bluuebunny/crossref_metadata_2025 huggingface dataset:
Vasculitis and peripheral neuropathy
Authors: Graf Jonathan , Imboden John
Published: November 2018

Purpose of review

Vasculitis of medium-sized and small vessels commonly affects peripheral nerves and can occur in context of a systemic vasculitis with multiorgan involvement or a nonsystemic vasculitis limited to the peripheral nervous system. This review summarizes the clinical and pathological features of systemic and nonsystemic vasculitis of the peripheral nervous system.

Recent findings

Vasculitis of peripheral nerves is a diffuse process that affects the vasa nervorum along the entire length of affected nerves but appears to cause injury primarily in a zone in the proximal-middle of the nerve that is particularly susceptible to ischemic injury. Nerve biopsy can help establish the diagnosis of a systemic vasculitis, particularly when other organ involvement is not clinically apparent, and is required for diagnosis of nonsystemic vasculitic neuropathy. Observational studies suggest that nonsystemic vasculitic neuropathy responds to immunosuppressive therapy but conclusive data are lacking.

The current review summarizes the clinical and pathological features of both systemic and nonsystemic vasculitis of the peripheral nervous system so that clinicians can better recognize, make a more timely diagnosis, and thus treat this condition more effectively in their patients.
Stem Cells for the Treatment of Intervertebral Disk Degeneration
Authors: Presciutti Steven M. , Drissi Hicham
Published: November 2018

Low back pain and neck pain are the first and fourth leading causes, respectively, of years lived with disability. The treatment of intervertebral disk degeneration remains a significant challenge. While there are still many obstacles to overcome, the use of stem cells for the treatment of disk degeneration has emerged as one of the most promising and exciting techniques to restore the structure and function of the degenerated disk. The use of stem cells in treating intervertebral disk disease as well as the obstacles that remain are reviewed here in an evidence-based manner.
Use of Mesenchymal Stem/Stromal Cells for Pediatric Orthopedic Applications
Authors: Guess Adam J. , Abzug Joshua M. , Otsuru Satoru
Published: November 2018

Cell-based therapies using mesenchymal stem/stromal cells (MSCs) have been extensively investigated both in preclinical and clinical settings. Because of their multipotency, MSCs have initially been expected to regenerate tissues by differentiating into native tissue cells. However, accumulating evidence suggests that the observed clinical benefits are largely from the trophic effects of MSCs. In pilot studies, systemic infusion of MSCs has been shown to clinically improve patients with osteogenesis imperfecta and hypophosphatasia even though donor cell engraftment was minimal, suggesting that the trophic effects of MSCs likely play a critical role in the treatment of these pediatric orthopedic diseases. Interestingly, genomic and proteomic analyses demonstrate variance in trophic activities among MSCs from different sources and donors, suggesting that the clinical outcomes could be dependent on the selection of therapeutic MSCs. The purpose of this review is to provide current information regarding MSCs that involve their therapeutic effects and review the clinical outcomes of MSC therapy in pediatric orthopedic diseases. In addition, the potential of cell-free therapy using extracellular vesicles released by MSCs is discussed. Understanding the mechanisms underlying MSC therapeutic actions is critical to selecting therapeutic MSCs for infusion, which will increase the efficacy and consistency of MSC therapy.
The Ewing Amputation: The First Human Implementation of the Agonist-Antagonist Myoneural Interface
Authors: Clites Tyler R. , Herr Hugh M. , Srinivasan Shriya S. , Zorzos Anthony N. , Carty Matthew J.
Published: November 2018

Background:

The agonist-antagonist myoneural interface (AMI) comprises a surgical construct and neural control architecture designed to serve as a bidirectional interface, capable of reflecting proprioceptive sensation of prosthetic joint position, speed, and torque from and advanced limb prosthesis onto the central nervous system. The AMI surgical procedure has previously been vetted in animal models; we here present the surgical results of its translation to human subjects.

Methods:

Modified unilateral below knee amputations were performed in the elective setting in 3 human subjects between July 2016 and April 2017. AMIs were constructed in each subject to control and interpret proprioception from the bionic ankle and subtalar joints. Intraoperative, perioperative, and postoperative residual-limb outcome measures were recorded and analyzed, including electromyographic and radiographic imaging of AMI musculature.

Results:

Mean subject age was 38 ± 13 years, and mean body mass index was 29.5 ± 5.5 kg/m2. Mean operative time was 346 ± 87 minutes, including 120 minutes of tourniquet time per subject. Complications were minor and included transient cellulitis and one instance of delayed wound healing. All subjects demonstrated mild limb hypertrophy postoperatively, and intact construct excursion with volitional muscle activation. All patients reported a high degree of phantom limb position perception with no reports of phantom pain.

Conclusions:

The AMI offers the possibility of improved prosthetic control and restoration of muscle-tendon proprioception. Initial results in this first cohort of human patients are promising and provide evidence as to the potential role of AMIs in the care of patients requiring below knee amputation.
A taxonomy of hospitals based on partnerships for population health management
Authors: Noh Eunjeong , Potthoff Sandra , Begun James W.
Published: November 2018

Background:

Hospitals face growing pressures and opportunities to engage with partner organizations in efforts to improve population health at the community level. Variation has been observed in the degree to which hospitals develop such partnerships.

Purpose:

The aim of this study was to generate a taxonomy of hospitals based on their partnerships with external organizations, employing the theoretical notion of organizations’ focus on exploration versus exploitation.

Methodology:

With 1,238 valid cases from the 2015 American Hospital Association Population Health Survey, our study uses items asking about the level of partnership strength for 36 named partner types. Excluding three variables with low reliability, 33 variables are classified into six partner groups by factor analysis. Then, cluster analysis is conducted to generate a taxonomy of hospitals based on their partnerships with the six partner groups.

Findings:

Of 1,238 hospitals, 26.1% are classified as exploratory hospitals that develop more collaborative relationships with partners outside the medical sector. Exploitative hospitals (18.3%) focus on relationships with traditional medical sector partners. Ambidextrous hospitals (27.0%) develop partnerships both in and outside the medical sector. Finally, independent hospitals (28.6%) do not establish strong partnerships. Larger hospitals, not-for-profit hospitals, and teaching hospitals are more likely to be classified as exploratory.

Practice Implications:

The four-cluster taxonomy can provide hospital and health system leaders and managers with a better understanding of the wide variation in partnerships that hospitals establish and insights into their different strategic options with regard to partnership development.
Report of Resistant Varicella Zoster Infection Treated With Donor Lymphocyte Infusion in a Pediatric Oncology Patient
Authors: Cooper Katherine , Makin Guy , Davies Emma , Turner Andrew , Hiwarkar Prashant , Wynn Robert
Published: November 2018

We report an 8-year-old boy with disseminated, life-threatening, drug treatment-resistant varicella zoster infection occurring during standard treatment for neuroblastoma in whom viral clearance and cure was effected by donor Lymphocyte infusion from his HLA (Human leukocyte antigen)-identical twin sibling.
Neonatal vincristine administration modulates intrinsic neuronal excitability in the rat dorsal root ganglion and spinal dorsal horn during adolescence
Authors: Schappacher Katie A. , Xie Wenrui , Zhang Jun-Ming , Baccei Mark L.
Published: November 2018

Our recent work has shown that the early-life administration of vincristine (VNC), commonly used to treat pediatric cancers, evokes mechanical pain hypersensitivity in rats that emerges during adolescence and persists into adulthood. However, the underlying mechanisms remain unclear, as nothing is known about how neonatal VNC treatment influences peripheral and central nociceptive processing at the cellular level. Here, we used in vitro intracellular microelectrode and whole-cell patch-clamp recordings to evaluate the consequences of early-life VNC administration on the intrinsic membrane properties of adolescent dorsal root ganglion and spinal superficial dorsal horn neurons. The results demonstrate that VNC treatment increased the prevalence and rate of repetitive firing in both large- and medium-diameter sensory neurons, while reducing repetitive firing in small-diameter neurons, in comparison with vehicle-treated littermate controls. By contrast, passive membrane properties and peripheral conduction velocities were similar between experimental groups across all classes of primary afferents. Within the adolescent superficial dorsal horn, neonatal VNC exposure significantly enhanced the intrinsic membrane excitability of lamina I spinoparabrachial neurons, as evidenced by a decrease in rheobase and elevation of repetitive firing frequency compared with controls. Meanwhile, putative interneurons within lamina I exhibited a reduction in repetitive action potential discharge after early-life chemotherapy. Collectively, these findings suggest that neonatal VNC treatment evokes cell type–specific changes in intrinsic excitability at multiple levels of the ascending pain pathway. Overall, this work lays an essential foundation for the future exploration of the ionic mechanisms that drive chemotherapy-induced chronic pain in children and adolescents.
Reduction of oxidative stress a key for enhanced postoperative recovery with fewer complications in esophageal surgery patients
Authors: Tsuchiya Masahiko , Shiomoto Kazumasa , Mizutani Koh , Fujioka Kazuya , Suehiro Koichi , Yamada Tokuhiro , Sato Eisuke F. , Nishikawa Kiyonobu
Published: November 2018

Background:

Oxidative stress may be an integral determinant of surgical stress severity. We examined whether the preoperative level of derivatives of reactive oxygen metabolites (d-ROMs), an oxidative stress biomarker based on total hydroperoxides in circulating blood, is predictive of increased risk of delayed recovery and complications after surgery, as well as the effects of anesthesia management on postoperative recovery in light of oxidative stress.

Methods:

Patients (American Society of Anesthesiologists physical status I-II) scheduled for a radical esophagectomy (n = 186) were randomly selected to receive inhalational sevoflurane (n = 94) or intravenous propofol (n = 92) anesthesia. Preoperative blood d-ROMs level, as well as pre-and postoperative plasma ferric-reducing ability, were analyzed to assess oxidative stress, with white blood cell (WBC) count, C-reactive protein (CRP) level, incidence of severe postoperative complications, and postoperative recovery process within 30 days after surgery also examined in a double-blind fashion.

Results:

Postoperative normalization of WBC and CRP was extended in patients with elevated preoperative d-ROMs [WBC versus d-ROMs: correlation coefficient (r) = 0.58 P < .001; CRP versus d-ROMs: r = 0.46 P < .001]. Receiver operating characteristics analysis of d-ROMs in relation to incidence of severe postoperative complications revealed an optimum d-ROMs threshold value of 410 UCarr and that patients with ≥410 UCarr had a greater risk of complications as compared to those with lower values (odds ratio = 4.7). Plasma ferric-reducing ability was decreased by 61 ± 185 mmol·l−1 (P < .001) after surgery, demonstrating development of surgery-related oxidative stress, the magnitude of which was positively correlated with preoperative d-ROMs level (r = 0.16, P = .043). A comparison of the 2 anesthesia management protocols showed that patients who received propofol, an antioxidant anesthetic, had no postoperative decrease in ferric-reducing ability, lower incidence of severe postoperative complications (7 of 92 versus 18 of 94, P = .030, odds ratio = 0.35), and faster uneventful recovery time (WBC normalization days 7.1 ± 5.2 versus 13.6 ± 10.2, P < .001) as compared to those who received sevoflurane.

Conclusions:

Elevated preoperative blood d-ROMs predicts greater intraoperative oxidative stress and increased postoperative complications with prolonged recovery, thus is useful for identifying high-risk patients for delayed and complicated surgical recovery. Reduction of oxidative stress is vital for enhanced recovery, with control by antioxidants such as propofol a possible solution.
Medullary thyroid carcinoma with breast metastasis
Authors: Meng Kexin , Chen Wanyuan , Tian Wei , Sun Kewang , Chen Hailong
Published: November 2018

Rationale:

Medullary thyroid carcinoma (MTC) is an aggressive subtype of thyroid cancer with frequent hematogenous metastasis. While its metastasis is usually observed in the lung, liver, or bone, it rarely migrates to the breast.

Patient concerns:

Here we report 2 cases with a complaint of breast lump after initial treatment of MTC.

Diagnoses:

In both patients, the MTC characteristics of breast nodules were confirmed by pathologic analysis of biopsy specimens.

Interventions:

The genetic mutations within the metastatic breast lesion were evaluated. Wide local excision was thus performed to 1st case, while no therapeutic intervention for another patient due to the wide-spread presence of the disease.

Outcomes:

No sign of relapse or metastasis was found in 1st case during a 14-month follow-up. For 2nd case, the breast nodule grew to 14 mm within 3 months before remaining stable for 10 months.

Lessons:

MTC can be a very indolent disease despite its aggressiveness. Reoperation should be considered for patients with local recurrence or resectable distant metastasis of MTC. The findings for both cases supported serum calcitonin as an important marker for the evaluation of disease. Future studies are needed to advance our understanding of its molecular features and improve strategies for its diagnosis and treatment.
Associations between ERAP1 polymorphisms and susceptibility to ankylosing spondylitis
Authors: Jiang Yuqing , Ren Yi , Zhou Dong , Xu Youjia
Published: November 2018

Background:

The genetic factor is importantly enrolled in the pathogenesis of ankylosing spondylitis (AS) and haplotype leukocyte antigen (HLA)-B27 is the most well-known. However, only 1% to 5% of B27-positive individuals will develop AS, and it confers only 20% to 30% of the overall genetic risks, indicating more genes other than HLA-B27 may play important roles in AS pathologies. The present study aims to investigate whether the polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) is associated with increased risk of AS susceptibility.

Methods:

The Cochrane library, Pubmed, and Embase databases were carefully searched for potential researches published before May 30, 2018. The title, abstract, and full text were assessed to determine whether the paper was suitable for inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were presented to assess the associations between ERAP1 polymorphisms and AS susceptibility.

Results:

The study finally enrolled 10 papers, 4 matched single nucleotide polymorphisms (SNPs) of ERAP1 (rs27044, rs27434, rs30187, and rs27037), and a total of 30552 patients (12492 with AS and 18060 for control). No significant difference was found between the AS susceptibility and polymorphisms of rs27044 and rs27434. However, there was a significant association between ERAP1 polymorphisms rs30187 and rs27037 (T vs C, OR, 1.322, 95% CI = 1.240–10410, P <.05; T vs G, OR, 1.247, 95% CI = 1.149–1.353; P <.05; respectively) and AS susceptibility.

Conclusion:

There was a significant association between ERAP1 polymorphisms (rs30187 and rs27037) and increased risk of AS susceptibility.
Suspended over length biliary stents versus conventional plastic biliary stents for the treatment of biliary stricture
Authors: Yan Xiue , Huang Yonghui , Chang Hong , Zhang Yaopeng , Yao Wei , Li Ke
Published: November 2018

To compare patency between suspended over length biliary stents (SOBSs; made from nasobiliary tube) and conventional plastic biliary stents (CPBSs).

We retrospectively analyzed 61 patients with extrahepatic biliary stricture who underwent SOBS placement (intrahepatic bile duct) and 74 patients who underwent CPBS placement. Stent patency and complications were compared.

The SOBS group was slightly older and contained more females than the CPBS group but other baseline characteristics were similar. Malignant biliary obstruction accounted for 57.4% (SOBS group) and 45.9% (CPBS group) of cases. Technical success rate, hospital stay and post-procedure complications were similar between groups. Median patency in the CPBS and SOBS group was 116 (2–360) days and 175 (3–480) days, respectively (P <.001). The SOBS group had lower stent occlusion rates than the CPBS group at 3 months (9.8% vs 36.5%), 4 months (22.0% vs 55.4%), 5 months (35.6% vs 67.6%), and 6 months (39.3% vs 77.0%) (all P <.01). In Cox regression analysis, stent type (SOBS vs CPBS) was the only factor associated with patency (hazard ratio [HR]: 3.449; 95% CI: 1.973-6.028; P <.001).

SOBS may have better medium-term patency than CPBS for benign/malignant biliary stricture.
Radiofrequency ablation in a patient with radiation enteritis
Authors: Shen Xing-jie , Liu Liang , Zhu Jing-yu
Published: November 2018

Rationale:

Radiation enteritis (RE) is one of the serious complications caused by the radiotherapy and it can occur in any segment of the intestine, including small intestine, colon, and rectum. It can cause a number of serious problems of the intestine, such as chronic ulcers, bleeding, intestinal stenosis, intestinal fistula, and perforation. At present, there is no standard treatment guideline for the RE.

Patient Concerns:

A 54-year-old male patient received surgery and chemotherapy for rectal cancer and radiofrequency ablation (RFA) for a single metastatic carcinoma of the liver. Three years later, he was diagnosed with recurrent lesion in the rectal anastomotic stoma and was treated with radiotherapy with a total dose of 70 Gy. Following this, he had persistent abdominal pain and diarrhea for 1 year.

Diagnoses:

Colonoscopy confirmed a diagnosis of RE.

Interventions:

Since intestinal probiotics, intestinal mucosal protectants, antidiarrheal drugs, and other treatments were not effective; the patient was treated by RFA.

Outcomes:

Clinical symptoms of the patient were gradually decreased after the RFA. Colonoscopy examination was performed 3 months later and intestinal mucosa was found to have healed well.

Lessons:

RFA is an effective treatment for patients with RE, and it is expected to be one of the standard treatments for the RE.
Spontaneous adrenal hematoma in pregnancy
Authors: Yang Ling , Zhu Yu-Chun , Liu Rong-Bo
Published: November 2018

Rational:

Spontaneous adrenal hematoma in pregnancy is a very rare condition. Herein we present an additional rare case of unilateral spontaneous adrenal hematoma in a pregnant woman, aiming to share this experience and summarize the signal characteristics of simple adrenal hematoma in magnetic resonance imaging (MRI).

Patient concerns:

A 28-year old pregnant woman was referred to our hospital with a vague paroxysmal left-side back pain at 17 weeks of gestation.

Diagnosis:

MR scan of the abdomen revealed an 8.1 × 7.7 × 6.8 cm round mass in the left adrenal region, which showed a rim of acute hemorrhage signal. Due to the stable condition of the patient and fetus, she was admitted for observation. Repeat MR scan was performed a month later, and it showed a stable mass with marginal subacute bleeding signal.

Interventions:

Laparoscope excision of the hematoma was performed.

Outcomes:

Simple adrenal hematoma was confirmed by pathological examinations. And the patient was discharged 3 days later with normal renal and adrenal functions.

Lessons:

The most important characteristic of adrenal hematoma is the high-signal rim on T1-weighted MR images, and the clinicians should make individualized treatment plan for every patient encountered in the future who might have different clinical conditions.
Association between polymorphisms in estrogen metabolism genes and breast cancer development in Chinese women
Authors: Qiu Juanjuan , Du Zhenggui , Liu Jingping , Zhou Yi , Liang Faqing , Lü Qing
Published: November 2018

We comprehensively identified polymorphisms in estrogen-metabolizing genes that may be associated with breast cancer initiation in Chinese women, via an ongoing prospective case–control study.

An ongoing prospective case–control study of 427 female case patients diagnosed with breast cancer from August 2013 to March 2015 and 536 women (case controls) with no prior history of cancer or benign breast tumors was performed. Buccal cell specimens were obtained using the cotton swabbing method. DNA was extracted from the buccal cells using the phenol/chloroform method. Genotype was carried out for 5 single nucleotide polymorphisms (rs4646903, rs1056836, rs1695, rs4970737, and rs4680) using direct sequencing.

The polymorphic genotypes of glutathione S-transferase (GSTP1) (P = .044) and catechol-O-methyltransferase (COMT) (P = .008) showed significantly different distributions, while that of cytochrome P450 (CYP1B1) (P = .051) showed a slight difference in distribution between healthy women and patients with breast cancer. Individuals with homozygous variant genotypes for GSTP1 or COMT exhibited a higher risk of developing breast cancer than those with wild-type genotypes; however, for CYP1B1, the homozygous variant genotype was associated with a lower risk, and the heterozygous genotype for these 3 genes was not associated with breast cancer development.

An individual's risk of breast cancer is only influenced by the specific combination of risk-associated alleles of COMT and GSTP1, despite the protective effects of the homozygous CYP1B1 genotype revealed by univariate analysis.
Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients
Authors: Lybeck Charlotte , Brenndörfer Erwin D. , Sällberg Matti , Montgomery Scott M. , Aleman Soo , Duberg Ann-Sofi
Published: November 2018

Objectives

Curing of hepatitis C virus (HCV) infection primarily aims to prevent severe liver complications. Our objectives were to investigate the long-term presence and impact of occult HCV infection (OCI) and to study the outcomes in terms of liver disease after virological cure.

Patients and methods

A total of 97 patients with achieved sustained virological response (SVR) during 1990–2005 were followed either by a clinical follow-up (FU) visit with blood sampling and liver elastography (n=54) or through national registries for outcomes (n=43). To diagnose OCI among patients with SVR, a highly sensitive method was used to detect HCV-RNA traces in whole blood. The FU duration was a median of 10.5 years, with samples up to 21.5 years after the end of treatment (EOT).

Results

The majority of patients [52 (96%)] were HCV-RNA negative at FU, and regression of fibrosis was statistically significant. OCI was found in two (4%) of them at 8 and 9 years after EOT. These patients had F1 and F2 fibrosis before treatment and F2 at FU, but no other abnormal findings. Three previously noncirrhotic men were diagnosed with hepatocellular carcinoma 8–11 years after EOT.

Conclusion

Occult infection could be detected many years after the achievement of SVR but was not associated with serious liver disease. The majority had persistent viral eradication and regression of fibrosis after SVR. However, an increased risk of hepatocellular carcinoma may persist in the long term after SVR even in noncirrhotic patients. Further studies with FU after direct-acting antiviral therapy and on the long-term impact after cure are needed.
Intractable Central Pain in a Patient With Diffuse Glioma
Authors: Horan Nicholas Aaron , Pugh Terrence MacArthur
Published: November 2018

Central neuropathic pain can be difficult to treat and, subsequently, cause a great amount of disability and distress to patients, which limits quality of life. Common etiologies include the following: stroke, spinal cord injury, multiple sclerosis, infection, vasculitis, and malignancy. This case is a description of an 18-yr-old male patient diagnosed with a grade IV diffuse glioma who experienced severe neuropathic pain refractory to first-line treatment options including the following: gabapentinoids, tricyclic antidepressants, and selective serotonin and norepinephrine reuptake inhibitors. The patient remained on high-dose oral gabapentin as well as methadone and high-dose oxycodone for pain control at the time of submission. The aims of this case report were to review the nociceptive pathways and to explore the role of opioids in central neuropathic pain secondary to neoplasm because a better understanding of these topics can aid physiatrists in better taking care of these patients and improving function and quality of life.
Differentiating Transition Zone Cancers From Benign Prostatic Hyperplasia by Histogram Analysis of Apparent Diffusion Coefficient Maps With Standard and Ultrahigh b-value Diffusion-weighted MR Imaging
Authors: Lu Zhi-hua , Ji Li-biao , Zhao Wen-lu , Zhang Yong-sheng , Wu Jiang-fen , Li Xin , Shen Jun-kang
Published: November 2018

Objective

To compare the diagnostic performance of standard and ultrahigh b-value Diffusion-weighted Imaging (DWI) using volumetric histogram analysis in differentiating transition zone (TZ) cancer from benign prostatic hyperplasia (BPH).

Methods

57 TZ cancer and 61 BPH patients received standard (1000 s/mm2) and ultrahigh b-value (2000 s/mm2) DWI. The diagnostic ability of ADC histogram parameters derived from two DWI for differentiating TZ cancer from BPH was determined by receiver operating characteristic curve.

Results

Median, minimum, the 10th, 25th percentile ADC in both ADC1000 and ADC2000 and skewness in ADC2000 had significant differences between TZ cancer and BPH (for all, P < 0.05).The 10th percentile ADC showed highest area under the ROC curve (AUC) in both ADC1000 and ADC2000.The 10th percentile ADC of ADC2000 showed significantly higher AUC than did ADC1000 (P = 0.0385).

Conclusions

The 10th percentile ADC obtained from ultrahigh b-value DWI performed better for differentiating TZ cancer from BPH.
Estimating the relative importance of demic and cultural diffusion in the spread of the Neolithic in Scandinavia
Authors: Fort Joaquim , Mercè Pareta Maria , Sørensen Lasse
Published: November 2018

Using a database of early farming sites in Scandinavia, we estimate that the spread rate of the Neolithic was in the range 0.44–0.66 km yr
−1
. This is substantially slower (by about 50%) than the rate in continental Europe. We interpret this result in the framework of a new mathematical model that includes horizontal cultural transmission (acculturation), vertical cultural transmission (interbreeding) and demic diffusion (reproduction and dispersal of farmers). To parametrize the model, we estimate reproduction rates of early farmers using archaeological data (sum-calibrated probabilities for the dates of early Neolithic Scandinavian sites) and use them in a wave-of-advance model for the first time. Comparing the model with the archaeological data, we find that the percentage of the spread rate due to cultural diffusion is below 50% (except for very extreme parameter values, and even for them it is below 54%). This strongly suggests that the spread of the Neolithic in Scandinavia was driven mainly by demic diffusion. This conclusion, obtained from archaeological data, agrees qualitatively with the implications of ancient genetic data, but the latter are yet too few in Scandinavia to produce any quantitative percentage for the spread rate due to cultural diffusion. We also find that, on average, fewer than eight hunter–gatherers were incorporated in the Neolithic communities by each group of 10 pioneering farmers, via horizontal and/or vertical cultural transmission.
Cardiac and skeletal actin substrates uniquely tune cardiac myosin strain-dependent mechanics
Authors: Wang Yihua , Ajtai Katalin , Burghardt Thomas P.
Published: November 2018

Cardiac ventricular myosin (βmys) translates actin by transducing ATP free energy into mechanical work during muscle contraction. Unitary βmys translation of actin is the step-size.
In vitro
and
in vivo
βmys regulates contractile force and velocity autonomously by remixing three different step-sizes with adaptive stepping frequencies. Cardiac and skeletal actin isoforms have a specific 1 : 4 stoichiometry in normal adult human ventriculum. Human adults with inheritable hypertrophic cardiomyopathy (HCM) upregulate skeletal actin in ventriculum probably compensating the diseased muscle's inability to meet demand by adjusting βmys force–velocity characteristics. βmys force–velocity characteristics were compared for skeletal versus cardiac actin substrates using ensemble
in vitro
motility and single myosin assays. Two competing myosin strain-sensitive mechanisms regulate step-size choices dividing single βmys mechanics into low- and high-force regimes. The actin isoforms alter myosin strain-sensitive regulation such that onset of the high-force regime, where a short step-size is a large or major contributor, is offset to higher loads probably by the unique cardiac essential light chain (ELC) N-terminus/cardiac actin contact at Glu6/Ser358. It modifies βmys force–velocity by stabilizing the ELC N-terminus/cardiac actin association. Uneven onset of the high-force regime for skeletal versus cardiac actin modulates force–velocity characteristics as skeletal/cardiac actin fractional content increases in diseased muscle.
Asymptotic convergence in distribution of the area bounded by prevalence-weighted Kaplan–Meier curves using empirical process modelling
Authors: Heuser Aaron , Huynh Minh , Chang Joshua C.
Published: November 2018

The Kaplan–Meier product-limit estimator is a simple and powerful tool in time to event analysis. An extension exists for populations stratified into cohorts where a population survival curve is generated by weighted averaging of cohort-level survival curves. For making population-level comparisons using this statistic, we analyse the statistics of the area between two such weighted survival curves. We derive the large sample behaviour of this statistic based on an empirical process of product-limit estimators. This estimator was used by an interdisciplinary National Institutes of Health–Social Security Administration team in the identification of medical conditions to prioritize for adjudication in disability benefits processing.
Simultaneous removal of fluoride and arsenic in geothermal water in Tibet using modified yak dung biochar as an adsorbent
Authors: Chunhui Luo , Jin Tian , Puli Zhu , Bin Zhou , Duo Bu , Xuebin Lu
Published: November 2018

Fluoride (F) and arsenic (As) are two typical and harmful elements that are found in high concentrations in geothermal water in Tibet. In this work, yak dung, an abundant source of biomass energy in Tibet, was made into biochars (BC1, BC2 and BC3) by pyrolysis under different conditions, and the better biochar was modified by FeCl
2
(Fe-BC3). The adsorption conditions were optimized to adsorb F and As in geothermal water. The results showed that BC3 can remove 90% F
−
and 20% As(V), which is the best effect of the three initial biochars. Fe-BC3 could remove 94% F
−
and 99.45% As(V) under the same conditions as BC3, which was an adsorbent dosage 10 g l
−1
, pH 5–6 and temperature of 25°C. It was also demonstrated that the removal rate did not decrease at 80°C. A quasi-second-order kinetic model best described the adsorption behaviour of ions on the surface of the biochar. The maximum adsorption capacity of F
−
and As(V) on Fe-BC3 was 3.928 mg g
−1
and 2.926 mg g
−1
, respectively. The features of Fe-BC3 were characterized by X-ray diffraction, Fourier transform infrared, Brunauer–Emmett–Teller, energy-dispersive spectrometer and scanning electron microscopy to understand the adsorption process.
Rethinking dopamine as generalized prediction error
Authors: Gardner Matthew P. H. , Schoenbaum Geoffrey , Gershman Samuel J.
Published: November 2018

Midbrain dopamine neurons are commonly thought to report a reward prediction error (RPE), as hypothesized by reinforcement learning (RL) theory. While this theory has been highly successful, several lines of evidence suggest that dopamine activity also encodes sensory prediction errors unrelated to reward. Here, we develop a new theory of dopamine function that embraces a broader conceptualization of prediction errors. By signalling errors in both sensory and reward predictions, dopamine supports a form of RL that lies between model-based and model-free algorithms. This account remains consistent with current canon regarding the correspondence between dopamine transients and RPEs, while also accounting for new data suggesting a role for these signals in phenomena such as sensory preconditioning and identity unblocking, which ostensibly draw upon knowledge beyond reward predictions.
The influence of cactus spine surface structure on puncture performance and anchoring ability is tuned for ecology
Authors: Crofts S. B. , Anderson P. S. L.
Published: November 2018

Spines are common morphological features found in almost all major biological groups offering an opportunity to explore large-scale evolutionary convergence across disparate clades. As an example, opuntioid cacti have spines with barbed ornamentation that is remarkably similar in form and scale to that found on porcupine quills, suggesting specific biomechanical convergence across the animal and plant kingdoms. While the mechanics of porcupine quills as defensive mechanisms has been previously tested, the mechanics of cactus spines (which have evolved to fill a number of functions including defence, climbing and dispersal) has not been characterized. Here we study the puncturing and anchoring ability of six species of cactus, including both barbed and non-barbed spines. We found that barbed spines require less work to puncture a variety of targets than non-barbed spines. Barbed spines also require more work than non-barbed spines to withdraw from biological materials, owing to their barbs engaging with tissue fibres. These results closely match those found previously for barbed versus non-barbed porcupine quills, implying biomechanical convergence. The variation in performance of barbed versus non-barbed spines, as well as between barbed spines from different species, is probably tied to the diversity of ecological functions of cactus spines.
CRISPR-based DNA and RNA detection with liquid-liquid phase separation
Authors: Spoelstra Willem Kasper , Jacques Jeroen M. , Nobrega Franklin L. , Haagsma Anna C. , Dogterom Marileen , Idema Timon , Brouns Stan J. J. , Reese Louis
Published: November 2018

The ability to detect specific nucleic acid sequences allows for a wide range of applications including identification of pathogens, clinical diagnostics, and genotyping. CRISPR-Cas proteins Cas12a and Cas13a are RNA-guided endonucleases that bind and cleave specific DNA and RNA sequences, respectively. After recognition of a target sequence both enzymes activate a unique, indiscriminate nucleic acid cleavage activity, which has been exploited for detection of sequence specific nucleotides using labelled reporter molecules. We here present a label-free detection approach that uses a readout based on solution turbidity caused by liquid-liquid phase separation (LLPS). Turbidity arises from coacervates of positively charged polyelectrolytes with long poly(dT) or poly(U) oligonucleotides. In the presence of a target sequence, long oligonucleotides are progressively shortened, changing the solution from turbid to transparent. We explain how oligonucleotide cleavage resolves LLPS by using a mathematical model which we validate with poly(dT) phase separation experiments. The deployment of LLPS complements CRISPR-based molecular diagnostic applications and facilitates easy and low-cost nucleotide sequence detection.
In Silico Determined Properties of Designed Superoxide Dismutase-1 Mutants Predict ALS-like Phenotypes In Vitro and In Vivo
Authors: DuVal Michèle G. , McAlary Luke , Habibi Mona , Garg Pranav , Sher Mine , Cashman Neil R. , Allison W. Ted , Plotkin Steven S.
Published: November 2018

The underlying physical causes of SOD1-related ALS are still not well-understood. We address this problem here by computationally designing two de novo mutants, A89R and K128N, which were predicted theoretically to be either significantly destabilizing or stabilizing respectively. We subjected these in silico designed mutants to a series of experimental tests, including in vitro measures of thermodynamic stability, cell-based aggregation and toxicity assays, and an in vivo developmental model of zebrafish motor neuron axonopathy. The experimental tests validated the theoretical predictions: A89R is an unstable, highly-deleterious mutant, and K128N is a stable, non-toxic mutant. Moreover, K128N is predicted computationally to form an unusually stable heterodimer with the familial ALS mutant A4V. Consistent with this prediction, co-injection of K128N and A4V into zebrafish shows profound rescue of motor neuron pathology. The demonstrated success of these first principles calculations to predict the physical properties of SOD1 mutants holds promise for rationally designed therapies to counter the progression of ALS.

Significance

Mutations in the protein superoxide dismutase cause ALS, and many of these mutants have decreased folding stability. We sought to pursue this thread using a synthetic biology approach, where we designed two de novo mutations, one stabilizing and one destabilizing, as predicted using computational molecular dynamics simulations. We then tested these mutants using in vitro, cell-based, and in vivo zebrafish models. We found that the unstable mutant was toxic, and induced a severe ALS phenotype in zebrafish; the predicted stable mutant, on the other hand, behaved even better than WT. In fact, it was able to rescue the ALS phenotype caused by mutant SOD1. We propose a mechanism for this rescue, which may provide an avenue for therapeutic intervention.
Multi-Scale Structural Analysis of Proteins by Deep Semantic Segmentation
Authors: Eguchi Raphael R. , Huang Po-Ssu
Published: November 2018

Recent advancements in computational methods have facilitated large-scale sampling of protein structures, leading to breakthroughs in protein structural prediction and enabling de novo protein design. Establishing methods to identify candidate structures that can lead to native folds or designable structures remains a challenge, since few existing metrics capture high-level structural features such as architectures, folds, and conformity to conserved structural motifs. Convolutional Neural Networks (CNNs) have been successfully used in semantic segmentation — a subfield of image classification in which a class label is predicted for every pixel. Here, we apply semantic segmentation to protein structures as a novel strategy for fold identification and structural quality assessment. We represent protein structures as 2D α-carbon distance matrices (“contact maps”), and train a CNN that assigns each residue in a multi-domain protein to one of 38 architecture classes designated by the CATH database. Our model performs exceptionally well, achieving a per-residue accuracy of 90.8% on the test set (95.0% average accuracy over all classes; 87.8% average within-structure accuracy). The unique aspect of our classifier is that it encodes sequence agnostic residue environments from the PDB and can assess structural quality as quantitative probabilities. We demonstrate that individual class probabilities can be used as a metric that indicates the degree to which a randomly generated structure assumes a specific fold, as well as a metric that highlights non-conformative regions of a protein belonging to a known class. These capabilities yield a powerful tool for guiding structural sampling for both structural prediction and design.

Significance

Recent computational advances have allowed researchers to predict the structure of many proteins from their amino acid sequences, as well as designing new sequences that fold into predefined structures. However, these tasks are often challenging because they require selection of a small subset of promising structural models from a large pool of stochastically generated ones. Here, we describe a novel approach to protein model selection that uses 2D image classification techniques to evaluate 3D protein models. Our method can be used to select structures based on the fold that they adopt, and can also be used to identify regions of low structural quality. These capabilities yield a powerful tool for both protein design and structure prediction.
Discovery and validation of candidate smoltification gene expression biomarkers across multiple species and ecotypes of Pacific salmonids
Authors: Houde Aimee Lee S. , Günther Oliver P. , Strohm Jeffrey , Ming Tobi J. , Li Shaorong , Kaukinen Karia H. , Patterson David A. , Farrell Anthony P. , Hinch Scott G. , Miller Kristina M.
Published: November 2018

Early marine survival of juvenile salmon is intimately associated with their physiological condition during ocean entry and especially smoltification. Smoltification is a developmental parr–smolt transformation allowing salmon to acquire the trait of seawater tolerance in preparation for marine living. Traditionally, this developmental process has been monitored using gill Na+/K+ATPase (NKA) activity or plasma hormones, but gill gene expression can be reliably used. Here, we describe the discovery of candidate genes from gill tissue for staging smoltification using comparisons of microarray studies with particular focus on the commonalities between anadromous Rainbow trout and Sockeye salmon datasets, as well as literature comparison encompassing more species. A subset of 37 candidate genes mainly from the microarray analyses was used for Taq-Man qPCR assay design and their monthly expression patterns were validated using gill samples from four groups, representing three species and two ecotypes: Coho salmon, Sockeye salmon, stream-type Chinook salmon, and ocean-type Chinook salmon. The best smoltification biomarkers, as measured by consistent changes across these four groups, were genes involved in ion regulation, oxygen transport, and immunity. Smoltification gene expression patterns (using the top 10 biomarkers) were confirmed by significant correlations with NKA activity and were associated with changes in body brightness, caudal fin darkness, and caudal peduncle length. We incorporate gene expression patterns of pre-smolt, smolt, and de-smolt trials from acute seawater transfers using a companion study to develop a preliminary seawater tolerance classification model for ocean-type Chinook salmon. This work demonstrates the potential of gene expression biomarkers to stage smoltification and classify juveniles as pre-smolt, smolt, or de-smolt.
Prediction in Human Auditory Cortex
Authors: Forseth KJ , Hickok G , Rollo Patrick , Tandon N
Published: November 2018

Spoken language is thought to be facilitated by an ensemble of predictive mechanisms, yet the neurobiology of prediction for both speech perception and production remains unknown. We used intracranial recordings (31 patients, 6580 electrodes) from depth probes implanted along the anteroposterior extent of the supratemporal plane during rhythm listening, speech perception, and speech production. This revealed a frequency-multiplexed encoding of sublexical features during entrainment and a traveling wave of high-frequency activity across Heschl’s gyrus. Critically, we isolated two predictive mechanisms in early auditory cortex with distinct anatomical and functional characteristics. The first mechanism, localized to bilateral Heschl’s gyrus and indexed by low-frequency phase, predicts the timing of acoustic events (“when”). The second mechanism, localized to planum temporale in the language-dominant hemisphere and indexed by gamma power, predicts the acoustic consequence of speech motor plans (“what”). This work grounds cognitive models of speech perception and production in human neurobiology, illuminating the fundamental acoustic infrastructure – both architecture and function – for spoken language.
Triamterene–furosemide salt: structural aspects and physicochemical evaluation
Authors: Peng Bo , Wang Jian-Rong , Mei Xuefeng
Published: November 2018

Furosemide (Fur) is a BCS class IV diuretic drug with low bioavailability due to its poor solubility and poor membrane permeability. Triamterene (Tri) is a potassium-sparing diuretic with low bioavailability due to its poor solubility. Here, a novel drug–drug salt composed of Tri and Fur was successfully synthesized. Tri–Fur was comprehensively characterized with single-crystal X-ray and powder X-ray diffraction techniques, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption. The apparent equilibrium solubility (in pH 2.0 buffer) of Tri–Fur is improved compared with Fur and a physical mixture of Tri with equimolar Fur by 15.3-fold and 12.2-fold enhancements, respectively. Its intrinsic dissolution rate (in pH 2.0 buffer) is also higher than for a Fur component with an enhancement of 9.5-fold. This study provides a valuable insight into the formation of dual pharmaceutical salts and demonstrates that Tri–Fur can be a potential alternative formulation.
The inverse perovskite BaLiF3: single-crystal neutron diffraction and analyses of potential ion pathways
Authors: Wiedemann Dennis , Meutzner Falk , Fabelo Oscar , Ganschow Steffen
Published: November 2018

Doped barium lithium trifluoride has attracted attention as component for scintillators, luminescent materials and electrodes. With lithium and fluoride, it contains two possibly mobile species, which may account for its ionic conductivity. In this study, neutron diffraction on oxide-containing BaLiF3 single-crystals is performed at up to 636.2°C. Unfortunately, ion-migration pathways could not be mapped by modelling anharmonic ion displacement or by inspecting the scattering-length density that was reconstructed via maximum-entropy methods. However, analyses of the topology and bond-valence site energies derived from the high-temperature structure reveal that the anions can migrate roughly along the edges of the LiF6 coordination octahedra with an estimated migration barrier of ∼0.64 eV (if a vacancy permits), whereas the lithium ions are confined to their crystallographic positions. This finding is not only valid for the title compound but for ion migration in all perovskites with Goldschmidt tolerance factors near unity.