bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel IVS7+1G>T mutation of life-threatening congenital factor VII deficiency in neonates
Authors: He Juan , Zhou Wei , Lv Hui , Tao Li , Chen XiaoWen , Wang Ling
Published: October 2019

In neonates, congenital factor VII deficiency (FVIID) is characterized by central nervous system bleeding and gastrointestinal hemorrhage, often resulting in poor prognosis and high mortality.

To improve understanding of FVIID in neonates in Asia, we retrospectively analyzed the clinical manifestations, diagnosis, treatment, clinical course, and genetic diagnosis of 2 cases of neonatal FVIID in the Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou, China, from January 2007 to December 2017 and performed a review of the relevant literature.

Both neonates were female and presented with severe gastrointestinal tract and intracranial hemorrhage. The laboratory findings were characterized by repeated and non–vitamin K1-dependent prolonged of the prothrombin time (PT), Factor VII (FVII) activity was 1.5% and 3%, respectively. Both neonates died of severe intracranial hemorrhage, at 31 days and 6 months after birth, respectively. Gene sequencing results revealed a homozygous mutation in the FVII gene splice site (IVS7+1G>T) in both cases. Upon review of relevant literature published since 1996, we identified 19 cases of neonatal FVIID. The patients were full-term neonates with onset of symptoms mostly within 7 days after birth (73.7%), which included gastrointestinal bleeding (blood stool, vomiting blood; 31.6%), nervous system signs (drowsiness, convulsions, poor response; 26.3%), severe intracranial hemorrhage (84.2%), significantly prolonged PT with significantly decreased FVII activity (89.5%), high mortality, and disability (68.4%). Gene sequencing was performed in 9 of the 19 children evaluated and revealed a mutation in the FVII gene in all cases.

FVIID can be clinically diagnosed based on the presence of prolonged PT that is difficult to correct and significantly decreased FVII activity (≤5%). As mutations in some sites are associated with severe bleeding, genetic diagnosis represents a useful tool for prenatal diagnosis of FVIID. In brief, we should pay great attention to the FVIID onset of the neonatal period, although it is rare but result in life-threatening bleeding with poor prognosis.
Clinical evaluation of monolithic zirconia crowns for posterior teeth restorations
Authors: Tang Zhenyu , Zhao Xinyi , Wang Hui , Liu Bin
Published: October 2019

Although all-ceramic crowns have excellent biocompatibility and esthetic appearance, chipping may occur. The mechanical properties of monolithic zirconia restorative material are superior to those of all-ceramic restorative materials, and chipping caused by chewing hard foods could be avoided. This study aimed to evaluate the clinical efficacy of monolithic zirconia crowns for posterior teeth restorations.

A total of 46 patients requiring posterior teeth restorations involving 49 teeth were treated with monolithic zirconia crown procedure. The treatment results were evaluated according to the modified California Dental Association criteria immediately after the procedure, and at 2, 24, 48, and 96 weeks after the procedure. The plaque index, gingival index, probing depth, crown marginal integrity, and attrition of the abutment teeth, antagonist teeth, corresponding contralateral teeth, and antagonist of the corresponding contralateral teeth were assessed. The patients were followed for up to 96 weeks.

The marginal adaptation results of all 46 patients were evaluated as excellent, resulting in an excellent rate of 100%. Regarding the crown color match, only 3 cases (6.1%) were evaluated as acceptable. Marginal adaptation, anatomic form, crown margin integrity, color match, and gross fracture did not show significant differences compared with the different time points (P = .999). Surface texture at different time did not change significantly (P = .807). During the 96-week follow-up, 1 crack in the antagonist teeth was found in 1 patient. There were no significant differences in wear of the antagonist teeth at different time points (P = .972). The rate of “excellent” evaluation for crown restorations was 93.9% to 100%.

The monolithic zirconia crown had no detectable adverse effects on the periodontal tissues, and the antagonist teeth attrition was small. Therefore, it has good potential in the clinical application of posterior teeth restorations in the short term.
Polymicrobial bacteremia after treatment of transcatheter arterial chemoembolization
Authors: Fang Xue-Yao , Hu Long-Hua , Hang Ya-Ping , Chen Yan-Hui , Xu Xiu-Hua , Hu Xiao-Yan , Liu Yan-Hua , Zhang Nan , Zhong Qiao-Shi
Published: October 2019

Rationale:

Bacteremia caused by polymicrobial infections are rare but dangerous. We report a case of hepatic abscess combined with polymicrobial bacteremia in a 49-year-old male patient after surgery and transcatheter arterial chemoembolization (TACE).

Patient concerns:

The patient was admitted to hospital with metastatic liver cancer for periodic chemotherapy and developed a high fever and tenderness to the liver following surgery and TACE.

Diagnosis:

Hepatic abscess combined with polymicrobial bacteremia.

Interventions:

The clinician formulated a therapy in accordance with the drug susceptibility test and the empirical drug use for anaerobic bacteria. A comprehensive treatment plan was adopted, on the basis of the combination of nitrazole and imipenem as anti-infection drugs as well as continuous abscess drainage.

Outcomes:

After comprehensive therapy, the patient was ultimately discharged without any residual symptoms.

Lessons:

Bloodstream infection caused by multiple bacteria increases the difficulty of anti-infection treatments, leading to poor treatment outcome and high mortality. Therefore, a fast and accurate diagnosis of polymicrobial bacteremia is key for initiation of an effective antimicrobial treatment. Additionally, pre-operative prophylactic antibiotics are advisable when patients have a history of abdominal surgery and are immune-compromised.
Isolated Rosai–Dorfman disease with craniocervical junction involvement in the foramen magnum
Authors: Wang Chao , Zou Yi , Zeng Qingze , Hong Hui , Zheng Congkuan
Published: October 2019

Rationale:

Rosai–Dorfman disease (RDD) is a rare benign histiocytic proliferative disease. RDD with cranio-spinal involvement in the foramen magnum is extremely rare. To the best of our knowledge, only 4 cases of RDD with craniocervical junction involvement have been reported so far. Herein, we present the fifth case of RDD with craniocervical junction.

Patient concerns:

A 26-year-old female presented with a sudden headache, accompanied by nausea and vomiting several times during the past half-month.

Diagnoses:

Magnetic resonance imaging (MRI) showed a well-defined, lobulated, homogenous mass in the left foramen magnum. The lesion was isointense on T1-weighted images (T1WI) and hypointense on T2-weighted images (T2WI), and showed homogeneously obvious enhancement following the intravenous administration of gadolinium. It was dural based and extending inferiorly along the spinal dura up to the cervical spinal canal. The brainstem was compressed and deflected to the right side. Initial diagnosis of meningioma with craniocervical junction involvement in the foramen magnum was made according to MRI findings. Final diagnosis of RDD was confirmed by histopathological and immunohistochemical examinations after subtotally surgical resection.

Interventions:

The bulk of lesion in the foramen magnum was removed surgically with suboccipital craniectomy because of brainstem compression.

Outcomes:

The patient recovered well and was discharged 17 days after the surgery.

Lessons:

RDD should be considered in patients with dural-based, extra-axial, well-circumscribed, hypo- to isointense on T1WI, hypo- to isointense on T2WI, enhancing intracranial or spinal lesions or both.
The association of speckle-type POZ protein with lymph node metastasis and prognosis in cancer patients
Authors: Cheng Fei , Zeng Chunyan , Zeng Ling , Wu Chayan , Chen Youxiang
Published: October 2019

Background:

Speckle-type POZ protein (SPOP) has recently been reported as a prognostic tumor biomarker. However, the predictive value of SPOP remains controversial in human cancers. The current meta-analysis was performed to obtain a comprehensive evaluation of the relationship between SPOP expression and prognosis of cancer patients.

Methods:

Embase, Pubmed, Web of Science, and Chinese Biomedical Literature database were systematically searched up to January 2, 2019. The pooled hazard ratios (HRs) and/or pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to quantitatively assess the relationship of SPOP expression with prognosis and lymph node metastasis (LNM).

Results:

A total of 9 studies with 928 patients were included in this meta-analysis. The results showed that low SPOP expression was significantly related to poor overall survival (high/low: HR = 0.55; 95% CI: 0.38–0.79, P = .001), especially for digestive system cancers (high/low: HR = 0.46; 95% CI: 0.27–0.78, P = .003). However, SPOP expression did not affect progression-free survival in cancer patients (high/low: HR = 2.07; 95% CI: 0.16–26.70, P = .578). Additionally, the association between SPOP overexpression and LNM was positive in patients with clear cell renal cell carcinoma (ccRCC) (OR = 5.26; 95% CI: 1.66–16.68, P = .005) but negative in cancer patients without ccRCC (OR = 0.36; 95% CI: 0.21–0.62, P < .001).

Conclusion:

Decreased SPOP expression could predict poor prognosis of cancer patients, suggesting that SPOP protein may be a useful prognostic biomarker in cancer patients.
Mechanisms of failure of chimeric antigen receptor T-cell therapy
Authors: Li Xiaoqing , Chen Weihong
Published: October 2019

Purpose of review

Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate.

Recent findings

We firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive receptors, PD-1, CTLA4, TIGIT, LAG-3, CD244, CD160, TIM3, which might be solved by some external pharmacological intervention methods [for instance, the use of FC (Fludarabine, Cyclophosphamide) lymphodepletion regimen, lenalidomide, PD-1 inhibitor, ibrutinib and humanized CD19-CART cells. Secondly, mechanism of CD19 relapse can be attributed to the preexisting of CD19- subclone, the loss or alternative RNA splicing on exon 2 of chromosome 16 on which CD19 gene is located, B-cell transcript factors – paired-box 5 (PAX5) and early B-cell factor 1 (EBF1) are down-regulated to cause lineage-switch from lymphoid to myeloid.

Although different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system.

Video abstract

Although Chimeric Antigen Receptor T (CART) cell therapy is best recognized for its antitumor effect in Relapsed/Refractory B-cell hematological cancers, it still shows a high relapse rate. We review mechanisms of failure of CART therapy. http://links.lww.com/COH/A18.
Proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein(a)-mediated risk of atherosclerotic cardiovascular disease: more than meets the eye?
Authors: Boffa Michael B. , Koschinsky Marlys L.
Published: October 2019

Purpose of review

Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue.

Recent findings

Although the ability of PCSK9i to lower Lp(a) by 15–30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated.

Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.
Impact of the microbiota on solid organ transplant rejection
Authors: Sepulveda Martin , Pirozzolo Isabella , Alegre Maria-Luisa
Published: October 2019

Purpose of review

The microbiota in mammalian hosts can affect maturation and function of the immune system and has been associated with health and disease. We will review new findings on how this dynamic environmental factor impacts alloimmunity and therapy in transplant hosts.

Recent findings

The microbiota changes after transplantation and immunosuppressive therapy. New data indicate that different microbial community structures have distinct impact on graft outcome, from promoting, to inhibiting or being neutral to transplant survival. In addition, we will address reciprocal interactions between the microbiota and immunosuppressive drugs, as well as the suitability of the microbiota as a predictive biomarker and its utility as adjunct therapy in transplantation.

Advances in microbiome sequencing and wider availability of gnotobiotic facilities are enabling mechanistic investigations into the commensal communities and pathways that modulate allograft outcome, responsiveness to immunosuppression and side effects of drugs. A better understanding of the functions of the microbiota may help mitigate drug toxicity, predict drug dosage and dampen alloimmunity in transplant patients.
Harnessing the Electronic Health Record to Distribute Transition Services to Adolescents With Inflammatory Bowel Disease
Authors: Huang Jeannie S. , Yueh Ryan , Wood Kalie , Ma Stacy , Cruz Rusvelda , Boyd Nancy , Kruth Robin , Parker Jacob
Published: October 2019

Objectives:

The aim of the study was to evaluate feasibility and utility of an electronic health record (EHR) activity to assess transitional readiness, deliver services to meet individual needs, and to track patient progress.

Methods:

We developed a Transition EHR activity (TEA) to track patients through a standardized process where transition readiness is annually assessed and services distributed based on need. The process assesses transition skills starting at age 12 years and sets goals through shared decision‐making, delivers resources according to need, reviews patients’ personal medical histories, and documents healthcare transfer to adult gastroenterology. We piloted TEA among patients with inflammatory bowel disease (IBD) ages ≥12 years. Distribution to patients was measured and tolerability assessed via patient self‐report evaluations.

Results:

Since launch, TEA has been distributed to all eligible patients (N = 53) with a median age of 16 (14,18) years (median [IQR]), 62% male, 58% white, 26% Hispanic at our weekly dedicated IBD clinic. All have performed the transition skills’ self‐assessment and practicum, and set transition goals with their healthcare provider. Of these individuals, 41 (77%) participated in survey feedback. On a utility rating scale of 0 (not helpful at all) to 10 (very helpful), patients reported median (IQR) utility scores of 8 (7,10) for the transition readiness assessment, 9 (7,10) for transition resources provided, and 9 (7,10) for the medical history summary. Most (91%) would recommend TEA to other patients.

Conclusions:

TEA standardized delivery of resources among pediatric IBD patients and was well received and friendly to clinical workflow.
Transglutaminases, neuronal cell death and neural repair: implications for traumatic brain injury and therapeutics
Authors: Basso Manuela , Milelli Andrea
Published: October 2019

Purpose of review

Traumatic brain injury (TBI) is one of the leading causes of death in the developed world. Despite advances at the bedside, pharmacological interventions have yet to be successful likely because of the need for a better understanding of disease mechanisms as potential targets for intervention. Recent evidence implicates a family of enzymes, namely transglutaminases, in the pathological mechanisms of TBI.

Recent findings

Transglutaminases are multifunctional, calcium-dependent enzymes that are significantly upregulated in TBI. They are known for their transamidase activity that consists of the covalent crosslinking of glutamines and lysines. Recent data support their ability to aminylate proteins with primary amines such as polyamines or monoamines like serotonin and histamine and to regulate gene transcription.

In this review, we will discuss data that support a role for transglutaminases, in particular transglutaminase 2, in mitochondrial damage, excitotoxicity and inflammation and their relationship to the pathobiology of TBI. We will review past evidence and outline the need for new experiments that could clarify the role of these enzymes in cell injury and death associated with traumatic brain injury.
Probing in-mouth texture perception with a biomimetic tongue
Authors: Thomazo Jean-Baptiste , Contreras Pastenes Javier , Pipe Christopher J. , Le Révérend Benjamin , Wandersman Elie , Prevost Alexis M.
Published: October 2019

An experimental biomimetic tongue–palate system has been developed to probe human in-mouth texture perception. Model tongues are made from soft elastomers patterned with fibrillar structures analogous to human filiform papillae. The palate is represented by a rigid flat plate parallel to the plane of the tongue. To probe the behaviour under physiological flow conditions, deflections of model papillae are measured using a novel fluorescent imaging technique enabling sub-micrometre resolution of the displacements. Using optically transparent Newtonian liquids under steady shear flow, we show that deformations of the papillae allow their viscosity to be determined from 1 Pa s down to the viscosity of water (1 mPa s), in full quantitative agreement with a previously proposed model (Lauga
et al.
2016
Front. Phys.
4
, 35 (
doi:10.3389/fphy.2016.00035
)). The technique is further validated for a shear-thinning and optically opaque dairy system.
The evolution and role of the hyposphene-hypantrum articulation in Archosauria: phylogeny, size and/or mechanics?
Authors: Stefanic Candice M. , Nesbitt Sterling J.
Published: October 2019

Living members of Archosauria, the reptile clade containing Crocodylia and Aves, have a wide range of skeletal morphologies, ecologies and body size. The range of body size greatly increases when extinct archosaurs are included, because extinct Archosauria includes the largest members of any terrestrial vertebrate group (e.g. 70-tonne titanosaurs, 20-tonne theropods). Archosaurs evolved various skeletal adaptations for large body size, but these adaptations varied among clades and did not always appear consistently with body size or ecology. Modification of intervertebral articulations, specifically the presence of a hyposphene-hypantrum articulation between trunk vertebrae, occurs in a variety of extinct archosaurs (e.g. non-avian dinosaurs, pseudosuchians). We surveyed the phylogenetic distribution of the hyposphene-hypantrum to test its relationship with body size. We found convergent evolution among large-bodied clades, except when the clade evolved an alternative mechanism for vertebral bracing. For example, some extinct lineages that lack the hyposphene-hypantrum articulation (e.g. ornithischians) have ossified tendons that braced their vertebral column. Ossified tendons are present even in small taxa and in small-bodied juveniles, but large-bodied taxa with ossified tendons reached those body sizes without evolving the hyposphene-hypantrum articulation. The hyposphene-hypantrum was permanently lost in extinct crownward members of both major archosaur lineages (i.e. Crocodylia and Aves) as they underwent phyletic size decrease, changes in vertebral morphology and shifts in ecology.
The mechanics of solid-state nanofoaming
Authors: Van Loock Frederik , Bernardo Victoria , Rodríguez Pérez Miguel Angel , Fleck Norman A.
Published: October 2019

Solid-state nanofoaming experiments are conducted on two polymethyl methacrylate (PMMA) grades of markedly different molecular weight using CO2as the blowing agent. The sensitivity of porosity to foaming time and foaming temperature is measured. Also, the microstructure of the PMMA nanofoams is characterized in terms of cell size and cell nucleation density. A one-dimensional numerical model is developed to predict the growth of spherical, gas-filled voids during the solid-state foaming process. Diffusion of CO2within the PMMA matrix is sufficiently rapid for the concentration of CO2to remain almost uniform spatially. The foaming model makes use of experimentally calibrated constitutive laws for the uniaxial stress versus strain response of the PMMA grades as a function of strain rate and temperature, and the effect of dissolved CO2is accounted for by a shift in the glass transition temperature of the PMMA. The maximum achievable porosity is interpreted in terms of cell wall tearing and comparisons are made between the predictions of the model and nanofoaming measurements; it is deduced that the failure strain of the cell walls is sensitive to cell wall thickness.
Intergenerational effects on offspring telomere length: interactions among maternal age, stress exposure and offspring sex
Authors: Marasco Valeria , Boner Winnie , Griffiths Kate , Heidinger Britt , Monaghan Pat
Published: October 2019

Offspring produced by older parents often have reduced longevity, termed the Lansing effect. Because adults usually have similar-aged mates, it is difficult to separate effects of maternal and paternal age, and environmental circumstances are also likely to influence offspring outcomes. The mechanisms underlying the Lansing effect are poorly understood. Variation in telomere length and loss, particularly in early life, is linked to longevity in many vertebrates, and therefore changes in offspring telomere dynamics could be very important in this context. We examined the effect of maternal age and environment on offspring telomere length in zebra finches. We kept mothers under either control (ad libitum food) or more challenging (unpredictable food) circumstances and experimentally minimized paternal age and mate choice effects. Irrespective of the maternal environment, there was a substantial negative effect of maternal age on offspring telomere length, evident in longitudinal and cross-sectional comparisons (average of 39% shorter). Furthermore, in young mothers, sons reared by challenged mothers had significantly shorter telomere lengths than sons reared by control mothers. This effect disappeared when the mothers were old, and was absent in daughters. These findings highlight the importance of telomere dynamics as inter-generational mediators of the evolutionary processes determining optimal age-specific reproductive effort and sex allocation.
Aberrant expression of the COX2/PGE2 axis is induced by activation of the RAF/MEK/ERK pathway in BRAFV595E canine urothelial carcinoma
Authors: Yoshitake R. , Saeki K. , Eto S. , Shinada M. , Nakano R. , Sugiya H. , Endo Y. , Fujita N. , Nishimura R. , Nakagawa T.
Published: October 2019

Cancer-promoting inflammation is an important event in cancer development. The cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis is a prominent inducer of inflammation. Canine urothelial carcinoma (cUC) uniquely overexpresses PGE2 and is often managed well with COX inhibitor monotherapy. In most cases, cUC tissue harbours homologous human BRAFV600E mutation, which causes aberrant activation of the RAF/MEK/ERK pathway in human cancer. However, mechanisms underlying aberrant PGE2 production and the importance of the BRAF mutation remain unclear. We show that activation of the RAF/MEK/ERK pathway in BRAF mutant cUC cells leads to COX2 overexpression and PGE2 production. Drug screening revealed that treatment with inhibitors of the arachidonic acid cascade (FDR<0.086), RAF/MEK/ERK pathway (FDR<0.067), and p38/JNK pathway (FDR<0.067) significantly reduced PGE2 production in cUC cells. We also validated the association between RAF/MEK/ERK pathway activation and COX2/PGE2 overexpression in BRAF mutant cUC cells using protein detection techniques. In histochemical analysis, BRAF mutant cUC tissue showed higher COX2 expression. Therefore, the driver mutation in the BRAF gene probably promotes tumour-promoting inflammation. These findings would benefit dogs suffering from cUC and can be extrapolated to human cancer. Finally, cUC can serve as a valuable model to elucidate the association between driver mutations and tumour-promoting inflammation.
Role of Proinsulin Self-Association in MutantINSgene-induced Diabetes of Youth
Authors: Sun Jinhong , Xiong Yi , Li Xin , Haataja Leena , Chen Wei , Mir Saiful A. , Madley Rachel , Larkin Dennis , Anjum Arfah , Dhayalan Balamurugan , Rege Nischay , Wickramasinghe Nalinda D. , Weiss Michael A. , Itkin-Ansari Pamela , Kaufman Randal J. , Ostrov David A. , Arvan Peter , Liu Ming
Published: October 2019

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin in the endoplasmic reticulum (ER) drive the molecular pathogenesis of Mutant-INS-gene induced Diabetes of Youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, proinsulin-WT dimerizes in the ER. Here, we suggest that the normal proinsulin-proinsulin contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that proinsulin Tyr-B16, which is a key residue in normal proinsulin dimerization, helps confer dominant-negative behavior of MIDY mutant proinsulin-C(A7)Y. Substitutions of Tyr-B16 with ether Ala, Asp, or Pro in proinsulin-C(A7)Y each decrease the abnormal interactions between the MIDY mutant and proinsulin-WT, rescuing proinsulin-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent proinsulin-proinsulin contact initiates dominant-negative behavior of misfolded proinsulin, pointing to a novel therapeutic target to enhance bystander proinsulin export for increased insulin production.
Local control of resource allocation is sufficient to model optimal dynamics in syntrophic systems
Authors: Ledder Glenn , Russo Sabrina E. , Muller Erik B. , Peace Angela , Nisbet Roger M.
Published: October 2019

Syntrophic systems are common in nature and include forms of obligate mutualisms in which each participating organism or component of an organism obtains from the other an essential nutrient or metabolic product that it cannot provide for itself. Models of how these complementary resources are allocated between partners often assume optimal behavior, but whether mechanisms enabling global control exist in syntrophic systems, and what form they might take, is unknown. Recognizing that growth of plant organs that supply complementary resources, like roots and shoots, can occur autonomously, we present a theory of plant growth in which root-shoot allocation is determined by purely local rules. Each organ uses as much as it can of its locally produced or acquired resource (inorganic nitrogen or photosynthate) and shares only the surplus. Subject to stoichiometric conditions that likely hold for most plants, purely local rules produce the same optimal allocation as would global control, even in a fluctuating environment, with sharing the surplus being the specific mechanism stabilizing syntrophic dynamics. Our local control model contributes a novel approach to plant growth modeling because it assumes a simple mechanism of root:shoot allocation that can be considered a higher-level physiological rule, from which the optimal growth outcome emerges from the system’s dynamics, rather than being built into the model. Moreover, our model is general, in that the mechanism of sharing the surplus can readily be adapted to many obligate syntrophic relationships.
Constraints on microbial communities, decomposition and methane production in deep peat deposits
Authors: Kluber L.A. , Johnston E.R. , Allen S.A. , Hendershot J.N. , Hanson P.J. , Schadt C.W.
Published: October 2019

Peatlands play outsized roles in the global carbon cycle. Despite occupying a rather small fraction of the terrestrial biosphere (∼3%), these ecosystems account for roughly one third of the global soil carbon pool. This carbon is largely comprised of undecomposed deposits of plant material (peat) that may be meters thick. The fate of this deep carbon stockpile with ongoing and future climate change is thus of great interest and has large potential to induce positive feedback to climate warming. Recentin situwarming of an ombrotrophic peatland indicated that the deep peat microbial communities and decomposition rates were resistant to elevated temperatures. In this experiment, we sought to understand how nutrient and pH limitations may interact with temperature to limit microbial activity and community composition. Anaerobic microcosms of peat collected from 1.5 to 2 meters in depth were incubated at 6°C and 15°C with elevated pH, nitrogen (NH4Cl), and/or phosphorus (KH2PO4) in a full factorial design. The production of CO2and CH4was significantly greater in microcosms incubated at 15°C, although the structure of the microbial community did not differ between the two temperatures. Increasing the pH from ∼3.5 to ∼5.5 altered microbial community structure, however increases in CH4production were non-significant. Contrary to expectations, N and P additions did not increase CO2and CH4production, indicating that nutrient availability was not a primary constraint in microbial decomposition of deep peat. Our findings indicate that temperature is a key factor limiting the decomposition of deep peat, however other factors such as the availability of O2or alternative electron donors and high concentrations of phenolic compounds, may also exert constraints. Continued experimental peat warming studies will be necessary to assess if the deep peat carbon bank is susceptible to increased temperatures over the longer time scales.
Thickness of deep layers in the fusiform face area predicts face recognition
Authors: McGugin Rankin W. , Newton Allen T. , Tamber-Rosenau Benjamin , Tomarken Andrew , Gauthier Isabel
Published: October 2019

People with superior face recognition have relatively thin cortex in face-selective brain areas, while those with superior vehicle recognition have relatively thick cortex in the same areas. We suggest that these opposite correlations reflect distinct mechanisms influencing cortical thickness (CT) for abilities acquired at different points in development. We explore a new prediction regarding the specificity of these effects through the depth of the cortex: that face recognition selectively and negatively correlates with thickness of the deepest laminar subdivision in face-selective areas. With ultra-high resolution MRI at 7T, we estimated the thickness of three laminar subdivisions, which we term MR layers, in the right fusiform face area (rFFA) in 14 adult male humans. Face recognition was negatively associated with the thickness of deep MR layers, while vehicle recognition was positively related to the thickness of all layers. Regression model comparisons provided overwhelming support for a model specifying that the magnitude of the association between face recognition and CT differs across MR layers (deep vs. superficial/middle) while the magnitude of the association between vehicle recognition and CT is invariant across layers. The total CT of rFFA accounted for 69% of the variance in face recognition, and thickness of the deep layer alone accounted for 84% of this variance. Our findings demonstrate the functional validity of MR laminar estimates in FFA. Studying the structural basis of individual differences for multiple abilities in the same cortical area can reveal effects of distinct mechanisms that are not apparent when studying average variation or development.

Significance Statement

Face and object recognition vary in the normal population and are only modestly related to each other. The recognition of faces and vehicles are both positively related to neural responses in the fusiform face area (FFA), but show different relations to the cortical thickness of FFA. Here, we use very high-resolution MRI, and find that face recognition ability (a skill acquired early in life) is negatively correlated with thickness of FFA’s deepest MR-defined layers, whereas recognition of vehicles (a skill acquired later in life) is positively related to thickness at of all cortical layers. Our methods can be used in the future to characterize sources of variability in human abilities and relate them to distinct mechanisms of neural plasticity.
Mapping short-latency cortical responses to electrical stimulation of thalamic motor nuclei by increasing sampling rate - a technical report
Authors: Toth Emilia , Chaitanya Ganne , Pati Sandipan
Published: October 2019

Direct electrical stimulation (DES) of the cortex is a clinically indispensable brain mapping technique that provides reliable information about the distribution of eloquent cortex and its connectivity to the white matter bundles. Here we present a technical report on mapping the short latency cortical responses to stimulation of the ventral anterior nucleus of human thalamus. Reliable downstream responses were noted in the regions connected to the ventral anterior nucleus i.e. superior and inferior frontal gyri, supplementary motor area and limbic substructures (cingulate gyrus and hippocampus).
The retinoblastoma tumor suppressor limits ribosomal readthrough during oncogene induced senescence
Authors: del Toro Neylen , Lessard Frédéric , Tardif Sarah , Bouchard Jacob , Bourdeau Véronique , Ferbeyre Gerardo , Brakier-Gingras Léa
Published: October 2019

The origin and evolution of cancer cells is considered to be mainly fueled by mutations affecting the DNA sequence. Although errors in translation could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called “caretakers” block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretakers genes will prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the retinoblastoma protein (RB) acts as caretaker tumor suppressor by preventing the readthrough of termination codons, a process that allows proteins to be synthetized with additional domains. In particular, we show that expression of oncogenicrasin normal human cells triggers a cellular senescence response characterized by a significant reduction of basal ribosomal readthrough. However, inactivation of the RB tumor suppressor pathway in these cells, using the viral oncoprotein E7 or the oncogenic kinase CDK4 increased readthrough. Conversely, activation of the RB pathway by the tumor suppressor PML, the ribosomal proteins RPS14/uS11 and RPL22/eL22 or the CDK4/6 inhibitor palbociclib reduced readthrough. We thus reveal a novel function for the RB pathway as a caretaker of translational errors with implications for tumor suppression and cancer treatment.
Monitoring G-quadruplex formation with DNA carriers and solid-state nanopores
Authors: Bošković Filip , Zhu Jinbo , Chen Kaikai , Keyser Ulrich F.
Published: October 2019

G-quadruplexes (Gq) are guanine-rich DNA structures formed by single-stranded DNA. They are of paramount significance to gene expression regulation, but also drug targets for cancer and human viruses. Current ensemble and single-molecule methods require fluorescent labels, which can affect Gq folding kinetics. Here we introduce, a single-molecule Gq nanopore assay (smGNA) to detect Gqs and kinetics of Gq formation. We use ~5 nm solid-state nanopores to detect various Gq structural variants attached to designed DNA carriers. Gqs can be identified by localizing their positions along designed DNA carriers establishing smGNA as a tool for Gq mapping. In addition, smGNA allows for discrimination of (un-)folded Gq structures, provides insights into single-molecule kinetics of G-quadruplex folding, and probes quadruplex-to-duplex structural transitions. smGNA can elucidate the formation of G-quadruplexes at the single-molecule level without labelling and has potential implications on the study of these structures both in single-stranded DNA and in genomic samples.
Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation
Authors: Letellier Mathieu , Lagardère Matthieu , Tessier Béatrice , Janovjak Harald , Thoumine Olivier
Published: October 2019

Neuroligins (Nlgs) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlg expression. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlg1 in CA1 hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 h selectively increased dendritic spine density and AMPA receptor-mediated EPSCs in wild-type neurons, but not in Nlg1 knock-out neurons or when endogenous Nlg1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP. Combined with computer simulations, our data support a model by which Nlg1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy thus highlights the impact of Nlg1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.

Impact Statement

Orthogonal to the traditional paradigms used to manipulate neuroligin expression level, the optogenetic trigger of tyrosine phosphorylation supports a strong role of endogenous neuroligin-1 in excitatory synaptic differentiation and potentiation.
Dynamic Clonal Hematopoiesis and Functional T-cell Immunity in a Super-centenarian
Authors: van den Akker Erik B. , Makrodimitris Stavros , Hulsman Marc , Brugman Martijn H. , Nikolic Tanja , Bradley Ted , Waisfisz Quinten , Baas Frank , Jakobs Marja E. , de Jong Daphne , Slagboom P. Eline , Staal Frank J.T. , Reinders Marcel J.T. , Holstege Henne
Published: October 2019

The aged hematopoietic system is characterized by decreased immuno-competence and by a reduced number of hematopoietic stem cells (HSCs) that actively generates new blood cell (age-related clonal hematopoiesis, ARCH). While both aspects are commonly associated with an increased risk of aging-related diseases, it is currently unknown to what extent these aspects co-occur during exceptional longevity. Here, we investigated these aspects in blood cells of an immuno-hematopoietically normal female who reached 111 years. Blood samples were collected across a 9-year period at ages 103, 110 and 111 years. We applied several genetic sequencing approaches to investigate clonality in peripheral blood samples and sorted cell subsets. Immuno-competence was characterized using flow cytometry, T-cell receptor excision circle (TREC) assays, and in vitro proliferation assays. We identified a single DNMT3A-mutated HSC clone with a complex subclonal architecture and observed ongoing subclonal dynamics within the 9-year timeframe of our sampling. The mutated HSC generated 78-87% myeloid cells, 6-7% of the B-cells, 6% of CD8+ T-cells, and notably 22% of the CD4+ T-cells. Intriguingly, we found that T-cells were capable of robust proliferation when challenged in vitro. Moreover, we observed a surprisingly high TREC content, indicative of recent generation of naive T-cells. Concluding, we observed long-term stability of extreme ARCH with ongoing clonal dynamics combined with functional T-cell immunity. Our results indicate that extreme ARCH does not compromise immuno-competence and that a clonally expanded CD4+ T-cell subset may serve as a potential hallmark of the supercentenarian immune system.

Key points

Longitudinal blood sampling from a female aged 103-111 revealed a dynamic clonal hematopoiesis contributing to myeloid and lymphoid subsets

Despite the highly advanced age and extreme clonal hematopoiesis we observed functional T-cell immunity
3D Printed Microheater Sensor-Integrated, Drug-Encapsulated Microneedle Patch System for Pain Management
Authors: Yin Mengtian , Xiao Li , Liu Qingchang , Kwon Sung-Yun , Zhang Yi , Sharma Poonam R , Jin Li , Li Xudong , Xu Baoxing
Published: October 2019

Microneedle patch device has been widely utilized for transdermal drug delivery in pain management, but is challenged by accurate control of drug release and subsequent diffusion to human body. The recent emerging wearable electronics that could be integrated with microneedle devices offers a facile approach to address such a challenge. Here a 3D printed microheater integrated drug-encapsulated microneedle patch system for drug delivery is presented. The ink solution comprised of polydimethylsiloxane (PDMS) and multiwalled carbon nanotubes (MWCNTs) with mass concentration of up to 45% is prepared and used to print crack-free stretchable microheaters on substrates with a broad range of materials and geometric curves. The adhesion strength of printed microheater on microneedle patch in elevated temperatures are measured to evaluate their integration performance. Assessments of encapsulated drug release into rat’s skin are confirmed by examining degradation of microneedles, skin morphologies, and released fluorescent signals. Results and demonstrations established here creates a new opportunity for developing sensor controlled smart microneedle patch systems by integrating with wearable electronics, potentially useful in clinic and biomedical research.
Motorized shoes induce robust sensorimotor adaptation in walking
Authors: Aucie Yashar , Zhang Xunjie , Sargent Randy , Torres-Oviedo Gelsy
Published: October 2019

The motor system has the flexibility to update motor plans according to systematic changes in the environment or the body. This capacity is studied in the laboratory through sensorimotor adaptation paradigms imposing sustained and predictable motor demands specific to the task at hand. However, these studies are tied to the laboratory setting. Thus, we asked if a portable device could be used to elicit locomotor adaptation outside the laboratory. To this end we tested the extent to which a pair of motorized shoes could induce similar locomotor adaptation to split-belt walking, which is a well-established sensorimotor adaptation paradigm in locomotion. We specifically compared two groups of young, healthy subjects adapted on the treadmill by moving their feet at different speeds with a split-belt treadmill or with a pair of motorized shoes. We found that the adaptation of joint motions and measures of spatial and temporal asymmetry, which are commonly used to quantify sensorimotor adaptation in locomotion, were indistinguishable between groups. We only found small differences in the join angle kinematics during baseline walking between the groups-potentially due to the relatively large weight and height of the motorized shoes. Our results indicate that robust sensorimotor adaptation in walking can be induced with a paired of motorized shoes, opening the exciting possibility to study sensorimotor adaptation during more realistic situations outside the laboratory.
The microbiomes of seven lichen genera reveal host specificity, a reduced core community and potential as source of antimicrobials
Authors: Sierra Maria A , Danko David C , Sandoval Tito A , Pishchany Gleb , Moncada Bibiana , Kolter Roberto , Mason Christopher E. , Zambrano Maria Mercedes
Published: October 2019

The High Andean Paramo ecosystem is a unique neotropical mountain biome considered a diversity and evolutionary hotspot. Lichens, which are complex symbiotic structures that contain diverse commensal microbial communities, are prevalent in Paramos. There they play vital roles in soil formation and mineral fixation. In this study we analyzed the microbiomes of seven lichen genera in two Colombian Paramos using 16S rRNA gene analyses and provide the first description of the bacterial communities associated with Cora and Hypotrachyna lichens. Paramo lichen microbiomes were diverse, and in some cases were distinguished based on the identity of the lichen host. The majority of the lichen-associated microorganisms were not present in all lichens sampled and could be considered transient or specialists. We also uncovered sixteen shared taxa that suggest a core lichen microbiome among this diverse group of lichens, broadening our concept of these symbiotic structures. Additionally, we identified strains producing compounds active against clinically relevant pathogens. These results indicate that lichen microbiomes from the Paramo ecosystem are diverse and host-specific but share a taxonomic core and can be a source of new bacterial taxa and antimicrobials.