Absence Of Segment Research Articles

Association between symptomatic intracranial atherosclerotic disease and the integrity of the circle of Willis

The relationship between the severity of intracranial atherosclerotic disease and the circle of Willis integrity is unclear. In this brief report, we investigate the associations between symptomatic intracranial atherosclerotic disease and the integrity of the circle of Willis. Patients with symptomatic intracranial atherosclerosis were enrolled and underwent intracranial artery magnetic resonance vessel wall imaging and time-of-flight angiography. The presence or absence of an intracranial atherosclerotic plaque and its maximum wall thickness and stenosis were evaluated. The presence or absence of the A1 segment of the bilateral anterior cerebral arteries (from the internal carotid artery to the anterior communicating artery segment is called anterior cerebral artery A1 segment), and anterior communicating artery, the P1 segment of the bilateral posterior cerebral arteries (The P1 segment of the posterior cerebral artery is a horizontally outward segment), and bilateral posterior communicating arteries were determined. The associations of the intracranial plaque features with the integrity of the circle of Willis were analyzed. Of the 110 recruited subjects (57.2 ± 11.1 years; 65% males), 51 had intracranial plaques, and 44 had stenosis. In patients with bilateral A1 and P1 segments (n = 85), intracranial stenosis was more severe in patients with an anterior communicating artery than those without an anterior communicating artery (19.7% ± 21.7% vs. 1.4% ± 3.3%, p = 0.046). In patients with bilateral A1 and P1 segments and an anterior communicating artery (n = 79), intracranial stenosis was more severe in patients with posterior communicating arteries than those without posterior communicating arteries (27.9% ± 23.7% vs. 13.5% ± 17.9%, p = 0.007). The odds ratio of intracranial stenosis was 1.214 (95% confidence interval (CI), 1.054-1.398; p = 0.007) in discriminating for the presence of posterior communicating arteries in patients with bilateral A1 and P1 segments and an anterior communicating artery after adjusting for confounding factors. The severity of intracranial atherosclerosis was independently associated with the presence of posterior communicating arteries in patients with a complete anterior part of the circle of Willis.

Evaluation of electrocardiographic predictors of brugada type response during flecainide challenge

Abstract Background/Introduction Brugada syndrome (BrS) is a hereditary channelopathy with an increased risk of sudden cardiac death. Most BrS patients manifest non type 1 Brugada pattern electrocardiography (ECG). Sodium channel blockade is a well-established diagnostic tool for Brugada syndrome. However, intravenous sodium channel blockade is not readily available in all parts of the world. In addition, severe ventricular arrhythmias during drug challenge have an estimated prevalence of 1%. Determining the predictors of a positive test would improve our understanding and facilitate appropriate use of these tests. Purpose We aimed to identify ECG predictors of Brugada type response during flecainide challenge and provide an independent assessment of current published ECG criteria predictive of a positive flecainide challenge. Methods We analysed the clinical and electrocardiographic data of 526 consecutive individuals referred from a national pre-participation exercise screening program who underwent flecainide challenge for an ECG suspicious of Brugada pattern. ECG recordings included both conventional and high precordial leads (1 and 2 space up ECGs in V1 and V2 – 1V1, 1V2, 2V1, 2V2). Twelve-lead ECGs were evaluated for the width of the β angle, β score, baseline J wave elevation, width of QRS, absence of isoelectric segment in lead II, ST/ QT ratio, presence of S wave in Leads II, III and V5 as well as the presence of R wave in aVR. Results Flecainide challenge was positive in 121 (23%) of the 526 cases. Baseline QRS duration was greater in the conventional lead placement [V1 (102.4±20.0 ms vs 97.6±14.0 ms, p=0.003), V2 (111.1±33.5 ms vs 100.9±13.1 ms, p=0.001)] as well as 1 space up [1V1 (108.9±21.0 ms vs 100.6±18.2 ms, p<0.001), 1V2 (117.4±26.6 ms vs 103.2±18.3, p<0.001)] and 2 space up [2V1 (113.6±23.4 ms vs 102.5±19.3 ms, p<0.001), 2V2 (121.6±26.1 ms vs 106.8±19.1 ms, p<0.001)] in cases with a subsequent positive response. A QRS duration of ≥120ms in V2 yielded a sensitivity of 16.5%, specificity of 93.8%, positive predictive value of 44.4% and negative predictive value of 79% for a positive flecainide challenge. Other predictors of positivity included that of a shorter ST duration in lead II (107.0±19.9 ms vs 118.1±24.4, p<0.001) and a shorter ST/ QT ratio (0.30±0.09 vs 0.32±0.07, p=0.006). Conclusion In this population, a wider QRS duration, shortened ST segment in lead II and ST/QT ratio were predictors of a positive response to flecainide challenge when BrS was suspected on a baseline ECG. Prior published ECG parameters such as β angle, β score, baseline J wave elevation, presence of S wave in Leads II, III and V5 as well as the presence of R wave in aVR did not perform as well in predicting for a positive response to flecainide challenge in our population. Funding Acknowledgement Type of funding sources: None. Baseline CharacteristicsECG Findings

The cellular modifier MOAG‐4/SERF drives amyloid formation through charge complementation

While aggregation‐prone proteins are known to accelerate aging and cause age‐related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG‐4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid‐promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG‐4 to neutralize charge. Our data indicate that MOAG‐4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation‐prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age‐related protein toxicity.

Comparison of Operative Risks and Benefits of Spliced Vein vs Prosthetic Conduits for Infrapopliteal Bypass

In the absence of adequate continuous segment of saphenous vein for infrapopliteal bypasses, early patency of prosthetic bypasses has been disappointing. Whether the performance of infrapopliteal bypasses can be improved if performed using spliced vein (SpV) grafts remains unclear. Our study investigates 30-day limb-related outcomes of SpV and prosthetic grafts for infrapopliteal (to tibial or peroneal arteries) bypasses.

Ikhin Tone and Nasality: Autosegmental Effects

In generative phonology, tone and nasality are described as suprasegmental phonological units. This implies that their survival depends on the segments on which they are grounded. Thus, when a tone bearing unit or nasality bearing unit disappears, any of these segments also disappears. In autosegmental theory, however, tone or nasality survives after the deletion of segment to which it is attached. This phenomenon is termed ‘stability’ which is the foundation for autosegmental phonological theory. Stability is the survival of tone and nasality after the deletion of segments on which they are grounded. Tone and nasality exhibit stability in Ikhin, a North-Central Edoid language spoken in Edo State, South-South, Nigeria. Previous study on Ikhin dwells mainly on the phonetics of the language. This study, therefore, investigates phonological processes such as vowel elision, glide formation and nasalization with a view to determining the stability or otherwise of tone and nasality. This paper confirms that in Ikhin, any process that involves the removal of a tone bearing unit must relate to stability and relate to the creation of contour tones. The study further confirms that nasality remains stable even in the absence of segment to which it is linked. Based on available data, it is argued that the deletion of a Tone Bearing Unit (TBU) or a Nasality Bearing Unit (NBU) does not necessarily involve the deletion of tone or nasality. Infact, it usual does not. The study concludes that tone and nasality are independent segments. They are as independent as consonant and vowel.

Impact of A1 Asymmetry on the Woven EndoBridge Device in Anterior Communicating Artery Aneurysms.

Woven EndoBridge (WEB) devices are increasingly used to treat intracranial aneurysms. A1 asymmetry contributes to anterior communicating artery aneurysm formation and to treatment instability after coiling. We sought to evaluate whether A1 asymmetry had an impact on angiographic outcome in anterior communicating artery aneurysms treated with the WEB. Anterior communicating artery aneurysms treated between July 2012 and July 2020 with the WEB from an institutional review board-approved database were reviewed. A1 asymmetry was categorized as the following: absence of the A1 segment on 1 side (unilateral A1) versus bilateral A1. Univariate and multivariable analyses assessed independent predictors of adequate (WEB Occlusion Scale A, B, and C) and complete occlusion (WEB Occlusion Scale A and B). Forty-eight individual aneurysms (47 patients) were included in the final analysis, of which 16 (33%) were acutely ruptured. The mean size was 6.5 (SD, 2.2) mm. Adequate and complete occlusion was achieved in 33 (69%) and 30 (63%) cases, respectively. Unilateral A1 was associated with significantly higher rates of adequate (92% versus 60% for bilateral A1; P = .03) and complete occlusion (92% versus 50% for bilateral A1; P < .01). Multivariable logistic regression confirmed unilateral A1 as an independent predictor of both adequate (OR = 10.6; 95% CI, 1.6-220.7; P = .04) and complete occlusion (OR = 9.5, 95% CI, 1.5-190.2; P = .04. A sensitivity analysis comparing unilateral "functional" A1 with bilateral "functional" A1 showed similar results. WEB shape modification was not influenced by the unilateral A1 configuration (P = .70). Anterior communicating artery aneurysms with a unilateral A1 configuration treated with WEB devices are associated with better angiographic outcome than those with bilateral A1. This finding supports the hypothesis that WEB devices are resistant to unilateral flow in the aneurysm as opposed to coils.

A comprehensive study of congenital unilateral absence of branch pulmonary artery associated with other congenital heart defects and ipsilateral non-unifocalizable major aorto-pulmonary collateral arteries: A single-center retrospective study.

Introduction:Congenital unilateral absence of pulmonary artery (UAPA) is a rare congenital anomaly with the complete absence of intrapericardial segment of one of the branch pulmonary arteries. Sixty percent are associated with other congenital heart defects (CHD) that often need correction.Aim:To analyze the data of patients with UAPA and ipsilateral non-unifocalizable major aortopulmonary collateral arteries (MAPCAs) associated with other CHD to identify the commonly associated CHD, their management strategies and outcomes.Materials and Methods:Retrospective data of patients admitted for congenital UAPA with other CHD was compiled from hospital records from 2002 to 2015. The associated CHD were categorized as group I with the decreased pulmonary flow and group II with increased pulmonary flow to the unaffected contralateral pulmonary artery. The determinants of their management were analyzed.Results:Sixty-five patients of UAPA and ipsilateral non-unifocalizable MAPCAs associated with other CHD were identified. Group I had 41 patients and Group II had 24. The most common CHD associated with UAPA was tetralogy of Fallot (TOF) in 31 patients (47.7%). Fifty-three patients underwent surgery, 48 (73.8%) underwent single lung corrective surgery, 5 (7.6%) palliative surgery and 12 (18.4) received no surgery. Four operated patients died in the immediate postoperative period. The lowest Mc Goon ratio and Nakata index to undergo corrective surgery were 1.0 and 87.4 mm2/m2. A follow-up of 21 patients was done, among which 11 patients who underwent single-stage corrective surgery, all are in NYHA class II and saturating above 95%.Conclusions:Congenital UAPA is a rare anomaly and associated with a variety of CHDs, TOF being the most common. Single lung corrective surgery in patients with ipsilateral non-unifocalizable MAPCAs has good immediate and long term survival.

Anomalous aortic origin of coronary arteries: is the unroofing procedure always appropriate?

Anomalous aortic origin of the coronary artery (AAOCA) with an interarterial ± an intramural course is a rare anomaly that carries a high risk of ischaemic events and even sudden death. The unroofing of the intramural course has been adopted as the gold standard surgical treatment. However, some anatomical forms need alternative techniques. We reviewed the surgical cohort with AAOCA managed at our institution between 2005 and 2019 and analysed the anatomical and clinical outcomes. Thirty-nine patients underwent surgical interventions. The median age was 14 years (10-26 years). Twenty-eight patients (72%) had right AAOCA, and 11 (28%) had left AAOCA. Thirty-one (80%) patients presented with symptoms. The symptoms were chest pain in 22 patients (56%), syncope in 5 patients (13%), cardiac arrest during exercise in 2 patients (5%), dyspnoea in 6 patients (15%) and dizziness in 13 patients (33%). An ischaemic test was performed in 32 patients: Only 4 patients (10%) had positive results from the ischaemic test. All patients had computed tomography angiography scans to confirm the precise anatomical features of the anomaly. Repair techniques included 30 unroofing procedures (77%) with an associated translocation of the pulmonary artery for 11 patients in our early experience. In 6 patients the unroofing procedure was not feasible because of the absence of an intramural distinct segment or was judged intraoperatively not appropriate. A reimplantation of the anomalous coronary artery was performed in 2 patients (5%); 3 patients had coronary artery bypass grafting procedures (7%); and 3 (8%) had an isolated translocation of the pulmonary artery. There were no early or late deaths. All patients were free of symptoms. Computed tomography angiography scans performed in 31 cases showed a patent, non-restrictive coronary artery ostium. Seventeen patients underwent postoperative ischaemia testing and showed no evidence of ischaemia. Surgical correction in AAOCA is mandatory both for symptomatic and for asymptomatic patients with evidence of myocardial ischaemia under stress or with a restricted coronary artery segment. Surgical unroofing remains the gold standard but is not appropriate for all forms: alternative techniques should be considered. Surgical results are promising.

Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness.

The self-formation of retinal tissue from pluripotent stem cells generated a tremendous promise for developing new therapies of retinal degenerative diseases, which previously seemed unattainable. Together with use of induced pluripotent stem cells or/and CRISPR-based recombineering the retinal organoid technology provided an avenue for developing models of human retinal degenerative diseases “in a dish” for studying the pathology, delineating the mechanisms and also establishing a platform for large-scale drug screening. At the same time, retinal organoids, highly resembling developing human fetal retinal tissue, are viewed as source of multipotential retinal progenitors, young photoreceptors and just the whole retinal tissue, which may be transplanted into the subretinal space with a goal of replacing patient’s degenerated retina with a new retinal “patch.” Both approaches (transplantation and modeling/drug screening) were projected when Yoshiki Sasai demonstrated the feasibility of deriving mammalian retinal tissue from pluripotent stem cells, and generated a lot of excitement. With further work and testing of both approaches in vitro and in vivo, a major implicit limitation has become apparent pretty quickly: the absence of the uniform layer of Retinal Pigment Epithelium (RPE) cells, which is normally present in mammalian retina, surrounds photoreceptor layer and develops and matures first. The RPE layer polarize into apical and basal sides during development and establish microvilli on the apical side, interacting with photoreceptors, nurturing photoreceptor outer segments and participating in the visual cycle by recycling 11-trans retinal (bleached pigment) back to 11-cis retinal. Retinal organoids, however, either do not have RPE layer or carry patches of RPE mostly on one side, thus directly exposing most photoreceptors in the developing organoids to neural medium. Recreation of the critical retinal niche between the apical RPE and photoreceptors, where many retinal disease mechanisms originate, is so far unattainable, imposes clear limitations on both modeling/drug screening and transplantation approaches and is a focus of investigation in many labs. Here we dissect different retinal degenerative diseases and analyze how and where retinal organoid technology can contribute the most to developing therapies even with a current limitation and absence of long and functional outer segments, supported by RPE.

Anatomical variants of anterior communicating artery complex. A study by Computerized Tomographic Angiography

Advances in imaging techniques have led to the identification of normal variations and abnormalities of cerebral arteries. Although the anterior communicating artery complex (ACAC) variations are usually asymptomatic, their description is essential in the radiologic report, since they can have clinical relevance. The aim of this study is to describe arterial anomalies of the ACAC and their prevalence. A retrospective observational descriptive analysis of ACAC variations in Computerized Tomographic Angiography (CTA) was performed. All CTA (426 studies) obtained in our center from 2015 to 2017 were included. Presence of aneurysm was recorded and its relationship with arterial variants was analyzed with a Chi-square test. The most common variants found in our study are linked to the A1 segment (42.3%) of the anterior cerebral artery (ACA): absence: 10.6%, hypoplasia: 31.2%, fenestration: 0.5%. A2 segment variants were present in 15.3% (absence: 0.2%; hypoplasia 8.5%; Azygos artery: 1.4%; triple ACA: 5.2%). Anterior Communicanting Artery was typical in 92.5%, absent in 4.7%, double/fenestrated in 0.9%, triple in 0.2%, X-shape in 1.2% and Y-shape in 0.2%. Aneurysms were present in 10.7%. Anterior circulation aneurysm involved the 50% of patients with aneurysm. Although the 60.9% of them showed artery variants, they did not reach statistical significance (p = 0.6). In conclusion, the Anterior Communicating Artery Complex presents variations in its anatomy. The most common anterior circulation vascular variants are the hypoplasia and the absence of the A1 segment. There does not appear to be a clear association between intracranial aneurysms and anatomical variations.

One-step vapor-phase synthesis of transparent high refractive index sulfur-containing polymers.

High refractive index polymers (HRIPs) have recently emerged as an important class of materials for use in a variety of optoelectronic devices including image sensors, lithography, and light-emitting diodes. However, achieving polymers having refractive index exceeding 1.8 while maintaining full transparency in the visible range still remains formidably challenging. Here, we present a unique one-step vapor-phase process, termed sulfur chemical vapor deposition, to generate highly stable, ultrahigh refractive index (n > 1.9) polymers directly from elemental sulfur. The deposition process involved vapor-phase radical polymerization between elemental sulfur and vinyl monomers to provide polymer films with controlled thickness and sulfur content, along with the refractive index as high as 1.91. Notably, the HRIP thin film showed unprecedented optical transparency throughout the visible range, attributed to the absence of long polysulfide segments within the polymer, which will serve as a key component in a wide range of optical devices.

Foreign DNA detection by high-throughput sequencing to regulate genome-edited agricultural products

Although the advent of several new breeding techniques (NBTs) is revolutionizing agricultural production processes, technical information necessary for their regulation is yet to be provided. Here, we show that high-throughput DNA sequencing is effective for the detection of unintended remaining foreign DNA segments in genome-edited rice. A simple k-mer detection method is presented and validated through a series of computer simulations and real data analyses. The data show that a short foreign DNA segment of 20 nucleotides can be detected and the probability that the segment is overlooked is 10−3 or less if the average sequencing depth is 30 or more, while the number of false hits is less than 1 on average. This method was applied to real sequencing data, and the presence and absence of an external DNA segment were successfully proven. Additionally, our in-depth analyses also identified some weaknesses in current DNA sequencing technologies. Hence, for a rigorous safety assessment, the combination of k-mer detection and another method, such as Southern blot assay, is recommended. The results presented in this study will lay the foundation for the regulation of NBT products, where foreign DNA is utilized during their generation.

Anomalous aortic origin of a coronary arteries: Is unroofing procedure always appropriate?

Anomalous aortic origin of the coronary artery (AAOCA) with an inter-arterial ± intra-mural course is rare anomaly that carries a high risk of ischemic event and even sudden death. Unroofing of the intramural course had been adopted as the gold standard. However, there are anatomical forms where the alternative techniques require to be considered. We reviewed our cohort between 1999 and 2019. Results 38 patients underwent surgical intervention. Median age was (Mean age was 42.5 ± 2.7 years). Twenty-eight patients (74%) had right AAOCA, 9(23%) left AAOCA and one (3.2%) both left and right AAOCA. One patient had a left coronary artery coursing within the subpulmonary muscular conus. Twenty-nine (76%) patients presented with symptoms, 9 (23%) patients were asymptomatic. Symptoms were chest pain for 24 patients, syncope or lipothymia for 15 patients, 1 patient had a cardiac arrest during exercise and for 8 patients the diagnosis was made by chance. Four patients had a positive ischemic test. Repair techniques included 27 unroofing procedures (67.7%) with an associated translocation of the pulmonary artery for 10 patients in early experience. For 6 patients the unroofing was not-feasible because of the absence of an intra-mural distinct segment or was intraoperatively judged not inappropriate and had a reimplantation of the AAOCA. Four patients had a coronary artery bypass grafting (CABG) and three translocation of the pulmonary artery. There was no early or late mortality. CT scan was performed in 31 cases showed a patent coronary artery ostium. Seventeen patients underwent postoperative ischemia testing with no evidence of ischemia. Surgical correction in AAOCA is mandatory for symptomatic and asymptomatic patients with evidence of myocardial ischemia under stress or restricted coronary artery segment. Surgical unroofing remains the gold standard but is not appropriated in all particular forms: alternative techniques should be considered in the latter. Surgical results are promising.

Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire

During V(D)J recombination, RAG proteins introduce DNA double-strand breaks (DSBs) at recombination signal sequences (RSSs) that contain either 12- or 23-nt spacer regions. Coordinated 12/23 cleavage predicts that DSBs at variable (V) gene segments should equal the level of breakage at joining (J) segments. Contrary to this, here we report abundant RAG-dependent DSBs at multiple Vκ gene segments independent of V-J rearrangement. We find that a large fraction of Vκ gene segments are flanked not only by a bone-fide 12 spacer but also an overlapping, 23-spacer flipped RSS. These compatible pairs of RSSs mediate recombination and deletion inside the Vκ cluster even in the complete absence of Jκ gene segments and support a V(D)J recombination center (RC) independent of the conventional Jκ-centered RC. We propose an improved model of Vκ-Jκ repertoire formation by incorporating these surprisingly frequent, evolutionarily conserved intra-Vκ cluster recombination events.

Circle of Willis anomalies in Turner syndrome: Absent A1 segment of the anterior cerebral artery.

Turner syndrome (TS) is the most common sex chromosome disorder in women and is associated with a higher than expected death rate secondary to cerebrovascular disease, including stroke. This study evaluates the cerebral vascular anatomy of individuals with TS. Twenty-one women with TS had brain magnetic resonance angiography (MRA). These MRAs were evaluated in a blinded manner with a control group of 25 men and 25 women who had MRA imaging for multiple indications including migraine headaches, psychiatric disorders, and seizures. Twenty-nine percent of women with TS were missing an A1 segment of the anterior cerebral artery (ACA) compared to 0% in the control group (p < .001). There were no other significant differences in the circle of Willis (COW) in women with TS compared with the control group. A complete COW was found in 3 of 21 (14%) of women with TS and 12 of 47 (26%) controls (p = .36). Women with TS have a significantly different intracranial vascular anatomy, specifically the absence of the A1 segment of the ACA when compared to male and female controls. More research in brain imaging in women with TS and stroke and other cerebrovascular diseases is needed to determine the clinical significance of this anomaly.

Molecular Architecture and Charging Effects Enhance the In Vitro and In Vivo Performance of Multi‐Arm Antimicrobial Agents Based on Star‐Shaped Poly(l‐lysine)

AbstractMolecular architecture is a largely neglected and unexplored factor that could impart a significant difference to the antimicrobial activity of antimicrobial peptides. In this article, the advantages (i.e., improved charging effect and enhanced proteolytic stability) of star‐shaped poly(l‐lysine)s (PLLs) over their linear analogs are extensively explored by the methods of computational simulation and experiments. A series of PEI‐g‐PLL with a hyperbranched polyethylenimine (PEI) core and PLL peripheral chains are designed as a class of versatile molecular scaffold for the development of star‐shaped antimicrobial peptides. Computational simulations and zeta‐potential measurements reveal that the change in PLL conformation from linear to star‐shaped significantly increases the cationic charge density, allowing enhanced binding affinity toward the bacterial membrane. The minimum inhibitory concentration and killing kinetics measurements demonstrate that PEI‐g‐PLLs exhibit higher antimicrobial activity and bactericidal efficiency in vitro than the linear PLL counterparts. The absence of hydrophobic segments in PEI‐g‐PLLs weakens the nonspecific interactions with eukaryotic cells and offers remarkable selectivity, as evidenced by their negligible hemolytic activity. Furthermore, PEI‐g‐PLLs demonstrate enhanced proteolytic stability and unprecedented antimicrobial activity in vivo. PEI‐g‐PLLs, with their high antimicrobial activity, enormous selectivity, and remarkable proteolytic stability, represent a new series of potent antimicrobial peptides to treat drug‐resistant infections.

The fundamental role of chromatin loop extrusion in physiological V(D)J recombination.

RAG endonuclease initiates IgH locus (Igh) V(D)J assembly in progenitor (pro)-B cells by joining Ds to JHs, before joining upstream VHs to DJH intermediates1. In mouse pro-B cells, the CTCF-binding element (CBE)-anchored chromatin loop domain2 at the 3’end of Igh contains an internal sub-domain spanning the 5’CBE anchor (IGCR1)3, the DHs, and a RAG-bound recombination center (RC)4. The RC comprises JH-proximal D (DQ52), 4 JHs, and the intronic enhancer (“iEμ”)5. Robust RAG cleavage is restricted to paired V(D)J segments flanked by complementary recombination signal sequences (12RSSs and 23RSSs)6. Ds are flanked downstream and upstream by 12RSSs that, respectively, mediate deletional joining with convergently-oriented JH-23RSSs and VH-23RSSs6. Despite 12/23 compatibility, inversional D to JH joining via upstream D-12RSSs is rare7,8. Plasmid-based assays attributed lack of inversional D to JH joining to sequence-based preference for downstream D-12RSSs9, as opposed to putative linear scanning mechanisms10,11. Given recent findings that RAG linearly scans convergent CBE-anchored chromatin loops4,12-14, potentially formed by cohesin-mediated loop extrusion15-18, we revisited a scanning role. Here, we report that JH-23RSS chromosomal orientation programs RC-bound RAG to linearly scan upstream chromatin in the 3’Igh sub-domain for convergently-oriented D-12RSSs and, thereby, to mediate deletional joining of all Ds, except RC-based DQ52 that joins by a diffusion-related mechanism. In a DQ52-based RC, formed in the absence of JHs, RAG bound by the downstream DQ52-RSS scans the downstream constant region exon-containing 3’Igh sub-domain in which scanning can be impeded by targeted nuclease-dead Cas9 (dCas9) binding, by transcription through repetitive Igh switch sequences, and by the 3’Igh CBE-based loop anchor. Notably, each scanning impediment focally increases RAG activity on potential substrate sequences within the impeded region. High resolution mapping of RC chromatin interactions reveals that such focal RAG targeting is associated with corresponding impediments to the loop extrusion process that drives chromatin past RC-bound RAG.

Diagnosis and prognosis of fetal inferior vena cava malformation by fetal echocardiography

Objective To summarize the characteristics of two-dimensional(2D) ultrasound, spatiotemporal imaging correlation(STIC) and vascular casting of fetal inferior vena cava(IVC) malformations, analyze the clinical characteristics and the prognosis of fetal IVC malformations, and explore the early diagnostic value of fetal echocardiography for fetal IVC malformations. Methods Sixty-one cases of fetal IVC malformation diagnosed by fetal echocardiography in Beijing Anzhen Hospital Maternal Fetal Medical Consultation Center were retrospectively analyzed. The clinical data, echocardiographic features, genetic testing information and prognosis were summarized. Results ①In the 61 cases of IVC malformation, there were 51 cases of absence of IVC, 46 cases of absence of liver segment, 5 cases of absence of left IVC hepatic segment, 9 cases of left IVC (including 5 cases of left IVC and absence of IVC hepatic segment), 5 cases of double IVC, and 1 case of right hepatic vein reflux. ②Ten fetuses of the 61 fetuses were simple IVC deformity without any other malformations. Other venous malformations included 7 cases of absence of right superior vena cava and persistent left superior venacava, 2 cases of absence of venous catheters, and 3 cases of persistent right umbilical vein, 2 cases were merged alone; 49 cases were merged with intracardiac structural malformations and arrhythmia. ③Thirty-eight pregnant women underwent Down′s screening or non-invasive DNA, all of which were at low risk.Four cases underwent amniocentesis, and no obviously abnormality was found. Sixteen cases underwent autopsy and genome sequencing after induced labor, one was single gene abnormalities (ZFPM2 classical mutation). ④STIC images were collected in 20 cases, and 19 cases were clearly visualized. ⑤Vascular cast was made to show the shape of blood vessel more clearly and stereoscopically in 4 cases of absent hepatic segment of IVC. ⑥Eleven fetuses were born and confirmed from the results of postnatal ultrasound, who were healthy in follow-up; 16 fetuses were induced labor; 33 fetuses were losed during follow-up; 1 fetus died after birth (arrhythmia). Conclusions Fetal echocardiography combined with STIC technology can clearly diagnose the anomalies of IVC. Vascular casting can provide stereoscopic and visual manifestations of the anomalies of IVC. The prognosis of simple anomalies of IVC is good. Key words: Echocardiography, Fetal; Inferior vena cava malformation; Spatiotemporal imaging correlation; Vascular cast

Effects of phonotactic predictability on sensitivity to phonetic detail

Japanese speakers systematically devoice or delete high vowels [i, u] between two voiceless consonants. Japanese listeners also report perceiving the same high vowels between consonant clusters even in the absence of a vocalic segment. Although perceptual vowel epenthesis has been described primarily as a phonotactic repair strategy, where a phonetically minimal vowel is epenthesized by default, few studies have investigated how the predictability of a vowel in a given context affects the choice of epenthetic vowel. The present study uses a forced-choice labeling task to test how sensitive Japanese listeners are to coarticulatory cues of high vowels [i, u] and non-high vowel [a] in devoicing and non-devoicing contexts. Devoicing contexts were further divided into high-predictability contexts, where the phonotactic distribution strongly favors one of the high vowels, and low-predictability contexts, where both high vowels are allowed, to specifically test for the effects of predictability. Results reveal a strong tendency towards [u] epenthesis as previous studies have found, but the results also reveal a sensitivity to coarticulatory cues that override the default [u] epenthesis, particularly in low-predictability contexts. Previous studies have shown that predictability affects phonetic implementation during production, and this study provides evidence predictability has similar effects during perception.

Rostral lumbar segments are the key controllers of hindlimb locomotor rhythmicity in the adult spinal rat.

The precise location and functional organization of the spinal neuronal locomotor-related networks in adult mammals remain unclear. Our recent neurophysiological findings provided empirical evidence that the rostral lumbar spinal cord segments play a critical role in the initiation and generation of the rhythmic activation patterns necessary for hindlimb locomotion in adult spinal rats. Since added epidural stimulation at the S1 segments significantly enhanced the motor output generated by L2 stimulation, these data also suggested that the sacral spinal cord provides a strong facilitory influence in rhythm initiation and generation. However, whether L2 will initiate hindlimb locomotion in the absence of S1 segments, and whether S1 segments can facilitate locomotion in the absence of L2 segments remain unknown. Herein, adult rats received complete spinal cord transections at T8 and then at either L2 or S1. Rats with spinal cord transections at T8 and S1 remained capable of generating coordinated hindlimb locomotion when receiving epidural stimulation at L2 and when ensembles of locomotor related loadbearing input were present. In contrast, minimal locomotion was observed when S1 stimulation was delivered after spinal cord transections at T8 and L2. Results were similar when the nonspecific serotonergic agonists were administered. These results demonstrate in adult rats that rostral lumbar segments are essential for the regulation of hindlimb locomotor rhythmicity. In addition, the more caudal spinal networks alone cannot control locomotion in the absence of the rostral segments around L2 even when loadbearing rhythmic proprioceptive afferent input is imposed.NEW & NOTEWORTHY The exact location of the spinal neuronal locomotor-related networks in adult mammals remains unknown. The present data demonstrate that when the rostral lumbar spinal segments (~L2) are completely eliminated in thoracic spinal adult rats, hindlimb stepping is not possible with neurochemical modulation of the lumbosacral cord. In contrast, eliminating the sacral cord retains stepping ability. These observations highlight the importance of rostral lumbar segments in generating effective mammalian locomotion.