Navigating Pubertal Goldilocks: The Optimal Pace for Hierarchical Brain Organization.

Adolescence is a timed process with an onset, tempo, and duration. Nevertheless, the temporal dimension, especially the pace of maturation, remains an insufficiently studied aspect of developmental progression. The primary objective is to estimate the precise influence of pubertal maturational tempo on the configuration of associative brain regions. To this end, the connection between maturational stages and the level of hierarchical organization of large-scale brain networks in 12-13-year-old females is analyzed. Skeletal maturity is used as a proxy for pubertal progress. The degree of maturity is defined by the difference between bone age and chronological age. To assess the level of hierarchical organization in the brain, the temporal dynamic of closed eye resting state high-density electroencephalography (EEG) in the alpha frequency range is analyzed. Different levels of hierarchical order are captured by the measured asymmetry in the directionality of information flow between different regions. The calculated EEG-based entropy production of participant groups is then compared with accelerated, average, and decelerated maturity. Results indicate that an average maturational trajectory optimally aligns with cerebral hierarchical order, and both accelerated and decelerated timelines result in diminished cortical organization. This suggests that a "Goldilocks rule" of brain development is favoring a particular maturational tempo.

Iron(II) Complexes of P3 -Chain Ligands: Structural Diversity.

Iron(II) complexes containing ligands with a R2 P-P-PR2 unit were synthesized by metathesis reactions. With R=tBu, a mixture of two isomers is formed; in one of them, the terminal phosphorus binds to the Fe center (ylidic structure), while in the other one, the central P atom is linked to Fe. Starting from differently functionalized parent triphosphanes and corresponding functionalized Fe complexes, the ratio of isomers does not change. The outcome of the reaction and therefore the binding modes of the triphosphane ligands in the resulting compounds can be influenced by the size of the substituents. In the case of R=iPr a chelate complex is formed (both terminal P atoms are linked to the Fe center). Applying the mixed-substituted triphosphane, the ylidic structure of the resulting complex is preferred. The new compounds were characterized by NMR spectroscopy in solution and single-crystal X-ray diffraction in solid-state. The synthetic work was supported by DFT calculations.

PARP2 promotes inflammation in psoriasis by modulating estradiol biosynthesis in keratinocytes.

Poly(ADP-ribose) polymerase 2 (PARP2) alongside PARP1 are responsible for the bulk of cellular PARP activity, and they were first described as DNA repair factors. However, research in past decades implicated PARPs in biological functions as diverse as the regulation of cellular energetics, lipid homeostasis, cell death, and inflammation. PARP activation was described in Th2-mediated inflammatory processes, but studies focused on the role of PARP1, while we have little information on PARP2 in inflammatory regulation. In this study, we assessed the role of PARP2 in a Th17-mediated inflammatory skin condition, psoriasis. We found that PARP2 mRNA expression is increased in human psoriatic lesions. Therefore, we studied the functional consequence of decreased PARP2 expression in murine and cellular human models of psoriasis. We observed that the deletion of PARP2 attenuated the imiquimod-induced psoriasis-like dermatitis in mice. Silencing of PARP2 in human keratinocytes prevented their hyperproliferation, maintained their terminal differentiation, and reduced their production of inflammatory mediators after treatment with psoriasis-mimicking cytokines IL17A and TNFα. Underlying these observations, we found that aromatase was induced in the epidermis of PARP2 knock-out mice and in PARP2-deficient human keratinocytes, and the resulting higher estradiol production suppressed NF-κB activation, and hence, inflammation in keratinocytes. Steroidogenic alterations have previously been described in psoriasis, and we extend these observations by showing that aromatase expression is reduced in psoriatic lesions. Collectively, our data identify PARP2 as a modulator of estrogen biosynthesis by epidermal keratinocytes that may be relevant in Th17 type inflammation. KEY MESSAGES : PARP2 mRNA expression is increased in lesional skin of psoriasis patients. PARP2 deletion in mice attenuated IMQ-induced psoriasis-like dermatitis. NF-κB activation is suppressed in PARP2-deficient human keratinocytes. Higher estradiol in PARP2-deficient keratinocytes conveys anti-inflammatory effect.

The adolescent pattern of sleep spindle development revealed by HD-EEG.

Sleep spindles are developmentally relevant cortical oscillatory patterns; however, they have mostly been studied by considering the entire spindle frequency range (11-15 Hz) without a distinction between the functionally and topographically different slow and fast spindles, using relatively few electrodes and analysing wide age-ranges. Here, we employ high-density night sleep electroencephalography in three age-groups between 12 and 20 years of age (30 females and 30 males) and analyse the adolescent developmental pattern of the four major parameters of slow and fast sleep spindles. Most of our findings corroborate those very few previous studies that also make a distinction between slow and fast spindles in their developmental analysis. We find spindle frequency increasing with age. A spindle density change is not obvious in our study. We confirm the declining tendencies for amplitude and duration, although within narrower, more specific age-windows than previously determined. Spindle frequency seems to be higher in females in the oldest age-group. Based on the pattern of our findings, we suggest that high-density electroencephalography, specifically targeting slow and fast spindle ranges and relatively narrow age-ranges would advance the understanding of both adolescent cortical maturation and development and the functional relevance of sleep spindles in general.

Overnight dynamics in scale-free and oscillatory spectral parameters of NREM sleep EEG.

Unfolding the overnight dynamics in human sleep features plays a pivotal role in understanding sleep regulation. Studies revealed the complex reorganization of the frequency composition of sleep electroencephalogram (EEG) during the course of sleep, however the scale-free and the oscillatory measures remained undistinguished and improperly characterized before. By focusing on the first four non-rapid eye movement (NREM) periods of night sleep records of 251 healthy human subjects (4-69 years), here we reveal the flattening of spectral slopes and decrease in several measures of the spectral intercepts during consecutive sleep cycles. Slopes and intercepts are significant predictors of slow wave activity (SWA), the gold standard measure of sleep intensity. The overnight increase in spectral peak sizes (amplitudes relative to scale-free spectra) in the broad sigma range is paralleled by a U-shaped time course of peak frequencies in frontopolar regions. Although, the set of spectral indices analyzed herein reproduce known age- and sex-effects, the interindividual variability in spectral slope steepness is lower as compared to the variability in SWA. Findings indicate that distinct scale-free and oscillatory measures of sleep EEG could provide composite measures of sleep dynamics with low redundancy, potentially affording new insights into sleep regulatory processes in future studies.

Scale-free and oscillatory spectral measures of sleep stages in humans.

Power spectra of sleep electroencephalograms (EEG) comprise two main components: a decaying power-law corresponding to the aperiodic neural background activity, and spectral peaks present due to neural oscillations. "Traditional" band-based spectral methods ignore this fundamental structure of the EEG spectra and thus are susceptible to misrepresenting the underlying phenomena. A fitting method that attempts to separate and parameterize the aperiodic and periodic spectral components called "fitting oscillations and one over f" (FOOOF) was applied to a set of annotated whole-night sleep EEG recordings of 251 subjects from a wide age range (4-69 years). Most of the extracted parameters exhibited sleep stage sensitivity; significant main effects and interactions of sleep stage, age, sex, and brain region were found. The spectral slope (describing the steepness of the aperiodic component) showed especially large and consistent variability between sleep stages (and low variability between subjects), making it a candidate indicator of sleep states. The limitations and arisen problems of the FOOOF method are also discussed, possible solutions for some of them are suggested.

Maturation-dependent vulnerability of emotion regulation as a response to COVID-19 related stress in adolescents.

BACKGROUND: The COVID-19 pandemic created unpredictable circumstances resulting in increased psychological strain. Here we investigate pandemic-related alterations in emotion regulation in adolescents assessed before and during the pandemic. We also take biological age into account in the response to the pandemic. METHODS: Mann-Whitney U tests were conducted to compare baseline data on the Difficulties in Emotion Regulation Scale (DERS) total scores of a pre-pandemic adolescent cohort (n = 241) with those obtained during the second wave of the pandemic (n = 266). We estimated biological age based on an ultrasonic boneage assessment procedure in a subgroup of males, including grammar school and vocational school students in the 9th and 10th grades, and analyzed their data independently. FINDINGS: There is a gender difference in the timing of vulnerability for pandemic-related stress in grammar school students: females are affected a year earlier than males. Vocational school male students mature faster than grammar school male students, and the timing of emotional vulnerability also precedes that of the grammar school students'. DISCUSSION: We interpret our findings within a developmental model suggesting that there might be a window of highest vulnerability in adolescent emotion regulation. The timing of the window is determined by both chronological and biological age, and it is different for females and males. APPLICATION TO PRACTICE: Defining the exact temporal windows of vulnerability for different adolescent cohorts allows for the timely integration of preventive actions into adolescent care to protect mental health during future chronic stressful situations.

Visual imagery vividness declines across the lifespan.

The capacity to elicit vivid visual mental images varies within an extensive range across individuals between hyper- and aphantasia. It is not clear, however, whether imagery vividness is constant across the lifespan or changes during development and later in life. Without enforcing the constraints of strict experimental procedures and representativity across the entire population, our purpose was to explore the self-reported level of imagery vividness and determine the relative proportions of aphantasic/hyperphantasic participants in different age groups. Relying on the frequently used Vividness of Visual Imagery Questionnaire, we collected data on a random sample of 2252 participants between the ages of 12-60 years. We found a novel developmental pattern that describes a declining ability to elicit vivid visual mental images in the group averages of different age groups from adolescence to middle age. This effect involves both a decreasing proportion of individuals with vivid visual imagery vividness and an increasing proportion of individuals with low imagery vividness as maturation (based on bone age assessments in adolescents) and ageing progress. These findings may shed some light on the developmental mechanisms of our internal, stimulus-independent processes, and might also help to determine genetic, maturational, and age-dependent factors in the cases of hyper- and aphantasia.

Pathological Diagnosis, Work-Up and Reporting of Breast Cancer 1st Central-Eastern European Professional Consensus Statement on Breast Cancer.

This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified on the basis of the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The recommendations cover non-operative, intraoperative and postoperative diagnostics, determination of prognostic and predictive markers and the content of cytology and histology reports. Furthermore, they address some specific issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, and some remarks about the future.

In Vivo Efficacy of Amphotericin B against Four Candida auris Clades.

Candida auris is a multidrug-resistant fungus against which in some clinical situations amphotericin B (AMB) remains the alternative or first line drug. We compared daily 1 mg/kg of AMB efficacy in a neutropenic murine bloodstream infection model against 10 isolates representing four C. auris clades (South Asian n = 2; East Asian n = 2; South African n = 2; South American n = 4; two of which were of environmental origin). Five days of AMB treatment significantly increased the survival rates in mice infected with isolates of the East Asian clade, and 1 isolate each from the South African and South American clades (originated from bloodstream), but not in mice infected with the South Asian and 2 environmental isolates from the South American clades. AMB treatment decreased the fungal burden in mice infected with the 2 isolates each from East Asian and South African, and 1 out of 2 bloodstream isolates from South American clades in the hearts (p < 0.01), kidneys (p < 0.01) and brain (p < 0.05). AMB treatment, regardless of clades, significantly decreased colony forming units in the urine at day 3. However, histopathological examination in AMB-treated mice revealed large aggregates of yeast cells in the kidneys and hearts, and focal lesions in the cerebra and cerebelli, regardless of precise C. auris clade. Our clade-specific data confirm that the efficacy of AMB against C. auris is weak, explaining the therapeutic failures in clinical situations. Our results draw attention to the necessity to maximize the killing at the start of treatment to avoid later complications in the heart and central nervous system.

Musical training improves fine motor function in adolescents.

BACKGROUND: Adolescence is a sensitive period in motor development but little is known about how long-term learning dependent processes shape hand function in tasks of different complexity. PROCEDURE: We mapped two fundamental aspects of hand function: simple repetitive and complex sequential finger movements, as a function of the length of musical instrumental training. We controlled maturational factors such as chronological and biological age of adolescent female participants (11 to 15 years of age, n = 114). RESULTS: We demonstrated that experience improves performance as a function of task complexity, the more complex task being more susceptible for experience driven performance changes. CONCLUSION: Overall, these results suggest that fine motor skills involving cognitive control and relying on long-range functional brain networks are substantially shaped by experience. On the other hand, performance in a simple repetitive task that explains fine motor speed is primarily determined by white matter development driven by maturational factors.

Topographical relocation of adolescent sleep spindles reveals a new maturational pattern in the human brain.

Current theories of human neural development emphasize the posterior-to-anterior pattern of brain maturation. However, this scenario leaves out significant brain areas not directly involved with sensory input and behavioral control. Suggesting the relevance of cortical activity unrelated to sensory stimulation, such as sleep, we investigated adolescent transformations in the topography of sleep spindles. Sleep spindles are known to be involved in neural plasticity and in adults have a bimodal topography: slow spindles are frontally dominant, while fast spindles have a parietal/precuneal origin. The late functional segregation of the precuneus from the frontoparietal network during adolescence suggests that spindle topography might approach the adult state relatively late in development, and it may not be a result of the posterior-to-anterior maturational pattern. We analyzed the topographical distribution of spindle parameters in HD-EEG polysomnographic sleep recordings of adolescents and found that slow spindle duration maxima traveled from central to anterior brain regions, while fast spindle density, amplitude and frequency peaks traveled from central to more posterior brain regions. These results provide evidence for the gradual posteriorization of the anatomical localization of fast sleep spindles during adolescence and indicate the existence of an anterior-to-posterior pattern of human brain maturation.

Ultrasonic bone age fractionates cognitive abilities in adolescence.

Adolescent development is not only shaped by the mere passing of time and accumulating experience, but it also depends on pubertal timing and the cascade of maturational processes orchestrated by gonadal hormones. Although individual variability in puberty onset confounds adolescent studies, it has not been efficiently controlled for. Here we introduce ultrasonic bone age assessment to estimate biological maturity and disentangle the independent effects of chronological and biological age on adolescent cognitive abilities. Comparing cognitive performance of female participants with different skeletal maturity we uncover the impact of biological age on both IQ and specific abilities. We find that biological age has a selective effect on abilities: more mature individuals within the same age group have higher working memory capacity and processing speed, while those with higher chronological age have better verbal abilities, independently of their maturity. Based on our findings, bone age is a promising biomarker of adolescent maturity.

Alternative female and male developmental trajectories in the dynamic balance of human visual perception.

The numerous multistable phenomena in vision, hearing and touch attest that the inner workings of perception are prone to instability. We investigated a visual example-binocular rivalry-with an accurate no-report paradigm, and uncovered developmental and maturational lifespan trajectories that were specific for age and sex. To interpret these trajectories, we hypothesized that conflicting objectives of visual perception-such as stability of appearance, sensitivity to visual detail, and exploration of fundamental alternatives-change in relative importance over the lifespan. Computational modelling of our empirical results allowed us to estimate this putative development of stability, sensitivity, and exploration over the lifespan. Our results confirmed prior findings of developmental psychology and appear to quantify important aspects of neurocognitive phenotype. Additionally, we report atypical function of binocular rivalry in autism spectrum disorder and borderline personality disorder. Our computational approach offers new ways of quantifying neurocognitive phenotypes both in development and in dysfunction.

Sleep-spindle frequency: Overnight dynamics, afternoon nap effects, and possible circadian modulation.

Homeostatic and circadian processes play a pivotal role in determining sleep structure, timing, and quality. In sharp contrast with the wide accessibility of the electroencephalogram (EEG) index of sleep homeostasis, an electrophysiological measure of the circadian modulation of sleep is still unavailable. Evidence suggests that sleep-spindle frequencies decelerate during biological night. In order to test the feasibility of measuring this marker in common polysomnographic protocols, the Budapest-Munich database of sleep records (N = 251 healthy subjects, 122 females, age range: 4-69 years), as well as an afternoon nap sleep record database (N = 112 healthy subjects, 30 females, age range: 18-30 years) were analysed by the individual adjustment method of sleep-spindle analysis. Slow and fast sleep-spindle frequencies were characterised by U-shaped overnight dynamics, with highest values in the first and the fourth-to-fifth sleep cycle and the lowest values in the middle of the sleeping period (cycles two to three). Age-related attenuation of sleep-spindle deceleration was evident. Estimated phases of the nadirs in sleep-spindle frequencies were advanced in children as compared to other age groups. Additionally, nap sleep spindles were faster than night sleep spindles (0.57 and 0.39 Hz difference for slow and fast types, respectively). The fine frequency resolution analysis of sleep spindles is a feasible method of measuring the assumed circadian modulation of sleep. Moreover, age-related attenuation of circadian sleep modulation might be measurable by assessing the overnight dynamics in sleep-spindle frequency. Phase of the minimal sleep-spindle frequency is a putative biomarker of chronotype.

Hematological, Micro-Rheological, and Metabolic Changes Modulated by Local Ischemic Pre- and Post-Conditioning in Rat Limb Ischemia-Reperfusion.

In trauma and orthopedic surgery, limb ischemia-reperfusion (I/R) remains a great challenge. The effect of preventive protocols, including surgical conditioning approaches, is still controversial. We aimed to examine the effects of local ischemic pre-conditioning (PreC) and post-conditioning (PostC) on limb I/R. Anesthetized rats were randomized into sham-operated (control), I/R (120-min limb ischemia with tourniquet), PreC, or PostC groups (3 × 10-min tourniquet ischemia, 10-min reperfusion intervals). Blood samples were taken before and just after the ischemia, and on the first postoperative week for testing hematological, micro-rheological (erythrocyte deformability and aggregation), and metabolic parameters. Histological samples were also taken. Erythrocyte count, hemoglobin, and hematocrit values decreased, while after a temporary decrease, platelet count increased in I/R groups. Erythrocyte deformability impairment and aggregation enhancement were seen after ischemia, more obviously in the PreC group, and less in PostC. Blood pH decreased in all I/R groups. The elevation of creatinine and lactate concentration was the largest in PostC group. Histology did not reveal important differences. In conclusion, limb I/R caused micro-rheological impairment with hematological and metabolic changes. Ischemic pre- and post-conditioning had additive changes in various manners. Post-conditioning showed better micro-rheological effects. However, by these parameters it cannot be decided which protocol is better.

Mesoporous Aerogel Microparticles Injected into the Abdominal Cavity of Mice Accumulate in Parathymic Lymph Nodes.

Mesoporous aerogel microparticles are promising drug delivery systems. However, their in vivo biodistribution pathways and health effects are unknown. Suspensions of fluorescein-labeled silica-gelatin hybrid aerogel microparticles were injected into the peritoneum (abdominal cavity) of healthy mice in concentrations of 52 and 104 mg kg-1 in a 3-week-long acute toxicity experiment. No physiological dysfunctions were detected, and all mice were healthy. An autopsy revealed that the aerogel microparticles were not present at the site of injection in the abdominal cavity at the end of the experiment. The histological study of the liver, spleen, kidneys, thymus and lymphatic tissues showed no signs of toxicity. The localization of the aerogel microparticles in the organs was studied by fluorescence microscopy. Aerogel microparticles were not detected in any of the abdominal organs, but they were clearly visible in the cortical part of the parathymic lymph nodes, where they accumulated. The accumulation of aerogel microparticles in parathymic lymph nodes in combination with their absence in the reticuloendothelial system organs, such as the liver or spleen, suggests that the microparticles entered the lymphatic circulation. This biodistribution pathway could be exploited to design passive targeting drug delivery systems for flooding metastatic pathways of abdominal cancers that spread via the lymphatic circulation.

Inflammatory or malignant? Lessons from a cystic lateral neck lesion with a sudden onset / Gyulladás vagy daganat? Egy hirtelen jelentkezo lateralis cysticus nyaki terime tanulságai

Összefoglaló. A lateralis cysticus nyaki terimék két leggyakoribb oka a branchiogen cysta és a cysticus nyaki áttét. Az átfedo lokalizáció (a leggyakrabban a IIA nyaki régióban), a betegek életkora és az esetenként hirtelen kezdet alapján a két leggyakoribb ok differenciáldiagnózisa nagy kihívást jelenthet. Egy hirtelen fellépo fájdalmas, bal oldali nyaki duzzanattal, dysphagiával és lázzal jelentkezo 72 éves férfi esetét ismertetjük. A nyak komputertomográfiás vizsgálata egy 6 cm legnagyobb átméroju, vastag falú, többrekeszes cysticus terimét igazolt. Infektív branchiogen cysta lehetoségére gondolva az elváltozást eltávolítottuk. A szövettan azonban p16-pozitív laphámrákot igazolt. A primer tumort végül az ipsilateralis tonsilla palatina állományában sikerült azonosítani. A beteg definitív radioterápiában részesült, és 18 hónappal a diagnózis után tumormentes. A nyaki cystákon, az infektív nyaki cystákon és a cysticus metastasisokon kívül a humán papillómavírussal összefüggo szájgarati laphámrákok infektív cysticus vagy necroticus metastasisait is figyelembe kell venni a lateralis cysticus nyaki terimék differenciáldiagnózisában. Orv Hetil. 2020; 162(15): 595-600. Summary. Branchial cleft cysts and cystic neck metastases are the two most common causes of cystic lateral neck masses. Based on the overlapping location (neck level IIA), patient age at onset and the occasionally sudden onset, their differential diagnosis is challenging. We present a 72-year-old male presenting with a suddenly emerging painful, left-sided neck swelling, dysphagia and fever. Computed tomography showed a 6 cm thick-walled multicystic mass. With the suspected diagnosis of an infected branchial cleft cyst, the lesion was removed. Histology confirmed p16 positive squamous cell carcinoma. Primary tumor was identified in the ipsilateral palatine tonsil. Definive radiotherapy was performed and the patient is free of disease at the 18-month follow-up. Beyond pure and infected branchial cleft cysts and pure cystic metastases, infected cystic or necrotic metastasis of human papillomavirus associated oropharyngeal squamous cell carcinoma should be included in the differential diagnosis of cystic lateral neck lesions. Orv Hetil. 2021; 162(15): 595-600.

An intra-abdominal desmoid tumor.

Desmoid tumor is a very rare neoplasm which develops from fibroblasts. These tumors do not have the ability to metastasize, but they can cause significant morbidity and mortality by local invasion and they are prone to local recurrence. We present a case of an aggressive fibromatosis in a 28-year-old male patient with no previous medical history. The tumor was in the retroperitoneum and eventually caused perforation of the coecum. During the operation, no metastasis was found; however, local lymphadenopathy was seen. After the surgical resection, no adjuvant therapy (radio or chemotherapy) was given to the patient and on follow-up (after three years), no recurrence was observed.

Zinc Transporter 9 (SLC30A9) Expression Is Decreased in the Vaginal Tissues of Menopausal Women.

Our aim was to compare zinc transporter (ZnT/SLC30A, and ZIP/SLC39A) expression between pre- and postmenopausal women in human vaginal tissues. Zinc transporter families are responsible for the maintenance of intracellular zinc concentrations. Zinc has significant effects on the extracellular matrix composition. Vaginal wall biopsies were obtained from seven premenopausal and seven postmenopausal women. mRNA expression of twenty-four zinc transporters was determined by quantitative real-time PCR. Zinc transporter expression at the protein level was assessed by immunohistochemistry. Student's t test and Mann-Whitney U test were used to compare data. ZnT4 and ZnT9 mRNA expression were significantly lower in postmenopausal women compared with premenopausal women (mean ± SD mRNA expression in relative units, 96.43 ± 140.61 vs. 410.59 ± 304.34, p = 0.03 and 0.62 ± 0.39 vs. 1.13 ± 0.31, p = 0.02). In addition, ZIP2, ZIP3, and ZIP6 mRNA expressions were significantly lower in postmenopausal women compared with premenopausal women (mean ± SD mRNA expression in relative units, 1.11 ± 0.61 vs. 2.29 ± 1.20, p = 0.04; 2.32 ± 1.90 vs. 15.82 ± 12.97, p = 0.02 and 1.10 ± 0.80 vs. 5.73 ± 4.72, p = 0.03). ZnT9 protein expression in the stratum spinosum was significantly lower in postmenopausal women (p = 0.012). Zinc transporters were expressed differentially in the vaginal tissues. ZnT9 expression was significantly lower in postmenopausal women compared with premenopausal women.