Localized JNK signaling regulates organ size during development.

A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control

Work Analysis with Resource-Aware Session Types

While there exist several successful techniques for supporting programmers in deriving static resource bounds for sequential code, analyzing the resource usage of message-passing concurrent processes poses additional challenges. To meet these challenges, this article presents an analysis for statically deriving worst-case bounds on the total work performed by message-passing processes. To decompose interacting processes into components that can be analyzed in isolation, the analysis is based on novel resource-aware session types, which describe protocols and resource contracts for inter-process communication. A key innovation is that both messages and processes carry potential to share and amortize cost while communicating. To symbolically express resource usage in a setting without static data structures and intrinsic sizes, resource contracts describe bounds that are functions of interactions between processes. Resource-aware session types combine standard binary session types and type-based amortized resource analysis in a linear type system. This type system is formulated for a core session-type calculus of the language SILL and proved sound with respect to a multiset-based operational cost semantics that tracks the total number of messages that are exchanged in a system. The effectiveness of the analysis is demonstrated by analyzing standard examples from amortized analysis and the literature on session types and by a comparative performance analysis of different concurrent programs implementing the same interface.Comment: 25 pages, 2 pages of references, 11 pages of appendix, Accepted at LICS 201

Quasi-Orthogonal Wideband Radar Waveforms Based on Chaotic Systems

Many radar applications, such as those involving multiple-input, multiple-output (MIMO) radar, require sets of waveforms that are orthogonal, or nearly orthogonal. As shown in the work presented here, a set of nearly orthogonal waveforms with a high cardinality can be generated using chaotic systems, and this set performs comparably to other waveform sets used in pulse compression radar systems. Specifically, the nearly orthogonal waveforms from chaotic systems are shown to possess many desirable radar properties including a compact spectrum, low range sidelobes, and an average transmit power within a few dB of peak power. Moreover, these waveforms can be generated at essentially any practical time length and bandwidth. Since these waveforms are generated from a deterministic process, each waveform can be represented with a small number of system parameters. Additionally, assuming these waveforms possess a large time-bandwidth product, a high number of nearly orthogonal chaotic waveforms exist for a given time and bandwidth. Thus the proposed generation procedure can potentially be used to generate a new transmit waveform on each pulse.United States. Air Force (Contract FA8721-05-C-0002)Massachusetts Institute of Technology. Research Laboratory of ElectronicsBAE SystemsTexas Instruments Incorporated. Leadership University Consortium Progra

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus

Background: A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. Methods: To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide. Results: No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect. Conclusions: The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.Intellectual and Developmental Disabilities Research Center at Washington University (NIH/NICHD) [P30 HD062171]; Simons Foundation (SFARI) [307705]; Canadian Institutes of Health Research; [R01 HD042541]SCI(E)[email protected]; [email protected]

Human 3D cellular model of hypoxic brain injury of prematurity.

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain

A Model for Introducing the Spiritual Disciplines to the Members of the Capital Memorial Seventh-day Adventist Church

This dissertation project developed out of the researcher\u27s own spiritual pilgrimage in a search for greater intimacy with God. An introduction to the ancient spiritual disciplines provided the means for that intimacy to develop and, subsequently, created a desire to share the disciplines in ministry with members of his congregation. A model was envisaged which could become a life-changing event in the life of the individual member. The development and use of this model was the subject of the project. The model includes an introduction to four basic disciplines: prayer, the devotional use of Scripture, meditation, and journaling. For each discipline, there is also a careful outline presented as to how the discipline may be practiced successfully. A retreat setting, which proved to be very successful, was selected for using the model for the first time. This entire process is carefully described and evaluated in the report with a recommendation that further retreats include more time and that a follow-up plan be in place well in advance. Included in the project was research into the spiritual formation process— with emphasis on the disciplines, its historical development, its place in Seventh-day Adventist theology, and how it was viewed by Ellen White, one of Adventism\u27s founders. The results from this research were included in the model to provide a background legitimacy for the disciplines as they were introduced. It was discovered that Adventist theologians have had much to say about the holiness God requires from those who are saved, but little practical advice as to how it occurs. In fact, there has been a debate over the years about faith and works with no apparent conclusion. There was convincing evidence, however, that Ellen White understood the spiritual formation process and knew the importance of the spiritual disciplines. Her extensive writing on the subject provided valuable affirmation for the model. Survey and evaluation instruments were created to determine the need for using the model and for its effectiveness. The survey results which are reported in the dissertation, confirm the need for assistance in developing intimacy with God among those who responded. Those who participated in the first use of the model gave a high effectiveness rating, although it was apparent that some adjustments would be helpful in order to reinforce the changes which would be required to develop the desired intimacy with God

Selecting the lorenz parameters for wideband radar waveform generation

Radar waveforms based on chaotic systems have occasionally been suggested for a variety of radar applications. In this paper, radar waveforms are constructed with solutions from a particular chaotic system, the Lorenz system, and are called Lorenz waveforms. Waveform properties, which include the peak autocorrelation function side-lobe and the transmit power level, are related to the system parameters of the Lorenz system. Additionally, scaling the system parameters is shown to correspond to an approximate time and amplitude scaling of Lorenz waveforms and also corresponds to scaling the waveform bandwidth. The Lorenz waveforms can be generated with arbitrary time lengths and bandwidths and each waveform can be represented with only a few system parameters. Furthermore, these waveforms can then be systematically improved to yield constant-envelope output waveforms with low autocorrelation function sidelobes and limited spectral leakage.United States. Air Force Office of Scientific Research (Contract number FA8721-05-C-0002

Developing an Enhanced Forest Inventory in Maine Using Airborne Laser Scanning: The Role of Calibration Plot Design and Data Quality

Forests provide essential ecosystem services such as carbon sequestration, clean water, lumber, and more. It is important that foresters be able to collect accurate forest inventories, especially in a changing climate. Foresters need to know what is in the forest not only to manage for the economic benefits, but also to manage for social acceptability and ecological soundness to prevent further degradation of these ecosystem services. One way to collect accurate and precise forest inventories is through the utilization of remote sensing products. These enhanced forest inventories (EFIs) can be done at varying resolutions that are contingent on the plot design creating wall-to-wall raster data and thus, complete spatial knowledge of these estimates can be determined. A popular remote sensing product to be used to create EFIs is airborne laser scanning (ALS). Although best practices guides have been created in other countries, research on the best plot type and design has not been done for Maine’ structurally diverse and intensively managed forests. The goal of this study was to investigate a range of forest designs to determine the best ground-based calibration plot specifications for developing EFI models from ALS data in Maine. We developed a model that compared fixed versus variable radius plots, sampling size and intensity, and sample design with ALS data to map EFI variables like percent softwood, volume, BA, and tree count. Data were collected from the Penobscot Experimental Forest (PEF) in summer 2022 that had two different plot types, two sample sizes and sampling intensities, and two different sample designs. Data from other study sites were provided to us from our partners that only included one plot type, sample size and intensity, and sample design each. For validation, we used data collected in the Demeritt Forest also in summer 2022. We assessed R2, root mean square error (RMSE), coefficient of variation (CV), and mean bias for models with varying forest inventory designs to establish the best calibration plot for ALS in our study areas. It was determined that a principal component analysis for plot placement gave better model results than randomly placed plots. Also, fixed radius plots (FRPs) and a smaller sample size generated better evaluation statistics when predicting percent softwood, volume, and tree count in the PEF. In contrast, VRPs with a smaller sample size provided better model outcomes when predicting basal area (BA). Once the best forest inventory calibration plot design was identified and validated, we applied it to the PEF to estimate aboveground biomass. Although there were obvious trends in our results, there is still more research to be done to ensure that our potential recommendations are correct. It seems that there was better model performance in spruce-fir forest types than other forest types like oak-pine. Our results provide insights on an optimal approach for specific conditions and underscore the importance of future research to assist decision-making on plot type and sample design for the broad range of conditions on forested landscapes in Maine

Detection Of The Lung Environment By Multi-Drug Resistant Gram-Negative Bacterial Pathogens

Nosocomial lung infections are a growing concern in the United States, with more than 300,000 cases reported annually. More than 30 % of which are caused by the Gram-negative bacteria, Pseudomonas aeruginosa and Klebsiella pneumoniae. Similarly, Gram-negative bacteria establish chronic infections in individuals with cystic fibrosis (CF) that are difficult or impossible to eradicate.P. aeruginosa has historically been one of the most prevalent pathogens of adults with CF. However, as antipseudomonal therapy has improved, more antibiotic resistant species have taken hold, including Stenotrophomonas maltophilia, which now colonizes more than 10 % of individuals with CF. Regardless of the cause or source, Gram-negative respiratory infections are becoming increasingly difficult to treat due to the rising incidence of multiple drug resistance among these organisms. To aid in the development of new therapeutics, a greater understanding of how these organisms transition from the environment to the host lung is needed. Here we utilized a combination of transcriptomics and molecular genetics to examine how P. aeruginosa, K. pneumoniae, and S. maltophilia, recognize and exploit the host lung milieu during the initiation of infection. One of the first components of the host lung environment that aspirated bacteria are exposed to is pulmonary surfactant (PS). This phospholipid-rich substance coats the distal airways of the lung and is thought to contain molecular cues that facilitate lung colonization by pathogenic bacteria. Here, we characterized the transcriptional response of K. pneumoniae to purified PS to examine how this organism interreacts with the host lung during colonization. This work revealed numerous virulence and colonization-related genes that are expressed by K. pneumoniae under these conditions. We also tested the contribution of other surfactant-induced transcripts to K. pneumoniae pathogenesis using engineered gene deletion strains and a mouse model of pneumonia. This work revealed the polyamine efflux pump, MdtJI, and glycine betaine transporter, ProU are required for K. pneumoniae virulence. Phosphatidylcholine is the primary constituent of PS. P. aeruginosa is capable of completely metabolizing the phosphocholine head group of this lipid, and readily does so when exposed to PS. We previously observed that the most highly expressed genes in P. aeruginosa in response to PS were those involved in the catabolism of a downstream choline metabolite, sarcosine. Although our group had previously characterized the choline catabolic pathway of P. aeruginosa, the transcriptional regulation of sarcosine catabolism was not known. We utilized a genetic screen to identify the regulator controlling the expression of the sarcosine catabolic genes in P. aeruginosa. This regulator, which we named SouR (Sarcosine oxidase utilization Regulator) is the first sarcosine-responsive regulator to be characterized. The thick, viscous mucus (sputum) that accumulates within the CF lung serves as the primary nutrient source for microbes colonizing the CF lung. Here, we characterized the transcriptional responses of three S. maltophilia strains during growth in synthetic CF sputum media (SCFM2) to gain insight into how this organism interreacts with the host lung. We also compared the SCFM2 transcriptomes of two S. maltophilia CF isolates with the SCFM2 transcriptome of the acute infection model strain, K279A. This revealed CF isolate-specific signatures in gene expression that reflect adaptation to the CF lung