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The influence of climate on premodern civil conflict and societal instability is debated. Here, the authors combine archeological, historical, and paleoclimatic datasets to show that drought between 1400-1450 cal. CE escalated civil conflict at Mayapan, the largest Postclassic Maya capital of the Yucatán Peninsula.

Abstract Background East Africa is home to 170 million people and prone to frequent outbreaks of viral haemorrhagic fevers and various bacterial diseases. A major challenge is that epidemics mostly happen in remote areas, where infrastructure for Biosecurity Level (BSL) 3/4 laboratory capacity is not available. As samples have to be transported from the outbreak area to the National Public Health Laboratories (NPHL) in the capitals or even flown to international reference centres, diagnosis is significantly delayed and epidemics emerge. Main text The East African Community (EAC), an intergovernmental body of Burundi, Rwanda, Tanzania, Kenya, Uganda, and South Sudan, received 10 million € funding from the German Development Bank (KfW) to establish BSL3/4 capacity in the region. Between 2017 and 2020, the EAC in collaboration with the Bernhard-Nocht-Institute for Tropical Medicine (Germany) and the Partner Countries’ Ministries of Health and their respective NPHLs, established a regional network of nine mobile BSL3/4 laboratories. These rapidly deployable laboratories allowed the region to reduce sample turn-around-time (from days to an average of 8h) at the centre of the outbreak and rapidly respond to epidemics. In the present article, the approach for implementing such a regional project is outlined and five major aspects (including recommendations) are described: (i) the overall project coordination activities through the EAC Secretariat and the Partner States, (ii) procurement of equipment, (iii) the established laboratory setup and diagnostic panels, (iv) regional training activities and capacity building of various stakeholders and (v) completed and ongoing field missions. The latter includes an EAC/WHO field simulation exercise that was conducted on the border between Tanzania and Kenya in June 2019, the support in molecular diagnosis during the Tanzanian Dengue outbreak in 2019, the participation in the Ugandan National Ebola response activities in Kisoro district along the Uganda/DRC border in Oct/Nov 2019 and the deployments of the laboratories to assist in SARS-CoV-2 diagnostics throughout the region since early 2020. Conclusions The established EAC mobile laboratory network allows accurate and timely diagnosis of BSL3/4 pathogens in all East African countries, important for individual patient management and to effectively contain the spread of epidemic-prone diseases.

In this article, we seek to solve the problem of stochastic filtering of the unobserved drift of the stock price in the presence of privileged information. Working within a finite time investment horizon, the privileged information which is a function of the future value of the stock price, is modeled such that its quality improves as we move towards the information reveal date. The hidden/unobserved drift is modeled as a Gaussian process. Combining the techniques of progressive enlargement of filtration and stochastic filtering of linear state-space models, we obtain explicit analytic results for the insider’s estimates of the unobserved drift process. In addition, we obtain the optimal portfolio strategy for an insider having the log utility function. Our numerical results reveal that when the quality of privileged information is high, the insider would require less initial capital as compared to the regular trader who has no access to the privileged information. Further, we show how the stock price volatility influences the value of the insider’s privileged information, with period of high volatility pointing to increased value of the privileged information.

Estimating post-mortem interval is an important aspect in forensic investigations. The aim of this study was to investigate if time-lapse imaging can be used to improve estimates of post-mortem interval using Megyesi et al.‘s [1] method for a human donor decomposing in an Australian environment. To achieve this, time-lapse images were taken every 30 min over a 6-month period. The Megyesi et al. [1] total body score (TBS) system was used to quantify the level of decomposition of the donor for each image. Linear regression was performed to determine if observing decomposition more than once a day leads to increased accuracy in predicting PMI (post-mortem interval).Decomposition initially progressed quickly and then plateaued at 1004 hours PMI, with a TBS of 24. Individual timestamps were created from the time-lapse images taken each day at 08:00 hrs, 11:00 hrs, 14:00 hrs, 15:00 hrs, and 17:00 hrs. All timestamps produced R2 values > 0.80, indicating that the Megyesi et al. [1] method accurately predicts PMI for this donor. The 08:00 hrs timestamp had the highest value R2 = 0.886, whilst the combined timestamp (which included the scores from all five images for each 24-hour period) R2 = 0.823 was the lowest.This study supports the validity of Megyesi et al.‘s [1] TBS model to estimate PMI. Two other interesting findings were that the results suggest that scoring TBS multiple times per day does not improve estimates of PMI, however scoring TBS at daybreak produces more accurate results than scoring TBS later in the day. This may be an important consideration in forensic scenarios. Keywords: Forensic anthropology, Taphonomy, Time-death interval, Australian facility for taphonomic experimental research

We investigate the filtering problem where the borrower’s time varying credit quality process is estimated using continuous time observation process and her (in this paper we refer to the borrower as female and the lender as male) ego-network data. The hidden credit quality is modeled as a hidden Gaussian mean-reverting process whilst the social network is modeled as a continuous time latent space network model. At discrete times, the network data provides unbiased estimates of the current credit state of the borrower and her ego-network. Combining the continuous time observed behavioral data and network information, we provide filter equations for the hidden credit quality and show how the network information reduces information asymmetry between the borrower and the lender. Further, we consider the case when the network information arrival times are random and solve stochastic optimal control problem for a lender having linear quadratic utility function.

Pada penelitian ini telah dikembangkan sebuah perangkat wearable functional electrical stimulation untuk merestorasi gerakan knee joint. Perangkat keras dirancang dengan menggunakan sensor accelerometer dan gyroscope yang dapat mengukur posisi dan kemiringan sudut, dan electrical stimulator yang menstimulasikan otot untuk melakukan knee extension dan knee flexion. Pada pengujian sistem sensor, dilakukan pengukuran pada model kaki statis yang digerakkan dan didapatkan nilai RMSE pada knee joint sebesar 0.714°. Pada pengujian rangkaian electrical stimulator tegangan maksimum yang dapat dihasilkan 95 Volt, frekuensi 20 Hz dan lebar pulsa 200 μS. Untuk menguji pada subyek, elektroda ditempatkan pada otot BFLH untuk melakukan knee flexion dan otot vastus femoris untuk knee extension. Besarnya tegangan pada saat stimulasi knee flexion umumnya lebih besar daripada stimulasi knee extension. Hasil pembacaan sensor pada subyek kemudian akan dijadikan sebagai feedback untuk sistem kendali cycle-to-cycle control yang dikendalikan oleh fuzzy rule based system. Untuk melakukan knee extension, metode yang digunakan adalah multiple input single output yang menggunakan nilai error dan desired range sebagai input, sedangkan dalam melakukan knee flexion digunakan single input single output yang hanya menggunakan nilai error sebagai input. Keluaran fuzzy system ini adalah ΔTB sebagai burst duration dari stimulasi yang dihasilkan

A period life table provides an estimate of the probability that a person will die at a particular age. Using data available online, we examine tables of expected years to live for males and females against age for three populations: the United States in 2007, the U.S. at the turn of the twentieth century, and the Roman Empire. Scatter plots of males and females for each population show how life expectancy increases with age (e.g., U.S. 2007: 50 year-old female > 40 year-old female > 45 year-old male). The three data sets allow historical comparisons (e.g., of gender disparity, larger now; of infant mortality, smaller now). Regression lines for the linear portion of the plots (ages 5 to 70) show the annual increase in the years to live (e.g., U.S. 2007: 0.11 years for men, 0.07 years for women). Residual plots show that, even though the coefficients of determination of the line exceed 0.99, a concave-up, decreasing function would be a better model. The residual plots also reveal a curious inflection for the males that is not evident for the females. Such examples from period life tables might be presented in a discussion of life expectancy; alternatively, one or more could add to an introduction to regression, particularly illustrating the value of residual plots in understanding a data set.

Background: On Aug 29, 2021, Operation Allies Welcome (OAW) was established to support the resettlement of more than 80 000 Afghan evacuees in the USA. After identification of measles among evacuees, incoming evacuee flights were temporarily paused, and mass measles vaccination of evacuees aged 6 months or older was introduced domestically and overseas, with a 21-day quarantine period after vaccination. We aimed to evaluate patterns of measles virus transmission during this outbreak and the impact of control measures., Methods: We conducted a measles outbreak investigation among Afghan evacuees who were resettled in the USA as part of OAW. Patients with measles were defined as individuals with an acute febrile rash illness between Aug 29, 2021, and Nov 26, 2021, and either laboratory confirmation of infection or epidemiological link to a patient with measles with laboratory confirmation. We analysed the demographics and clinical characteristics of patients with measles and used epidemiological information and whole-genome sequencing to track transmission pathways. A transmission model was used to evaluate the effects of vaccination and other interventions., Findings: 47 people with measles (attack rate: 0·65 per 1000 evacuees) were reported in six US locations housing evacuees in four states. The median age of patients was 1 year (range 0-26); 33 (70%) were younger than 5 years. The age distribution shifted during the outbreak towards infants younger than 12 months. 20 (43%) patients with wild-type measles virus had rash onset after vaccination. No fatalities or community spread were identified, nor further importations after flight resumption. In a non-intervention scenario, transmission models estimated that a median of 5506 cases (IQR 10-5626) could have occurred. Infection clusters based on epidemiological criteria could be delineated into smaller clusters using phylogenetic analyses; however, sequences with few substitution count differences did not always indicate single lines of transmission., Interpretation: Implementation of control measures limited measles transmission during OAW. Our findings highlight the importance of integration between epidemiological and genetic information in discerning between individual lines of transmission in an elimination setting., Funding: US Centers for Disease Control and Prevention., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

On August 29, 2021, the United States government oversaw the emergent establishment of Operation Allies Welcome (OAW), led by the U.S. Department of Homeland Security (DHS) and implemented by the U.S. Department of Defense (DoD) and U.S. Department of State (DoS), to safely resettle U.S. citizens and Afghan nationals from Afghanistan to the United States. Evacuees were temporarily housed at several overseas locations in Europe and Asia* before being transported via military and charter flights through two U.S. international airports, and onward to eight U.S. military bases, † with hotel A used for isolation and quarantine of persons with or exposed to certain infectious diseases. § On August 30, CDC issued an Epi-X notice encouraging public health officials to maintain vigilance for measles among Afghan evacuees because of an ongoing measles outbreak in Afghanistan (25,988 clinical cases reported nationwide during January-November 2021) (1) and low routine measles vaccination coverage (66% and 43% for the first and second doses, respectively, in 2020) (2)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: Intramedullary abscesses are rare infections of the spinal cord. Intramedullary abscesses often have a complex presentation, making a high index of suspicion essential for prompt diagnosis and management., Case Presentation: We present two cases of intramedullary abscesses referred to and ultimately managed at our institution. Delayed diagnosis occurred in both instances due to the rarity of intramedullary abscesses and their propensity to mimic other pathologies. For both patients, prompt surgical management and the rapid institution of broad-spectrum antibiotics were critical in preventing further neurological decline., Conclusions: Although rare, it is critical to consider intramedullary abscesses on the differential for any MRI lesions that are hyperintense on T2 and peripherally enhancing on T1 post-contrast sequences, as even short delays in treatment can lead to severe neurological damage., (© 2022. The Author(s).)

Background: While vibration therapy has shown encouraging results across many fields of medicine in the last decade, its role as originally envisioned for bone health remains uncertain. Especially regarding its efficacy in promoting fracture healing, mixed and incomplete outcomes suggest a need to clarify its potential. In particular, the definitive effect of vibration, when isolated from the confounding mechanical inputs of gait and stabilizing instrumentation, remains largely unknown., Methods: Four cohorts of C57BL/6 male mice underwent single-leg, open fibula fracture. Vibration was applied at 0.3 g to two groups for 20 min/d. At 3 and 6 weeks, fibulae were harvested for microcomputed tomography and 3-point bending to failure., Findings: In bone volume and tissue volume, the groups at each healing time point were statistically not different. At 3 weeks, however, the ratio of bone-to-tissue volume was lower for the vibrated group than control. Likewise, while bone mineral density did not differ, tissue volume density was lowest with vibration. At 6 weeks, mean differences were nominal. Biomechanically, vibration consistently trended ahead of control in strength and stiffness, but did not achieve statistical significance., Interpretation: At this stage of therapeutic development, vibration therapy in isolation does not demonstrate a clear efficacy for bone healing, although further treatment permutations and translational uses remain open for investigation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline., Research Question: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient?, Study Design and Methods: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family., Results: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease., Interpretation: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8 , a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA ( TR ) accumulated at the expense of mature TR , consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8 -null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8 -/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8 -/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones., (© 2019 Gable et al.; Published by Cold Spring Harbor Laboratory Press.)

Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1 , in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Four subcluster L2 mycobacteriophages, Finemlucis, Miley16, Wilder, and Zakai, that infect Mycobacterium smegmatis mc 2 155 were isolated. The four phages are closely related to each other and code for 12 to 14 tRNAs and 130 to 132 putative protein-coding genes, including tyrosine integrases, cro , immunity repressors, and excise genes involved in the establishment of lysogeny., (Copyright © 2017 Herren et al.)

Introduction: Although lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported, suggesting that there may be genetic susceptibility factors. We systematically tested whether germline mutations in eight candidate genes may be risk factors for lung adenocarcinoma., Methods: We studied lung adenocarcinoma cases for which germline sequence data had been generated as part of The Cancer Genome Atlas project but had not been previously analyzed. We selected eight genes, ATM serine/threonine kinase gene (ATM), BRCA2, DNA repair associated gene (BRCA2), checkpoint kinase 2 gene (CHEK2), EGFR, parkin RBR E3 ubiquitin protein ligase gene (PARK2), telomerase reverse transcriptase gene (TERT), tumor protein p53 gene (TP53), and Yes associated protein 1 gene (YAP1), on the basis of prior anecdotal association with lung cancer or genome-wide association studies., Results: Among 555 lung adenocarcinoma cases, we detected 14 pathogenic mutations in five genes; they occurred at a frequency of 2.5% and represented an OR of 66 (95% confidence interval: 33-125, p < 0.0001 [chi-square test]). The mutations fell most commonly in ATM (50%), followed by TP53, BRCA2, EGFR, and PARK2. Most (86%) of these variants had been reported in other familial cancer syndromes. Another 12 cases (2%) carried ultrarare variants that were predicted to be deleterious by three protein prediction programs; these most frequently involved ATM and BRCA2., Conclusions: A subset of patients with lung adenocarcinoma, at least 2.5% to 4.5%, carry germline variants that have been linked to cancer risk in Mendelian syndromes. The genes fall most frequently in DNA repair pathways. Our data indicate that patients with lung adenocarcinoma, similar to other solid tumors, include a subset of patients with inherited susceptibility., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.

Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis-emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1(+/-) mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1(+/-) mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation., (Copyright © 2016, American Association for the Advancement of Science.)

Over multiple response opportunities, recall may be inconsistent. For example, an eyewitness may report information at trial that was not reported during initial questioning-a phenomenon called reminiscence . Such inconsistencies are often assumed by lawyers to be inaccurate and are sometimes interpreted as evidence of the general unreliability of the rememberer. In two experiments, we examined the output-bound accuracy of inconsistent memories and found that reminisced memories were indeed less accurate than memories that were reported consistently over multiple opportunities. However, reminisced memories were just as accurate as memories that were reported initially but not later, indicating that it is the inconsistency of recall, and not the later addition to the recall output, that predicts lower accuracy. Finally, rememberers who exhibited more inconsistent recall were less accurate overall, which, if confirmed by more ecologically valid studies, may indicate that the common legal assumption may be correct: Witnesses who provide inconsistent testimony provide generally less trustworthy information overall.

Background: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease., Methods: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita., Results: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed., Conclusions: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.

Recent advances have defined a role for abnormally short telomeres in a broad spectrum of genetic disorders. They include rare conditions such as dyskeratosis congenita as well pulmonary fibrosis and emphysema. Now, there is new evidence that some familial cancers, such as melanoma, are caused by mutations that lengthen telomeres. Here, we examine the significance of these short and long telomere length extremes for understanding the molecular basis of age-related disease and cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

During pancreas development, endocrine precursors and their progeny differentiate, migrate, and cluster to form nascent islets. The transcription factor Neurogenin 3 (Neurog3) is required for islet development in mice, but its role in these dynamic morphogenetic steps has been inferred from fixed tissues. Moreover, little is known about the molecular genetic functions of NEUROG3 in human islet development. We developed methods for gene transduction by viral microinjection in the epithelium of cultured Neurog3-null mutant fetal pancreas, permitting genetic complementation in a developmentally relevant context. In addition, we developed methods for quantitative assessment of live-cell phenotypes in single developing islet cells. Delivery of wild-type NEUROG3 rescued islet differentiation, morphogenesis, and live cell deformation, whereas the patient-derived NEUROG3(R107S) allele partially restored indicators of islet development. NEUROG3(P39X), a previously unreported patient allele, failed to restore islet differentiation or morphogenesis and was indistinguishable from negative controls, suggesting that it is a null mutation. Our systems also permitted genetic suppression analysis and revealed that targets of NEUROG3, including NEUROD1 and RFX6, can partially restore islet development in Neurog3-null mutant mouse pancreata. Thus, advances described here permitted unprecedented assessment of gene functions in regulating crucial dynamic aspects of islet development in the fetal pancreas., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases., Methods: We identified a family with pulmonary fibrosis, idiopathic infertility, and short telomeres., Results: Exome sequencing of blood-derived DNA revealed two mutations in the telomere-binding protein TINF2. The first was a 15-base-pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele, indicating that the deletion seen in the blood was acquired and may have a protective advantage because it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to that described for Fanconi anemia. No mutations were identified in over 40 uncharacterized pulmonary fibrosis probands suggesting that mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of TERT and TR mutation carriers (five of 45)., Conclusions: Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis and suggest that infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.

On 3 November 2012, in the wake of Superstorm Sandy, the 227th Preventive Medicine Medical Detachment deployed to support relief operations in New Jersey and New York State. The unit was on the severe weather support mission (SWRF) and ordered to provide preventive medicine support to relief personnel within the affected area. In addition, teams from the 227th conducted environmental surveillance in the two-state region where Army Corps of Engineers were pumping floodwaters from affected neighborhoods. The 227th rapid deployment highlights the complexities associated with defense support to civil authorities and provides excellent teaching points that may enhance units expeditionary posture, regardless of mission., (2014.)

We investigated the Acinetobacter baylyi gene ACIAD1960, known from previous work to be expressed during long-term stationary phase. The protein encoded by this gene had been annotated as a Conserved Hypothetical Protein, surrounded by putative tellurite resistance ("Ter") proteins. Sequence analysis suggested that the protein belongs to the DUF1796 putative papain-like protease family. Here, we show that the purified protein, subsequently named StiP, has cysteine protease activity. Deletion of stiP causes hypersensitivity to tellurite, altered population dynamics during long-term batch culture, and most strikingly, dramatic alteration of normal cell morphology. StiP and associated Ter proteins (the StiP-Ter cluster) are therefore important for regulating cell morphology, likely in response to oxidative damage or depletion of intracellular thiol pools, triggered artificially by tellurite exposure. Our finding has broad significance because while tellurite is an extremely rare compound in nature, oxidative damage, the need to maintain a particular balance of intracellular thiols, and the need to regulate cell morphology are ubiquitous.

Unlabelled: Liver regeneration is impaired following partial hepatectomy (PH) in mice with genetic obesity and hepatic steatosis and also in wild-type mice fed a high-fat diet. These findings contrast with other data showing that liver regeneration is impaired in mice in which hepatic lipid accumulation is suppressed by either pharmacologic leptin administration or by disrupted glucocorticoid signaling. These latter findings suggest that hepatic steatosis may actually be required for normal liver regeneration. We have reexamined this relationship using several murine models of altered hepatic lipid metabolism. Liver fatty acid (FA) binding protein knockout mice manifested reduced hepatic triglyceride (TG) content compared to controls, with no effect on liver regeneration or hepatocyte proliferation. Examination of early adipogenic messenger RNAs revealed comparable induction in liver from both genotypes despite reduced hepatic steatosis. Following PH, hepatic TG was reduced in intestine-specific microsomal TG transfer protein deleter mice, which fail to absorb dietary fat, increased in peroxisome proliferator activated receptor alpha knockout mice, which exhibit defective FA oxidation, and unchanged (from wild-type mice) in liver-specific FA synthase knockout mice in which endogenous hepatic FA synthesis is impaired. Hepatic TG increased in the regenerating liver in all models, even in animals in which lipid accumulation is genetically constrained. However, in no model -- and over a >90-fold range of hepatic TG content -- was liver regeneration significantly impaired following PH., Conclusion: Although hepatic TG content is widely variable and increases during liver regeneration, alterations in neither exogenous or endogenous lipid metabolic pathways, demonstrated to promote or diminish hepatic steatosis, influence hepatocyte proliferation.

The structural mechanism of allosteric communication between retinoid X receptor (RXR) and its heterodimer partners remains controversial. As a first step towards addressing this question, we report a nuclear magnetic resonance (NMR) study on the GW1929-bound peroxisome proliferator-activated receptor gamma (PPARgamma) ligand-binding domain (LBD) with and without the 9-cis-retinoic acid (9cRA)-bound RXRalpha LBD. Sequence-specific 13C(alpha), 13C(beta), and 13CO resonance assignments have been established for over 95% of the 275 residues in the PPARgamma LBD monomer. The 1HN, 15N, and 13CO chemical shift perturbations induced by the RXRalpha LBD binding are located at not only the heterodimer interface that includes the C-terminal residue Y477 but also residues Y473 and K474 in the activation function-2 (AF-2) helix. This result suggests that 9cRA-bound RXRalpha can affect the PPARgamma AF-2 helix in solution and demonstrates that NMR is a powerful new tool for studying the mechanism of allosteric ligand activation in RXR heterodimers.

Rapid advances in genome sequencing and gene expression microarray technologies are providing unprecedented opportunities to identify specific genes involved in complex biological processes, such as development, signal transduction, and disease. The vast amount of data generated by these technologies has presented new challenges in bioinformatics. To help organize and interpret microarray data, new and efficient computational methods are needed to: (1) distinguish accurately between different biological or clinical categories (e.g., malignant vs. benign), and (2) identify specific genes that play a role in determining those categories. Here we present a novel and simple method that exhaustively scans microarray data for unambiguous gene expression patterns. Such patterns of data can be used as the basis for classification into biological or clinical categories. The method, termed the Characteristic Attribute Organization System (CAOS), is derived from fundamental precepts in systematic biology. In CAOS we define two types of characteristic attributes ('pure' and 'private') that may exist in gene expression microarray data. We also consider additional attributes ('compound') that are composed of expression states of more than one gene that are not characteristic on their own. CAOS was tested on three well-known cancer DNA microarray data sets for its ability to classify new microarray samples. We found CAOS to be a highly accurate and robust class prediction technique. In addition, CAOS identified specific genes, not emphasized in other analyses, that may be crucial to the biology of certain types of cancer. The success of CAOS in this study has significant implications for basic research and the future development of reliable methods for clinical diagnostic tools.

Avian systematics has a rich history, as evolutionary biologists have long been interested in this conspicuous and diverse group of vertebrates. Many prominent scientists, and evolutionary biologists in particular, have focused their efforts on birds. Perhaps no other group of vertebrates is so well studied. Yet, despite the attention paid to this group, much about the history of the class Aves remains controversial, both with respect to the origin of birds and the history since that origin. This puts avian systematists in a unique position, with so much information available and so many unanswered questions to pursue. The fact that avian ordinal relationships are still the center of much controversy speaks to the difficulty of the problem. While many prominent morphologists have worked on avian relationships, relatively few morphological studies have identified characters with informative variation for interordinal relationships. Molecular data offer the hope for phylogenetic information not present (or not discovered) in avian anatomy. Since the first study of avian proteins for the purposes of systematics (Sibley, 1960), several prominent molecular systematists have devoted tremendous time and resources to solving the problems of avian relationships using molecular characters (see Barrowclough, 1992 and Sheldon and Bledsoe, 1993 and references therein). So far, their efforts have not produced adequate resolution, at least not in the minds of most practicing systematists. Here, we first outline what we think we do know about higher order avian systematics and discuss some specific cases of molecular data applied to this question. Next, we consider some of the problems which may be blocking a clearer understanding of avian relationships. We then go on to offer some new directions for systematists working on this difficult group.

Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.

Nucleotide transitions are frequently down-weighted relative to transversions in phylogenetic analysis. This is based on the assumption that transitions, by virtue of their greater evolutionary rate, exhibit relatively more homoplasy and are therefore less reliable phylogenetic characters. Relative amounts of homoplastic and consistent transition and transversion changes in mitochondrial protein coding genes were determined from character-state reconstructions on a highly corroborated phylogeny of mammals. We found that although homoplasy was related to evolutionary rates and was greater for transitions, the absolute number of consistent transitions greatly exceeded the number of consistent transversions. Consequently, transitions provided substantially more useful phylogenetic information than transversions. These results suggest that down-weighting transitions may be unwarranted in many cases. This conclusion was supported by the fact that a range of transition: transversion weighting schemes applied to various mitochondrial genes and genomic partitions rarely provided improvement in phylogenetic estimates relative to equal weighting, and in some cases weighting transitions more heavily than transversions was most effective.

Patterns of molecular evolution in birds have long been considered anomalous. Compared with other vertebrates, birds have reduced levels of genetic divergence between groups of similar taxonomic ranks for a variety of nuclear and mitochondrial markers. This observation led to the avian constraint hypothesis, which identifies increased functional constraint on avian proteins as the cause for the reduction in genetic divergence. Subsequent investigations provided additional support for the avian constraint hypothesis when rates of molecular evolution were found to be slower in birds than in mammals in a variety of independent calibrations. It is possible to test the avian constraint hypothesis as an explanation for this avian slowdown by comparing DNA sequence data from protein-coding regions in birds and homologous regions in mammals. The increased selective constraints should lead to a reduction in the proportion of amino acid replacement substitutions. To test for such a decrease, we calculated the numbers of amino acid replacement substitutions per replacement site (dN) and silent substitutions per silent site (dS) for the complete mitochondrial cytochrome b gene using 38 avian and 43 mammalian comparisons that were phylogenetically independent. We find that dN/dS is significantly smaller in birds than in mammals. This difference cannot be explained by differences in codon bias affecting dS values. We suggest that the avian slowdown can be explained, at least in part, by a decreased tolerance for amino acid substitutions in avian species relative to mammalian species.

Variation in rates of molecular evolution now appears to be widespread. The demonstration that body size is correlated with rates of molecular evolution suggests that physiological and ecological factors may be involved in molecular rate variation, but large-scale comparative studies are still lacking. Here, we use complete cytochrome b sequences from 85 species of tube-nosed seabirds (order Procellariiformes) and 5 outgroup species of penguins (order Sphenisciformes) to test for an association between body mass and rates of molecular evolution within the former avian order. Cladistic analysis of the 90 sequences estimates a phylogeny largely consistent with the traditional taxonomy of the Procellariiformes. The Diomedeidae, Procellariidae, and Pelecanoididae are monophyletic, while the Hydrobatidae are basal and paraphyletic. However, the two subfamilies within the Hydrobatidae (Hydrobatinae and Oceanitinae) are monophyletic. A likelihood ratio test detects significant deviation from clocklike evolution in our data. Using a sign test for an association between body mass and branch length in the seabird phylogeny, we find that larger taxa tend to have shorter terminal branch lengths than smaller taxa. This observation suggests that rates of mitochondrial DNA evolution are slower for larger taxa. Rate calibrations based on the fossil record reveal concordant body size effects. We interpret these results as evidence for a metabolic rate effect, as the species in this order exhibit large differences in metabolic rates, which are known to be highly correlated with body mass in this group. Our results support previous findings of body size effects and show that this effect can be significant even within a single avian order. This suggests that even lineage-specific molecular clocks may not be tenable if calibrations involve taxa with different metabolic rates.