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Abstract The invasion of Anopheles stephensi in Africa warrants investigation of neighboring countries. In this study, genetic analysis was applied to determine the status of An. stephensi in southern Yemen. Cytochrome c oxidase subunit I (COI) and internal transcribed spacer 2 (ITS2) were sequenced in An. stephensi collected in Dar Sa’ad (Aden City), Tuban, Rodoom, Al Mukalla, and Sayhut, and phylogenetic analysis confirmed An. stephensi identity. Our analyses revealed that the ITS2 sequences were identical in all An. stephensi, while COI analysis revealed two haplotypes, one previously reported in northern Horn of Africa and one identified in this study for the first time. Overall, these findings revealed low levels of mitochondrial DNA diversity, which is consistent with a more recent population introduction in parts of southern Yemen relative to the Horn of Africa. Further, whole genomic analysis is needed to elucidate the original connection with invasive populations of An. stephensi in the Horn of Africa. Graphical Abstract

Abstract Anopheles stephensi invasion in Ethiopia poses a risk of increased malaria disease burden in the region. Thus, understanding the insecticide resistance profile and population structure of the recently detected An. stephensi population in Fiq, Ethiopia, is critical to inform vector control to stop the spread of this invasive malaria species in the country. Following entomological surveillance for An. stephensi in Fiq, Somali region, Ethiopia, we confirmed the presence of An. stephensi morphologically and molecularly in Fiq. Characterization of larval habitats and insecticide susceptibility tests revealed that Fiq An. stephensi is most often found in artificial containers and is resistant to most adult insecticides tested (organophosphates, carbamates, pyrethroids) except for pirimiphos-methyl and PBO-pyrethroids. However, the immature larval stage was susceptible to temephos. Further comparative genomic analyses with previous An. stephensi populations from Ethiopia using 1704 biallelic SNPs revealed genetic relatedness between Fiq An. stephensi and east-central Ethiopia An. stephensi populations, particularly Jigjiga An. stephensi. Our findings of the insecticide resistance profile, coupled with the likely source population of Fiq An. stephensi, can inform vector control strategies against this malaria vector in Fiq and Jigjiga to limit further spread out of these two locations to other parts of the country and continent.

We detected malaria vector Anopheles stephensi mosquitoes in the Al Hudaydah governorate in Yemen by using DNA sequencing. We report 2 cytochrome c oxidase subunit I haplotypes, 1 previously found in Ethiopia, Somalia, Djibouti, and Yemen. These findings provide insight into invasive An. stephensi mosquitoes in Yemen and their connection to East Africa.

Abstract Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.

The integrator complex is required for the synthesis of protein coding and non-coding RNA and contains the protein INTS13. Here, the authors find germline mutations in INTS13 in two families with oral facial digital syndrome and show that the mutation affects the c-terminal domain of the protein and disrupts cilliogenesis.

Abstract Malaria control in Somaliland depends on the effective identification of potential malaria vectors, particularly those that may be invasive. The malaria vector Anopheles stephensi has been detected in multiple countries in the Horn of Africa (HOA), but data on its geographic distribution and population genetic diversity are incomplete. We implemented a vector surveillance program and performed molecular analysis of Anopheles in three urban areas in Somaliland. Our study confirmed the presence of both the invasive An. stephensi and the long-established HOA malaria vector Anopheles arabiensis. Further analysis of An. stephensi genetic diversity revealed three cytochrome oxidase I (COI) haplotypes, all of which have been observed in other countries in East Africa and one also observed in South Asia. We also detected the knockdown resistance (kdr) L1014F mutation, which is associated with pyrethroid resistance; this finding supports the need for further assessment of the potential for insecticide resistance. The detection of multiple haplotypes previously observed in other regions of East Africa indicates that An. stephensi is an established population in Somaliland and likely shares its origin with other newly identified An. stephensi populations in East Africa. The detection of genetic diversity in An. stephensi in Somaliland provides a basis for future studies on the history of the species in the region and its dispersal throughout East Africa. Graphical Abstract

Abstract Background The recent detection of the South Asian malaria vector Anopheles stephensi in the Horn of Africa (HOA) raises concerns about the impact of this mosquito on malaria transmission in the region. Analysis of An. stephensi genetic diversity and population structure can provide insight into the history of the mosquito in the HOA to improve predictions of future spread. We investigated the genetic diversity of An. stephensi in eastern Ethiopia, where detection suggests a range expansion into this region, in order to understand the history of this invasive population. Methods We sequenced the cytochrome oxidase subunit I (COI) and cytochrome B gene (CytB) in 187 An. stephensi collected from 10 sites in Ethiopia in 2018. Population genetic, phylogenetic, and minimum spanning network analyses were conducted for Ethiopian sequences. Molecular identification of blood meal sources was also performed using universal vertebrate CytB sequencing. Results Six An. stephensi COI-CytB haplotypes were observed, with the highest number of haplotypes in the northeastern sites (Semera, Bati, and Gewana towns) relative to the southeastern sites (Kebridehar, Godey, and Degehabur) in eastern Ethiopia. We observed population differentiation, with the highest differentiation between the northeastern sites compared to central sites (Erer Gota, Dire Dawa, and Awash Sebat Kilo) and the southeastern sites. Phylogenetic and network analysis revealed that the HOA An. stephensi are more genetically similar to An. stephensi from southern Asia than from the Arabian Peninsula. Finally, molecular blood meal analysis revealed evidence of feeding on cows, goats, dogs, and humans, as well as evidence of multiple (mixed) blood meals. Conclusion We show that An. stephensi is genetically diverse in Ethiopia and with evidence of geographical structure. Variation in the level of diversity supports the hypothesis for a more recent introduction of An. stephensi into southeastern Ethiopia relative to the northeastern region. We also find evidence that supports the hypothesis that HOA An. stephensi populations originate from South Asia rather than the Arabian Peninsula. The evidence of both zoophagic and anthropophagic feeding support the need for additional investigation into the potential for livestock movement to play a role in vector spread in this region. Graphical Abstract

Background The Rwanda Human Resources for Health Program (HRH Program) is a 7-year (2012-2019) health professional training initiative led by the Government of Rwanda with the goals of training a large, diverse, and competent health workforce and strengthening the capacity of academic institutions in Rwanda. Methods The data for this organizational case study was collected through official reports from the Rwanda Ministry of Health (MoH) and 22 participating US academic institutions, databases from the MoH and the College of Medicine and Health Sciences (CMHS) in Rwanda, and surveys completed by the co-authors. Results In the first 5 years of the HRH Program, a consortium of US academic institutions has deployed an average of 99 visiting faculty per year to support 22 training programs, which are on track to graduate almost 4600 students by 2019. The HRH Program has also built capacity within the CMHS by promoting the recruitment of Rwandan faculty and the establishment of additional partnerships and collaborations with the US academic institutions. Conclusion The milestones achieved by the HRH Program have been substantial although some challenges persist. These challenges include adequately supporting the visiting faculty; pairing them with Rwandan faculty (twinning); ensuring strong communication and coordination among stakeholders; addressing mismatches in priorities between donors and implementers; the execution of a sustainability strategy; and the decision by one of the donors not to renew funding beyond March 2017. Over the next 2 academic years, it is critical for the sustainability of the 22 training programs supported by the HRH Program that the health-related Schools at the CMHS significantly scale up recruitment of new Rwandan faculty. The HRH Program can serve as a model for other training initiatives implemented in countries affected by a severe shortage of health professionals.

Upon Notch pathway activation, the receptor is cleaved to release the Notch intracellular domain (NICD), which translocates to the nucleus to activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box). We show that mutations in the N1-Box inhibit NICD1 degradation and that the N1-Box is transferable for the promotion of degradation of heterologous proteins in Xenopus egg extracts and in cultured human cells. Mutation of the N1-Box enhances Notch1 activity in cultured human cells and zebrafish embryos. Human cancer mutations within the N1-Box enhance Notch1 signaling in transgenic zebrafish, highlighting the physiological relevance of this destruction signal. We find that binding of the Notch nuclear factor, CSL, to the N1-Box blocks NICD1 turnover. Our studies reveal a mechanism by which degradation of NICD1 is regulated by the N1-Box to minimize stochastic flux and to establish a threshold for Notch1 pathway activation.

Cdc14 is an evolutionarily conserved serine/threonine phosphatase. Originally identified in Saccharomyces cerevisiae as a cell cycle regulator, its role in other eukaryotic organisms remains unclear. In Drosophila melanogaster, Cdc14 is encoded by a single gene, thus facilitating its study. We found that Cdc14 expression is highest in the testis of adult flies and that cdc14 null flies are viable. cdc14 null female and male flies do not display altered fertility. cdc14 null males, however, exhibit decreased sperm competitiveness. Previous studies have shown that Cdc14 plays a role in ciliogenesis during zebrafish development. In Drosophila, sensory neurons are ciliated. We found that the Drosophila cdc14 null mutants have defects in chemosensation and mechanosensation as indicated by decreased avoidance of repellant substances and decreased response to touch. In addition, we show that cdc14 null mutants have defects in lipid metabolism and resistance to starvation. These studies highlight the diversity of Cdc14 function in eukaryotes despite its structural conservation.

Malaria remains a major threat to global health with [approximately equal to]247 million cases reported in 2021 (2). An invasive malaria vector, Anopheles stephensi mosquito, has emerged in Africa; the [...]

Summary We previously reported that the small nuclear RNA processing complex, Integrator, is required for dynein recruitment to the nuclear envelope at mitotic onset in cultured human cells. We now report an additional role for INT in ciliogenesis. Depletion of INT subunits from cultured human cells results in loss of primary cilia. We provide evidence that the requirements for INT in dynein localization and ciliogenesis are uncoupled: proteins essential for ciliogenesis are not essential for dynein recruitment to the nuclear envelope, while depletion of known regulators of perinuclear dynein has minimal effects on ciliogenesis. Taken together, our data support a model in which INT ensures proper processing of distinct pools of transcripts encoding components that independently promote perinuclear dynein enrichment and ciliogenesis.

Motivated by the ubiquity of control-affine systems in optimal control theory, we investigate the geometry of point-affine control systems with metric structures in dimensions two and three. We compute local isometric invariants for point-affine distributions of constant type with metric structures for systems with 2 states and 1 control and systems with 3 states and 1 control, and use Pontryagin's maximum principle to find geodesic trajectories for homogeneous examples. Even in these low dimensions, the behavior of these systems is surprisingly rich and varied.

Motivated by control-affine systems in optimal control theory, we introduce the notion of a point-affine distribution on a manifold X – i.e., an affine distribution F together with a distinguished vector field contained in F. We compute local invariants for point-affine distributions of constant type when dim(X) = n, rank(F) = n–1, and when dim(X) = 3, rank(F) = 1. Unlike linear distributions, which are characterized by integer-valued invariants – namely, the rank and growth vector – when dim(X) ≤ 4, we find local invariants depending on arbitrary functions even for rank 1 point-affine distributions on manifolds of dimension 2.

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.

The invasion of Anopheles stephensi in Africa warrants investigation of neighboring countries. In this study, genetic analysis was applied to determine the status of An. stephensi in southern Yemen. Cytochrome c oxidase subunit I (COI) and internal transcribed spacer 2 (ITS2) were sequenced in An. stephensi collected in Dar Sa'ad (Aden City), Tuban, Rodoom, Al Mukalla, and Sayhut, and phylogenetic analysis confirmed An. stephensi identity. Our analyses revealed that the ITS2 sequences were identical in all An. stephensi, while COI analysis revealed two haplotypes, one previously reported in northern Horn of Africa and one identified in this study for the first time. Overall, these findings revealed low levels of mitochondrial DNA diversity, which is consistent with a more recent population introduction in parts of southern Yemen relative to the Horn of Africa. Further, whole genomic analysis is needed to elucidate the original connection with invasive populations of An. stephensi in the Horn of Africa. [ABSTRACT FROM AUTHOR]

In normal hearing (NH), the perception of the gender of a speaker is strongly affected by two anatomically related vocal characteristics: the fundamental frequency (F0), related to vocal pitch, and the vocal tract length (VTL), related to the height of the speaker. Previous studies on gender categorization in cochlear implant (CI) users found that performance was variable, with few CI users performing at the level of NH listeners. Data collected with recorded speech produced by multiple talkers suggests that CI users might rely more on F0 and less on VTL than NH listeners. However, because VTL cannot be accurately estimated from recordings, it is difficult to know how VTL contributes to gender categorization. In the present study, speech was synthesized to systematically vary F0, VTL, or both. Gender categorization was measured in CI users, as well as in NH participants listening to unprocessed (only synthesized) and vocoded (and synthesized) speech. Perceptual weights for F0 and VTL were derived from the performance data. With unprocessed speech, NH listeners used both cues (normalized perceptual weight: F0 = 3.76, VTL = 5.56). With vocoded speech, NH listeners still made use of both cues but less efficiently (normalized perceptual weight: F0 = 1.68, VTL = 0.63). CI users relied almost exclusively on F0 while VTL perception was profoundly impaired (normalized perceptual weight: F0 = 6.88, VTL = 0.59). As a result, CI users' gender categorization was abnormal compared to NH listeners. Future CI signal processing should aim to improve the transmission of both F0 cues and VTL cues, as a normal gender categorization may benefit speech understanding in competing talker situations. © 2014 Association for Research in Otolaryngology.