bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulations of the Milky Way’s Central Molecular Zone – II. Star formation
Authors: Sormani Mattia C , Tress Robin G , Glover Simon C O , Klessen Ralf S , Battersby Cara D , Clark Paul C , Hatchfield H Perry , Smith Rowan J
Published: July 2020

The Milky Way’s Central Molecular Zone (CMZ) has emerged in recent years as a unique laboratory for the study of star formation. Here we use the simulations presented in Tress et al. to investigate star formation in the CMZ. These simulations resolve the structure of the interstellar medium at sub-parsec resolution while also including the large-scale flow in which the CMZ is embedded. Our main findings are as follows. (1) While most of the star formation happens in the CMZ ring at $R\gtrsim 100 \, {\rm pc}$, a significant amount also occurs closer to Sgr A* at $R \lesssim 10\, {\rm pc}$. (2) Most of the star formation in the CMZ happens downstream of the apocentres, consistent with the ‘pearls-on-a-string’ scenario, and in contrast to the notion that an absolute evolutionary timeline of star formation is triggered by pericentre passage. (3) Within the time-scale of our simulations (∼100 Myr), the depletion time of the CMZ is constant within a factor of ∼2. This suggests that variations in the star formation rate are primarily driven by variations in the mass of the CMZ, caused, for example, by active galactic nuclei (AGN) feedback or externally induced changes in the bar-driven inflow rate, and not by variations in the depletion time. (4) We study the trajectories of newly born stars in our simulations. We find several examples that have age and 3D velocity compatible with those of the Arches and Quintuplet clusters. Our simulations suggest that these prominent clusters originated near the collision sites where the bar-driven inflow accretes on to the CMZ, at symmetrical locations with respect to the Galactic Centre, and that they have already decoupled from the gas in which they were born.
Have hierarchical three-body mergers been detected by LIGO/Virgo?
Authors: Veske Doğa , Márka Zsuzsa , Sullivan Andrew G , Bartos Imre , Rainer Corley K , Samsing Johan , Márka Szabolcs
Published: July 2020

One of the proposed channels of binary black hole mergers involves dynamical interactions of three black holes. In such scenarios, it is possible that all three black holes merge in a so-called hierarchical merger chain, where two of the black holes merge first and then their remnant subsequently merges with the remaining single black hole. Depending on the dynamical environment, it is possible that both mergers will appear within the observable time window. Here, we perform a search for such merger pairs in the public available LIGO and Virgo data from the O1/O2 runs. Using a frequentist p-value assignment statistics, we do not find any significant merger pair candidates, the most significant being GW170809-GW151012 pair. Assuming no observed candidates in O3/O4, we derive upper limits on merger pairs to be ∼11–110 yr−1 Gpc−3, corresponding to a rate that relative to the total merger rate is ∼0.1−1.0. From this, we argue that both a detection and a non-detection within the next few years can be used to put useful constraints on some dynamical progenitor models.
3-Dimensional architecture of the human multi-tRNA synthetase complex
Authors: Khan Krishnendu , Baleanu-Gogonea Camelia , Willard Belinda , Gogonea Valentin , Fox Paul L
Published: July 2020

In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). AARSs have critical roles in interpretation of the genetic code during protein synthesis, and in non-canonical functions unrelated to translation. Nonetheless, the structure and function of the MSC remain unclear. Partial or complete crystal structures of all MSC constituents have been reported; however, the structure of the holo-MSC has not been resolved. We have taken advantage of cross-linking mass spectrometry (XL-MS) and molecular docking to interrogate the three-dimensional architecture of the MSC in human HEK293T cells. The XL-MS approach uniquely provides structural information on flexibly appended domains, characteristic of nearly all MSC constituents. Using the MS-cleavable cross-linker, disuccinimidyl sulfoxide, inter-protein cross-links spanning all MSC constituents were observed, including cross-links between eight protein pairs not previously known to interact. Intra-protein cross-links defined new structural relationships between domains in several constituents. Unexpectedly, an asymmetric AARS distribution was observed featuring a clustering of tRNA anti-codon binding domains on one MSC face. Possibly, the non-uniform localization improves efficiency of delivery of charged tRNA’s to an interacting ribosome during translation. In summary, we show a highly compact, 3D structural model of the human holo-MSC.
Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination
Authors: Wüst Hannah M , Wegener Amélie , Fröb Franziska , Hartwig Anna C , Wegwitz Florian , Kari Vijayalakshmi , Schimmel Margit , Tamm Ernst R , Johnsen Steven A , Wegner Michael , Sock Elisabeth
Published: July 2020

Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.
Safety of Low-Dose Tanezumab in the Treatment of Hip or Knee Osteoarthritis: A Systemic Review and Meta-analysis of Randomized Phase III Clinical Trials
Authors: Yu Yang , Lu Shi-Tao , Sun Jin-Peng , Zhou Wei
Published: July 2020

Objectives

To evaluate the safety of low-dose tanezumab in the treatment of knee or hip osteoarthritis (OA).

Methods

Databases were searched up to September 2019 for phase III randomized controlled trials (RCTs). Eleven phase III RCTs comprising 11,455 patients were eligible. The pooled estimates of safety outcomes were assessed and expressed using relative risks (RRs) and 95% confidence intervals with a random-effects model.

Results

Tanezumab significantly increased the incidence of rapidly progressive OA (RPOA; RR = 9.07, 95% CI = 1.21–67.90, P = 0.03) and abnormal peripheral sensation (APS; RR = 2.68, 95% CI = 1.64–4.37, P < 0.00001) compared with placebo. No significant difference was found in terms of incidence of total joint replacement (TJR; RR = 1.13, 95% CI = 0.76–1.68, P = 0.55) or withdrawal due to adverse effects (AEs; RR = 1.26, 95% CI = 0.79–2.00, P = 0.33). The tanezumab group showed a statistically higher incidence of RPOA (RR = 3.96, 95% CI = 2.23–7.04, P < 0.00001) and APS (RR = 1.2, 95% CI = 1.44–2.56, P < 0.00001) compared with the nonsteroidal anti-inflammatory drugs and opioids group. No significant difference was found in terms of TJR (RR = 1.51, 95% CI = 0.65–3.47, P = 0.33) and withdrawal (RR = 0.54, 95% CI = 0.20–1.40, P = 0.20). Subgroup analysis revealed that 2.5 mg of tanezumab did not show an advantage over 5 mg of tanezumab in reducing AEs.

Conclusions

These results demonstrate that RPOA and APS should be the most concerning AEs when using tanezumab in OA patients. Additional data are needed to define the optimal dose to minimize risk and to determine the optimal subjects to receive this treatment.
High-drug-loading capacity of redox-activated biodegradable nanoplatform for active targeted delivery of chemotherapeutic drugs
Authors: Zhang Hai , Yan Jianqin , Mei Heng , Cai Shengsheng , Li Sai , Cheng Furong , Cao Jun , He Bin
Published: July 2020

Challenges associated with low-drug-loading capacity, lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy. Herein, we constructed active-targeting, redox-activated polymeric micelles (HPGssML) self-assembled aptamer-decorated, amphiphilic biodegradable poly (benzyl malolactonate-co-ε-caprolactone) copolymer with disulfide linkage and π-conjugated moieties. HPGssML with a homogenous spherical shape and nanosized diameter (∼150 nm) formed a low critical micellar concentration (10−3 mg/mL), suggesting good stability of polymeric micelles. The anticancer drug, doxorubicin (DOX), can be efficiently loaded into the core of micelles with high-drug-loading content via strong π–π interaction, which was verified by a decrease in fluorescence intensity and redshift in UV adsorption of DOX in micelles. The redox sensitivity of polymeric micelles was confirmed by size change and in vitro drug release in a reducing environment. Confocal microscopy and flow cytometry assay demonstrated that conjugating aptamers could enhance specific uptake of HPGssML by cancer cells. An in vitro cytotoxicity study showed that the half-maximal inhibitory concentration (IC50) of DOX-loaded HPGssML was two times lower than that of the control group, demonstrating improved antitumor efficacy. Therefore, the multifunctional biodegradable polymeric micelles can be exploited as a desirable drug carrier for effective cancer treatment.
Measuring Reasoning in Paranoia: Development of the Fast and Slow Thinking Questionnaire
Authors: Hardy Amy , Tolmeijer Eva , Edwards Victoria , Ward Thomas , Freeman Daniel , Emsley Richard , Green Catherine , Rus-Calafell Maria , Greenwood Kathryn , Bebbington Paul , Kuipers Elizabeth , Fowler David , Sacadura Catarina , Collett Nicola , McGourty Alison , Dunn Graham , Garety Philippa
Published: July 2020

Paranoid thoughts are common across the psychosis continuum. It is well established that reasoning biases (conceived as an overreliance on fast thinking and lack of willingness and/or ability to engage in slow thinking) contribute to paranoia. Targeted therapies have shown promise in improving reasoning in order to reduce paranoia. Psychometrically robust and easy-to-use measures of these thinking styles will assist research and clinical practice. Existing assessments include experimental tasks that are complex to administer or self-report measures that have limitations in comprehensively assessing cognitive biases in paranoia. We have developed the first questionnaire to assess fast and slow thinking biases related to paranoid thoughts, and here report on its evaluation. In study 1, we generated, evaluated, and extracted items reflecting reasoning, and assessed their reliability and validity in a non-clinical sample (n = 209). In study 2, we replicated the factor analysis and psychometric evaluation in a clinical sample (n = 265). The resultant Fast and Slow Thinking (FaST) questionnaire consists of two 5-item scales reflecting fast and slow thinking and is therefore brief and suitable for use in both research and clinical practice. The fast thinking scale is reliable and valid. Reliability and criterion validity of the slow scale shows promise. It had limited construct validity with objective reasoning assessments in the clinical group, possibly due to impaired meta-cognitive awareness of slow thinking. We recommend the FaST questionnaire as a new tool for improving understanding of reasoning biases in paranoia and supporting targeted psychological therapies.
“The Other Side”: Assessing the Polarization of Gender Knowledge Through a Feminist Analysis of the Affective-Discursive in Anti-Feminist Online Communities
Authors: Rothermel Ann-Kathrin
Published: July 2020

Given the current polarization of gender knowledge in the public discourse, this article investigates the “other side” of gender knowledge production. Building on feminist standpoint literature, I conduct a close reading of the affective-discursive dynamics of knowledge production in two anti-feminist online communities in the United States and India. I find that anti-feminist communities appropriate feminist practices of consciousness-raising to construct a shared sense of victimization. This appropriation is, however, incomplete. In contrast to feminist practices, anti-feminist knowledge generation is premised on the polarizing themes of “ultimate victimhood” and “ultimate other,” which lead to violence and exclusion, rather than liberation.
Perianal Crohn’s Disease
Authors: Lightner Amy L.
Published: July 2020

Case Summary:

A 22-year-old man presents to your office with a perianal abscess and occasional mild crampy abdominal pain. You take him to the operating room for an examination under anesthesia (EUA) with incision and drainage of the abscess and note a transphincteric fistula tract through which you place a seton and 2 large skin tags. The anal canal and rectum are without ulceration, but there are mild proctitis and nonprolapsing internal hemorrhoids. Because of a concern for Crohn’s disease (CD), he undergoes magnetic resonance enterography and colonoscopy. The magnetic resonance enterography shows inflammation in 20 cm of the distal terminal ileum, and colonoscopy reveals approximately 10 ulcers <5 mm in the terminal ileum without significant narrowing. He is seen in consultation for the initiation of a monoclonal antibody and returns to see you in the office after his first 3 infusions. He is feeling well, has significantly decreased drainage from the perianal fistula, but would really like his seton and skin tags removed while you are there.
RETINAL TISSUE PERFUSION REDUCTION BEST DISCRIMINATES EARLY STAGE DIABETIC RETINOPATHY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Authors: Liu Zhiping , Jiang Hong , Townsend Justin H. , Wang Jianhua
Published: July 2020

Purpose:

To determine retinal microcirculation measured as retinal tissue perfusion (RTP) in patients with type 2 diabetes mellitus and mild nonproliferative diabetic retinopathy, and to compare its discrimination ability to that of retinal microvasculature and microstructure.

Methods:

Thirty eyes of 18 patients with mild nonproliferative diabetic retinopathy and 20 eyes of 20 age-matched and gender-matched normal controls were imaged. Retinal blood flow velocity and flow rate were measured using a retinal function imager. Retinal vessel density (Dbox) and intraretinal layer thicknesses were measured using optical coherence tomography angiography. Retinal tissue perfusion was measured as retinal blood flow divided by the volume of the inner retina.

Results:

Compared with normal control, RTP, vessel density, and the thickness of the retinal nerve fiber layer in patients with mild nonproliferative diabetic retinopathy showed significant reduction (P < 0.05). Retinal tissue perfusion had the best discrimination power (area under the curve = 0.97), with a sensitivity of 93.3% and specificity of 85.0%. In the eyes with mild nonproliferative diabetic retinopathy, RTP correlated with arteriolar blood flow velocity (r = 0.403, P = 0.027) but was unrelated to vessel density in any layer (r = −0.010 to 0.261, P > 0.05).

Conclusion:

Because of its highest discrimination power, RTP may become a promising biomarker for detecting early-stage diabetic retinopathy.
Flanged Sutureless Intrascleral Fixation of Dislocated Hard 1-Piece Polymethyl Methacrylate Intraocular Lenses
Authors: Walsh Mark K. , Williams Mark T.
Published: July 2020

Purpose:

To describe the vitreoretinal surgical technique and report the outcomes of our method of sutureless flanged intrascleral haptic fixation of dislocated 1-piece polymethyl methacrylate intraocular lenses with rigid haptics.

Methods:

Ciliary sulcus–based scleral tunnels were created by placing valved 27-gauge (g) trocar cannulas limbus parallel with conjunctival displacement. After complete vitrectomy, the rigid haptics were then externalized using 27g forceps. Cautery was then used to form flanges at the haptic tips. The haptics were then pushed back into the mouths of the scleral tunnels.

Results:

Flanged intrascleral fixation was successfully achieved in eight eyes of seven patients. The average age at the time of surgery was 75 ± 13.7 years, with a mean follow-up of 17.9 ± 16.3 months (range 3–42 months). Intraocular lens dislocation/subluxation was the most common indication for surgery. All patients fully recovered to their potential acuity by their third postoperative visit. The most significant complication was erosion of one haptic in one patient, which was successfully managed without requiring intraocular lens exchange. There were no complications of subsequent dislocation, endophthalmitis, retinal detachment, or uveitis–glaucoma–hyphema syndrome.

Conclusion:

Flanged sutureless intrascleral fixation of dislocated 1-piece polymethyl methacrylate intraocular lenses with rigid haptics can be safely and successfully performed, avoiding the large wound creation accompanying intraocular lens exchange and the disadvantages of suture-based techniques.
Intrascleral Fixation of Flanged Polypropylene Suture(s) for Iridodialysis Repair
Authors: Ou Zhongmin , Zhang Qi , Jin Haiying
Published: July 2020

Purpose:

We will describe a minimally invasive technique for the repair of iridodialysis, without conjunctival dissections, using intrasceral fixation of a 6-0 polypropylene suture with a flanged tip.

Methods:

A flange was created at the end of the suture with thermoplasticity. An ab interno passing of the needle attached to the suture was performed through the peripheral part of the iris and was further passed out from the eye 1.5 mm to 2 mm behind the limbus. Intrascleral fixation of the exterior suture was performed with the aid of the attached needle. After adjusting the tension of the iris relocation, the externalized end of the suture was cut flush to the sclera with scissors. For a wide dialysis, the same manipulations were repeated until the repair was completed.

Results:

The technique was used in three eyes of three patients. No visual impairments of monocular diplopia and glare were observed after surgery. Postoperatively, the irises remained well positioned, with no suture erosion, suture loosening, hypotony, scleral atrophy, or chronic inflammation being observed within the follow-up period. Mild postoperative hyphema was observed in one eye of blunt trauma.

Conclusion:

The present technique provides minimal surgical invasion for the repair of iridodialysis without creations of scleral flap/groove/pocket and conjunctival dissection.
A Mixed Methods Study of the Association of Non-Veterans Affairs Care With Veterans’ and Clinicians’ Experiences of Care Coordination
Authors: Benzer Justin K. , Gurewich Deborah , Singer Sara J. , McIntosh Nathalie M. , Mohr David C. , Vimalananda Varsha G. , Charns Martin P.
Published: July 2020

Background:

Poor coordination between the Department of Veterans Affairs (VA) and non-VA care may negatively impact health care quality. Recent legislation is intended to increase Veterans’ access to care, in part through increased use of non-VA care. However, a possible consequence may be diminished patient experiences of coordination.

Objective:

The objective of this study was to determine VA patients’ and clinicians’ experiences of coordination across VA and non-VA settings.

Design:

Observational mixed methods using patient surveys and clinician interviews. Sampled patients were diagnosed with type 2 diabetes mellitus and either cardiovascular or mental health comorbidities.

Participants and Measures:

Patient perspectives on coordination were elicited between April and September 2016 through a national survey supplemented with VA administrative records (N=5372). Coordination was measured with the 8-dimension Patient Perceptions of Integrated Care survey. Receipt of non-VA care was measured through patient self-report. Clinician perspectives were elicited through individual interviews (N=100) between May and October 2017.

Results:

Veterans who received both VA and non-VA care reported significantly worse care coordination experiences than Veterans who only receive care in VA. Clinicians report limited information exchange capabilities, which, combined with bureaucratic and opaque procedures, adversely impact clinical decision-making.

Conclusions:

VA is working through a shift in how Veterans receive health care by increasing access to care from non-VA providers. Study findings suggest that VA should prioritize coordination of care in addition to access. This could include requiring monitoring of patient-experienced care coordination, surveys of referring and consulting clinicians, and pilot testing and evaluation of interventions to improve coordination.
Pediatric nail disorders: a review
Authors: Smith Robert J. , Rubin Adam I.
Published: July 2020

Purpose of review

Nail disorders represent an uncommon subset of complaints seen in pediatric dermatology. There is a wide array of disorders that can affect the nail unit in children, including infectious, inflammatory, neoplastic, congenital, and traumatic processes. In order to enhance familiarity with pediatric nail conditions, we review the background and treatment of the more common entities seen in pediatric onychology, including onychomycosis, onychomadesis, nail psoriasis, trachyonychia, longitudinal melanonychia, onychophagia, and onychocryptosis.

Recent findings

Nail involvement in pediatric patients with psoriasis may indicate increased risk for both overall disease severity and the development psoriatic arthritis. In the evaluation of longitudinal melanonychia, the clinical findings that raise concern for subungual melanoma in adults are often found in benign nail unit nevi in children. In the systemic treatment of pediatric onychomycosis, new data raises the possibility that laboratory monitoring may be approached differently. In the approach to onychophagia, emerging pharmacotherapies include N-acetylcysteine.

Most nail disorders in pediatric patients have an overall favorable prognosis. However, nail abnormalities can lead to patient and parental anxiety, decreased quality of life, pain, and functional impairment. Clinicians should be aware of these more common diverse entities in order to identify them and apply state of the art management for these issues. Additionally, the reader will learn factors related to these nail disorders, which may require systemic work-up and/or specialist referral.
Alloimmunity in pancreas transplantation
Authors: Aziz Fahad , Mandelbrot Didier , Parajuli Sandesh , Al-Qaoud Talal , Redfield Robert , Kaufman Dixon , Odorico Jon S.
Published: July 2020

Purpose of review

Despite significant improvement in pancreas allograft survival, rejection continues to be a major clinical problem. This review will focus on emerging literature related to the impact of pretransplant and de-novo DSA (dnDSA) in pancreas transplant recipients, and the diagnosis and treatment of T-cell-medicated rejection (TCMR) and antibody-mediated rejection (ABMR) in this complex group of patients.

Recent findings

Recent data suggest that pretransplant DSA and the emergence of dnDSA in pancreas transplant recipients are both associated with increased risk of ABMR. The pancreas allograft biopsy is essential for the specific diagnosis of TCMR and/or ABMR, distinguish rejection from other causes of graft dysfunction, and to guide-targeted therapy. This distinction is important especially in the setting of solitary pancreas transplants but also in simultaneous pancreas-kidney transplants where solid evidence has now emerged demonstrating discordant biopsy findings. Treatment of rejection in a functioning pancreas can prolong allograft survival.

The accurate and timely diagnosis of active alloimmune destruction in pancreas transplant recipients is paramount to preserving graft function in the long term. This review will discuss new, rapidly evolving information that is valuable for the physician caring for these patients to achieve optimal immunological outcomes.
Impulsiveness and Emotional Dysregulation as Stable Features in Borderline Personality Disorder Outpatients Over Time
Authors: Martino Francesca , Gammino Lorenzo , Sanza Michele , Berardi Domenico , Pacetti Monica , Sanniti Alice , Tangerini Giulia , Menchetti Marco
Published: July 2020

Large-scale longitudinal studies show that specific borderline personality disorder (BPD) symptoms are more likely to remit over time, suggesting that clinical features of BPD may vary between younger patients and older ones. The objective of the present report is to provide a direct comparison between younger (age 18–25 years; n = 44) and older (age 40–59 years; n = 49) BPD patients on the nine DSM-4 BPD criteria (self-harm, emotional dysregulation, impulsiveness, and work and social functioning). Younger and older patients reported similar levels of impulsiveness, emotional dysregulation, and work and social functional impairment. Younger adults were more likely to show anger and self-damaging behaviors compared with older patients, which in turn were more likely to endorse chronic emptiness. In conclusion, older patients with BPD are still impaired in impulsiveness, emotional regulation, and social functioning; treatments for older BPD population should be long term and focused on emotion dysregulation and impulsive behaviors.
Structural imaging of the retina in psychosis spectrum disorders: current status and perspectives
Authors: Jerotic Stefan , Ignjatovic Zora , Silverstein Steven M. , Maric Nadja P.
Published: July 2020

Purpose of review

Structural changes of the retina in schizophrenia and other psychotic disorders seem plausible as these conditions are accompanied by widespread morphological abnormalities of the brain. Advances in structural retinal imaging have led to the possibility of precise quantification of individual retinal layers, using optical coherence tomography (OCT) scanners.

Recent findings

The aggregation of information related to OCT findings in schizophrenia has resulted in three metaanalyses, which are currently described. Areas where retinal changes were reported include retinal nerve fiber layer (RNFL), ganglion cell layer complex (GCC), macular volume, and macular thickness, but findings on affected retinal segments vary to some extent across studies. Discrepancies in individual studies could be because of small samples, heterogeneity within schizophrenia (phase of the illness, illness duration, predominant symptomatology), inconsistent reporting of antipsychotic therapy, insufficient control of confounding variables (somatic comorbidities, smoking, and so on), and use of the different types of OCT scanners.

Exploration of potential disturbances in retinal architecture could provide new insights into neuronal changes associated with psychosis spectrum disorders, with potential to elucidate the nature and timing of developmental, progressive, inflammatory, and degenerative aspects of neuropathology and pathophysiology, and to assist with characterizing heterogeneity and facilitating personalized treatment approaches.
Improving the physical health of the mentally ill: recent advances
Authors: Stanley Susanne H.
Published: July 2020

Purpose of review

This review of the literature examines the most recent advances in the battle to improve the physical health of people with severe mental illness. Covering the 2018/2019 time period, the article offers a glance of future healthcare models and research directions.

Recent findings

A systematic search of the PubMed and Cochrane databases, along with additional journal articles available online but not yet allocated to a journal edition, produced a total of 24 journal articles suitable for review. The review period was from January 2018 to December 2019. The four main themes of investigation, intervention, integration and training emerged.

The uptake and integration of primary care into mental health services for people with SMI is still facing many barriers. Healthy lifestyle and physical activity interventions need to run alongside medical treatment for both mental and physical health in order to provide holistic care. To do this, clarification of professional roles and responsibility need to be defined and adhered to, along with additional training for staff and coordination of services.
Effects of cell cycle variability on lineage and population measurements of messenger RNA abundance
Authors: Perez-Carrasco Ruben , Beentjes Casper , Grima Ramon
Published: July 2020

Many models of gene expression do not explicitly incorporate a cell cycle description. Here, we derive a theory describing how messenger RNA (mRNA) fluctuations for constitutive and bursty gene expression are influenced by stochasticity in the duration of the cell cycle and the timing of DNA replication. Analytical expressions for the moments show that omitting cell cycle duration introduces an error in the predicted mean number of mRNAs that is a monotonically decreasing function of
η
, which is proportional to the ratio of the mean cell cycle duration and the mRNA lifetime. By contrast, the error in the variance of the mRNA distribution is highest for intermediate values of
η
consistent with genome-wide measurements in many organisms. Using eukaryotic cell data, we estimate the errors in the mean and variance to be at most 3% and 25%, respectively. Furthermore, we derive an accurate negative binomial mixture approximation to the mRNA distribution. This indicates that stochasticity in the cell cycle can introduce fluctuations in mRNA numbers that are similar to the effect of bursty transcription. Finally, we show that for real experimental data, disregarding cell cycle stochasticity can introduce errors in the inference of transcription rates larger than 10%.
Fractal analysis of concurrently prepared latex rubber casts of the bronchial and vascular systems of the human lung
Authors: Essey Montanna , Maina John N.
Published: July 2020

Fractal geometry (FG) is a branch of mathematics that instructively characterizes structural complexity. Branched structures are ubiquitous in both the physical and the biological realms. Fractility has therefore been termed nature's design. The fractal properties of the bronchial (airway) system, the pulmonary artery and the pulmonary vein of the human lung generates large respiratory surface area that is crammed in the lung. Also, it permits the inhaled air to intimately approximate the pulmonary capillary blood across a very thin blood–gas barrier through which gas exchange to occur by diffusion. Here, the bronchial (airway) and vascular systems were simultaneously cast with latex rubber. After corrosion, the bronchial and vascular system casts were physically separated and cleared to expose the branches. The morphogenetic (Weibel's) ordering method was used to categorize the branches on which the diameters and the lengths, as well as the angles of bifurcation, were measured. The fractal dimensions (
D
F
) were determined by plotting the total branch measurements against the mean branch diameters on double logarithmic coordinates (axes). The diameter-determined
D
F
values were 2.714 for the bronchial system, 2.882 for the pulmonary artery and 2.334 for the pulmonary vein while the respective values from lengths were 3.098, 3.916 and 4.041. The diameters yielded
D
F
values that were consistent with the properties of fractal structures (i.e. self-similarity and space-filling). The data obtained here compellingly suggest that the design of the bronchial system, the pulmonary artery and the pulmonary vein of the human lung functionally comply with the Hess–Murray law or ‘the principle of minimum work’.
Effects of malleable kinetochore morphology on measurements of intrakinetochore tension
Authors: Renda Fioranna , Magidson Valentin , Tikhonenko Irina , Fisher Rebecca , Miles Christopher , Mogilner Alex , Khodjakov Alexey
Published: July 2020

The distance between fluorescent spots formed by various kinetochore proteins (delta) is commonly interpreted as a manifestation of intrakinetochore tension (IKT) caused by microtubule-mediated forces. However, large-scale changes of the kinetochore architecture (such as its shape or dimensions) may also contribute to the value of delta. To assess contributions of these non-elastic changes, we compare behaviour of delta values in human kinetochores with small yet mechanically malleable kinetochores against compound kinetochores in Indian muntjac (IM) cells whose architecture remains constant. Due to the micrometre-scale length of kinetochore plates in IM, their shape and orientation are discernible in conventional light microscopy, which enables precise measurements of IKT independent of contributions from changes in overall architecture of the organelle. We find that delta in IM kinetochores remains relatively constant when microtubule-mediated forces are suppressed by Taxol, but it prominently decreases upon detachment of microtubules. By contrast, large decreases of delta observed in Taxol-treated human cells coincide with prominent changes in length and curvature of the kinetochore plate. These observations, supported by computational modelling, suggest that at least 50% of the decrease in delta in human cells reflects malleable reorganization of kinetochore architecture rather than elastic recoil due to IKT.
Core regulatory circuitries in defining cancer cell identity across the malignant spectrum
Authors: Jahangiri Leila , Tsaprouni Loukia , Trigg Ricky M. , Williams John A. , Gkoutos Georgios V. , Turner Suzanne D. , Pereira Joao
Published: July 2020

Gene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors create and engage super-enhancers by recruiting acetylation writers depositing permissive H3K27ac chromatin marks. These super-enhancers are largely associated with BET proteins, including BRD4, that influence higher-order chromatin structure. The orchestration of these events triggers accessibility of RNA polymerase machinery and the imposition of lineage-specific gene expression. In cancers, CRCs drive cell identity by superimposing developmental programmes on a background of genetic alterations. Further, the establishment and maintenance of oncogenic states are reliant on CRCs that drive factors involved in tumour development. Hence, the molecular dissection of CRC components driving cell identity and cancer state can contribute to elucidating mechanisms of diversion from pre-determined developmental programmes and highlight cancer dependencies. These insights can provide valuable opportunities for identifying and re-purposing drug targets. In this article, we review the current understanding of CRCs across solid and liquid malignancies and avenues of investigation for drug development efforts. We also review techniques used to understand CRCs and elaborate the indication of discussed CRC transcription factors in the wider context of cancer CRC models.
The Godbillon-Vey invariant as topological vorticity compression and obstruction to steady flow in ideal fluids
Authors: Machon Thomas
Published: July 2020

If the vorticity field of an ideal fluid is tangent to a foliation, additional conservation laws arise. For a class of zero-helicity vorticity fields, the Godbillon-Vey (GV) invariant of foliations is defined and is shown to be an invariant purely of the vorticity, becoming a higher-order helicity-type invariant of the flow. GV ≠ 0 gives both a global topological obstruction to steady flow and, in a particular form, a local obstruction. GV is interpreted as helical compression and stretching of vortex lines. Examples are given where the value of GV is determined by a set of distinguished closed vortex lines.
Human first-order tactile neurons can resolve spatial details on the scale of single fingerprint ridges
Authors: Jarocka Ewa , Pruszynski J Andrew , Johansson Roland S
Published: July 2020

Fast-adapting type 1 (FA-1) and slow-adapting type 1 (SA-1) first-order tactile neurons provide detailed spatiotemporal tactile information when we touch objects with fingertips. The distal axon of these neuron types branches in the skin and innervates many receptor organs associated with fingerprint ridges (Meissner corpuscles and Merkel cell neurite complexes, respectively), resulting in heterogeneous receptive fields that include many highly sensitive zones or ‘subfields’. Using raised dots that tangentially scanned a neuron’s receptive field, here we examined the spatial resolution capacity of FA-1 and SA-1 neurons afforded by their heterogeneous receptive fields and its constancy across scanning speed and direction. We report that the resolution of both neuron types on average corresponds to a spatial period of ∼0.4 mm and provide evidence that a subfield’s spatial selectivity arises because its associated receptor organ measures mechanical events limited to a single fingerprint ridge. Accordingly, the sensitivity topography of a neuron’s receptive fields is quite stable over repeated mappings and over scanning speeds representative of real-world hand use. The sensitivity topography is substantially conserved also for different scanning directions, but the subfields can be relatively displaced by direction-dependent shear deformations of the skin surface.

Significance Statement

The branching of the distal axon of first-order tactile neurons with receptor-organs associated with fingerprint ridges (Meissner and Merkel end-organs) results in cutaneous receptive fields composed of several distinct subfields spread across multiple ridges. We show that the spatial selectivity of the subfields typically corresponds to the dimension of the ridges (∼0.4 mm) and that neurons’ subfield layout is well preserved across tangential movement speeds and directions representative of natural use of the fingertips. We submit that the receptor-organ underlying a subfield essentially measures mechanical events at an individual ridge. That neurons receive convergent input from multiple subfields does not preclude the possibility that spatial details can be resolved on the scale of single fingerprint ridges by a population code.
Development and Validation of a Web-based Prediction Model for Acute Kidney Injury after surgery
Authors: Woo Sang H. , Zavodnick Jillian , Ackermann Lily , Maarouf Omar , Zhang Jingjing , Cowan Scott W.
Published: July 2020

Background and objectives

Acute kidney injury after surgery is associated with high mortality and morbidity. The purpose of this study is to develop and validate a risk prediction tool for the occurrence of postoperative acute kidney injury requiring renal replacement therapy.

Design, setting, participants, measurements

This retrospective cohort study had 2,299,502 surgical patients over 2015-2017 from the American College of Surgeons National Surgical Quality Improvement Program Database (ACS-NSQIP). Eleven predictors were selected for the predictive model: age, history of congestive heart failure, diabetes, ascites, emergency surgery, preoperative serum creatinine, hematocrit, sodium, preoperative sepsis, preoperative acute renal failure and surgery type. The predictive model was trained using 2015-2016 data (n=1,487,724) and further tested using 2017 data (n=811,778). A risk model was developed using multivariate logistic regression and machine learning methods.

Main outcomes

The primary outcome was postoperative 30-day acute kidney injury requiring renal replacement therapy(AKI-D)

Results

The unadjusted 30-day postoperative mortality rate associated with AKI-D was 37.5%. The renal risk prediction model had high AUC (area under the receiver operating characteristic curve, training cohort: 0.89, test cohort: 0.90) for postoperative AKI-D.

Conclusions

This model provides a clinically useful bedside predictive tool for postoperative acute kidney injury requiring dialysis.
N and O glycosylation of the SARS-CoV-2 spike protein
Authors: Sanda Miloslav , Morrison Lindsay , Goldman Radoslav
Published: July 2020

Covid-19 pandemic outbreak is the reason of the current world health crisis. The development of effective antiviral compounds and vaccines requires detailed descriptive studies of the SARS-CoV-2 proteins. The SARS-CoV-2 spike (S) protein mediates virion binding to the human cells through its interaction with the ACE2 cell surface receptor and is one of the prime immunization targets. A functional virion is composed of three S1 and three S2 subunits created by furin cleavage of the spike protein at R682, a polybasic cleavage sites that differs from the SARS-CoV spike protein of 2002. We observe that the spike protein is O-glycosylated on a threonine (T678) near the furin cleavage site occupied by core-1 and core-2 structures. In addition, we have identified eight additional O-glycopeptides on the spike glycoprotein and we confirmed that the spike protein is heavily N-glycosylated. Our recently developed LC-MS/MS methodology allowed us to identify LacdiNAc structural motives on all occupied N-glycopeptides and polyLacNAc structures on six glycopeptides of the spike protein. In conclusion, our study substantially expands the current knowledge of the spike protein’s glycosylation and enables the investigation of the influence of the O-glycosylation on its proteolytic activation.
The severity of microstrokes depends on local vascular topology and baseline perfusion
Authors: Schmid Franca , Conti Giulia , Jenny Patrick , Weber Bruno
Published: July 2020

1

Cortical microinfarcts are caused by blood flow disturbances and are linked to pathologies like cerebral amyloid angiopathy and dementia. Despite their relevance for disease progression, microinfarcts often remain undetected and the smallest scale of disturbance has not yet been identified. We employ blood flow simulations in realistic microvascular networks from the mouse cortex to quantify the impact of single capillary occlusions. We reveal that the severity of a microstroke is strongly affected by the local vascular topology and the baseline flow rate in the occluded capillary. The largest changes in flow rate are observed in capillaries with two in- and two outflows. Interestingly, this specific topological configuration only occurs with a frequency of 8%, while the majority of capillaries are likely designed to efficiently supply oxygen and nutrients. Taken together, microstrokes likely induce a cascade of local disturbances in the surrounding tissue, which might accumulate and impair energy supply locally.
Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
Authors: Marzolini Catia , Stader Felix , Stoeckle Marcel , Franzeck Fabian , Egli Adrian , Bassetti Stefano , Hollinger Alexa , Osthoff Michael , Weisser Maja , Gebhard Caroline E. , Baettig Veronika , Geenen Julia , Khanna Nina , Tschudin-Sutter Sarah , Mueller Daniel , Hirsch Hans H. , Battegay Manuel , Sendi Parham
Published: July 2020

Background

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP).

Methods

LPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination.

Results

The median age of study participants was 59 (range 24–85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4–10) and 8 days (IQR 5–10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/mL (IQR 18.9–31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values.

Conclusions

High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.
Partial Prediction of the Virus COVID-19 Spread in Russia Based on SIR and SEIR Models
Authors: Tomchin Dmitry , Fradkov Alexander
Published: July 2020

The possibility to predict the spread of COVID-19 in Russia is studied. Particular goal is to predict the time instant when the number of infected achieves its maximum (peak). Such a partial prediction allows one to use simple epidemoics models: SIR and SEIR. Simplicity and small number of parameters are significant advantages of SIR and SEIR models under conditions of a lack of numerical initial data and structural incompleteness of models. The prediction is carried out according to public WHO datasets from March 10 to April 20, 2020. Comparison of forecast results by SIR and SEIR models are given. In both cases, the peak number of infected persons while maintaining the current level of quarantine measures is forecasted at the end of May 2020 or later. It coincides with the real data obtained in May-June, 2020. The results confirm usefulness of simple nonlinear dynamical models for partial prediction of complex epidemic processes.
Cardioids reveal self-organizing principles of human cardiogenesis
Authors: Hofbauer Pablo , Jahnel Stefan , Papai Nora , Giesshammer Magdalena , Penc Mirjam , Tavernini Katherina , Grdseloff Nastasja , Meledeth Christy , Deyett Alison , Schmidt Clara , Ctortecka Claudia , Šalic Šejla , Novatchkova Maria , Mendjan Sasha
Published: July 2020

Organoids that self-organize into tissue-like structures have transformed our ability to model human development and disease. To date, all major organs can be mimicked using self-organizing organoids with the notable exception of the human heart. Here, we established self-organizing cardioids from human pluripotent stem cells that intrinsically specify, pattern and morph into chamber-like structures containing a cavity. Cardioid complexity can be controlled by signaling that instructs the separation of cardiomyocyte and endothelial layers, and by directing epicardial spreading, inward migration and differentiation. We find that cavity morphogenesis is governed by a mesodermal WNT-BMP signaling axis and requires its target HAND1, a transcription factor linked to human heart chamber cavity defects. In parallel, a WNT-VEGF axis coordinates myocardial self-organization with endothelial patterning and specification. Human cardioids represent a powerful platform to mechanistically dissect self-organization and congenital heart defects, serving as a foundation for future translational research.

Highlights

- Cardioids form cardiac-like chambers with inner endothelial lining and interact with epicardium

- Cardioid self-organization and lineage complexity can be controlled by signaling

- WNT-BMP signaling directs cavity formation in self-organized cardioids via HAND1

- WNT-VEGF coordinate endothelial patterning with myocardial cavity morphogenesis