Earliest known human burial in Africa.

The origin and evolution of hominin mortuary practices are topics of intense interest and debate1-3. Human burials dated to the Middle Stone Age (MSA) are exceedingly rare in Africa and unknown in East Africa1-6. Here we describe the partial skeleton of a roughly 2.5- to 3.0-year-old child dating to 78.3 ± 4.1 thousand years ago, which was recovered in the MSA layers of Panga ya Saidi (PYS), a cave site in the tropical upland coast of Kenya7,8. Recent excavations have revealed a pit feature containing a child in a flexed position. Geochemical, granulometric and micromorphological analyses of the burial pit content and encasing archaeological layers indicate that the pit was deliberately excavated. Taphonomical evidence, such as the strict articulation or good anatomical association of the skeletal elements and histological evidence of putrefaction, support the in-place decomposition of the fresh body. The presence of little or no displacement of the unstable joints during decomposition points to an interment in a filled space (grave earth), making the PYS finding the oldest known human burial in Africa. The morphological assessment of the partial skeleton is consistent with its assignment to Homo sapiens, although the preservation of some primitive features in the dentition supports increasing evidence for non-gradual assembly of modern traits during the emergence of our species. The PYS burial sheds light on how MSA populations interacted with the dead.

Brain iron acquisition depends on age and sex in iron-deficient mice.

Adequate and timely delivery of iron is essential for brain development. The uptake of transferrin-bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H-ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1- and Tf-bound iron. In the present study, we used C57BL/6J male and female mice at a developing (post-natal day (PND) 15) and adult age (PND 85). In developing mice, ID results in increased iron delivery from both FTH1 and Tf for both males and females. The amount of iron uptake from FTH1 was higher than the Tf and this difference between the iron delivery was much greater in females. In contrast, in the adult model, ID was associated with increased brain iron uptake by both FTH1 and Tf but only in the males. There was no increased uptake from either protein in the females. Moreover, transferrin receptor expression on the microvasculature as well as whole brain iron, and H and L ferritin levels revealed the male brains became iron deficient but not the female brains. Last, under normal dietary conditions, 55 Fe uptake was higher in the developing group from both delivery proteins than in the adult group. These results indicate that there are differences in iron acquisition between the developing and adult brain for FTH1 and Tf during nutritional ID and demonstrate a level of regulation of brain iron uptake that is age and sex-dependent.

Exosomes are involved in iron transport from human blood-brain barrier endothelial cells and are modified by endothelial cell iron status.

Iron is essential for normal brain development and function. Hence, understanding the mechanisms of iron efflux at the blood-brain barrier and their regulation are critical for the establishment of brain iron homeostasis. Here, we have investigated the role of exosomes in mediating the transfer of H-ferritin (FTH1)- or transferrin (Tf)-bound iron across the blood-brain barrier endothelial cells (BBBECs). Our study used ECs derived from human-induced pluripotent stem cells that are grown in bicameral chambers. When cells were exposed to 55Fe-Tf or 55Fe-FTH1, the 55Fe activity in the exosome fraction in the basal chamber was significantly higher compared to the supernatant fraction. Furthermore, we determined that the release of endogenous Tf, FTH1, and exosome number is regulated by the iron concentration of the endothelial cells. Moreover, the release of exogenously added Tf or FTH1 to the basal side via exosomes was significantly higher when ECs were iron loaded compared to when they were iron deficient. The release of exosomes containing iron bound to Tf or FTH1 was independent of hepcidin regulation, indicating this mechanism by-passes a major iron regulatory pathway. A potent inhibitor of exosome formation, GW4869, reduced exosomes released from the ECs and also decreased the Tf- and FTH1-bound iron within the exosomes. Collectively, these results indicate that iron transport across the blood-brain barrier is mediated via the exosome pathway and is modified by the iron status of the ECs, providing evidence for a novel alternate mechanism of iron transport into the brain.

Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation.

Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H-ferritin is critical. Endothelial cells of the blood-brain barrier are the site of iron transport regulation. The movement of iron through endothelial cells into the brain can be divided into three distinct processes: uptake, transcytosis, and release. Each process possesses external and internal influences on the regulation at each stage. This review discusses the mechanisms of iron uptake, transcytosis, and release at the blood-brain barrier, as well as the elements that contribute to regulation. Additionally, we explore the dysregulation of brain iron in Alzheimer's disease, Parkinson's disease, and restless legs syndrome.

Amyloid-ß exposed astrocytes induce iron transport from endothelial cells at the blood-brain barrier by altering the ratio of apo- and holo-transferrin.

Excessive brain iron accumulation is observed early in the onset of Alzheimer's disease, notably prior to widespread proteinopathy. These findings suggest that increases in brain iron levels are due to a dysregulation of the iron transport mechanism at the blood-brain barrier. Astrocytes release signals (apo- and holo-transferrin) that communicate brain iron needs to endothelial cells in order to modulate iron transport. Here we use iPSC-derived astrocytes and endothelial cells to investigate how early-disease levels of amyloid-ß disrupt iron transport signals secreted by astrocytes to stimulate iron transport from endothelial cells. We demonstrate that conditioned media from astrocytes treated with amyloid-ß stimulates iron transport from endothelial cells and induces changes in iron transport pathway proteins. The mechanism underlying this response begins with increased iron uptake and mitochondrial activity by the astrocytes, which in turn increases levels of apo-transferrin in the amyloid-ß conditioned astrocyte media leading to increased iron transport from endothelial cells. These novel findings offer a potential explanation for the initiation of excessive iron accumulation in early stages of Alzheimer's disease. What's more, these data provide the first example of how the mechanism of iron transport regulation by apo- and holo-transferrin becomes misappropriated in disease that can lead to iron accumulation. The clinical benefit from understanding early dysregulation in brain iron transport in AD cannot be understated. If therapeutics can target this early process, they could possibly prevent the detrimental cascade that occurs with excessive iron accumulation.

Apo- and holo-transferrin differentially interact with hephaestin and ferroportin in a novel mechanism of cellular iron release regulation.

BACKGROUND: Apo- (iron free) and holo- (iron bound) transferrin (Tf) participate in precise regulation of brain iron uptake at endothelial cells of the blood-brain barrier. Apo-Tf indicates an iron-deficient environment and stimulates iron release, while holo-Tf indicates an iron sufficient environment and suppresses additional iron release. Free iron is exported through ferroportin, with hephaestin as an aid to the process. Until now, the molecular mechanisms of apo- and holo-Tf influence on iron release was largely unknown. METHODS: Here we use a variety of cell culture techniques, including co-immunoprecipitation and proximity ligation assay, in iPSC-derived endothelial cells and HEK 293 cells to investigate the mechanism by which apo- and holo-Tf influence cellular iron release. Given the established role of hepcidin in regulating cellular iron release, we further explored the relationship of hepcidin to transferrin in this model. RESULTS: We demonstrate that holo-Tf induces the internalization of ferroportin through the established ferroportin degradation pathway. Furthermore, holo-Tf directly interacts with ferroportin, whereas apo-Tf directly interacts with hephaestin. Only pathophysiological levels of hepcidin disrupt the interaction between holo-Tf and ferroportin, but similar hepcidin levels are unable to interfere with the interaction between apo-Tf and hephaestin. The disruption of the holo-Tf and ferroportin interaction by hepcidin is due to hepcidin's ability to more rapidly internalize ferroportin compared to holo-Tf. CONCLUSIONS: These novel findings provide a molecular mechanism for apo- and holo-Tf regulation of iron release from endothelial cells. They further demonstrate how hepcidin impacts these protein-protein interactions, and offer a model for how holo-Tf and hepcidin cooperate to suppress iron release. These results expand on our previous reports on mechanisms mediating regulation of brain iron uptake to provide a more thorough understanding of the regulatory mechanisms mediating cellular iron release in general.

Eruptive cherry angiomas-a novel cutaneous manifestation of immunoglobulin type gamma 4-related disease.

Immunoglobulin type gamma 4-related disease (IgG4-RD) is a fibroinflammatory condition that can have systemic and/or cutaneous manifestations. The most common cutaneous features are erythematous papules, nodules and/or plaques, typically involving the head and neck (J Am Acad Dermatol. 2016;75:197). We report a case of IgG4-RD presenting with eruptive cherry angiomas, a novel cutaneous presentation.

Excellent outcomes of transformed lymphomas in the rituximab era without autologous stem cell transplantation: an Australian single-centre experience.

BACKGROUND: Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There are minimal data on HT in the Australian setting. AIMS: To characterise patients with biopsy-proven HT and their outcomes identified at a tertiary Australian Hospital. METHODS: All patients with biopsy-proven HT during a 15-year period (2002-2017) were included. Clinico-pathological data were systematically collected from review of patient records. Survival estimates were assessed using the Kaplan-Meier method and compared using the log-rank test. Associations between variables and clinical outcomes were evaluated using Cox's proportional hazards model. RESULTS: A cohort of 45 patients was identified with a median age of 66 years and the majority (59%) having high-risk disease (Revised-International Prognostic Index score ≥3). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) induction was used in 69%, with an overall response rate of 82% (complete response (CR), 75%). Sixty-one percent of these induction responders received consolidation, with autologous stem cell transplant (ASCT) performed in only 17% and rituximab maintenance given to 31%. With a median follow up of 47 months (range: 4-136), the 5-year overall survival (OS) was 69% (95% CI: 52%, 81%). Chemotherapy-naivety at HT was associated with a superior rate of CR (84% vs 54%, P = 0.057) and 5-year OS (82% vs 46%, P = 0.012). Rituximab maintenance was associated with a durable progression-free survival in induction responders. CONCLUSIONS: Excellent OS was observed in this modern cohort of patients treated with rituximab-containing induction and low rate of consolidation by ASCT, particularly in those who were chemotherapy-naïve at HT.

Assessing maintenance techniques and in-situ pavement conditions to restore hydraulic function of permeable interlocking concrete pavements.

Permeable pavements are increasingly implemented to mitigate the negative hydrologic outcomes associated with impervious surfaces. However, the hydraulic function of permeable pavements is hindered by clogging in their joint openings, and systematic maintenance is needed to ensure hydraulic functionality throughout the design lifespan of these systems. To quantify the effectiveness of various maintenance measures, surface infiltration rates (SIRs) were measured before and after five different maintenance techniques were applied to five permeable interlocking concrete pavements (PICPs) in central Ohio, USA. Three maintenance techniques, the Municipal Cleaning Vehicle (MCV), the Rejuvenater, and a pressure washer and the Rejuvenater performed in series, significantly improved median SIRs from 16 to 26, 5 to 106, and 11 to 37 mm/min, respectively. However, pressure washing alone resulted in no significant difference to PICP SIR (median SIRs increased from 8 to 20 mm/min). Regenerative air street sweeping significantly worsened SIRs when performed during wet weather (median SIRs decreased from 19 to 4 mm/min) but had no significant impact on SIRs during dry weather (median SIRs decreased from 21 to 18 mm/min). This work captured the maintenance effectiveness of two techniques for the first or second time, namely the Rejuvenater and MCV, to investigate their use as a suitable maintenance technique. Further, the maintenance techniques were tested on multiple PICPs, thus the effect of in-situ pavement conditions had on hydraulic improvement via maintenance could be addressed. Differences in general upkeep, traffic, and runoff routed to a PICP affected the depth of clogging below the pavement surface, which forestalled hydraulic improvement. Though shown to improve the SIR of PICP systems, results indicate that the maintenance techniques were not capable of restoring pavement hydraulics to initial conditions. These results demonstrate the need for regular, routine maintenance and topping up of joint aggregate before clogging migrates deeper into the pavement profile.

Transferrin and H-ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype.

Iron delivery to the developing brain is essential for energy and metabolic support needed for processes such as myelination and neuronal development. Iron deficiency, especially in the developing brain, can result in a number of long-term neurological deficits that persist into adulthood. There is considerable debate that excess access to iron during development may result in iron overload in the brain and subsequently predispose individuals to age-related neurodegenerative diseases. There is a significant gap in knowledge regarding how the brain acquires iron during development and how biological variables such as development, genetics, and sex impact brain iron status. In this study, we used a mouse model expressing a mutant form of the iron homeostatic regulator protein HFE, (Hfe H63D), the most common gene variant in Caucasians, to determine impact of the mutation on brain iron uptake. Iron uptake was assessed using 59 Fe bound to either transferrin or H-ferritin as the iron carrier proteins. We demonstrate that at postnatal day 22, mutant mice brains take up greater amounts of iron compared with wildtype. Moreover, we introduce H-ferritin as a key protein in brain iron transport during development and identify a sex and genotype effect demonstrating female mutant mice take up more iron by transferrin, whereas male mutant mice take up more iron from H-ferritin at PND22. Furthermore, we begin to elucidate the mechanism for uptake using immunohistochemistry to profile the regional distribution and temporal expression of transferrin receptor and T-cell immunoglobulin and mucin domain 2, the latter is the receptor for H-ferritin. These data demonstrate that sex and genotype have significant effects on iron uptake and that regional receptor expression may play a large role in the uptake patterns during development. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14731.

Kimura disease of the breast: Case report and literature review of current management.

We report a rare case of Kimura disease in a 50-year old female patient who attended our tertiary level Breast Surgery Clinic.

Foley catheter for induction of labour: a UK observational study.

We conducted a prospective observational study of all inductions using Foley's catheter at our center between 2016 and 2018. Outcome data collected included induction to delivery time, mode of delivery, complication rates, patient and staff satisfaction. Ninety-nine women were included in our study. Median induction to delivery time was 28.3 h (IQR 19.7-34 h), 20 (20.2%) women required Caesarean section. No relevant complications were recorded. Patients and staff were satisfied with the technique overall.These results show transcervical Foley's catheter is a safe and effective method of induction of labour in the UK setting. It was shown to be feasible in the outpatient and previous Caesarean section groups.Impact statementWhat is already known on the subject? Foley catheter as an induction agent has already been shown to be as clinically effective as slow release prostaglandins with lower costs.What do the results of this study add? No study has been published on its use for routine inductions in the UK. Our results show that Foley's catheter is a safe, effective method for inducing labour in the UK.What are the implications of these findings for clinical practice and/or further research? This suggests this technique should be implemented more widely in the UK.

RAN and orthographic processing: What can syllable frequency tell us about this relationship?

Many explanations accounting for rapid automatized naming's (RAN) relationship with reading have been proposed. One of the most debated perspectives argues that RAN measures orthographic processing, defined as the ability to process groups of letters or entire words as single units. Given that reading familiar spelling patterns will rely on orthographic processing more than reading unfamiliar spelling patterns, manipulating orthographic syllable frequency can be a useful tool to examine RAN's relationship with orthographic familiarity. To meet this aim, RAN's concurrent and longitudinal contribution to reading speed of nonwords composed of high and low syllable frequency, as well as real words, was assessed in a sample of 142 Spanish children. RAN, phonological skills, and visual skills were measured in kindergarten and Grade 5, whereas reading speed was measured in Grade 5 only. Both longitudinal and concurrent path analyses revealed that RAN made a comparable contribution to the reading of both types of nonwords as well as to real-word reading. This suggests that the reading-related cognitive ability measured by RAN operates at a grapho-phonemic, grapho-syllabic, and whole-word level. The current results do not support the view of RAN as a measure of orthographic processing.

Climate challenges, vulnerabilities, and food security.

This paper identifies rare climate challenges in the long-term history of seven areas, three in the subpolar North Atlantic Islands and four in the arid-to-semiarid deserts of the US Southwest. For each case, the vulnerability to food shortage before the climate challenge is quantified based on eight variables encompassing both environmental and social domains. These data are used to evaluate the relationship between the "weight" of vulnerability before a climate challenge and the nature of social change and food security following a challenge. The outcome of this work is directly applicable to debates about disaster management policy.

Mental health symptoms and verbal fluency in elderly people: Evidence from the Spanish longitudinal study of aging.

OBJECTIVES: Depression and loneliness are highly prevalent in old age. Moreover these mental health symptoms adversely affect the verbal fluency of the elderly. We examined the relationship between depression and loneliness with verbal fluency in people aged 50 years or older. METHOD: Research data were collected during the pilot study of the Longitudinal Aging Study in Spain (ELES) in which a representative sample of non-institutionalized Spanish older people was assessed. Here, the cross-sectional data for 962 participants were analysed using hierarchical regressions, controlling for age, education level, overall cognitive functioning, social networks and satisfaction with family. RESULTS: Higher levels of cognitive functioning were associated with higher verbal fluency. Females showed higher levels of phonological fluency. Neither depression nor loneliness were significant predictors of phonological fluency but loneliness was a significant predictor of semantic fluency. For mild levels of loneliness, the rate of decline in semantic fluency slows in the oldest ages. In contrast, for severe loneliness the rate of decline in semantic fluency increases in the oldest ages. CONCLUSIONS: Depressive symptoms, loneliness and cognitive impairment are all prominent in ageing and therefore their impact on ageing needs to be better understood. Early detection of loneliness, along with the implementation of intervention for individuals diagnosed with loneliness is advisable in order to avoid negative repercussions for the verbal fluency of these individuals.

The role of HFE genotype in macrophage phenotype.

BACKGROUND: Iron regulation is essential for cellular energy production. Loss of cellular iron homeostasis has critical implications for both normal function and disease progression. The H63D variant of the HFE gene is the most common gene variant in Caucasians. The resulting mutant protein alters cellular iron homeostasis and is associated with a number of neurological diseases and cancer. In the brain, microglial and infiltrating macrophages are critical to maintaining iron homeostasis and modulating inflammation associated with the pathogenic process in multiple diseases. This study addresses whether HFE genotype affects macrophage function and the implications of these findings for disease processes. METHODS: Bone marrow macrophages were isolated from wildtype and H67D HFE knock-in mice. The H67D gene variant in mice is the human equivalent of the H63D variant. Upon differentiation, the macrophages were used to analyze iron regulatory proteins, cellular iron release, migration, phagocytosis, and cytokine expression. RESULTS: The results of this study demonstrate that the H67D HFE genotype significantly impacts a number of critical macrophage functions. Specifically, fundamental activities such as proliferation in response to iron exposure, L-ferritin expression in response to iron loading, secretion of BMP6 and cytokines, and migration and phagocytic activity were all found to be impacted by genotype. Furthermore, we demonstrated that exposure to apo-Tf (iron-poor transferrin) can increase the release of iron from macrophages. In normal conditions, 70% of circulating transferrin is unsaturated. Therefore, the ability of apo-Tf to induce iron release could be a major regulatory mechanism for iron release from macrophages. CONCLUSIONS: These studies demonstrate that the HFE genotype impacts fundamental components of macrophage phenotype that could alter their role in degenerative and reparative processes in neurodegenerative disorders.

What Predicts What? Self-Reported and Behavioral Impulsivity and High-Risk Patterns of Alcohol Use in Spanish Early Adolescents: A 2-Year Longitudinal Study.

BACKGROUND: The directionality of the relationship between impulsivity and heavy drinking patterns remains unclear. Recent research suggests it could be reciprocal and depends on different facets of impulsivity and different patterns of drinking. The aim of this study was to analyze this potential reciprocal relationship between self-reported and behavioral measures of impulsivity and sensation seeking with specific patterns of heavy drinking in a sample of Spanish adolescents across 2 years. METHODS: The study has a cross-lagged prospective design in which participants were evaluated 3 times over 2 years (once a year). Participants were 1,430 adolescents (53.9% male; mean age at study commencement = 13.02, SD = 0.51) from 22 secondary schools in Spain. Computerized versions of the following instruments were used: 2 subscales of Impulsive Sensation Seeking, 2 behavioral measures (Stroop Test and Delay Discounting [DD] task), frequency of intoxication episodes (IE), and the Rutgers Alcohol Problem Index to evaluate alcohol-related problems (ARP). Random intercepts cross-lagged panel models of reciprocal relationships between impulsivity measures and alcohol use outcomes were used. RESULTS: Individual levels of self-reported impulsivity and sensation seeking significantly predicted prospective involvement in IE and ARP. Performance in behavioral measures (Stroop Test and DD) did not predict subsequent heavy drinking or alcohol problems. No measure of drinking was found to be a significant predictor of prospective changes in impulsivity. CONCLUSIONS: Within-person levels of self-reported impulsivity and sensation seeking significantly predicted further heavy drinking from as early as 13 years old, whereas behavioral measures were not predictive. In our study, neither IE nor ARP predicted prospective changes in impulsivity. Further studies should address additional specific relationships between facets of impulsivity and specific outcomes of heavy drinking.

Iowa Stream Nitrate, Discharge and Precipitation: 30-Year Perspective.

We evaluated Iowa Department of Natural Resources nitrate (NO3-N) and US Geological Survey hydrological data from 1987 to 2016 in nine agricultural watersheds to assess how transport of this pollutant has changed in the US state of Iowa. When the first 15 years of the 30-year water-quality record is compared to the second 15 years (1987-2001 and 2002-2016), three different metrics used to quantify NO3-N transport all indicate levels of this pollutant are increasing. Yield of NO3-N (kg ha-1) averaged 18% higher in the second 15 years, while flow-weighted average concentrations (mg L-1) were 12% higher. We also introduced the new metric of NO3-N yield (g ha-1) per mm precipitation to assess differences between years and watersheds, which averaged 21 g NO3-N ha-1 per 1 mm of precipitation across all watersheds and was 13% higher during the second half of the record. These increases of NO3-N occurred within a backdrop of increasing wetness across Iowa, with precipitation and discharge levels 8 and 16% higher in the last half of the record, indicating how NO3-N transport is amplified by increasing precipitation levels. The implications of this are that in future climate scenarios where rainfall is more abundant, detaining water and increasing evapotranspiration within the cropping system will be necessary to control NO3-N losses. Land use changes that include use of cover crops, living mulches, and perennial plants should be expanded to improve water quality and affect the water balance within agricultural basins.

Regulatory mechanisms for iron transport across the blood-brain barrier.

Many critical metabolic functions in the brain require adequate and timely delivery of iron. However, most studies when considering brain iron uptake have ignored the iron requirements of the endothelial cells that form the blood-brain barrier (BBB). Moreover, current models of BBB iron transport do not address regional regulation of brain iron uptake or how neurons, when adapting to metabolic demands, can acquire more iron. In this study, we demonstrate that both iron-poor transferrin (apo-Tf) and the iron chelator, deferoxamine, stimulate release of iron from iron-loaded endothelial cells in an in vitro BBB model. The role of the endosomal divalent metal transporter 1 (DMT1) in BBB iron acquisition and transport has been questioned. Here, we show that inhibition of DMT1 alters the transport of iron and Tf across the endothelial cells. These data support an endosome-mediated model of Tf-bound iron uptake into the brain and identifies mechanisms for local regional regulation of brain iron uptake. Moreover, our data provide an explanation for the disparity in the ratio of Tf to iron transport into the brain that has confounded the field.