Earliest known hominin activity in the Philippines by 709 thousand years ago.

Over 60 years ago, stone tools and remains of megafauna were discovered on the Southeast Asian islands of Flores, Sulawesi and Luzon, and a Middle Pleistocene colonization by Homo erectus was initially proposed to have occurred on these islands1-4. However, until the discovery of Homo floresiensis in 2003, claims of the presence of archaic hominins on Wallacean islands were hypothetical owing to the absence of in situ fossils and/or stone artefacts that were excavated from well-documented stratigraphic contexts, or because secure numerical dating methods of these sites were lacking. As a consequence, these claims were generally treated with scepticism 5 . Here we describe the results of recent excavations at Kalinga in the Cagayan Valley of northern Luzon in the Philippines that have yielded 57 stone tools associated with an almost-complete disarticulated skeleton of Rhinoceros philippinensis, which shows clear signs of butchery, together with other fossil fauna remains attributed to stegodon, Philippine brown deer, freshwater turtle and monitor lizard. All finds originate from a clay-rich bone bed that was dated to between 777 and 631 thousand years ago using electron-spin resonance methods that were applied to tooth enamel and fluvial quartz. This evidence pushes back the proven period of colonization 6 of the Philippines by hundreds of thousands of years, and furthermore suggests that early overseas dispersal in Island South East Asia by premodern hominins took place several times during the Early and Middle Pleistocene stages1-4. The Philippines therefore may have had a central role in southward movements into Wallacea, not only of Pleistocene megafauna 7 , but also of archaic hominins.

The impact of temperature on vascular function in connection with vascular laser treatment.

Pulsed dye lasers are used effectively in the treatment of psoriasis with long remission time and limited side effects. It is, however, not completely understood which biological processes underlie its favorable outcome. Pulsed dye laser treatment at 585-595 nm targets hemoglobin in the blood, inducing local hyperthermia in surrounding blood vessels and adjacent tissues. While the impact of destructive temperatures on blood vessels has been well studied, the effects of lower temperatures on the function of several cell types within the blood vessel wall and its periphery are not known. The aim of our study is to assess the functionality of isolated blood vessels after exposure to moderate hyperthermia (45 to 60°C) by evaluating the function of endothelial cells, smooth muscle cells, and vascular nerves. We measured blood vessel functionality of rat mesenteric arteries (n=19) by measuring vascular contraction and relaxation before and after heating vessels in a wire myograph. To this end, we elicited vascular contraction by addition of either high potassium solution or the thromboxane analogue U46619 to stimulate smooth muscle cells, and electrical field stimulation (EFS) to stimulate nerves. For measurement of endothelium-dependent relaxation, we used methacholine. Each vessel was exposed to one temperature in the range of 45-60°C for 30 seconds and a relative change in functional response after hyperthermia was determined by comparison with the response per stimulus before heating. Non-linear regression was used to fit our dataset to obtain the temperature needed to reduce blood vessel function by 50% (Half maximal effective temperature, ET50). Our findings demonstrate a substantial decrease in relative functional response for all three cell types following exposure to 55°C-60°C. There was no significant difference between the ET50 values of the different cell types, which was between 55.9°C and 56.9°C (P>0.05). Our data show that blood vessel functionality decreases significantly when exposed to temperatures between 55°C-60°C for 30 seconds. The results show functionality of endothelial cells, smooth muscle cells, and vascular nerves is similarly impaired. These results help to understand the biological effects of hyperthermia and may aid in tailoring laser and light strategies for selective photothermolysis that contribute to disease modification of psoriasis after pulsed dye laser treatment.

Treating eating disorders by professionals with similar experiences: A systematic review.

OBJECTIVE: Although a significant number of professionals who provide eating disorder (ED) treatment have lived experience with an ED in the past, there is no consensus on whether these professionals should use these experiences in treatment. This review aims to evaluate current literature on recovered professionals with an ED past treating ED patients, unravelling advantages and disadvantages in treatment, the impact on professionals and their surroundings, and implications for practice. METHOD: A systematic literature search was conducted which included 10 articles. We analysed qualitative data through a systematic synthesis. Strength of evidence was calculated for each subtheme. RESULTS: Three themes and 14 subthemes were divided into categories. The category 'treatment (patient-professional interaction)' was divided into: advantages, disadvantages and other implications for treatment. Additionally, the category 'professionals themselves' included subthemes that directly impact or relate to ED professionals: recovery as a non-linear process, the significant role of self-care and adverse feelings of professionals. Finally, the category 'work settings' included: company culture and training, supervision and professional development. DISCUSSION: Recovered ED professionals are a promising addition to ED treatment due to the enhanced expertise of the professional. However, attention should be paid to the risk of distorted boundaries between patient and professional.

An early modern human presence in Sumatra 73,000-63,000 years ago.

Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka) and in island southeast Asia (ISEA) before 60 ka (93-61 ka) predates accepted archaeological records of occupation in the region. Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal or non-skeletal evidence. AMH evidence from this period is rare and lacks robust chronologies owing to a lack of direct dating applications, poor preservation and/or excavation strategies and questionable taxonomic identifications. Lida Ajer is a Sumatran Pleistocene cave with a rich rainforest fauna associated with fossil human teeth. The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel-dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations, palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA. Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.

Quality controls on cord blood unit contiguous segments: recommendation of the SFGM-TC.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. Literature and intra-laboratories studies suggest that attached segment is representative of cord blood unit (CBU). Nevertheless, some discrepancies have been observed when analyzing large data registries. To address these issues, we have listed recommendations to increase the standardization of segment processing and quality control (QC), information on units of measurement and specifications and action to be taken in case of out of specifications QC results on segment.

Genomic analyses elucidate S-locus evolution in response to intra-specific losses of distyly in Primula vulgaris.

Distyly, a floral dimorphism that promotes outcrossing, is controlled by a hemizygous genomic region known as the S-locus. Disruptions of genes within the S-locus are responsible for the loss of distyly and the emergence of homostyly, a floral monomorphism that favors selfing. Using whole-genome resequencing data of distylous and homostylous individuals from populations of Primula vulgaris and leveraging high-quality reference genomes of Primula we tested, for the first time, predictions about the evolutionary consequences of transitions to selfing on S-genes. Our results reveal a previously undetected structural rearrangement in CYPᵀ associated with the shift to homostyly and confirm previously reported, homostyle-specific, loss-of-function mutations in the exons of the S-gene CYPᵀ. We also discovered that the promoter and intronic regions of CYPᵀ in distylous and homostylous individuals are conserved, suggesting that down-regulation of CYPᵀ via mutations in its promoter and intronic regions is not a cause of the shift to homostyly. Furthermore, we found that hemizygosity is associated with reduced genetic diversity in S-genes compared with their paralogs outside the S-locus. Additionally, the shift to homostyly lowers genetic diversity in both the S-genes and their paralogs, as expected in primarily selfing plants. Finally, we tested, for the first time, long-standing theoretical models of changes in S-locus genotypes during early stages of the transition to homostyly, supporting the assumption that two copies of the S-locus might reduce homostyle fitness.

[Modeling T2 high severe asthma using human induced pluripotent stem cells (hiPSC)]. / Modélisation de l'asthme sévère par la technologie des cellules humaines souches pluripotentes induites (hiPSC).

Severe asthma patients with persistent airflow obstruction are characterized by functional obstruction due to mucus plugs containing mucins, fibrin, and eosinophil derived Charcot- Leyden crystals. The molecular mechanisms underlying this endotype are not clearly understood. Developing new models is crucial to respiratory research insofar as critical differences exist between human and rodent airway epithelium. We (and other teams) have shown that it is possible to reconstitute in vitro a complex and functional airway epithelium displaying all the features described in vivo from human-induced pluripotent stem cells (hiPSC). Our aim is to establish a human in vitro model of severe asthma that will recapitulate airway epithelium remodeling and mucus plugs.

[Production of innervated bronchial epithelium from a blood sample]. / Fabrication d'un épithélium bronchique innervé à partir d'une prise de sang.

Asthma is a frequent respiratory disease, with severe asthma occurring in 3 to 5% of cases. Chronic inflammation of the bronchial epithelium is essential to its pathophysiology. When activated by the bronchial environment, the peripheral sensory nervous system contributes to inflammation of the airways. However, due to a lack of reliable models, the mechanisms of action remain largely unknown. Using induced pluripotent stem cells reprogrammed from blood cells, we have set up a model of bronchial epithelium innervated by sensory neurons. This model will ensure better understanding of the mechanisms of action underlying neurogenic inflammation.

TB/HIV integration at primary care level: A quantitative assessment at 3 clinics in Johannesburg, South Africa.

BACKGROUND: In 2004 the World Health Organization WHO) released the Interim Policy on Collaborative TB/ HIV activities. According to the policy, for people living with HIV (PLWH), activities include intensified case finding, isoniazid preventive therapy (IPT) and infection control. For TB patients, activities included HIV counselling and testing HCT), prevention messages, and cotrimoxazole preventive therapy (CPT), care and support, and antiretroviral therapy ART) for those with HIV-associated TB. While important progress has been made in implementation, targets of the WHO Global Plan to Stop TB have not been reached. OBJECTIVE: To quantify TB/HIV integration at 3 primary healthcare clinics in Johannesburg, South Africa. METHODS: Routinely collected TB and HIV data from the HCT register, TB 'suspect' register, TB treatment register, clinic files and HIV electronic database, collected over a 3-month period, were reviewed. RESULTS: Of 1 104 people receiving HCT: 306 (28%) were HIV-positive; a CD4 count was documented for 57%; and few received TB screening or IPT. In clinic encounters among PLWH, 921 (15%) had documented TB symptoms; only 10% were assessed by smear microscopy, and few asymptomatic PLWH were offered IPT. Infection control was poorly documented and implemented. HIV status was documented for 155 (75%) of the 208 TB patients; 90% were HIV-positive and 88% had a documented CD4 count. Provision of CPT and ART was poorly documented. CONCLUSION: The coverage of most TB/HIV collaborative activities was below Global Plan targets. The lack of standardised recording tools and incomplete documentation impeded assessment at facility level and limited the accuracy of compiled data.

Impact of inspiratory muscle training in patients with COPD: what is the evidence?

A meta-analysis including 32 randomised controlled trials on the effects of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients was performed. Overall and subgroup analyses with respect to training modality (strength or endurance training, added to general exercise training) and patient characteristics were performed. Significant improvements were found in maximal inspiratory muscle strength (P(I,max); +13 cmH2O), endurance time (+261 s), 6- or 12-min walking distance (+32 and +85 m respectively) and quality of life (+3.8 units). Dyspnoea was significantly reduced (Borg score -0.9 point; Transitional Dyspnoea Index +2.8 units). Endurance exercise capacity tended to improve, while no effects on maximal exercise capacity were found. Respiratory muscle endurance training revealed no significant effect on P(I,max), functional exercise capacity and dyspnoea. IMT added to a general exercise programme improved P(I,max) significantly, while functional exercise capacity tended to increase in patients with inspiratory muscle weakness (P(I,max) <60 cmH2O). IMT improves inspiratory muscle strength and endurance, functional exercise capacity, dyspnoea and quality of life. Inspiratory muscle endurance training was shown to be less effective than respiratory muscle strength training. In patients with inspiratory muscle weakness, the addition of IMT to a general exercise training program improved P(I,max) and tended to improve exercise performance.

Transcriptome analysis reveals dialogues between human trophectoderm and endometrial cells during the implantation period.

BACKGROUND: Crosstalk between human trophectoderm (TE) and endometrial cells during the implantation window is a complex and not well-understood process. The aims of this study were (i) to evaluate the global gene expression profile in TE cells from Day 5 human blastocysts issued from IVF, (ii) to compare these data with the transcriptomic profile of endometrial cells in stimulated cycles for IVF and (iii) to identify potential early dialogues between maternal and embryonic cells during the implantation window. METHODS: Endometrial biopsies (n = 18) from normal responder patients were performed on the day of embryo transfer (Day 5 after human chorionic gonadotrophin administration). TE biopsies from five blastocysts donated for research purposes were mechanically extracted. DNA microarray analysis was carried out to identify the specific gene expression profiles and the biological pathways activated during the implantation window in endometrial and TE cells. RESULTS: Several cytokines (such as PDGFA, placenta growth factor, IGF2BP1 and IGF2BP3) were up-regulated in human TE cells, whereas some of the corresponding receptors (PDGFRA and KDR) were over-expressed in the receptive endometrium, suggesting that these molecules are involved in the early dialogue between blastocyst and maternal endometrial cells. In addition, several adhesion molecules and extracellular matrix proteins (MCAM, ITGAE and LAMA1) were also over-expressed in the TE, while others (ALCAM, CEACAM1, PECAM1, ITGB8 and LAMA2) were restricted to the receptive endometrium. CONCLUSION: The present study shows that several growth factors, cytokines, integrins and adhesion molecules are expressed in the TE and endometrium at the time of implantation. These results could contribute to the understanding of the mechanisms involved in the early dialogue between blastocyst and endometrium during implantation. Such results should be confirmed by further studies.

[Modelling the bronchial epithelium in chronic obstructive pulmonary disease using human induced pluripotential stem cells]. / Modélisation de l'épithélium bronchique dans la bronchopneumopathie chronique obstructive par les cellules souches pluripotentes induites humaines.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease leading to irreversible destruction of the terminal bronchioles. Although the precise patho-physiological mechanisms remain to be elucidated, the bronchial epithelium seems to play a pivotal role in the disease. Recent studies have highlighted a great heterogeneity among COPD patients, with various disease courses including, in about half the cases, an origin in childhood. Modelling of COPD is a major goal but currently available models are imperfect. Our work aims to create a new in vitro cellular model to study the pathology of the disease. The differentiation of human induced pluripotential stem cells (hiPSCs) in bronchial epithelium is a step towards a better understanding of the developmental origin and the identification of new therapeutic targets.

Taphonomy and chronosequence of the 709 ka Kalinga site formation (Luzon Island, Philippines).

The recently described site of Kalinga in the Philippines adds to our understanding of Early-Middle Pleistocene hominin behaviour. Yet, disentangling the natural from the anthropogenic modifications that have taken place in such an old archaeological site is challenging. In this paper we use a set of taphonomic tools at hand to rectify the distortion made by natural processes during the formation of the Kalinga site. From the description of the ribs completeness, surface damages and scattering in the excavation, one can reconstruct the butchery, transport and deposition sequence of the rhino carcass and its post-depositional disturbances and diagenetic evolution of the site. We conclude that the rhino and the stone artefacts potentially used to deflesh the carcass were transported by a mudflow from its butchery place over a few meters only and got stuck and mixed with an older faunal assemblage that was transported by a small stream.

Identification of new biomarkers of human endometrial receptivity in the natural cycle.

BACKGROUND: Identification of new markers assessing endometrial receptivity may help in improving the clinical outcome of IVF. This study aimed at identifying genes expressed in human endometrium during the implantation window that could be used as such markers. METHODS: A series of normoresponder patients (n = 31) underwent endometrial biopsies (n = 62, 2 per patient) during the early secretory phase, 2 days after the LH surge (LH + 2) and the mid-secretory phase (LH + 7) of the same natural cycle that preceded a new ICSI attempt for male infertility factor. Samples were analyzed using DNA microarrays and gene expression profiles at the time of the implantation window were computed. Systems biology analysis allowed the identification of biological pathways that were over-represented in this signature. A new approach for class prediction applied to microarray experiments was then used to identify biomarkers putatively involved in endometrial receptiveness. RESULTS: Five genes expressed during the implantation window were all up-regulated in the LH + 7 samples compared with LH + 2 [laminin beta3 (P = 0.002), microfibril-associated protein 5 (P = 0.009), angiopoietin-like 1 (P = 0.005), endocrine gland-derived vascular endothelial growth factor (P = 0.049) and nuclear localized factor 2 (P = 0.007)]. Increased expression was validated by quantitative RT-PCR. CONCLUSIONS: Five genes have been identified for the first time as being up-regulated during the implantation window and are proposed as new biomarkers for exploration of endometrial receptiveness. As the endometrial biopsy procedure can be performed during a natural cycle, it would be worth testing this approach as a novel strategy in patients with poor implantation after IVF or ICSI.

Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients.

BACKGROUND: The adjunction of exogenous hormones for controlled ovarian stimulation (COS) may alter endometrial receptiveness. In order to identify the genes misregulated under COS, we compared the endometrium gene expression profiles, from the same patients, in a natural cycle and in a subsequent COS cycle. METHODS: For the same normal-responder patients (n = 21), endometrial biopsies (n = 84) were collected during the pre-receptive (LH + 2) and receptive stages (LH + 7) of a natural cycle and, subsequently, on oocyte retrieval day (hCG + 2) and on transfer day (hCG + 5) of a stimulated cycle. Samples were analyzed using DNA microarrays. Gene expression profiles and biological pathways involved in endometrial receptivity were analyzed. RESULTS: Although endometrium transition profiles from pre-receptive to receptive phases are similar between patients, COS regimens alter endometrial receptivity in comparison with natural cycle. Under COS conditions, two endometrial profiles were identified and were associated either with a moderately altered receptivity profile for the majority of the patients or a strongly altered profile for a sub-category of patients. The receptive endometrium transcription profile under COS was defective for biological functions such as TGFbeta signaling, leukocyte transendothelial migration and the cell cycle. CONCLUSIONS: Gonadotrophin treatments in COS cycles led to disruptions of the transcriptional activation of genes involved in normal endometrial receptivity. We propose that when the receptiveness of the endometrium is seriously compromised by the COS protocol, fresh embryo replacement should be cancelled, the embryo frozen and thawed embryo replacement should be performed under natural cycles.

LH/hCGR gene expression in human cumulus cells is linked to the expression of the extracellular matrix modifying gene TNFAIP6 and to serum estradiol levels on day of hCG administration.

BACKGROUND: Recent studies suggest a role for luteinizing hormone and human chorionic gonadotrophin receptor (LH/hCGR) signalling in the regulation of the oocyte-cumulus oophorus cell interplay. The present study aimed at assessing the LH/hCGR gene expression in cumulus cells (CCs) surrounding oocytes in patients undergoing controlled ovarian hyperstimulation (COS) before ICSI and to relate the LH/hCGR expression to other COS quality parameters. METHODS: CCs from single oocytes of normal responder patients were analysed by DNA microarrays. Concomitantly, estradiol levels on the day of hCG administration, CC morphology, total collected oocyte and metaphase II oocyte number were assessed in relation to LH/hCGR gene expression in CC. RESULTS: The transcriptome analysis of CC indicated a variable expression of LH/hCGR among the patients and intra-patients. LH/hCGR mRNA expression was negatively correlated with serum estradiol level on the day of hCG administration. Eighty-five genes were significantly modulated between CCs from patients with a high and a low LH/hCGR expression. These genes are involved principally in steroid metabolism and in the ovulation process and include TNFAIP6, a gene expressed during CC-oocyte complex (COC) expansion. There were no significant differences in LH/hCGR gene expression profile between COS protocols. CONCLUSIONS: LH/hCGR is expressed in CC under COS conditions. LH/hCGR expression level is associated with TNFAIP6 gene expression and negatively correlated with serum estradiol level on the day of hCG administration.

Relevance of aquatic environments for hominins: a case study from Trinil (Java, Indonesia).

Knowledge about dietary niche is key to understanding hominin evolution, since diet influences body proportions, brain size, cognition, and habitat preference. In this study we provide ecological context for the current debate on modernity (or not) of aquatic resource exploitation by hominins. We use the Homo erectus site of Trinil as a case study to investigate how research questions on possible dietary relevance of aquatic environments can be addressed. Faunal and geochemical analysis of aquatic fossils from Trinil Hauptknochenschicht (HK) fauna demonstrate that Trinil at approximately 1.5Ma contained near-coastal rivers, lakes, swamp forests, lagoons, and marshes with minor marine influence, laterally grading into grasslands. Trinil HK environments yielded at least eleven edible mollusc species and four edible fish species that could be procured with no or minimal technology. We demonstrate that, from an ecological point of view, the default assumption should be that omnivorous hominins in coastal habitats with catchable aquatic fauna could have consumed aquatic resources. The hypothesis of aquatic exploitation can be tested with taphonomic analysis of aquatic fossils associated with hominin fossils. We show that midden-like characteristics of large bivalve shell assemblages containing Pseudodon and Elongaria from Trinil HK indicate deliberate collection by a selective agent, possibly hominin.

[Human embryonic stem cells: from the human embryo transgressed to the regenerative medicine of tomorrow]. / Les cellules souches embryonnaires humaines: de la transgression de l'embryon humain à la médecine régénératrice de demain.

Human embryonic stem cells (hESC) are derived from the inner cell mass (ICM) of the human blastocyst at day 5 or 6 of the early embryo development. These cells display two cardinal features: they are able to differentiate into cell types from many if not all human tissue (pluripotency) and they proliferate strongly and indefinitely without senescence in vitro. Therefore, hESC are a source of choice for stem cells for regenerative medicine and are a reference model to study the biology of pluripotency. Since 2004, the French law (loi de Bioéthique) authorizes hESC research under certain conditions.

67Gallium citrate scintigraphy to assess metastatic spread in a dog with an oral melanoma.

Gallium scintigraphy was used to evaluate therapeutic response in a 10-year-old, male, Dutch sheepdog, suffering from an oral melanoma. Treatment was performed with a combination of carboplatin and hypofractionated radiation. Nineteen weeks after radiation therapy, the left submandibular lymph node was surgically removed because of metastatic disease. Thirty weeks after radiation therapy, 67Gallium scintigraphy was performed to assess for residual disease and metastasis. Increased uptake in the right submandibular lymph node area was noted and identified as a melanoma metastasis on cytology. Surgical excision was performed. Twenty-one weeks later, the dog was euthanased because of advanced pulmonary metastases. This report of a case of oral melanoma illustrates the advantages of 67Gallium scintigraphy in monitoring for the presence of metastatic disease and effectiveness of therapy.

A non-invasive test for assessing embryo potential by gene expression profiles of human cumulus cells: a proof of concept study.

Identification of new criteria for embryo quality is required to improve the clinical outcome of in vitro fertilization. The aim of this study was to determine the gene expression profile of cumulus cells (CC) surrounding the oocyte as biomarkers for embryo potential and to identify genes to be used as prognostic indicators of successful pregnancy. CC from single oocytes were analysed using DNA microarrays. Gene expression profiles of CC surrounding the oocyte associated with good embryonic quality and pregnancy outcome were computed. We observed that CC issued from oocytes that developed into embryos with a good morphology had differing gene expression profile according to the pregnancy outcome of the embryo. We demonstrated that the expression of BCL2L11, PCK1 and NFIB in CC is significantly correlated with embryo potential and successful pregnancy. These results were confirmed by quantitative RT-PCR. The gene expression profiling of human CC correlates with embryo potential and pregnancy outcome. BCL2L11, PCK1 and NFIB genes are proposed as biomarkers for predicting pregnancy. Our findings suggest a non-invasive approach, offering a new potential strategy for competent embryo selection. This approach should be validated in single-embryo transfer programmes.