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We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r2/2 rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development,organogenesis, and homeostasis.

We report absolute optical frequencies of electronic transitions from the X-2 Pi(3/2), v '' = 0, J '' = 3/2 rovibronic ground state to the 12 lowest levels of the A (2)Sigma(+), v' = 0 vibronic state in (OH)-O-16, as well as to the 16 lowest levels of the same vibronic state in (OD)-O-16. The absolute frequencies of these transitions have been determined with a relative uncertainty of a few parts in 10(11) , representing a similar to 1000-fold improvement over previous measurements. To reach this level of precision, an optical frequency comb has been used to transfer the stability of a narrow-linewidth I-2-stabilized reference laser onto the 308-nm spectroscopy laser. The comb is also used to compare the optical frequency of the spectroscopy laser to an atomic clock reference, providing absolute accuracy. Measurements have been carried out on OH and OD molecules in a highly collimated molecular beam, reducing possible pressure shifts and minimizing Doppler broadening. Systematic shifts due to retroreflection quality, the Zeeman effect, and the ac Stark effect have been considered during the analysis of the measured spectra; particularly in the case of the OD isotopologue, these effects can result in shifts of the fitted line positions of as much as 300 kHz. The transition frequencies extracted in the analysis were also used to determine spectroscopic constants for the A (2)Sigma(+), v' = 0 vibronic state. The constants fitted in this work differ significantly from those reported in previous works that measured the A-X transitions, resulting in typical deviations of the predicted optical transition frequencies of similar to 150 MHz, but they generally agree quite well with the constants determined using hyperfine-resolved measurements of splittings within the A state.

The cytokine leukaemia inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESCs) through activation of the transcription factor Stat3. However, the contribution of other ancillary pathways stimulated by LIF in ESCs, such as the MAPK and PI3K pathways, is less well understood. We show here that naive-type mouse ESCs express high levels of a novel effector of the MAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal pleckstrin homology (PH) membrane-binding domain. Although not essential for rapid unrestricted growth of ESCs under optimal conditions, the novel Gab1 variant (Gab1β) is required for LIF-mediated cell survival under conditions of limited nutrient availability. This enhanced survival is absolutely dependent upon a latent palmitoylation site that targets Gab1β directly to ESC membranes. These results show that constitutive association of Gab1 with membranes through a novel mechanism promotes LIF-dependent survival of murine ESCs in nutrient-poor conditions., Highlighted Article: Embryonic stem cells rely upon expression of a novel lipid-modified Gab1 adaptor protein to promote survival under nutrient-poor conditions.

The Malaria Policy Advisory Committee to the World Health Organization met for the first time from 31 January to 2 February 2012 in Geneva, Switzerland. This article provides a summary of the discussions, conclusions and recommendations from that meeting, as part of the newly launched Malaria Journal thematic series “WHO Malaria Policy Advisory Committee: Reports and Recommendations”. Summaries are provided, referencing the relevant background documents, for the meeting sessions on global malaria control, drug resistance and containment, rapid diagnostic test procurement criteria, larviciding, classification of countries for elimination, estimating malaria cases and deaths, and seasonal malaria chemoprevention. Policy statements, position statements, and guidelines that will arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization member states by the World Health Organization Global Malaria Programme.

The Malaria Policy Advisory Committee to the World Health Organization held its fourth meeting in Geneva, Switzerland from 11 to 13 September, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting. Meeting sessions included: recommendations for achieving universal coverage of long-lasting insecticide-treated nets; guidance on estimating the longevity of insecticide-treated nets; improving capacity in entomology and vector control; a review of the latest evidence on intermittent preventive treatment in pregnancy; improving dissemination of Malaria Policy Advisory Committee guidance; updates on the development of the global technical strategy for malaria control and elimination (2016–2025) and the global strategy for control and elimination of Plasmodium vivax; updates from the drug resistance and containment technical expert group, the evidence review group on malaria burden estimation, a consultation on malaria case management indicators, and the constitution of the surveillance, monitoring and evaluation technical expert group; subnational elimination criteria; and consideration for future evidence review groups, including diagnosis in low transmission settings and testing for Glucose-6-Phosphate Dehydrogenase Deficiency. Policy statements, position statements and guidelines that arise from the Malaria Policy Advisory Committee meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.

The skull and post-cranium have been used for the determination of sex for unknown human remains. However, in forensic cases where skeletal remains often exhibit postmortem damage and taphonomic changes the calcaneus may be used for the determination of sex as it is a preservationally favored bone. The goal of the present research was to derive discriminant function equations from the calcaneus for estimation of sex from a contemporary Greek population. Nine parameters were measured on 198 individuals (103 males and 95 females), ranging in age from 20 to 99 years old, from the University of Athens Human Skeletal Reference Collection. The statistical analyses showed that all variables were sexually dimorphic. Discriminant function score equations were generated for use in sex determination. The average accuracy of sex classification ranged from 70% to 90% for the univariate analysis, 82.9% to 87.5% for the direct method, and 86.2% for the stepwise method. Comparisons to other populations were made. Overall, the cross-validated accuracies ranged from 48.6% to 56.1% with males most often identified correctly and females most often misidentified. The calcaneus was shown to be useful for sex determination in the twentieth century Greek population. © 2015 The Chartered Society of Forensic Sciences.

The determination of sex is an important part of building the biological profile for unknown human remains. Many of the bones traditionally used for the determination of sex are often found fragmented or incomplete in forensic and archaeological cases. The goal of the present research was to derive discriminant function equations from the talus, a preservationally favoured bone, for sexing skeletons from a contemporary Greek population. Nine parameters were measured on 182 individuals (96 males and 86 females) from the University of Athens Human Skeletal Reference Collection. The individuals ranged in age from 20 to 99 years old. The statistical analyses showed that all measured parameters were sexually dimorphic. Discriminant function score equations were generated for use in sex determination. The average accuracy of sex classification ranged from 65.2% to 93.4% for the univariate analysis, 90%-96.5% for the direct method and 86.7% for the stepwise method. Comparisons to other populations were made. Overall, the cross-validated accuracies ranged from 65.5% to 83.2% and males were most often correctly identified. The talus was shown to be useful for sex determination in the modern Greek population. © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Background: Community health workers (CHWs) are an increasingly important component of health systems and programs. Despite the recognized role of supervision in ensuring CHWs are effective, supervision is often weak and under-supported. Little is known about what constitutes adequate supervision and how different supervision strategies influence performance, motivation, and retention.Objective: To determine the impact of supervision strategies used in low- and middle-income countries and discuss implementation and feasibility issues with a focus on CHWs.Design: A search of peer-reviewed, English language articles evaluating health provider supervision strategies was conducted through November 2013. Included articles evaluated the impact of supervision in low- or middle-income countries using a controlled, pre-/post- or observational design. Implementation and feasibility literature included both peer-reviewed and gray literature.Results: A total of 22 impact papers were identified. Papers were from a range of low- and middle-income countries addressing the supervision of a variety of health care providers. We classified interventions as testing supervision frequency, the supportive/facilitative supervision package, supervision mode (peer, group, and community), tools (self-assessment and checklists), focus (quality assurance/problem solving), and training. Outcomes included coverage, performance, and perception of quality but were not uniform across studies. Evidence suggests that improving supervision quality has a greater impact than increasing frequency of supervision alone. Supportive supervision packages, community monitoring, and quality improvement/problem-solving approaches show the most promise; however, evaluation of all strategies was weak.Conclusion: Few supervision strategies have been rigorously tested and data on CHW supervision is particularly sparse. This review highlights the diversity of supervision approaches that policy makers have to choose from and, while choices should be context specific, our findings suggest that high-quality supervision that focuses on supportive approaches, community monitoring, and/or quality assurance/problem solving may be most effective.Keywords: supervision; community health worker; lay health worker; health worker; low-income country; developing country; ICCM(Published: 8 May 2014)Citation: Glob Health Action 2014, 7: 24085 - http://dx.doi.org/10.3402/gha.v7.24085

The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting. Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016–2025). Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.

National audience; no abstract

The Malaria Eradication Research Agenda (malERA) Consultative Group on Monitoring, Evaluation, and Surveillance present a research and development agenda for the tools required to monitor and evaluate progress toward malaria eradication., Monitoring, evaluation, and surveillance measure how well public health programs operate over time and achieve their goals. As countries approach malaria elimination, these activities will need to shift from measuring reductions in morbidity and mortality, to detecting infections (with or without symptoms) and measuring transmission. Thus, the monitoring and evaluation and surveillance research and development agenda needs to develop the tools and strategies that will replace passive surveillance of morbidity with active and prompt detection of infection, including confirmation of interruption of transmission by detecting present and past infections, particularly in mobile populations. The capacity to assess trends and respond without delay will need to be developed, so that surveillance itself becomes an intervention. Research is also needed to develop sensitive field tests that can detect low levels of parasitaemia, together with strategies for their implementation. Other areas to explore include the rigorous evaluation of the utility of more detailed maps of disease and infection incidence and prevalence, the development of new maps to inform programmatic responses and the use of surveillance technologies based on cell phone or real-time internet Web-based reporting. Because any new strategies for monitoring and evaluation and surveillance for eradication have major implications for program implementation, research is also needed to test systems of delivery for acceptability, feasibility, efficiency, cost-effectiveness, and community engagement. Finally, there is a clear need to systematically review the information from past elimination efforts for malaria and other infectious diseases.

A lithographically-etched chip containing 1254 microscopic electrodes at a center-to-center spacing of 40 micron is used to produce an array of electric field strength minima 25 micron above the surface with a spacing between neighboring minima of 120 micron. These minima are produced by applying a series of six potentials to the electrodes. For polar molecules in low field seeking states, the electric field minima are potential energy minima and thus act as traps. By varying the potentials in a controlled manner, the field minima can be translated with respect to the electrodes at a constant distance from the surface. Experiments were performed with CO in the metastable a 3-Pi-1, v = 0, J = 1 state, which has a strong, linear Stark shift with low field seeking components, a 6 eV internal energy that enables easy detection through an Auger process, and a radiative lifetime of 2.6 ms, which is long enough for the experiments here. CO molecules in a pulsed molecular beam are directly excited to the metastable state with a 5 ns laser pulse. The metastable CO molecules pass through a skimmer and arrive to the chip traveling parallel to the surface and perpendicular to the electrodes. While above the chip, the molecules are manipulated by the electric fields and subsequently ejected from the other side toward the detector. Metastable 12-CO molecules have been guided over the chip at constant velocities and decelerated. As the final velocity decreases (i.e. the deceleration increases), the decelerated molecules arrive at the detector successively later, and the number of decelerated molecules reaching the detector also decreases. While this effect is expected, the fraction of molecules lost is much greater than trajectory simulations predict. Most of this excess loss at higher decelerations results from non-adiabatic transitions to untrapped states. At zero electric field, the low field seeking level of the a 3-Pi-1, v = 0, J = 1 state of 12-C-16-O is exactly degenerate with a level that is only weakly affected by the fields. As the molecules pass near the zero field region at the center of a microtrap, they can transition to this level, after which they are lost from the trap. One way to avoid this loss channel is to use 13-C-16-O instead of 12-C-16-O, which results in a breaking of this degeneracy by 50 MHz due to hyperfine structure. Because of this splitting, ensembles of metastable 13-C-16-O molecules can and have been decelerated to zero velocity above the chip and held for variable durations ranging from 0 ms to 2.5 ms. It is observed that fewer molecules are detected after longer trapping times on the chip, but the rate of this loss is consistent with the 2.6 ms radiative lifetime of the metastable CO molecules. Further experiments demonstrate that the Zeeman splitting due to an external magnetic field perpendicular to the electric field is a valid and more general way to prevent non-adiabatic losses in 12-CO., Ein lithographisch gefertigter Chip, der 1254 mikroskopische Elektroden mit einem Mitten-Abstand von 40 µm besitzt, wird genutzt, um eine lineare Anordnung von Minima des elektrischen Feldes zu generieren in einem Abstand von 120 µm und eine Höhe von 25 µm über der Oberfläche. Hierzu werden sechs Spannungen benötigt, die extern angelegt werde. Für polare Moleküle in einem tieffeld-suchenden Zustand sind diese Feldminima auch mechanische Minima und fungieren als Fallen. Werden die angelegten Spannungen in definierter Weise variiert, bewegen sich die Feldminima längs der Struktur mit konstantem Abstand zur Oberfläche. Experimente wurden mit CO im metastabilen a 3-Pi-1, v = 0, J = 1 Zustand durchgeführt, der eine starke lineare Stark-Verschiebung für tieffeld-suchende Komponenten aufweist. Er hat eine Anregungsenergie von 6 eV, die einfachen Nachweis über einen Augerprozess erlaubt, und eine natürliche Lebensdauer von 2,6 ms, die für die hier beschriebenen Experimente ausreicht. Metastabiles CO wird in einem gepulsten Molekularstrahl durch direkte Anregung mit einem 5 ns Laserpuls produziert. Die Moleküle durchlaufen einen Skimmer und erreichen den Chip in einer Flugbahn parallel zur Oberfläche und senkrecht zur Elektrodenrichtung. Über dem Chip selbst werden sie durch die elektrischen Felder geführt und verlassen ihn in Richtung des Detektors. Metastabile 12-CO Moleküle wurden bei konstanten Geschwindigkeiten geführt und auch abgebremst. Wenn die Endgeschwindigkeit abnimmt, reduziert sich wie erwartet die Zahl der detektierten Moleküle. Allerdings ist dieser Effekt weitaus stärker als aus den Simulationsrechnungen zu erwarten war. Als wesentlicher Verlustmechanismus, der bei stärkerer Abbremsung deutlich wird, konnte der nichtadiabatische Übergang in Zustände identifiziert werden, die nicht eingefangen sind. Bei elektrischem Nullfeld ist das tieffeld-suchende Niveau des a 3-Pi-1, v = 0, J = 1 Zustands von 12-C-16-O streng mit einem Niveau entartet, das nur schwach mit dem elektrischen Feld wechselwirkt. Durchlaufen die Moleküle in den Mikrofallen nun einen Bereich nahe der Nullfeld-Region, kann ein Übergang in diesen Zustand erfolgen, so dass das Molekül die Falle verläßt. Eine Möglichkeit, diesen Verlustkanal zu unterdrücken, bietet das 13-C-16-O Isotopolog, bei dem aufgrund der Hyperfeinstrukturwechselwirkung diese Entartung aufgehoben ist mit einem Abstand von 50 MHz. So war es möglich Ensembles von metastabilem 13-C-16-O sogar bis zum Stillstand über dem Chip abzubremsen und für einen Zeitraum zwischen 0 und 2,5 ms zu halten. Die Zahl der nachgewiesenen Moleküle nahm zwar für längere Haltezeiten ab, aber die Verlustrate ist vereinbar mit der natürlichen Lebensdauer des metastabilen CO von 2,6 ms. Weitere Experimente zeigen, daß nichtadiabatische Verluste in 12-CO ebenfalls unterdrückt werden, wenn zusätzlich ein magnetisches senkrecht zum elektrischen Feld angelegt wird.

We present a combined experimental and theoretical study on the radiative lifetime of CO in the a³Π1,2, v=0 state. CO molecules in a beam are prepared in selected rotational levels of this metastable state, Stark-decelerated and electrostatically trapped. From the phosphorescence decay in the trap, the radiative lifetime is measured to be 2.63±0.03 ms for the a³Π1, v=0, J=1 level. From spin-orbit coupling between the a³Π and the A¹Π state a 20% longer radiative lifetime of 3.16 ms is calculated for this level. It is concluded that coupling to other ¹Π states contributes to the observed phosphorescence rate of metastable CO.