A multiscale computational framework for the development of spines in molluscan shells.

From mathematical models of growth to computer simulations of pigmentation, the study of shell formation has given rise to an abundant number of models, working at various scales. Yet, attempts to combine those models have remained sparse, due to the challenge of combining categorically different approaches. In this paper, we propose a framework to streamline the process of combining the molecular and tissue scales of shell formation. We choose these levels as a proxy to link the genotype level, which is better described by molecular models, and the phenotype level, which is better described by tissue-level mechanics. We also show how to connect observations on shell populations to the approach, resulting in collections of molecular parameters that may be associated with different populations of real shell specimens. The approach is as follows: we use a Quality-Diversity algorithm, a type of black-box optimization algorithm, to explore the range of concentration profiles emerging as solutions of a molecular model, and that define growth patterns for the mechanical model. At the same time, the mechanical model is simulated over a wide range of growth patterns, resulting in a variety of spine shapes. While time-consuming, these steps only need to be performed once and then function as look-up tables. Actual pictures of shell spines can then be matched against the list of existing spine shapes, yielding a potential growth pattern which, in turn, gives us matching molecular parameters. The framework is modular, such that models can be easily swapped without changing the overall working of the method. As a demonstration of the approach, we solve specific molecular and mechanical models, adapted from available theoretical studies on molluscan shells, and apply the multiscale framework to evaluate the characteristics of spines from three distinct populations of Turbo sazae.

Heterogeneity in maternal mRNAs within clutches of eggs in response to thermal stress during the embryonic stage.

BACKGROUND: The origin of variation is of central interest in evolutionary biology. Maternal mRNAs govern early embryogenesis in many animal species, and we investigated the possibility that heterogeneity in maternal mRNA provisioning of eggs can be modulated by environmental stimuli. RESULTS: We employed two sibling species of the ascidian Ciona, called here types A and B, that are adapted to different temperature regimes and can be hybridized. Previous study showed that hybrids using type B eggs had higher susceptibility to thermal stress than hybrids using type A eggs. We conducted transcriptome analyses of multiple single eggs from crosses using eggs of the different species to compare the effects of maternal thermal stress on heterogeneity in egg provisioning, and followed the effects across generations. We found overall decreases of heterogeneity of egg maternal mRNAs associated with maternal thermal stress. When the eggs produced by the F1 AB generation were crossed with type B sperm and the progeny ('ABB' generation) reared unstressed until maturation, the overall heterogeneity of the eggs produced was greater in a clutch from an individual with a heat-stressed mother compared to one from a non-heat-stressed mother. By examining individual genes, we found no consistent overall effect of thermal stress on heterogeneity of expression in genes involved in developmental buffering. In contrast, heterogeneity of expression in signaling molecules was directly affected by thermal stress. CONCLUSIONS: Due to the absence of batch replicates and variation in the number of reads obtained, our conclusions are very limited. However, contrary to the predictions of bet-hedging, the results suggest that maternal thermal stress at the embryo stage is associated with reduced heterogeneity of maternal mRNA provision in the eggs subsequently produced by the stressed individual, but there is then a large increase in heterogeneity in eggs of the next generation, although itself unstressed. Despite its limitations, our study presents a proof of concept, identifying a model system, experimental approach and analytical techniques capable of providing a significant advance in understanding the impact of maternal environment on developmental heterogeneity.

Scrotal epidermoid cysts penetrating the penile corpora cavernosa: Two case reports.

Introduction: Epidermoid cysts are tumors and that rarely occur in intrascrotal extratesticular tissues. It is extremely rare for the tumors to penetrate the penile corpora cavernosa. Case presentation: We encountered a 4-year-old and a 6-year-old boy with intrascrotal tumors that penetrated the penile corpora cavernosa. Both the patients underwent tumor resection. In the former case, some of the tumor within the corpora cavernosa was left behind, while in the latter case, the tumor was completely resected. Pathological examination in both cases confirmed the diagnosis of epidermoid cysts. Conclusion: We should consider the possibility of epidermoid cysts in children presenting with intrascrotal tumors. Moreover, care should be taken when handling the corpora cavernosa during surgery.

Aberrant Water Structure Dynamics in B16 Melanoma-Bearing Mice by Time Domain Refractometry Analysis.

Living bodies comprise approximately 55-75% water to maintain homeostasis. However, little is known about the comprehensive differences in in vivo water molecule dynamics (water structure dynamics; WSD) between physiological and pathophysiological statuses. Here, we examined the WSD of ex vivo tumor tissues and organs from tumor-bearing mice with engrafted mouse malignant melanoma cells (B16-F10) in the right flanks to compare with those in healthy mice, using time domain reflectometry of dielectric spectroscopy at days 9, 11, and 14 after engrafting. The relaxation parameters of relaxation time (τ), relaxation time distribution parameter (ß), and relaxation strength (∆ε) were measured on tumor tissues and lung, liver, kidney, and skin tissues. Immediately afterward, the water contents (%) in the tumor and the other organs were calculated by measuring their weights before and after freeze-drying. Each parameter of the tumor was compared to that of pooled values of other organs in tumor-bearing (TO) and healthy mice (HO). The tumor water content temporarily increased compared to that of HO at day 11; the tumor volume was also prone to increase. In contrast, tumor tissues exhibited significantly higher values of ß close to 1 of ultrapure water and ∆ε compared to TO and HO at all times. Moreover, ß in the viscera of TO was prone to increase compared to that of HO with significantly higher levels at day 11. Conclusively, tumor-bearing mice exhibited systemically aberrant WSD, unlike healthy mice. Thus, dielectric spectroscopy in terms of WSD may provide novel pathophysiological perspectives in tumor-bearing living bodies.

Three cases of subcorneal pustular dermatosis with immunohistochemical examinations.

Subcorneal pustular dermatosis, a rare, benign skin disease, is a type of neutrophilic dermatosis. The authors reported three cases of subcorneal pustular dermatosis. In case 1, a 9-year-old girl developed a skin rash with blisters following a mycoplasma infection and had a flare-up due to a common cold. She was successfully treated with a topical corticosteroid. In case 2, a 70-year-old woman who had been treated for rheumatoid arthritis with adalimumab, salazosulfapyridine, and leflunomide developed 3- to 5-mm pustules on her trunk and thighs 4 days after flu vaccination. The rash disappeared with drug withdrawal and treatment with diaminodiphenyl sulfone. In case 3, an 81-year-old man, who was diagnosed with pyoderma gangrenosum at 61 years old, developed multiple small flaccid pustules on his trunk and extremities due to an infection in the arteriovenous shunt area on the forearm. The pustule disappeared with intravenous antibiotic therapy; however, the pustules subsequently flared up along with ulcers typical of pyoderma gangrenosum. He was given oral prednisolone therapy, which was effective for the small pustules and some ulcers. Immunohistochemical examination of the three cases revealed neutrophilic infiltration in the subcorneal layer of the epidermis. The pustules contained neutrophils as well as some CD68+ and a few CD1a+ cells. The epidermis and dermis were more predominantly infiltrated by CD4+ cells than by CD8+ cells. Positive stainings for interleukin 8, interleukin 36γ, and phospho-extracellular signal-regulated kinases 1 and 2 were observed in the upper layers of the epidermis below the pustules. Although the pathogenesis of subcorneal pustular dermatosis has not been clarified, the current results suggest that a variety of inflammatory cells, including those responsible for both innate and acquired immunity, are involved in the accumulation of neutrophils in subcorneal pustular dermatosis.

A propensity score-matched comparison between Mako robotic arm-assisted system and conventional technique in total hip arthroplasty for patients with osteoarthritis secondary to developmental dysplasia of the hip.

BACKGROUND: The clinical effectiveness of robotic arm-assisted systems remains unclear for total hip arthroplasty (THA) in patients suffering from osteoarthritis secondary to developmental dysplasia of the hip (DDH). METHODS: Patients with DDH who underwent primary THA were included in this study. We conducted a propensity score-matched comparison between THAs using a robotic arm-assisted system (Mako group) versus those using the manual procedure (manual group) to compare the absolute differences in cup placement angles measured using postoperative computed tomography and those planned preoperatively. RESULTS: A total of 217 patients with osteoarthritis due to DDH met the inclusion criteria. Eighty-four patients were matched as the Mako group and 84 as the manual group. The differences were smaller in the Mako group than the manual group in terms of both inclination and anteversion angles (1.1 ± 1.0 versus 4.2 ± 3.1, respectively; 95% CI, 2.4 to 3.8; p < 0.0001, and 1.2 ± 1.1 versus 5.8 ± 4.0, respectively; 95% CI, 3.7 to 5.5; p < 0.0001). CONCLUSIONS: The robotic arm-assisted system may provide more accurate cup placement in THA for DDH.

Extraction of phase information approximating the demagnetization field within a thin-foiled magnet using electron holography observation.

This paper proposes a method that provides a phase image related to the demagnetization field (Hd) within a thin-foil permanent magnet using electron holography. The observation of Hd remains a significant challenge because electron holography in principle allows only imaging of the magnetic flux density (B), which is a mixture of the contributions from magnetization (M), stray magnetic field (Hs) outside of the specimen and Hd inside of the specimen. The phase map approximating Hd, which was determined by processing of the electron holography observation from a Nd2Fe14B single-crystalline specimen, showed a good agreement with the prediction by micromagnetic theory. With respect to permanent magnets, this method can be applied to examinations about the coercivity mechanism, which is sensitive to the demagnetization field. Graphical Abstract.

Urodynamics findings pre- and post-untethering surgery in children with filum lipoma: A single-institution experience.

OBJECTIVES: We aimed to investigate the changes in urodynamics and voiding cystourethrogram parameters on pre- and post-untethering surgery in patients aged under 2 years with filum lipoma. METHODS: Sixty-two patients were enrolled in this study. The changes in urodynamics and voiding cystourethrogram parameters were compared before untethering surgery and 6 months after untethering surgery. These parameters were bladder volume, bladder deformity, vesicoureteral reflux during voiding cystourethrogram, detrusor overactivity, bladder compliance, and post-void residual volume in urodynamics. RESULTS: Bladder volume during voiding cystourethrogram and bladder compliance increased significantly from 89.8 ± 49.5 mL to 114.5 ± 50.5 mL (P = 0.0069) and 10.2 ± 6.2 mL/mmH2 O to 17.0 ± 13.3 mL/mmH2 O (P = 0.0008), respectively, at 6-month follow-up. Six patients required combination management with clean intermittent catheterization at 25.1 ± 8.2 months (14.3 ± 6.5-months follow-up) because of elevated post-void residual volumes. CONCLUSIONS: According to voiding cystourethrogram results, bladder function and urodynamics in patients with filum lipoma significantly improved after untethering surgery. Non-invasive assessment based on measurements of post-void residual should be considered as a postoperative follow-up method.

Co-expression network analysis of environmental canalization in the ascidian Ciona.

BACKGROUND: Canalization, or buffering, is defined as developmental stability in the face of genetic and/or environmental perturbations. Understanding how canalization works is important in predicting how species survive environmental change, as well as deciphering how development can be altered in the evolutionary process. However, how developmental gene expression is linked to buffering remains unclear. We addressed this by co-expression network analysis, comparing gene expression changes caused by heat stress during development at a whole-embryonic scale in reciprocal hybrid crosses of sibling species of the ascidian Ciona that are adapted to different thermal environments. RESULTS: Since our previous work showed that developmental buffering in this group is maternally inherited, we first identified maternal developmental buffering genes (MDBGs) in which the expression level in embryos is both correlated to the level of environmental canalization and also differentially expressed depending on the species' gender roles in hybrid crosses. We found only 15 MDBGs, all of which showed high correlation coefficient values for expression with a large number of other genes, and 14 of these belonged to a single co-expression module. We then calculated correlation coefficients of expression between MDBGs and transcription factors in the central nervous system (CNS) developmental gene network that had previously been identified experimentally. We found that, compared to the correlation coefficients between MDBGs, which had an average of 0.96, the MDBGs are loosely linked to the CNS developmental genes (average correlation coefficient 0.45). Further, we investigated the correlation of each developmental to MDBGs, showing that only four out of 62 CNS developmental genes showed correlation coefficient > 0.9, comparable to the values between MDBGs, and three of these four genes were signaling molecules: BMP2/4, Wnt7, and Delta-like. CONCLUSIONS: We show that the developmental pathway is not centrally located within the buffering network. We found that out of 62 genes in the developmental gene network, only four genes showed correlation coefficients as high as between MDBGs. We propose that loose links to MDBGs stabilize spatiotemporally dynamic development.

Long-term outcomes of living-donor kidney transplant children weighing less than 15 kg: Comparison of the surgical approach.

INTRODUCTION: Kidney transplantation (KTx) is the most effective treatment for end-stage renal disease in children. OBJECTIVES: We aimed to compare the long-term outcomes and surgical complications of the intraperitoneal approach (IPA) and extraperitoneal approach (EPA) for KTx in children weighing <15 kg. STUDY DESIGN: We performed a retrospective cohort study on pediatric kidney transplant recipients, weighing <15 kg, who received their first living-related kidney transplant between January 1987 and December 2015. Patients were divided into two groups based on the surgical approach (IPA or EPA) during transplant, and clinical data were extracted from the medical records. RESULTS: The median follow-up duration was 14.1 years (interquartile range, 9.0-19.2). Comparing the two groups (IPA group, n = 62; EPA group, n = 38), the median age and body weight were significantly lower in the IPA group (4.2 vs. 4.8 years, P = 0.03; 11.7 vs. 13.0 kg, P < 0.01). There were 26 surgical complications (26%) in 19 patients during the follow-up period. The surgical complication rate was higher in the IPA group (39% vs. 6%). DISCUSSION: We assessed the long-term outcomes of the surgical approaches used for pediatric patients weighing <15 kg who underwent KTx and received a size-mismatched adult donor kidney. There was no significant difference in renal transplantation prognosis using the surgical approach, but IPA-related complications were more frequent in the long term. Therefore, our data suggest that in cases of donor-recipient size mismatch in pediatric KTx, the EPA, associated with fewer surgical complications, is preferable to the IPA if the patient's body size has sufficient space for allograft placement. CONCLUSION: The transplant approach did not influence the long-term outcomes in children weighing <15 kg, but EPA had fewer surgical complications and was technically safe.

Drinking Molecular Hydrogen Water Is Beneficial to Cardiovascular Function in Diet-Induced Obesity Mice.

Molecular hydrogen (MH) reportedly exerts therapeutic effects against inflammatory diseases as a suppressor of free radical chain reactions. Here, the cardiovascular protective effects of the intake of molecular hydrogen water (MHW) were investigated using high-fat diet-induced obesity (DIO) mice. MHW was prepared using supplier sticks and degassed water as control. MHW intake for 2 weeks did not improve blood sugar or body weight but decreased heart weight in DIO mice. Moreover, MHW intake improved cardiac hypertrophy, shortened the width of cardiomyocytes, dilated the capillaries and arterioles, activated myocardial eNOS-Ser-1177 phosphorylation, and restored left ventricular function in DIO mice. MHW intake promoted the histological conversion of hypertrophy to hyperplasia in white and brown adipose tissues (WAT and BAT) with the upregulation of thermogenic and cardiovascular protective genes in BAT (i.e., Ucp-1, Vegf-a, and eNos). Furthermore, the results of a colony formation assay of bone-marrow-derived endothelial progenitor cells (EPCs) indicated that MHW activated the expansion, differentiation, and mobilization of EPCs to maintain vascular homeostasis. These findings indicate that the intake of MHW exerts cardiovascular protective effects in DIO mice. Hence, drinking MHW is a potential prophylactic strategy against cardiovascular disorders in metabolic syndrome.

Chromosomal Inversion Polymorphisms in Two Sympatric Ascidian Lineages.

Chromosomal rearrangements can reduce fitness of heterozygotes and can thereby prevent gene flow. Therefore, such rearrangements can play a role in local adaptation and speciation. In particular, inversions are considered to be a major potential cause for chromosomal speciation. There are two closely related, partially sympatric lineages of ascidians in the genus Ciona, which we call type-A and type-B animals in the present study. Although these invertebrate chordates are largely isolated reproductively, hybrids can be found in wild populations, suggesting incomplete prezygotic barriers. Although the genome of type-A animals has been decoded and widely used, the genome for type-B animals has not been decoded at the chromosomal level. In the present study, we sequenced the genomes of two type-B individuals from different sides of the English Channel (in the zone of sympatry with type-A individuals) and compared them at the chromosomal level with the type-A genome. Although the overall structures were well conserved between type A and type B, chromosomal alignments revealed many inversions differentiating these two types of Ciona; it is probable that the frequent inversions have contributed to separation between these two lineages. In addition, comparisons of the genomes between the two type-B individuals revealed that type B had high rates of inversion polymorphisms and nucleotide polymorphisms, and thus type B might be in the process of differentiation into multiple new types or species. Our results suggest an important role of inversions in chromosomal speciation of these broadcasting spawners.

Late Dislocation of In-the-Bag Intraocular Lens in Three Patients with Multiple Chorioretinal Atrophy Associated with Sarcoidosis.

PURPOSE: A late dislocation of an in-the-bag intraocular lens (IOL) is strongly associated with pseudoexfoliation and less with retinitis pigmentosa, prior vitreoretinal surgery, and uveitis. We present our findings of late in-the-bag IOL dislocation in three patients with multiple chorioretinal atrophy associated with sarcoidosis. METHODS: Observational study of three elderly female Japanese patients with a history of uveitis from sarcoidosis who presented with a late dislocation of an in-the-bag IOL. RESULTS: The late in-the-bag IOL dislocation occurred in the convalescent/quiescent stage of the sarcoidosis. Peripheral multifocal chorioretinal atrophy was the main manifestation in all patients who were diagnosed with definite or presumed sarcoidosis. The dislocated IOLs were successfully removed and new IOLs were implanted with scleral suture fixation followed by no remarkable active uveitis. CONCLUSION: Clinicians should be aware that patients with peripheral multifocal chorioretinal atrophy associated with sarcoidosis can have a late in-the-bag IOL dislocation.

[CLINICAL EXPERIENCE OF TRANSURETHRAL INJECTION USING DEXTRANOMER-HYALURONIC ACID COPOLYMER (Deflux®) FOR CASES OF SECONDARY VESICOURETERAL REFLUX AFTER URETEROCYSTONEOSTOMY].

(Objective) We reviewed the clinical efficacy of transurethral Deflux® injection therapy (Deflux® injection therapy) in patients with secondary vesicoureteral reflux (VUR) after ureterocystoneostomy. (Methods) We retrospectively evaluated data for Deflux® injection therapy in 4 patients after ureterocystoneostomy with secondary VUR due to lower urinary tract dysfunction treated at this hospital from 2010 through 2018. The indications for surgery were febrile urinary tract infection or new renal scarring, and the outcomes of treatment with Deflux® injection therapy were evaluated. (Results) There were 2 male and 2 female patients. Three patients had unexplained lower urinary tract dysfunction, all patients were using clean intermittent catherization, and 3 patients had operated by the Cohen method for VUR. Preoperative examinations revealed that all patients had unilateral VUR, and reflux was assessed as Grade III in 1 patient and Grade IV in 3 patients. The median age at initial surgery was 12.8 years, and Deflux® injection therapy was performed unilaterally in all patients. Deflux® injection therapy was performed by a combined HIT/STING technique in 2 patients and by the HIT technique alone in 2 patients, with a median injection volume of 2.4 ml. The therapeutic outcome for initial Deflux® injection therapy was resolution of VUR in 1 patient (25%) and persistence of VUR in 3 patients. Treatment was repeated for 2 of the 3 patients with persistent VUR, and resolution was reported for 1 of these patients. (Conclusion) The initial success rate for Deflux® injection therapy in VUR with bladder dysfunction was a low 25%, suggesting that caution is required in choosing this treatment option.

[TETHERED CORD SYNDROME IN CHILDREN WITH DAYTIME INCONTINENCE].

(Introduction) In tethered cord syndrome, the lower end of the spinal cord is moored to the caudal tissue, causing various neuropathies. Bladder dysfunction often appears early. We herein evaluated children with daytime urinary incontinence in whom tethered cord syndrome was eventually diagnosed. (Method) Eighteen children (9 males and 9 females) with daytime urinary incontinence were enrolled between March 2011 and October 2017. The causes of their urinary incontinence were investigated using spinal MRI and changes in clinical symptoms before and after untethering surgery. (Results) The average age at the first visit was 6.3 years (range: 4-9 years). Urodynamic testing and a voiding cystourethrogram (VCUG) were performed in all cases of refractory daytime incontinence, and all patients with abnormal findings on either test underwent spinal MRI. The diagnosis based on spinal MRI findings was filum lipoma in eight, occult tethered cord syndrome in four, low set conus in four, conus lipoma in one, and sacral meningeal cyst in one, patient. The average observation period after untethering surgery was 66.3 months (range: 22-116 months). All the patients achieved a cure postoperatively. Four patients were treated for nocturnal enuresis by oral medication, and three patients required urological management via clean, intermittent catheterization. (Conclusions) When treating children with daytime continence, one should consider the possibility of tethered cord syndrome, the diagnosis of which can be aided by urodynamic assessment of bladder function.

Seminal Vesicle Cysts With Upper Urinary Tract Abnormalities: A Single-center Case Series of Pediatric Zinner Syndrome.

Seminal vesicle cysts are usually congenital and frequently accompanied by upper urinary tract abnormalities due to mesonephric duct maldevelopment. Zinner syndrome, first described in 1914, refers to a triad of features consisting of seminal vesicle cysts, ejaculatory duct obstruction, and unilateral (mostly ipsilateral) renal agenesis. We herein present four pediatric patients with Zinner syndrome diagnosed at a children's medical center. A remnant ureteral structure was observed in three (75%) patients. Interestingly, a multicystic dysplastic kidney was present in one (25%) patient before it eventually disappeared. These findings suggest possible involvement of renal dysgenesis rather than agenesis in Zinner syndrome.

siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand.

Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5' nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analog, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analog at the 5'-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.

Macular Hole Formation in Eye After Cryotherapy and Intravitreal Bevacizumab Treatment for Vasoproliferative Tumor.

PURPOSE: To report a case of a full-thickness macular hole (MH) that developed after cryotherapy and intravitreal bevacizumab injection (IVB) to treat a retinal vasoproliferative tumor (VPT). METHODS: Case report of a man with a retinal VPT. RESULTS: A 64-year-old Japanese man complained of blurred vision in his right eye. At the initial examination, his best-corrected visual acuity (BCVA) was 20/25 in the right eye and 20/20 in the left eye. Ophthalmoscopy showed a VPT in the lower peripheral retina of the right eye. An exudative retinal detachment and hard exudates were seen around the tumor. Cryotherapy and intravitreal injections of bevacizumab (IVB) were performed. Although the exudative changes were reduced, a MH developed two months after the initial IVB treatment. He underwent 25-gauge pars plana vitrectomy, and the MH was closed. His postoperative BCVA was 20/32 and the VPT was inactive. The reduced BCVA was due to damage of the outer retinal layers. CONCLUSION: Our findings indicate that cryotherapy and IVB are effective treatments for VPT although the possibility of developing a MH should be considered.