bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary Study of Coping, Perceived Control, and Depressive Symptoms in Youth with Sickle Cell Anemia
Authors: Prussien Kemar V. , Siciliano Rachel E. , Ciriegio Abagail E. , Lee Chelsea A. , DeBaun Michael R. , Jordan Lori C. , Compas Bruce E.
Published: April 2021

Objective:

The primary objective of this study was to test perceived controllability of stressors as a moderator of the association between coping and depressive symptoms in children and adolescents with sickle cell anemia (SCA).

Method:

Twenty-eight children and adolescents (Mage = 11.71, SD = 4.31; 60.7% female) with SCA were enrolled. Caregivers provided reports of child and adolescent coping using the Response to Stress Questionnaire (RSQ), perceived control of stressors using the RSQ, and depressive symptoms using the Child Behavior Checklist. Children and adolescents also completed Wechsler assessments of working memory and verbal comprehension.

Results:

Secondary control coping (i.e., cognitive reappraisal, positive thinking, acceptance, and distraction) was a significant predictor of depressive symptoms such that greater use of secondary control coping was related to fewer reported depressive symptoms when accounting for perceived control of stress and neurocognitive variables. Furthermore, perceived control of peer-related stress was a significant moderator of the association between secondary control coping and depressive symptoms such that there was a significant negative association of secondary control coping with depressive symptoms only for low perceived control.

Conclusion:

Secondary control coping may be particularly helpful for reducing depressive symptoms when adolescents' peer-related stressors are perceived as uncontrollable. Interventions to reduce internalizing problems in this population should consider teaching children and adolescents secondary control coping skills in addition to skills in identifying uncontrollable sources of stress.
Subjective Well-Being and Self-Esteem in Preterm Born Adolescents: An Individual Participant Data Meta-Analysis
Authors: Bilgin Ayten , Brylka Asteria , Wolke Dieter , Trower Hayley , Baumann Nicole , Lemola Sakari
Published: April 2021

Objective:

To study self-reported well-being and self-esteem among adolescents born very preterm (VPT; <32 wk of gestation) and moderate to late preterm (MLPT; 32–36 wk of gestation) compared with those born full-term (FT) in an individual participant data (IPD) meta-analysis.

Methods:

We obtained IPD from the following 4 data sources: The Avon Longitudinal Study of Parents and Children (United Kingdom), the Millennium Cohort Study (United Kingdom), the Basel Study of Preterm Children (Switzerland), and the Bavarian Longitudinal Study (Germany) and conducted two-step random-effects IPD meta-analysis. A total of 986 MLPT, 412 VPT, and 12,719 FT born adolescents reported on subjective well-being and 927 MLPT, 175 VPT, and 13,312 FT born adolescents reported on global self-esteem.

Results:

Adolescents born VPT or MLPT were not different from those born FT regarding general subjective well-being; family, school, and physical appearance–related well-being; and global self-esteem. However, adolescents born VPT reported lower well-being in peer relationships than those born FT (β = −0.209, 95% confidence interval = −0.336 to −0.082). There was no main effect of fetal growth restriction (FGR) and no moderation by FGR, sex, parental education, and ethnicity. No significant heterogeneity between cohorts was found, although some heterogeneity estimates were moderate.

Conclusion:

Adolescents born preterm mostly report no lower well-being and self-esteem than adolescents born FT. However, they perceive their peer relationships as poorer than those born FT.
Pudendal Nerve Terminal Motor Latency Compared by Anorectal Manometry Diagnosing Fecal Incontinence
Authors: Han Seung Hee , Choi Kyungyeul , Shim Ga Yang , Kim JongKyu
Published: April 2021

Objective

The aim of the study was to compare the clinical value of pudendal nerve terminal motor latency in fecal incontinence patients with that of another diagnostic test—anorectal manometry.

Design

This study used a cross-sectional design. Medical records of fecal incontinence patients who underwent pudendal nerve terminal motor latency and anorectal manometry testing were reviewed. Greater than 2.4 ms of pudendal nerve terminal motor latency was determined to be abnormal. Anorectal manometry was performed using a station pull-through technique. Mean resting anal pressure, maximal resting anal pressure, mean squeezing anal pressure, and maximal squeezing anal pressure were investigated. For normal and abnormal pudendal nerve terminal motor latency groups, comparative analyses were performed on anorectal manometry results.

Results

A total of 31 patients were included. Thirteen patients showed normal pudendal nerve terminal motor latency. For anorectal manometry results, there was no significant difference between normal and abnormal pudendal nerve terminal motor latency groups. Fourteen patients had diabetes mellitus. Subgroup analysis of the 14 diabetic patients showed no significant difference between normal and abnormal pudendal nerve terminal motor latency groups. For 17 nondiabetic patients, there was a significant difference between the groups with positive correlations with mean/maximal resting anal pressures.

Conclusions

Pudendal nerve terminal motor latency significantly correlates with anorectal manometry in fecal incontinence only in nondiabetic patients.
Systemic Lupus Erythematosus and Common Variable Immunodeficiency
Authors: Azar Antoine , Aldaoud Nawras , Hardenbergh Dylan , Krimins Rebecca , Son James , Shiroky Jennifer , Timlin Homa
Published: April 2021

Systemic lupus erythematosus (SLE) and common variable immunodeficiency (CVID) are both conditions defined by immune system dysfunction: one hyperactive, the other hypoactive. Although uncommon, these diseases can coexist in the same individual. This review aims to assess the state of the literature on the relationship between SLE and CVID, particularly when workup for CVID should be considered in individuals with SLE and how CVID in individuals with SLE should be treated.
The Value of Musculoskeletal Ultrasound for Evaluation of Postinfectious Lyme Arthritis
Authors: Miller John B. , Albayda Jemima , Aucott John N.
Published: April 2021

Background

Inflammatory arthritis is the most common late manifestation of untreated Lyme disease in the United States. While antimicrobial therapy is effective in resolving swelling and pain for 90% of patients, many patients have persistent inflammation, termed postinfectious Lyme arthritis (PILA). Current outcome measures for Lyme arthritis have several limitations, as improvement is considered a dichotomous outcome based solely on physical examination. There is growing interest in the use of ultrasonography to better define outcomes in inflammatory arthritis, and this is particularly relevant for conditions such as late Lyme arthritis and PILA, which are monoarticular or oligoarticular. We describe results from a series of 5 patients who underwent ultrasound evaluations leading to a diagnosis of PILA.

Methods

This is a case series describing 5 patients with PILA who were referred for evaluation and treatment of symptomatic joints.

Results

Musculoskeletal ultrasound showed significant joint pathology, even in cases with minimal clinical findings. Synovitis, effusions, enthesitis/tendinopathy, and bone erosions were seen and helped confirm the presence of ongoing inflammatory arthritis.

Conclusions

Marked inflammatory change—with synovitis, enthesitis and erosions—can be seen in selected patients with PILA. Systematic sonographic evaluation of patients with PILA is needed to further evaluate pathology and treatment response.
Hand-assisted Laparoscopic Surgery for Colorectal Liver Metastasis: Analysis of Short-term and Long-term Results
Authors: Mahamid Ahmad , Sawaied Munier , Berger Yael , Halim Nasser A. , Goldberg Natalia , Abu-Zaydeh Omar , Bitterman Arie , Sadot Eran , Haddad Riad
Published: April 2021

Background:

There is scant data regarding the outcomes of hand-assisted laparoscopic surgery (HALS) for colorectal liver metastasis (CRLM). The aim of this study is to report our experience and analyze the short-term and long-term results.

Materials and Methods:

Retrospective study of patients undergoing HALS for CRLM in 2 university affiliated medical centers.

Results:

Two hundred and thirty-eight liver procedures were performed on 145 patients including 205 parenchymal sparing resections and 33 anatomic resections. The median number of metastases was 1 (range: 1 to 8), 38 patients (26.2%) had 3 or more metastases, and 41 patients (28.3 had a bi-lobar disease. The tumor size was 20 (2 to 90) mm, and 52 patients (36.6%) had a tumor larger than 30 mm. Nighty-nine patients (67.8%) received neoadjuvant chemotherapy. In 8 patients (5.5%) the laparoscopic liver resection was combined with ablation, and 16 patients (11%) underwent a synchronous resection of colorectal cancer. The median operative time, blood loss during surgery, and postoperative hospital stay were 163 minutes, 300 mL, and 4 days, respectively. The median modified Iwate complexity score was 4 (0 to 10) and the conversion rate to open surgery was 5.5%. The overall and major complication rates were 23.8% and 3.6%, respectively. The mortality rate was 0.7%. R0 resections were achieved in 91% of patients. Median overall survival for all the cohort (intend to treat) was 59 months, and the 8- and 10-year overall survival rates were 47.3% and 24.9%, respectively.

Conclusions:

This study shows that HALS is a safe and efficacious treatment for selected patients with CRLM.
Scarless Completion Thyroidectomy After Initial Transoral Approach for Differentiated Thyroid Cancer: How and When to Start?
Authors: Wu Yi-Ju , Chi Shun-Yu , Chan Yi-Chia , Chou Fong-Fu , Wee Sin-Yong , Wu Kun-Ta
Published: April 2021

Background:

With growing literature, the feasibility of transoral endoscopic thyroidectomy vestibular approach (TOETVA) has been confirmed as a valid method for managing differentiated thyroid cancer. Completion thyroidectomy (CT) is recommended in patients who have been diagnosed with differentiated thyroid cancer after unilateral lobectomy by TOETVA. In this retrospective study, the authors addressed the critical questions of how and when to do the second operation of CT to avoid a neck scar.

Materials and Methods:

The authors retrospectively reviewed our patients who had received TOETVA in our hospital from August 2016 to December 2019. Those who received CT after initial TOETVA as cTOETVA were further separated according to the approaching methods. Demographic data, operative variables, and postoperative variables were collected and analyzed.

Results:

A total of 97 patients were enrolled using TOETVA. Malignancies were present in 42 patients (43.3%) using TOETVA. There were 3 approaching methods of cTOETVA and separated into reopen transcervical approach (re-TCA), retransoral TOETVA (re-TOETVA), and transaxillary approach (TAA) groups. There were no significant complications among patients for cTOETVA. Of the 8 patients for the cTOETVA, 3 received re-TCA, 3 re-TOETVA, and 2 TAA.

Conclusions:

The outcomes are encouraging and demonstrate the feasibility of scarless completion thyroidectomy after initial TOETVA. The re-TOETVA procedure should be completed within 14 days after the initial TOETVA procedure, TAA beyond 14 days, and re-TCA may be completed at any time. The cTOETVA techniques using re-TOETVA or TAA have better cosmetic results than re-TCA in oncological equivalency.
Reasons for non-attendance to cervical cancer screening and acceptability of HPV self-sampling among Bruneian women: A cross-sectional study
Authors: Chaw Liling , Lee Shirley HF , Hazwani Ja’afar Nurul Iffah , Lim Edwin , Sharbawi Roslin
Published: April 2021

Objective

Uptake for cervical cancer screening remains well below the 80% target as recommended by Brunei’s National Cervical Cancer Prevention and Control plan. We conducted a pilot study to determine the reasons for non-attendance and explore their acceptance of human papillomavirus (HPV) self-sampling as an alternative to the Pap test.

Methods

A cross-sectional study was conducted at a primary healthcare center in Brunei, from January to December 2019. We recruited screening non-attendees, defined as women who were eligible for Pap test but who either never, or did not have one within the recommended screening interval of 3 years. This recruitment was done conveniently among women attending outpatient care and/or child health services at the primary healthcare center. Participants were first asked to complete a self-administered paper-based questionnaire on their reasons for screening non-attendance, and then invited for HPV self-sampling. Among those who agreed to participate in HPV self-sampling, they were asked to complete a second questionnaire on the self-sampling procedure and their samples were tested for high-risk HPV (hr-HPV). Results were analyzed using descriptive and inferential statistics.

Result

We enrolled 174 screening non-attendees, out of which 97 (55.7%) also participated in HPV self-sampling. The main reasons for not attending Pap test screening were fear of bad results (16.1%, n = 28); embarrassment (14.9%, n = 26) and lack of time due to home commitments (10.3%, n = 18). When compared to those who agreed to participate in HPV self-sampling, those who declined were significantly older (p = 0.002) and less likely to agree that they are susceptible to cervical cancer (p = 0.023). They preferred to receive Pap test-related information from healthcare workers (59.0%, n = 155), social messaging platforms (28.7%, n = 51) and social media (26.4%, n = 47). HPV self-sampling kits were positively received among the 97 participants, where > 90% agreed on its ease and convenience. Nine (9.3%) tested positive for hr-HPV, out of which eight were non-16/18 HPV genotypes.

Conclusion

Our findings suggest that promoting awareness on cervical cancer, clarifying any misconceptions of Pap test results, and highlighting that the disease is preventable and that early detection through screening can facilitate successful treatment would help increase screening uptake among Bruneian non-attendees. Response to HPV self-sampling was highly positive, suggesting the possibility of implementing this strategy in the local setting. Our high detection of non-16/18 HPV genotypes suggest high prevalence of other hr-HPV genotypes in Brunei. Larger studies should be conducted to further validate our findings.
Spatiotemporal specification of human green and red cones
Authors: Hadyniak Sarah E. , Eldred Kiara C. , Brenerman Boris , Hussey Katarzyna A. , Hagen Joanna F. D. , McCoy Rajiv C. , Sauria Michael E. G. , Kuchenbecker James A. , Reh Thomas , Glass Ian , Neitz Maureen , Neitz Jay , Taylor James , Johnston Robert J.
Published: April 2021

Trichromacy is unique to primates among mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similarM- andL-opsinmRNAs.M-opsin, but notL-opsin, was observed during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in theNR2F2gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.
Furanoditerpenoid biosynthesis in the bioenergy crop switchgrass is catalyzed by an alternate metabolic pathway
Authors: Muchlinski Andrew , Jia Meirong , Tiedge Kira , Fell Jason S. , Pelot Kyle A. , Chew Lisl , Davisson Danielle , Chen Yuxuan , Siegel Justin , Lovell John T. , Zerbe Philipp
Published: April 2021

Specialized diterpenoid metabolites are important mediators of stress resilience in monocot crops. A deeper understanding of how species-specific diterpenoid-metabolic pathways and functions contribute to plant chemical defenses can enable crop improvement strategies. Here, we report the genomics-enabled discovery of five cytochrome P450 monooxygenases (CYP71Z25-29) that form previously unknown furanoditerpenoids in the monocot bioenergy crop switchgrass (Panicum virgatum). Combinatorial pathway reconstruction showed that CYP71Z25-29 catalyze furan ring addition to diterpene alcohol intermediates derived from distinct class II diterpene synthases, thus bypassing the canonical role of class I diterpene synthases in plant diterpenoid metabolism. Transcriptional co-expression patterns and presence of select diterpenoids in droughted switchgrass roots support possible roles of CYP71Z25-29 in abiotic stress responses. Integrating molecular dynamics, structural analysis, and targeted mutagenesis, identified active site determinants controlling distinct CYP71Z25-29 catalytic specificities and, combined with broad substrate promiscuity for native and non-native diterpenoids, highlights the potential of these P450s for natural product engineering.

Significance Statement

Diterpenoids play important roles in stress resilience and chemically mediated interactions in many plant species, including major food and bioenergy crops. Enzymes of the cytochrome P450 monooxygenase family catalyze the various functional decorations of core diterpene scaffolds that determine the large diversity of biologically active diterpenoids. This study describes the identification and mechanistic analysis of an unusual group of cytochrome P450 monooxygenases, CYP71Z25-29, from the bioenergy crop switchgrass (Panicum virgatum). These enzymes catalyze the furan ring addition directly to class II diterpene synthase products, thus bypassing the conserved pairwise reaction of class II and class I diterpene synthases in labdane diterpenoid metabolism. Insight into the distinct substrate-specificity of CYP71Z25-29 offers opportunity for engineering of furanoditerpenoid bioproducts.
Frequency and neural correlates related to psychosis in motor neurone disease
Authors: Wilcox A. , Jones P. S , Roberts R. C. , Rowe J. B.
Published: April 2021

Psychosis is a challenging feature of the syndromes motor neurone disease (MND), frontotemporal dementia and their overlap. Clinically evident psychosis affects 5-10% of patients, and more in those with C9orf72 expansions. However, subthreshold psychosis features may be overlooked in the context of overriding concern for physical impairment. This prospective study aimed to establish the prevalence and severity of psychosis features in a population-representative sample of MND, and to identify the neural correlates of psychosis by structural magnetic resonance imaging. A three-tiered system was applied to recruit people with MND, with cognitive and psychosis screening (Tier 1: N=111 with the Edinburgh ALS Cognitive and Behavioural Screen), in-depth neuropsychiatric assessment (Tier 2: N-=60) and imaging (Tier 3: N=30). Age-, education- and sex-matched healthy controls were recruited to Tier 2 (N=30) and Tier 3 (N=20). Overt psychosis was identified in 10% of the Tier 1 cohort, whilst 46% showed milder and diverse neuropsychiatric change. Grey matter correlates of psychosis included atrophy of the cingulate cortex and the hippocampus. White matter correlates included compromised integrity along frontotemporal and temporal-parietal association pathways, especially those connecting the anterior temporal lobe. These grey and white matter changes in MND represent vulnerability to psychosis and are qualitatively similar to volumetric and white matter abnormalities observed in other primary psychotic disorders. Neuropsychiatric features are common, even though overt psychosis is identified in a minority of people with motor neurone disease.
Prevalence and polymorphism of a mussel transmissible cancer in Europe
Authors: Hammel Maurine , Simon Alexis , Arbiol Christine , Villalba Antonio , Burioli Erika AV , Pépin Jean-François , Lamy Jean-Baptiste , Benabdelmouna Abdellah , Bernard Ismael , Houssin Maryline , Charrière Guillaume M , Destoumieux-Garzon Delphine , Welch John , Metzger Michael J , Bierne Nicolas
Published: April 2021

Transmissible cancers are parasitic malignant cell lineages that acquired the ability to infect new hosts from the same species, or sometimes related species. First described in dogs and Tasmanian devils, transmissible cancers were later discovered in some marine bivalves affected by a leukemia-like disease. InMytilusmussels, two lineages of Bivalve Transmissible Neoplasia (BTN), both emerged in aM. trossulusfounder individual, have been described to date (MtrBTN1 and MtrBTN2). Here, we performed an extensive screening of genetic chimerism, a hallmark of transmissible cancer, by genotyping hundred SNPs of thousands of EuropeanMytilusmussels. The genetic analysis allowed us to simultaneously obtain the genotype of hosts-M. edulis,M. galloprovincialisor hybrids- and the genotype of tumors of heavily infected individuals. In addition, a subset of individuals were systematically genotyped and analysed by histology in order to screen for possible non-transmissible cancers. We detected MtrBTN2 at low prevalence inM. edulis, and also inM. galloprovincialisand hybrids although at a much lower prevalence. No MtrBTN1 or new BTN were found but a few individuals with non-transmissible neoplasia were observed at a single polluted site on the same sampling date. We observed a diversity of MtrBTN2 genotypes that appeared more introgressed or more ancestral than MtrBTN1 and reference healthyM. trossulusindividuals. The observed polymorphism is most likely due to somatic null alleles caused by structural variations or point mutations in primer-binding sites leading to enhanced detection of the host alleles. Despite low prevalence, two divergent sublineages, confirmed by mtCOI sequences, are co-spreading in the same geographic area, suggesting a complex diversification of MtrBTN2 since its emergence and host species shift.
Single-Cell Transcriptomic Analysis of Livers During NLRP3 Inflammasome Activation Reveals a Novel Immune Niche
Authors: Calcagno David , Chu Angela , Gaul Susanne , Taghdiri Nika , Toomu Avinash , Leszczynska Aleksandra , Kaufmann Benedikt , Wree Alexander , Geisler Lukas , Hoffman Hal M. , Feldstein Ariel E. , King Kevin R.
Published: April 2021

The NOD-like receptor protein 3 (NLRP3) inflammasome is a central contributor to human acute and chronic liver disease, yet the molecular and cellular mechanisms by which its activation precipitates injury remain incompletely understood. Here, we present single cell transcriptomic profiling of livers from a global transgenic Tamoxifen-inducible constitutively-activatedNlrp3A350Vmutant mouse, and we investigate the changes in parenchymal and non-parenchymal liver cell gene expression that accompany inflammation and fibrosis. Our results demonstrate that NLRP3 activation causes chronic extramedullary myelopoiesis marked by an increase in proliferating myeloid progenitors that differentiate into neutrophils, monocytes, and monocyte-derived macrophages, results that were corroborated by flow cytometry and histological staining. We observed prominent neutrophil infiltrates with increased Ly6gHIand Ly6gINTcells exhibiting transcriptomic signatures of granulopoiesis typically found in the bone marrow. This was accompanied by a marked increase in Ly6cHImonocytes differentiating into Cd11bHITim4HIClec4fHImacrophages that express proinflammatory transcriptional programs similar to macrophages of non-alcoholic steatohepatitis (NASH) models. NLRP3 activation also downregulated metabolic pathways in hepatocytes and shifted hepatic stellate cells towards an activated pro-fibrotic state based on expression of collagen and extracellular matrix (ECM) regulatory genes. These results, which highlight abundant neutrophils and extramedullary granulopoiesis define an inflamed and fibrotic hepatic single cell microenvironment, precipitated solely by NLRP3 activation. Clinically, our data support the notion that neutrophils and NLRP3 should be explored as therapeutic targets in NASH-like inflammation.
The unique neuronal structure and neuropeptide repertoire in the ctenophore Mnemiopsis leidyi shed light on the evolution of animal nervous systems
Authors: Sachkova Maria Y , Nordmann Eva-Lena , Soto-Àngel Joan J , Meeda Yasmin , Górski Bartłomiej , Naumann Benjamin , Dondorp Daniel , Chatzigeorgiou Marios , Kittelmann Maike , Burkhardt Pawel
Published: April 2021

The ctenophore nerve net represents one of the earliest evolved nervous system of animals. Due to the uncertainties of their phylogenetic placement of ctenophores and the absence of several key bilaterian neuronal genes, it has been hypothesized that their neurons have evolved independently. Whether this is indeed the case remains unclear, and thus the evolutionary history of neurons is still contentious. Here, we have characterized the neuropeptide repertoire of the ctenophore Mnemiopsis leidyi. Using the machine learning NeuroPID tool1 129 new putative neuropeptide precursors were predicted. Sixteen of them are detected in the subepithelial nerve net (SNN), aboral organ (AO) and epithelial sensory cells (ESC) of early cydippid-stage M. leidyi by in situ hybridization (ISH) and immunohistochemistry (IHC). Four of these neuropeptides increase the animals’ swimming velocity in a behavioral essay. The new neuropeptides were used as markers to identify neuronal cell types in single cell transcriptomic data2. To unravel the neuronal architecture, we 3D reconstructed the SNN underlying the comb plates using serial block-face scanning electron microscopy (SBF-SEM). For the first time, we confirm a more than 100 years old hypothesis about anastomoses between neurites of the same cell in ctenophores and reveal that they occur through a continuous membrane. Our findings reveal the unique neuronal structure and neuropeptide repertoire of ctenophores and are important for reconstructing the evolutionary origin of animal neurons and nervous systems.
Pkd1andWnt5agenetically interact to control lymphatic vascular morphogenesis in mice
Authors: Chau Tevin CY. , Baek Sungmin , Coxam Baptiste , Skoczylas Renae , Rondon-Galeano Maria , Bower Neil I. , Wainwright Elanor N. , Stacker Steven SA. , Cooper Helen M. , Lagendijk Anne K. , Harvey Natasha L. , François Mathias , Hogan Benjamin M.
Published: April 2021

Lymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and and morphogenesis. Canonical and non-canonical WNT signalling pathways are known to control LEC polarity and development of lymphatic vessels and valves.PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by whichPkd1acts during lymphangiogenesis remains unclear. Here we find that loss of non-canonical WNT signalling componentsWnt5aandRykphenocopy lymphatic defects seen inPkd1knockout mice. To investigate genetic interaction, we generatedPkd1/Wnt5adouble knockout mice. Loss ofWnt5asuppressed phenotypes seen in the lymphatic vasculature ofPkd1−/−mice and Pkd1 deletion suppressed phenotypes observed inWnt5a−/−mice. Thus, we report mutually suppressive roles forPkd1andWnt5a,with developing lymphatic networks restored to a more wild-type state in double mutant mice. This genetic interaction betweenPkd1and the non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. Our work suggests thatPkd1acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks.
Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling
Authors: van der Stel Anne-Xander , Gordon Emily R. , Sengupta Arnab , Martínez Allyson K. , Klepacki Dorota , Perry Thomas N. , del Valle Alba Herrero , Vazquez-Laslop Nora , Sachs Matthew S. , Cruz-Vera Luis R. , Innis C. Axel
Published: April 2021

Free L-tryptophan (L-Trp) induces the expression of theEscherichia colitryptophanase operon, leading to the production of indole from L-Trp. Tryptophanase operon expression is controlled via a mechanism involving the tryptophan-dependent stalling of ribosomes engaged in translation oftnaC, a leader sequence upstream oftnaAthat encodes a 24-residue peptide functioning as a sensor for L-Trp. Although extensive biochemical characterization has revealed the elements of the TnaC peptide and the ribosome that are responsible for translational arrest, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a variant of TnaC (R23F) in which stalling by L-Trp is enhanced because of reduced cleavage of TnaC(R23F)-peptidyl-tRNA. In contrast to previous data originated from lower resolution structural studies, we show that the TnaC–ribosome complex captures a single L-Trp molecule to undergo tryptophan-dependent termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. In addition, we show that the conformation of the L-Trp binding site is not altered by the R23F mutation. This leads us to propose a model in which rates of TnaC-peptidyl-tRNA cleavage by release factor and binding of the L-Trp ligand to the translating ribosome determine the tryptophan sensitivity of the wild-type and mutant TnaC variants. Thus, our study reveals a strategy whereby a nascent peptide assists the bacterial ribosome in sensing a small metabolite.
Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood
Authors: Portilla Aitzkoa Lopez de Lapuente , Ekdahl Ludvig , Cafaro Caterina , Ali Zain , Miharada Natsumi , Thorleifsson Gudmar , Žemaitis Kristijonas , Arrizabalaga Antton Lamarca , Thodberg Malte , Pertesi Maroulio , Dhapola Parashar , Bao Erik , Niroula Abhishek , Bali Divya , Norddahl Gudmundur , Damboriena Nerea Ugidos , Sankaran Vijay G. , Karlsson Göran , Thorsteinsdottir Unnur , Larsson Jonas , Stefansson Kari , Nilsson Björn
Published: April 2021

Understanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studiedin vitroand in animal models, but less is known about the mechanismsin vivoin humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to thePPM1Hgene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology.PPM1His expressed in HSPCs, and the allele that confers higher blood CD34+cell levels downregulatesPPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site inPPM1Hintron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, andPPM1HshRNA- knockdown increased CD34+and CD34+90+cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulationin vivoin humans, and identifyingPPM1Has a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.
Mild impairment of mitochondrial function increases longevity and pathogen resistance through ATFS-1-driven activation of p38-regulated innate immunity
Authors: Campos Juliane C. , Wu Ziyun , Rudich Paige D. , Soo Sonja K. , Mistry Meeta , Ferreira Julio C.B. , Blackwell T. Keith , Van Raamsdonk Jeremy M.
Published: April 2021

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants inC. elegans,we found that disrupting subunits of the mitochondrial electron transport chain resulted in upregulation of genes involved in innate immunity, which we found to be dependent on not only the canonical p38-mediated innate immune signaling pathway but also on the mitochondrial unfolded protein response. Both of these pathways are absolutely required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitochondrial unfolded protein response can act on the same innate immunity genes to promote resistance to bacterial pathogens, and that input from the mitochondria can extend longevity by signaling through these two pathways. Combined, this indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.

Significance Statement

In this work, we explore the relationship between mitochondrial function, aging and innate immunity. We find that mild impairment of mitochondrial function results in upregulation of genes involved in innate immunity, increased resistance to bacterial pathogens and lifespan extension, all of which are dependent on two evolutionarily conserved signaling pathways. This work demonstrates how changes in functional status of the mitochondria can trigger activation of innate immunity, and that the underlying mechanisms are important for the longevity of the organism. This work advances our understanding of connections between metabolism and immunity. As the pathways studied here are conserved up to mammals, these insights may help us to understand the role of mitochondrial health, innate immunity and lifespan in humans.
Differential mutational profile of SARS-CoV-2 proteins across deceased and asymptomatic patients
Authors: Laskar Rezwanuzzaman , Ali Safdar
Published: April 2021

The SARS-CoV-2 infection spread at an alarming rate with many places showed multiple peaks in incidence. Present study involves a total of 332 SARS-CoV-2 sequences from 114 Asymptomatic and 218 Deceased patients from twenty-one different countries. The mining of mutations was done using the GISAID CoVSurver (www.gisaid.org/epiflu-applications/covsurver-mutations-app) with the reference sequence ‘hCoV-19/Wuhan/WIV04/2019’ present in NCBI with Accession number NC-045512.2. The impact of the mutations on SARS-CoV-2 proteins mutation was predicted using PredictSNP1(loschmidt.chemi.muni.cz/predictsnp1) which is a meta-server integrating six predictor tools: SIFT, PhD-SNP, PolyPhen-1, PolyPhen-2, MAPP and SNAP. The iStable integrated server (predictor.nchu.edu.tw/iStable) was used to predict shifts in the protein stability due to mutations. A total of 372 variants were observed in the 332 SARS-CoV-2 sequences with several variants incident in multiple patients accounting for a total of 1596 incidences. Asymptomatic and Deceased specific mutants constituted 32% and 62% of the repertoire respectively indicating their exclusivity. However, the most prevalent mutations were those present in both. Though some parts of the genome are more variable than others but there was clear difference between incidence and prevalence. NSP3 with 68 variants had total occurrence of only 105 whereas Spike protein had 346 occurrences with just 66 variants. For Deleterious variants, NSP3 had the highest incidence of 25 followed by NSP2 (16), ORF3a (14) and N (14). Spike protein had just 7 Deleterious variants out of 66. Deceased patients have more Deleterious than Neutral variants as compared to the symptomatic ones. Further, it appears that the Deleterious variants which decrease protein stability are more significant in pathogenicity of SARS-CoV-2.
Large-scale identification of protein histidine methylation in human cells
Authors: Kapell Sebastian , Jakobsson Magnus E.
Published: April 2021

Methylation can occur on histidine, lysine and arginine residues in proteins and often serves a regulatory function. Histidine methylation has recently attracted notable attention through the discovery of the human histidine methyltransferase enzymes SETD3 and METTL9. There are currently no methods to enrich histidine methylated peptides for mass spectrometry analysis and large-scale analyses of the modification are hitherto absent. In the present study we query ultra-comprehensive proteomic datasets to generate a resource of histidine methylation sites in human cells. We use this resource to explore the frequency, localization, targeted domains, protein types and sequence requirements of histidine methylation and benchmark all analyses to methylation events on lysine and arginine. Our results demonstrate that histidine methylation is widespread in human cells and tissues and that the modification is over-represented in regions of mono-spaced histidine repeats. We also report colocalization of the modification with functionally important phosphorylation sites and disease associated mutations to identify regions of likely regulatory and functional importance. Taken together, we here report a system level analysis of human histidine methylation and our results represent a comprehensive resource enabling targeted studies of individual histidine methylation events.
Balance training improves feedback control of perturbed balance in older adults
Authors: Alizadehsaravi Leila , Bruijn Sjoerd M. , van Dieën Jaap H.
Published: April 2021

Recovering balance after perturbations becomes challenging with aging, but an effective balance training could reduce such challenges. In this study, we examined the effect of balance training on feedback control after unpredictable perturbations by investigating balance performance, recovery strategy, and muscle synergies. We assessed the effect of balance training on unipedal perturbed balance in twenty older adults (>65 years) after short-term (one session) and long-term (3-weeks) training. Participants were exposed to random medial and lateral perturbations consisting of 8-degree rotations of a robot-controlled balance platform. We measured full-body 3D kinematics and activation of 9 muscles (8 stance leg muscles, one trunk muscle) during 2.5 s after the onset of perturbation. The perturbation was divided into 3 phases: phase1 from the onset to maximum rotation of the platform, phase 2 from the maximum rotation angle to the 0-degree angle and phase 3 after platform movement. Balance performance improved after long-term training as evidenced by decreased amplitudes of center of mass acceleration and rate of change of body angular momentum. The rate of change of angular momentum did not directly contribute to return of the center of mass within the base of support, but it reoriented the body to an aligned and vertical position. The improved performance coincided with altered activation of synergies depending on the direction and phase of the perturbation. We concluded that balance training improves control of perturbed balance, and reorganizes feedback responses, by changing temporal patterns of muscle activation. These effects were more pronounced after long-term than short-term training.
Differences in Regional Grey Matter Volume Predict the Extent to which Openness influences Judgments of Beauty and Pleasantness of Interior Architectural Spaces
Authors: Skov Martin , Vartanian Oshin , Navarrete Gorka , Modroño Cristian , Chatterjee Anjan , Leder Helmut , Gonzalez-Mora José L. , Nadal Marcos
Published: April 2021

Hedonic evaluation of sensory objects varies from person to person. While this variability has been linked to differences in experience and personality traits, little is known about why stimuli lead to different evaluations in different people. We used linear mixed effect models to determine the extent to which the openness, contour, and ceiling height of interior architectural spaces influenced the beauty and pleasantness ratings of 18 participants. Then, by analyzing structural brain images acquired for the same group of participants we asked if any regional grey matter volume (rGMV) co‐varied with these differences in the extent to which openness, contour and ceiling height influence beauty and pleasantness ratings. Voxel‐based morphometry analysis revealed that the influence of openness on pleasantness ratings correlated with rGMV in the anterior prefrontal cortex (BA 10), and the influence of openness on beauty ratings correlated with rGMV in the temporal pole (BA 38) and posterior cingulate cortex (BA 31). There were no significant correlations involving contour or ceiling height. Our results suggest that regional variance in grey matter volume may play a role in the computation of hedonic valuation, and account for differences in the way people weigh certain attributes of interior architectural spaces.
A Tool for Reliable Detection of Aflatoxin Biosynthetic Gene Clusters in Aflatoxigenic and AtoxigenicAspergillus flavusIsolates
Authors: Mitema Alfred , Feto Naser Aliye , Okoth Sheila , Rafudeen Mohamed Suhail
Published: April 2021

Molecular techniques and phenotypic characterisation have been used to differentiate aflatoxigenic and atoxigenicAspergillus flavusstrains. However, there is a lack of a consistent and reliable tool for discrimination between these strains ofA. flavus. Here we report, an optimised real-time qPCR-based tool for reliable differentiation between aflatoxigenic and atoxigenic strains ofA. flavus. Accordingly, expression profiles and deletion patterns of genes responsible for aflatoxin production in five representative aflatoxigenic and atoxigenicA. flavusstrains (KSM012, KSM014, HB021, HB026 and HB027) were examined using the optimised real-time qPCR tool. We observed that under induced conditions,aflP, aflS, aflRandaflOtranscripts were the most upregulated genes across the tested isolates whileaflSandaflOwere always expressed in both induced and uninduced isolates. However,aflRandaflPdid not give clear distinctions between non-toxin and toxin producing isolates. The deletion patterns were prominent foraflDandaflRwhereasalfO, aflSandaflPhad no deletions among the isolates. Significant variation in transcript abundance foraflD, aflRandaflSwere observed for aflatoxigenic isolate KSM014 under induced and uninduced states. False detection ofaflDgene transcript in atoxigenic strain KSM012 was evident in both induced and uninduced conditions. With the exception of KSM012,aflPgene did not exhibit significant variation in expression in the isolates between induced and uninduced conditions. One-way ANOVA and Post-test analysis for linear trends revealed that aflatoxin biosynthetic cluster genes show significant (P < 0.05) differences between atoxigenic and aflatoxigenic isolates. Our optimized qPCR-based tool reliably discriminated between aflatoxigenic and atoxigenicA. flavusisolates and could complement existing detection methods.
New metabolic alterations and predictive marker pipecolic acid in sera for esophageal squamous cell carcinoma
Authors: Liu Lei , Wu Jia , Shi Minxin , Wang Fengying , Lu Haimin , Liu Jibing , Chen Weiqin , Yu Guanzhen , Liu Dan , Yang Jing , Luo Qin , Ni Yan , Jin Xing , Jin Xiaoxia , Chen Wen-Lian
Published: April 2021

Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with dismal prognosis. Although several serum metabolomic investigations have been reported, ESCC tumor-associated metabolic alterations along with predictive biomarkers in sera were not defined. Here we enrolled 34 treatment-naive ESCC patients and collected their pre-and post-esophagectomy sera together with sera from 34 healthy volunteers for metabolomic survey. Our comprehensive analysis discerned ESCC tumor-associated metabolic alterations as represented by a panel of 12 serum metabolites. Notably, postoperative abrosia and parenteral nutrition significantly perturbed the serum metabolome. Furthermore, we performed examination using sera from carcinogen-induced mice at dysplasia and ESCC stages, and identified three ESCC tumor-associated metabolites conserved between mice and humans. Notably, among these metabolites, pipecolic acid was progressively increased in mouse sera from dysplasia to cancerization, and it could accurately discriminate between mice at dysplasia stage and healthy control mice. Furthermore, this metabolite was essential for ECSS cells to oppose oxidative stress-induced DNA damage and cell proliferation arrest. Together, this study uncovered 12 ESCC tumor-associated serum metabolites with potential for monitoring therapeutic efficacy and disease relapse, presented evidence for refining parenteral nutrition composition, and highlighted serum pipecolic acid as an attractive biomarker for prediction of ESCC tumorigenesis.
CRISPR-mediated knock-in of transgenes into the malaria vectorAnopheles funestus
Authors: Quinn Charlotte , Anthousi Amalia , Wondji Charles , Nolan Tony
Published: April 2021

The ability to introduce mutations, or transgenes, of choice to precise genomic locations has revolutionised our ability to understand how genes and organisms work.

In many mosquito species that are vectors of various human disease, the advent of CRISPR genome editing tools has shed light on basic aspects of their biology that are relevant to their efficiency as disease vectors. This allows a better understanding of how current control tools work and opens up the possibility of novel genetic control approaches, such as gene drives, that deliberately introduce genetic traits into populations. Yet for theAnopheles funestusmosquito, a significant vector of malaria in sub-Saharan Africa and indeed the dominant vector species in many countries, transgenesis has yet to be achieved.

We describe herein an optimised transformation system based on the germline delivery of CRISPR components that allows efficient cleavage of a previously validated genomic site and preferential repair of these cut sites via homology-directed repair (HDR), which allows introduction of exogenous template sequence, rather than end-joining repair. The rates of transformation achieved are sufficiently high that it should be able to introduce alleles of choice to a target locus, and recover these, without the need to include additional dominant marker genes. Moreover, the high rates of HDR observed suggest that gene drives, which employ an HDR-type mechanism to ensure their proliferation in the genome, may be well suited to work inAn. funestus.