that the AUD patient subpopulation had a higher number of AKI patients than the non-AUD subpopulation, and that patients with both AKI and either AUD, HRS, or alcohol-related cirrhosis were shown to have higher rates of mortality than the non-AUD subpopulation with AKI.

Trial Registration

Not applicable.
Colonoscopy and reduction of colorectal cancer risk by molecular tumor subtypes: a population-based case-control study
Authors: Hoffmeister Michael , Bläker Hendrik , Jansen Lina , Alwers Elizabeth , Amitay Efrat L. , Carr Prudence R. , Kloor Matthias , Herpel Esther , Roth Wilfried , Chang-Claude Jenny , Brenner Hermann
Published: January 2020

Objective

In previous studies, the protective effect of colonoscopy was generally stronger for distal than for proximal colorectal cancer (CRC). This study aimed to investigate whether the association of colonoscopy and CRC risk varies according to major molecular pathological features and pathways of CRC.

Design

Population-based case-control study from Germany, including 2132 patients with a first diagnosis of CRC and information on major molecular tumor markers, and 2486 control participants without CRC. Detailed participant characteristics were collected by standardized questionnaires and information on previous colonoscopy was derived from medical records. Polytomous logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between previous colonoscopy and subtypes of CRC.

Results

Overall, we observed strong risk reduction of CRC after colonoscopy that was weaker for microsatellite instable (MSI) than for non-MSI CRC (p for heterogeneity <0.01), for CpG island methylator phenotype (CIMP) high CRC than for CIMP low/negative CRC (p het<0.01), for BRAF-mutated than for BRAF non-mutated CRC (p het=0.01), for KRAS non-mutated than for KRAS-mutated CRC (p het=0.04), and for CRC classified into the sessile serrated pathway than for CRC of the traditional pathway (p het<0.01). After colonoscopy with detection of adenomas, no risk reduction was found for sessile serrated pathway CRC.

Conclusion

Our study extends the molecular understanding of existing differences in risk reduction of proximal and distal CRC reported by previous studies, and may imply important information for improving strategies for timely detection of relevant precursors.

Summary Box

What is already known about this subject?

Colonoscopy is an effective tool not only for early detection but also for prevention of colorectal cancer.

In previous studies, risk reduction after colonoscopy was generally stronger for cancer of the distal colon and rectum than for cancer of the proximal colon.

What are the new findings?

This observational study found variation of colorectal cancer risk reduction after colonoscopy according to major molecular subtypes characteristic of the proximal colon (MSI, CIMP-high, BRAF mutation), and for colorectal cancer potentially developing via the sessile serrated pathway.

How might it impact on clinical practice in the foreseeable future?

This study contributes to the identification of molecular characteristics and associated phenotypes of potentially missed or more aggressive precursors.

The study provides important information for improving strategies for a timely detection of relevant precursors at colonoscopy.
metPropagate: network-guided propagation of metabolomic information for prioritization of neurometabolic disease genes
Authors: Graham Emma , Richmond Phillip A , Tarailo-Graovac Maja , Engelke Udo , Kluijtmans Leo A.J. , Coene Karlien L.M , Wevers Ron A. , Wasserman Wyeth , van Karnebeek Clara D.M. , Mostafavi Sara
Published: January 2020

Many inborn errors of metabolism (IEMs) are amenable to treatment, therefore early diagnosis before irreversible damage occurs is imperative. Despite recent advances, the genetic basis of many metabolic phenotypes remains unknown. For discovery purposes, Whole Exome Sequencing (WES) variant prioritization coupled with phenotype-guided clinical and bioinformatics expertise is currently the primary method used to identify novel disease-causing variants; however, it can be challenging to identify the causal candidate gene given the large number of plausible variants. Using untargeted metabolomics (UM) to prioritize metabolically relevant candidate genes is a promising approach to diagnosing known or novel IEMs in a single patient. Here, we present a network-based bioinformatics approach, metPropagate, that uses UM data from a single patient and a group of controls to prioritize candidate genes. We validate metProp on 107 patients with diagnosed IEMs and 11 patients with novel IEMs diagnosed through the TIDE gene discovery project at BC Children’s Hospital. The metPropagate method ranks candidate genes by considering the network of interactions between them. This is done by using a graph smoothing algorithm called label propagation to quantify the metabolic disruption in genes’ local neighbourhood. metPropagate was able to prioritize the causative gene in the top 20th percentile of candidate genes for 91% of patients with known IEM disorders. For novel IEMs, metPropagate placed the causative gene in the top 20th percentile in 9/11 patients. Using metPropagate, the causative gene was ranked higher than Exomiser’s phenotype-based ranking in 6/11 patients. The results of this study indicate that for diagnostic and gene discovery purposes, network-based analysis of metabolomics data can lend support to WES gene-discovery methods by providing an additional mode of evidence to help identify causal genes.
The Impact of Income Support Systems on Healthcare Quality and Functional Capacity in Workers with Low Back Pain: A Realist Review
Authors: Di Donato Michael , Iles Ross , Lane Tyler , Buchbinder Rachelle , Collie Alex
Published: January 2020

Background

Low back pain (LBP) is a leading cause of work disability. While absent from work, workers with LBP may receive income support from a system such as workers’ compensation or social security. Current evidence suggests that income support systems can influence recovery from LBP, but provides little insight as to why and how these effects occur. This study examines how and in what contexts income support systems impact the healthcare quality for people with work disability and LBP and their functional capacity.

Methods

We performed a realist review, a type of literature review that seeks to explain how social interventions and phenomena in certain contexts generate outcomes, rather than simply whether they do. Five initial theories about the relationship between income support systems and outcomes were developed, tested, and refined by acquiring and synthesising academic literature from purposive and iterative electronic database searching. This process was supplemented with grey literature searches for policy documents and legislative summaries, and semi-structured interviews with experts in income support, healthcare and LBP.

Results

Income support systems influence healthcare quality through funding restrictions, healthcare provider administrative burden, and allowing employers to select providers. They also influence worker functional capacity through the level of participation and financial incentives for employers, measures to prove the validity of the worker’s LBP, and certain administrative procedures. These mechanisms are often exclusively context-dependent, and generate differing and unintended outcomes depending on features of the healthcare and income support system, as well as other contextual factors such as socioeconomic status and labour force composition.

Discussion

Income support systems impact the healthcare quality and functional capacity of people with work disability and LBP through context-dependent financial control, regulatory and administrative mechanisms. Research and policy design should consider how income support systems may indirectly influence workers with LBP via the workplace.
Genome wide sequencing provides evidence of adaptation to heterogeneous environments for the ancient relictualCircaeaster agrestis(Circaeasteraceae, Ranunculales)
Authors: Zhang Xu , Sun Yanxia , Landis Jacob B. , Zhang Jianwen , Yang Linsen , Lin Nan , Zhang Huajie , Guo Rui , Li Lijuan , Zhang Yonghong , Deng Tao , Sun Hang , Wang Hengchang
Published: January 2020

Investigating the interaction between environmental heterogeneity and local adaptation is critical to understand the evolutionary history of a species, providing the premise for studying the response of organisms to rapid climate change. However, for most species how exactly the spatial heterogeneity promotes population divergence and how genomic variations contribute to adaptive evolution remain poorly understood.

We examine the contributions of geographical and environmental variables to population divergence of the relictual, alpine herbCircaeaster agrestis, as well as genetic basis of local adaptation using RAD-seq and plastome data.

We detected significant genetic structure with an extraordinary disequilibrium of genetic diversity among regions, and signals of isolation-by-distance along with isolation-by-resistance. The populations were estimated to begin diverging in the late Miocene, along with a possible ancestral distribution of the Hengduan Mountains and adjacent regions. Both environmental gradient and redundancy analyses revealed significant association between genetic variation and temperature variables. Genome-environment association analyses identified 16 putatively adaptive loci related to biotic and abiotic stress resistance.

Our genome wide data provide new insights into the important role of environmental heterogeneity in shaping genetic structure, and access the footprints of local adaptation in an ancient relictual species, informing conservation efforts.
Deep Brain Stimulation: Imaging on a group level
Authors: Treu Svenja , Strange Bryan , Oxenford Simon , Kühn Andrea , Li Ningfei , Horn Andreas
Published: January 2020

Deep Brain Stimulation (DBS) is an established treatment option for movement disorders and is investigated to treat a growing number of other brain disorders. It has been shown that DBS effects are highly dependent on exact electrode placement, which is especially important when probing novel indications or stereotactic targets. Thus, considering precise electrode placement is crucial when investigating efficacy of DBS targets. To measure clinical improvement as a function of electrode placement, neuroscientific methodology and specialized software tools are needed. Such tools should have the goal to make electrode placement comparable across patients and DBS centers, and include statistical analysis options to validate and define optimal targets. Moreover, to allow for comparability across different research sites, these need to be performed within an algorithmically and anatomically standardized and openly available group space. With the publication of Lead-DBS software in 2014, an open-source tool was introduced that allowed for precise electrode reconstructions based on pre- and postoperative neuroimaging data. Here, we introduce Lead Group, implemented within the Lead-DBS environment and specifically designed to meet aforementioned demands. In the present article, we showcase the various processing streams of Lead Group in a retrospective cohort of 51 patients suffering from Parkinson’s disease, who were implanted with DBS electrodes to the subthalamic nucleus (STN). Specifically, we demonstrate various ways to visualize placement of all electrodes in the group and map clinical improvement values to subcortical space. We do so by using active coordinates and volumes of tissue activated, showing converging evidence of an optimal DBS target in the dorsolateral STN. Second, we relate DBS outcome to the impact of each electrode on local structures by measuring overlap of stimulation volumes with the STN. Finally, we explore the software functions for connectomic mapping, which may be used to relate DBS outcomes to connectivity estimates with remote brain areas. We isolate a specific fiber bundle – which structurally resembles the hyperdirect pathway – that is associated with good clinical outcome in the cohort. The manuscript is accompanied by a walkthrough tutorial through which users are able to reproduce all main results presented in the present manuscript. All data and code needed to reproduce results are openly available.

Highlights

We present a novel toolbox to carry out DBS imaging analyses on a group-level

Group electrodes are visualized in 2D and 3D and related to clinical regressors

A favorable target and connectivity profiles for the treatment of PD are validated
Complementary effects of adaptation and gain control on sound encoding in primary auditory cortex
Authors: Pennington Jacob , David Stephen
Published: January 2020

An important step toward understanding how the brain represents complex natural sounds is to develop accurate models of auditory coding by single neurons. A common model for auditory coding is the linear-nonlinear spectro-temporal receptive field (LN model). The LN model accounts for many features of auditory tuning, but it cannot account for long-lasting effects of sensory context on sound-evoked activity. Two mechanisms that may support these contextual effects are short-term plasticity (STP) and contrast-dependent gain control (GC), each of which has inspired an expanded version of the LN model. Both of these models improve performance over the LN model, but they have never been compared directly. Thus, it is unclear whether they account for distinct processes or describe the same phenomenon in different ways. To address this question, we recorded activity of neurons in primary auditory cortex of awake ferrets during presentation of natural sounds. We then fit models incorporating one nonlinear mechanism (GC or STP) or both (GC+STP) using this single dataset, and measured the correlation between the models’ predictions and the recorded neural activity. Both the STP and GC models performed significantly better than the LN model, but the GC+STP model performed better than either individual model. We also quantified the similarity between STP and GC model predictions and found only modest equivalence between them. Similar results were observed for a smaller dataset collected in clean and noisy acoustic contexts. These results suggest that the STP and GC models describe distinct, complementary processes in the auditory system.

Significance Statement

Computational models are used widely to study neural sensory coding. However, models developed in separate studies are often difficult to compare because of differences in stimuli and experimental preparation. This study develops an approach for making systematic comparisons between models that measures the net benefit of incorporating additional nonlinear elements into models of auditory encoding. This approach was then used to compare two different hypotheses for how sensory context, that is, slow changes in the statistics of the acoustic environment, influences activity in auditory cortex. Both models accounted for complementary aspects of the neural response, indicating that a hybrid model incorporating elements of both models provides the most complete characterization of auditory processing.
Integrating Proteomes for Lung Tissue and Lavage Reveals Pathways that Link Responses in Allergen-Challenged Mice
Authors: Mahood Thomas H , Pascoe Christopher D , Karakach Tobias K , Jha Aruni , Basu Sujata , Ezzati Peyman , Spicer Victor , Mookherjee Neeloffer , Halayko Andrew J
Published: January 2020

To capture interplay between biological pathways we analyzed the proteome from matched lung tissue and bronchoalveolar lavage fluid (BALF) of individual allergen-naïve and house dust mite (HDM)-challenged BALB/c mice, a model of allergic asthma. Unbiased label-free LC-MS/MS analysis quantified 2,675 proteins from tissue and BALF of allergen-naïve and HDM-exposed mice. In comparing the four datasets we found significantly greater diversity in proteins between lung tissue and BALF than in the changes induced by HDM challenge. The biological pathways enriched after allergen exposure were compartment-dependent. Lung tissue featured innate immune responses and oxidative stress, while BALF most strongly revealed changes in metabolism. We combined lung tissue and BALF proteomes, which principally highlighted oxidation reduction (redox) pathways, a finding influenced chiefly by the lung tissue dataset. Integrating lung and BALF proteomes also uncovered new proteins and biological pathways that may mediate lung tissue and BALF interactions after allergen challenge, for example, B Cell Receptor signaling. We demonstrate that enhanced insight is fostered when different biological compartments from the lung are investigated in parallel. Integration of proteomes from lung tissue and BALF compartments reveals new information about protein networks in the response to environmental challenge and interaction between intracellular and extracellular process.
Investigating the Genetic Architecture of Non-Cognitive Skills Using GWAS-by-Subtraction
Authors: Demange Perline A. , Malanchini Margherita , Mallard Travis T. , Biroli Pietro , Cox Simon R. , Grotzinger Andrew D. , Tucker-Drob Elliot M. , Abdellaoui Abdel , Arseneault Louise , Caspi Avshalom , Corcoran David , Domingue Benjamin , Mitchell Colter , van Bergen Elsje , Boomsma Dorret I. , Harris Kathleen M. , Ip Hill F. , Moffitt Terrie E. , Poulton Richie , Prinz Joseph , Sugden Karen , Wertz Jasmin , Williams Benjamin , de Zeeuw Eveline L. , Belsky Daniel W. , Harden K. Paige , Nivard Michel G.
Published: January 2020

Educational attainment (EA) is influenced by cognitive abilities and by other characteristics and traits. However little is known about the genetic architecture of these “non-cognitive” contributions to EA. Here, we use Genomic Structural Equation Modelling and results of prior genome-wide association studies (GWASs) of EA (N = 1,131,881) and cognitive test performance (N = 257,841) to estimate SNP associations with variation in EA that is independent of cognitive ability. We identified 157 genome-wide significant loci and a polygenic architecture accounting for 57% of genetic variance in EA. Phenotypic and biological annotation revealed that (1) both cognitive and non-cognitive contributions to EA were genetically correlated with socioeconomic success and longevity; and (2) non-cognitive contributions to EA were related to personality, decision making, risk-behavior, and increased risk for psychiatric disorders; (3) non-cognitive and cognitive contributions to EA were enriched in the same tissues and cell types, but (4) showed different associations with gray-matter neuroimaging phenotypes.
Longitudinal cancer evolution from single cells
Authors: Ramazzotti Daniele , Angaroni Fabrizio , Maspero Davide , Ascolani Gianluca , Castiglioni Isabella , Piazza Rocco , Antoniotti Marco , Graudenzi Alex
Published: January 2020

The rise of longitudinal single-cell sequencing experiments on patient-derived cell cultures, xenografts and organoids is opening new opportunities to track cancer evolution in single tumors and to investigate intra-tumor heterogeneity. This is particularly relevant when assessing the efficacy of therapies over time on the clonal composition of a tumor and in the identification of resistant subclones.

We here introduce LACE (Longitudinal Analysis of Cancer Evolution), the first algorithmic framework that processes single-cell somatic mutation profiles from cancer samples collected at different time points and in distinct experimental settings, to produce longitudinal models of cancer evolution. Our approach solves a Boolean matrix factorization problem with phylogenetic constraints, by maximizing a weighted likelihood function computed on multiple time points, and we show with simulations that it outperforms state-of-the-art methods for both bulk and single-cell sequencing data.

Remarkably, as the results are robust with respect to high levels of data-specific errors, LACE can be employed to process single-cell mutational profiles as generated by calling variants from the increasingly available scRNA-seq data, thus obviating the need of relying on rarer and more expensive genome sequencing experiments. This also allows to investigate the relation between genomic clonal evolution and phenotype at the single-cell level.

To illustrate the capabilities of LACE, we show its application to a longitudinal scRNA-seq dataset of patient-derived xenografts of BRAFV600E/Kmutant melanomas, in which we characterize the impact of concurrent BRAF/MEK-inhibition on clonal evolution, also by showing that distinct genetic clones reveal different sensitivity to the therapy. Furthermore, the analysis of a longitudinal dataset of breast cancer PDXs from targeted scDNA-sequencing experiments delivers a high-resolution characterization of intra-tumor heterogeneity, also allowing the detection of a late de novo subclone.
Improved bacterial recombineering by parallelized protein discovery
Authors: Wannier Timothy M. , Nyerges Akos , Kuchwara Helene M. , Czikkely Márton , Balogh Dávid , Filsinger Gabriel T. , Borders Nathaniel C. , Gregg Christopher J. , Lajoie Marc J. , Rios Xavier , Pál Csaba , Church George M.
Published: January 2020

Exploiting bacteriophage-derived homologous recombination processes has enabled precise, multiplex editing of microbial genomes and the construction of billions of customized genetic variants in a single day. The techniques that enable this, Multiplex Automated Genome Engineering (MAGE) and directed evolution with random genomic mutations (DIvERGE), are however currently limited to a handful of microorganisms for which single-stranded DNA-annealing proteins (SSAPs) that promote efficient recombineering have been identified. Thus, to enable genome-scale engineering in new hosts, highly efficient SSAPs must first be found. Here we introduce a high-throughput method for SSAP discovery that we call Serial Enrichment for Efficient Recombineering (SEER). By performing SEER inE. colito screen hundreds of putative SSAPs, we identify highly active variants PapRecT and CspRecT. CspRecT increases the efficiency of single-locus editing to as high as 50% and improves multiplex editing by 5 to 10-fold inE. coli, while PapRecT enables efficient recombineering inPseudomonas aeruginosa, a concerning human pathogen. CspRecT and PapRecT are also active in other, clinically and biotechnologically relevant enterobacteria. We envision that the deployment of SEER in new species will pave the way toward pooled interrogation of genotype-to-phenotype relationships in previously intractable bacteria.
A global map of root biomass across the world’s forests
Authors: Huang Yuanyuan , Ciais Phillipe , Santoro Maurizio , Makowski David , Chave Jerome , Schepaschenko Dmitry , Abramoff Rose , Goll Daniel S. , Yang Hui , Chen Ye , Wei Wei , Piao Shilong
Published: January 2020

Abstract (150 words limits)

Root plays a key role in plant growth and functioning. Here we combine 10307 field measurements of forest root biomass worldwide with global observations of forest structure, climatic conditions, topography, land management and soil characteristics to derive a spatially-explicit global high-resolution (~ 1km) root biomass dataset, including fine and coarse roots. In total, 142 ± 32 Pg of live dry matter biomass is stored below-ground, that is a global average root:shoot biomass ratio of 0.25 ± 0.10. Our estimations of total root biomass in tropical, temperate and boreal forests are 44-226% smaller than earlier studies1–3. The smaller estimation is attributable to the updated forest area, spatially explicit above-ground biomass density used to predict the patterns of root biomass, new root measurements and upscaling methodology. We show specifically that the root shoot allometry is one underlying driver that leads to methodological overestimation of root biomass in previous estimations.
Carbon limitation leads to thermodynamic regulation of aerobic metabolism
Authors: Garayburu-Caruso Vanessa A. , Stegen James C. , Song Hyun-Seob , Renteria Lupita , Wells Jaqueline , Garcia Whitney , Resch Charles T. , Goldman Amy , Chu Rosalie , Toyoda Jason , Graham Emily B.
Published: January 2020

Organic matter (OM) metabolism in freshwater ecosystems is a critical source of uncertainty in global biogeochemical cycles, yet aquatic OM cycling remains poorly understood. Here, we present the first work to explicitly test OM thermodynamics as a key regulator of aerobic respiration, challenging long-held beliefs that organic carbon and oxygen concentrations are the primary determinants of respiration rates. We pair controlled microcosm experiments with ultrahigh-resolution OM characterization to demonstrate a clear relationship between OM thermodynamic favorability and aerobic respiration under carbon limitation. We also demonstrate a shift in the regulation of aerobic respiration from OM thermodynamics to nitrogen content when carbon is in excess, highlighting a central role for OM thermodynamics in aquatic biogeochemical cycling particularly in carbon-limited ecosystems. Our work therefore illuminates a structural gap in aquatic biogeochemical models and presents a new paradigm in which OM thermodynamics and nitrogen content interactively govern aerobic respiration.
Linked-read sequencing enables haplotype-resolved resequencing at population scale
Authors: Lutgen Dave , Ritter Raphael , Olsen Remi-André , Schielzeth Holger , Gruselius Joel , Ewels Phil , García Jesús T. , Shirihai Hadoram , Schweizer Manuel , Suh Alexander , Burri Reto
Published: January 2020

The feasibility to sequence entire genomes of virtually any organism provides unprecedented insights into the evolutionary history of populations and species. Nevertheless, many population genomic inferences – including the quantification and dating of admixture, introgression and demographic events, and the inference of selective sweeps – are still limited by the lack of high-quality haplotype information. In this respect, the newest generation of sequencing technology now promises significant progress. To establish the feasibility of haplotype-resolved genome resequencing at population scale, we investigated properties of linked-read sequencing data of songbirds of the genusOenantheacross a range of sequencing depths. Our results based on the comparison of downsampled (25x, 20x, 15x, 10x, 7x, and 5x) with high-coverage data (46-68x) of seven bird genomes suggest that phasing contiguities and accuracies adequate for most population genomic analyses can be reached already with moderate sequencing effort. At 15x coverage, phased haplotypes span about 90% of the genome assembly, with 50 and 90 percent of the phased sequence located in phase blocks longer than 1.25-4.6 Mb (N50) and 0.27-0.72 Mb (N90), respectively. Phasing accuracy reaches beyond 99% starting from 15x coverage. Higher coverages yielded higher contiguities (up to about 7 Mb/1Mb (N50/N90) at 25x coverage), but only marginally improved phasing accuracy. Finally, phasing contiguity improved with input DNA molecule length; thus, higher-quality DNA may help keeping sequencing costs at bay. In conclusion, even for organisms with gigabase-sized genomes like birds, linked-read sequencing at moderate depth opens an affordable avenue towards haplotype-resolved genome resequencing data at population scale.
The structure and global distribution of the endoplasmic reticulum network is actively regulated by lysosomes
Authors: Lu Meng , van Tartwijk Francesca W. , Lin Julie Qiaojin , Nijenhuis Wilco , Parutto Pierre , Fantham Marcus , Christensen Charles N. , Avezov Edward , Holt Christine E. , Tunnacliffe Alan , Holcman David , Kapitein Lukas C. , Schierle Gabriele Kaminski , Kaminski Clemens F.
Published: January 2020

The endoplasmic reticulum (ER) comprises morphologically and functionally distinct domains, sheets and interconnected tubules. These domains undergo dynamic reshaping, in response to changes in the cellular environment. However, the mechanisms behind this rapid remodeling within minutes are largely unknown. Here, we report that ER remodeling is actively driven by lysosomes, following lysosome repositioning in response to changes in nutritional status. The anchorage of lysosomes to ER growth tips is critical for ER tubule elongation and connection. We validate this causal link via the chemo- and optogenetically driven re-positioning of lysosomes, which leads to both a redistribution of the ER tubules and its global morphology. Lysosomes sense metabolic change in the cell and regulate ER tubule distribution accordingly. Dysfunction in this mechanism during axonal extension may lead to axonal growth defects. Our results demonstrate a critical role of lysosome-regulated ER dynamics and reshaping in nutrient responses and neuronal development.