Author Correction: New infant cranium from the African Miocene sheds light on ape evolution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

New infant cranium from the African Miocene sheds light on ape evolution.

The evolutionary history of extant hominoids (humans and apes) remains poorly understood. The African fossil record during the crucial time period, the Miocene epoch, largely comprises isolated jaws and teeth, and little is known about ape cranial evolution. Here we report on the, to our knowledge, most complete fossil ape cranium yet described, recovered from the 13 million-year-old Middle Miocene site of Napudet, Kenya. The infant specimen, KNM-NP 59050, is assigned to a new species of Nyanzapithecus on the basis of its unerupted permanent teeth, visualized by synchrotron imaging. Its ear canal has a fully ossified tubular ectotympanic, a derived feature linking the species with crown catarrhines. Although it resembles some hylobatids in aspects of its morphology and dental development, it possesses no definitive hylobatid synapomorphies. The combined evidence suggests that nyanzapithecines were stem hominoids close to the origin of extant apes, and that hylobatid-like facial features evolved multiple times during catarrhine evolution.

Morphological affinities of a fossil ulna (KNM-WS 65401) from Buluk, Kenya.

The morphological affinities of a primate proximal ulna (KNM-WS 65401) recovered from the late Early Miocene site Buluk, Kenya, are appraised. Nineteen three-dimensional landmarks on ulnae from 36 extant anthropoid species (n = 152 individuals) and KNM-WS 65401, as well as a subset of 14 landmarks on six ulnae belonging to other East African Miocene catarrhine taxa, were collected. To quantify ulnar shape, three-dimensional geometric morphometric techniques were used and linear dimensions commonly cited in the literature were derived from the landmark data. KNM-WS 65401 is situated between monkeys and hominoids in the principal components morphospace. KNM-WS 65401 shares features such as a short olecranon process, broad trochlear notch, and laterally oriented radial notch with extant hominoids, whereas features such as an anteriorly directed trochlear notch and flat, proximodistally elongated, and anteroposteriorly narrow radial notch are shared with extant monkeys. Principal component scores and linear metrics generally align KNM-WS 65401 with both suspensors and arboreal quadrupeds, but quadratic and linear discriminant analyses of principal component score data provide posterior probabilities of 80% and 83%, respectively, for assignment of KNM-WS 65401 to the suspensory group. Compared with fossil ulnae from other Miocene primates, KNM-WS 65401 is morphologically most distinct from KNM-LG 6, attributed to Dendropithecus macinnesi, and morphologically most similar to KNM-WK 16950R, attributed to Turkanapithecus kalakolensis. The KNM-WS 65401 individual likely possessed more enhanced capabilities for elbow joint extension, perhaps during suspensory behaviors, compared with other Miocene primates in the sample.

Primitive Old World monkey from the earliest Miocene of Kenya and the evolution of cercopithecoid bilophodonty.

Old World monkeys (Cercopithecoidea) are a highly successful primate radiation, with more than 130 living species and the broadest geographic range of any extant group except humans. Although cercopithecoids are highly variable in habitat use, social behavior, and diet, a signature dental feature unites all of its extant members: bilophodonty (bi: two, loph: crest, dont: tooth), or the presence of two cross-lophs on the molars. This feature offers an adaptable Bauplan that, with small changes to its individual components, permits its members to process vastly different kinds of food. Old World monkeys diverged from apes perhaps 30 million years ago (Ma) according to molecular estimates, and the molar lophs are sometimes incompletely developed in fossil species, suggesting a mosaic origin for this key adaptation. However, critical aspects of the group's earliest evolution remain unknown because the cercopithecoid fossil record before ∼18 Ma consists of only two isolated teeth, one from Uganda and one from Tanzania. Here we describe a primitive Old World monkey from Nakwai, Kenya, dated at ∼22 Ma, that offers direct evidence for the initial key steps in the evolution of the cercopithecoid dentition. The simple dentition and absence of bilophodonty in the Nakwai monkey indicate that the initial radiation of Old World monkeys was first characterized by a reorganization of basic molar morphology, and a reliance on cusps rather than lophs suggests frugivorous diets and perhaps hard object feeding. Bilophodonty evolved later, likely in response to the inclusion of leaves in the diet.

Using the "Hallmarks of Cancer" as a framework for medical students and clinicians to understand oncogenesis.

Two landmark reviews in 2000 and 2011, describing the "Hallmarks of Cancer", provided a new and valuable framework for understanding the process of oncogenesis as a progressive accumulation of characteristics, each characteristic essential for a tumor to become a clinically relevant, metastatic neoplasia. The process of oncogenesis is conceptually important for physicians, both for clinical reasons, and for their engagement in oncological research. However, these reviews are written for specialists in the field, which presents barriers for novice learners. Therefore, to allow students, and also clinicians external to the oncological field, to access this valuable framework for understanding oncogenesis, we have created a condensed summary of the original reviews. Our institutions use a "flipped" approach to the large-group components of our preclinical education. We have successfully used our Hallmarks of Cancer summary as the prework for sessions on oncogenesis for five years at one institution, and nine years at the other, typically at the end of cancer blocks within integrated, multidisciplinary courses. We report here survey results indicating learners strongly appreciate the summary as both preparation material for participation in relevant flipped classroom sessions, and as a general review of oncogenesis. This condensed summary of the original Hallmarks of Cancer reviews makes many of the key concepts of oncogenesis available to medical students in their preclinical years, as well as to physicians outside the field of oncology.

New dentognathic fossils of Noropithecus bulukensis (Primates, Victoriapithecidae) from the late Early Miocene of Buluk, Kenya.

The late Early Miocene site of Buluk, Kenya, has yielded fossil remains of several catarrhine primates, including 16 dentognathic specimens of the stem cercopithecoid Noropithecus bulukensis. With the exception of the large sample of Victoriapithecus macinnesi from the middle Miocene of Maboko Island, Kenya, the majority of stem cercopithecoid taxa are represented by small sample sizes. We describe and analyze 91 new cercopithecoid fossils collected from Buluk between 2004 and 2018, including several previously undescribed tooth positions for N. bulukensis, and provide the first evaluation of dental metric and morphological variation in this sample. The results show that the expanded Buluk sample exhibits high levels of dental variation in the postcanine tooth row, similar to V. macinnesi at Maboko, but this variation is consistent with a single-species hypothesis. Subtle differences in the shape of the I1, breadth of the C1 and P3, relative breadth of M1, upper and lower molar distal shelf lengths, the degree of M2 basal flare, and a less-developed lower molar distal lophid differentiate the dentition of N. bulukensis from V. macinnesi. Although differences exist between the N. bulukensis and V. macinnesi dental samples, the high degree of variation within each sample complicates the identification of many individual specimens. New partial maxillae and mandibles allow reassessment of previously described diagnostic differences between N. bulukensis and V. macinnesi, negating upper molar arcade shape as a diagnostic feature and confirming the existence of differences in mandibular symphyseal morphology. Overall, new fossils from Buluk provide new evidence of the dentognathic anatomy of a medium-sized cercopithecoid that coexisted with a diverse group of noncercopithecoid catarrhines at the end of the early Miocene.

Age, wage, and job placement: older women's experiences entering the retail sector.

Older women seeking employment often find opportunities limited to low-wage jobs, such as those in retail. We report findings about job placement and starting wages for hourly workers hired at a women's apparel retailer from August 2006 to December 2009. We examine competing hypotheses regarding the role of age in explaining women's job placement and starting wages. Although newly hired women age 55+ earn higher wages and are placed in higher-quality jobs than the youngest women (ages 18-22), they are less likely to be placed in better-quality jobs than their midlife counterparts. Overall, wage differences are largely explained by job quality.

Serum indoleamine 2,3-dioxygenase activity is associated with reduced immunogenicity following vaccination with MVA85A.

BACKGROUND: There is an urgent need for improved vaccines to protect against tuberculosis. The currently available vaccine Bacille Calmette-Guerin (BCG) has varying immunogenicity and efficacy across different populations for reasons not clearly understood. MVA85A is a modified vaccinia virus expressing antigen 85A from Mycobacterium tuberculosis which has been in clinical development since 2002 as a candidate vaccine to boost BCG-induced protection. A recent efficacy trial in South African infants failed to demonstrate enhancement of protection over BCG alone. The immunogenicity was lower than that seen in UK trials. The enzyme Indoleamine 2,3-dioxygenase (IDO) catalyses the first and rate-limiting step in the breakdown of the essential amino acid tryptophan. T cells are dependent on tryptophan and IDO activity suppresses T-cell proliferation and function. METHODS: Using samples collected during phase I trials with MVA85A across the UK and South Africa we have investigated the relationship between vaccine immunogenicity and IDO using IFN-γ ELISPOT, qPCR and liquid chromatography mass spectrometry. RESULTS: We demonstrate an IFN-γ dependent increase in IDO mRNA expression in peripheral blood mononuclear cells (PBMC) following MVA85A vaccination in UK subjects. IDO mRNA correlates positively with the IFN-γ ELISPOT response indicating that vaccine specific induction of IDO in PBMC is unlikely to limit the development of vaccine specific immunity. IDO activity in the serum of volunteers from the UK and South Africa was also assessed. There was no change in serum IDO activity following MVA85A vaccination. However, we observed higher baseline IDO activity in South African volunteers when compared to UK volunteers. In both UK and South African serum samples, baseline IDO activity negatively correlated with vaccine-specific IFN-γ responses, suggesting that IDO activity may impair the generation of a CD4+ T cell memory response. CONCLUSIONS: Baseline IDO activity was higher in South African volunteers when compared to UK volunteers, which may represent a potential mechanism for the observed variation in vaccine immunogenicity in South African and UK populations and may have important implications for future vaccination strategies. TRIAL REGISTRATION: Trials are registered at ClinicalTrials.gov; UK cohort NCT00427830, UK LTBI cohort NCT00456183, South African cohort NCT00460590, South African LTBI cohort NCT00480558.

Intra- and interspecific variation in macaque molar enamel thickness.

Enamel thickness has played an important role in studies of primate taxonomy, phylogeny, and functional morphology, although its variation among hominins is poorly understood. Macaques parallel hominins in their widespread geographic distribution, relative range of body sizes, and radiation during the last five million years. To explore enamel thickness variation, we quantified average and relative enamel thickness (AET and RET) in Macaca arctoides, Macaca fascicularis, Macaca fuscata, Macaca mulatta, Macaca nemestrina, and Macaca sylvanus. Enamel area, dentine area, and enamel-dentine junction length were measured from mesial sections of 386 molars scanned with micro-computed tomography, yielding AET and RET indices. Intraspecific sex differences were not found in AET or RET. Macaca fuscata had the highest AET and RET, M. fascicularis showed the lowest AET, and M. arctoides had the lowest RET. The latitudinal distribution of macaque species was associated with AET for these six species. Temperate macaques had thicker molar enamel than did tropical macaques, suggesting that thick enamel may be adaptive in seasonal environments. Additional research is needed to determine if thick enamel in temperate macaques is a response to intensified hard-object feeding, increased abrasion, and/or a broader diet with a greater range of food material properties. The extreme ecological flexibility of macaques may prohibit identification of consistent trends between specific diets and enamel thickness conditions. Such complications of interpretation of ecological variability, dietary diversity, and enamel thickness may similarly apply for fossil Homo species.

Oldest evidence of abundant C4 grasses and habitat heterogeneity in eastern Africa.

The assembly of Africa's iconic C4 grassland ecosystems is central to evolutionary interpretations of many mammal lineages, including hominins. C4 grasses are thought to have become ecologically dominant in Africa only after 10 million years ago (Ma). However, paleobotanical records older than 10 Ma are sparse, limiting assessment of the timing and nature of C4 biomass expansion. This study uses a multiproxy design to document vegetation structure from nine Early Miocene mammal site complexes across eastern Africa. Results demonstrate that between ~21 and 16 Ma, C4 grasses were locally abundant, contributing to heterogeneous habitats ranging from forests to wooded grasslands. These data push back the oldest evidence of C4 grass-dominated habitats in Africa-and globally-by more than 10 million years, calling for revised paleoecological interpretations of mammalian evolution.

Single-subject design study of 2 types of supramalleolar orthoses for young children with down syndrome.

PURPOSE: This study examined the effects of 2 types of supramalleolar orthoses on gross motor skills of young children with Down syndrome. METHODS: Two children participated in this prospective single-subject, alternating treatment design with 3 conditions: baseline phase with shoes but without orthoses (A), first intervention phase (B1), and second intervention phase (B2). The Gross Motor Function Measure was used to collect data on motor skills. The 2-standard deviation band method was used for data analysis. RESULTS: Both children demonstrated improvement, using the SureStep compared to shoes only, and 1 child also improved with the DAFO #4. Both families chose to continue using the SureStep at the conclusion of the study. CONCLUSIONS: Orthoses for young children with Down syndrome continue to be the standard of care; however, research has yet to confirm the most effective type of orthosis or when developmentally to introduce orthoses.

Ganciclovir-resistant cytomegalovirus retinitis in a 4-month-old infant.

We present a case of ganciclovir-resistant cytomegalovirus retinitis (CMV) in a 4-month-old boy with congenital CMV infection. This case highlights the potential utility of a combination of intermittent viral load monitoring and retinal examinations in cases of congenital CMV with retinitis.

Drosophila histone deacetylase-3 controls imaginal disc size through suppression of apoptosis.

Histone deacetylases (HDACs) execute biological regulation through post-translational modification of chromatin and other cellular substrates. In humans, there are eleven HDACs, organized into three distinct subfamilies. This large number of HDACs raises questions about functional overlap and division of labor among paralogs. In vivo roles are simpler to address in Drosophila, where there are only five HDAC family members and only two are implicated in transcriptional control. Of these two, HDAC1 has been characterized genetically, but its most closely related paralog, HDAC3, has not. Here we describe the isolation and phenotypic characterization of hdac3 mutations. We find that both hdac3 and hdac1 mutations are dominant suppressors of position effect variegation, suggesting functional overlap in heterochromatin regulation. However, all five hdac3 loss-of-function alleles are recessive lethal during larval/pupal stages, indicating that HDAC3 is essential on its own for Drosophila development. The mutant larvae display small imaginal discs, which result from abnormally elevated levels of apoptosis. This cell death occurs as a cell-autonomous response to HDAC3 loss and is accompanied by increased expression of the pro-apoptotic gene, hid. In contrast, although HDAC1 mutants also display small imaginal discs, this appears to result from reduced proliferation rather than from elevated apoptosis. The connection between HDAC loss and apoptosis is important since HDAC inhibitors show anticancer activities in animal models through mechanisms involving apoptotic induction. However, the specific HDACs implicated in tumor cell killing have not been identified. Our results indicate that protein deacetylation by HDAC3 plays a key role in suppression of apoptosis in Drosophila imaginal tissue.

CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function.

The immune response of naive CD4 T cells to influenza virus is initiated in the draining lymph nodes and spleen, and only after effectors are generated do antigen-specific cells migrate to the lung which is the site of infection. The effector cells generated in secondary organs appear as multiple subsets which are a heterogeneous continuum of cells in terms of number of cell divisions, phenotype and function. The effector cells that migrate to the lung constitute the more differentiated of the total responding population, characterized by many cell divisions, loss of CD62L, down-regulation of CCR7, stable expression of CD44 and CD49d, and transient expression of CCR5 and CD25. These cells also secrete high levels of interferon gamma and reduced levels of interleukin 2 relative to those in the secondary lymphoid organs. The response declines rapidly in parallel with viral clearance, but a spectrum of resting cell subsets reflecting the pattern at the peak of response is retained, suggesting that heterogeneous effector populations may give rise to corresponding memory populations. These results reveal a complex response, not an all-or-none one, which results in multiple effector phenotypes and implies that effector cells and the memory cells derived from them can display a broad spectrum of functional potentials.

Alternative ESC and ESC-like subunits of a polycomb group histone methyltransferase complex are differentially deployed during Drosophila development.

The Extra sex combs (ESC) protein is a Polycomb group (PcG) repressor that is a key noncatalytic subunit in the ESC-Enhancer of zeste [E(Z)] histone methyltransferase complex. Survival of esc homozygotes to adulthood based solely on maternal product and peak ESC expression during embryonic stages indicate that ESC is most critical during early development. In contrast, two other PcG repressors in the same complex, E(Z) and Suppressor of zeste-12 [SU(Z)12], are required throughout development for viability and Hox gene repression. Here we describe a novel fly PcG repressor, called ESC-Like (ESCL), whose biochemical, molecular, and genetic properties can explain the long-standing paradox of ESC dispensability during postembryonic times. Developmental Western blots show that ESCL, which is 60% identical to ESC, is expressed with peak abundance during postembryonic stages. Recombinant complexes containing ESCL in place of ESC can methylate histone H3 with activity levels, and lysine specificity for K27, similar to that of the ESC-containing complex. Coimmunoprecipitations show that ESCL associates with E(Z) in postembryonic cells and chromatin immunoprecipitations show that ESCL tracks closely with E(Z) on Ubx regulatory DNA in wing discs. Furthermore, reduced escl+ dosage enhances esc loss-of-function phenotypes and double RNA interference knockdown of ESC/ESCL in wing disc-derived cells causes Ubx derepression. These results suggest that ESCL and ESC have similar functions in E(Z) methyltransferase complexes but are differentially deployed as development proceeds.

A Role for Monomethylation of Histone H3-K27 in Gene Activity in Drosophila.

Polycomb repressive complex 2 (PRC2) is a conserved chromatin-modifying enzyme that methylates histone H3 on lysine-27 (K27). PRC2 can add one, two, or three methyl groups and the fully methylated product, H3-K27me3, is a hallmark of Polycomb-silenced chromatin. Less is known about functions of K27me1 and K27me2 and the dynamics of flux through these states. These modifications could serve mainly as intermediates to produce K27me3 or they could each convey distinct epigenetic information. To investigate this, we engineered a variant of Drosophila melanogaster PRC2 which is converted into a monomethyltransferase. A single substitution, F738Y, in the lysine-substrate binding pocket of the catalytic subunit, E(Z), creates an enzyme that retains robust K27 monomethylation but dramatically reduced di- and trimethylation. Overexpression of E(Z)-F738Y in fly cells triggers desilencing of Polycomb target genes significantly more than comparable overexpression of catalytically deficient E(Z), suggesting that H3-K27me1 contributes positively to gene activity. Consistent with this, normal genomic distribution of H3-K27me1 is enriched on actively transcribed Drosophila genes, with localization overlapping the active H3-K36me2/3 chromatin marks. Thus, distinct K27 methylation states link to either repression or activation depending upon the number of added methyl groups. If so, then H3-K27me1 deposition may involve alternative methyltransferases beyond PRC2, which is primarily repressive. Indeed, assays on fly embryos with PRC2 genetically inactivated, and on fly cells with PRC2 chemically inhibited, show that substantial H3-K27me1 accumulates independently of PRC2. These findings imply distinct roles for K27me1 vs. K27me3 in transcriptional control and an expanded machinery for methylating H3-K27.

Fossil lemurs from Egypt and Kenya suggest an African origin for Madagascar's aye-aye.

In 1967 G.G. Simpson described three partial mandibles from early Miocene deposits in Kenya that he interpreted as belonging to a new strepsirrhine primate, Propotto. This interpretation was quickly challenged, with the assertion that Propotto was not a primate, but rather a pteropodid fruit bat. The latter interpretation has not been questioned for almost half a century. Here we re-evaluate the affinities of Propotto, drawing upon diverse lines of evidence to establish that this strange mammal is a strepsirrhine primate as originally suggested by Simpson. Moreover, our phylogenetic analyses support the recognition of Propotto, together with late Eocene Plesiopithecus from Egypt, as African stem chiromyiform lemurs that are exclusively related to the extant aye-aye (Daubentonia) from Madagascar. Our results challenge the long-held view that all lemurs are descended from a single ancient colonization of Madagascar, and present an intriguing alternative scenario in which two lemur lineages dispersed from Africa to Madagascar independently, possibly during the later Cenozoic.

Motor and functional outcomes of a patient post-stroke following combined activity and impairment level training.

The purpose of this single-subject report was to determine the effect of a targeted training regimen aimed at improving motor and functional outcomes for a patient with chronic deficits after stroke. A 51-year-old woman with hemiparesis, 6 months post-stroke, participated in this prospective study. During the baseline, intervention, and immediate retention phases, performance was established by using repeated measures of four dependent variables: Fugl-Meyer assessment, Berg Balance Scale, 10-meter walk, and 6-minute walk. Two standard deviation band analyses were conducted on the four dependent variables with repeated measures. The Frenchay Activities Index and step length/single-limb support time measured at baseline and immediate retention were compared. During intervention, the participant was involved in a combined treatment protocol including body weight supported (BWS) treadmill training and strengthening exercises. Results indicated significant improvements in motor activity, balance, gait speed, and endurance. Progression was found in self-perceived participation. Although an improvement in step length symmetry occurred following training, a decrease in single-limb support time symmetry was found. BWS treadmill training, combined with strength training, significantly improved motor and functional performance in this participant with chronic deficits after stroke.

Effects of age, task complexity, and exercise on reaction time of women during ambulation tasks.

PURPOSE: Reaction time (RT) is defined as the time lapse between the onset of a stimulus and the initiation of a response. The purpose of Study 1 was to compare RTs of young and elderly women during ambulation. The purpose of Study 2 was to investigate the effects of regular exercise on RTs of elderly women during ambulation tasks. METHODS: Reaction times were measured using a portable computer, 2 transistor radios, and a radio interface box. The computer generated an auditory signal to which participants reacted by pushing a hand-held switch. Reaction times were compared in Study 1 between 17 healthy elderly women and 13 university students and in Study 2 between 15 exercising and 16 non-exercising elderly women. Testing of each participant occurred during sitting, walking on tile, and walking on foam padded carpet. RESULTS: The results of Study 1 revealed differences in RT between the 2 groups and between the sitting and the 2 walking conditions, but no interaction between group and task complexity. The results of Study 2 revealed differences among all conditions, but not between groups. CONCLUSIONS: The surprising result of Study 1 was that the elderly were not compromised to a greater extent than the young by increased task complexity. This suggests less age related RT decline during familiar activities. Results of Study 2 showed that level of exercise did not differentiate elderly participants' performance on RT. This may be because the active lifestyle of both groups of participants was more important in maintaining RT than a formal exercise program.

Vitamin D insufficiency in male osteoporosis.

Osteoporosis is an important public health issue among men, affecting up to 20% of all men in the United States >50 years of age. The social and economic costs of male osteoporosis are profound but can be minimized by a preventive approach, including early identification and treatment of men at risk for this potentially crippling disease. As part of this preventive approach, clinicians should screen susceptible patients for vitamin D deficiency, a commonly occurring, highly correctable risk factor for osteoporosis. Appropriate detection of vitamin D deficiency in men at risk for osteoporosis and adequate correction of this deficiency will significantly reduce morbidity and mortality associated with male osteoporosis.