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ABSTRACT Biological invasions pose significant threats to ecological and economic stability, with invasive pests like the Asian longhorned beetle (Anoplophora glabripennis Motschulsky, ALB) causing substantial damage to forest ecosystems. Effective pest management relies on comprehensive knowledge of the insect's biology and invasion history. This study uses genomics to address these knowledge gaps and inform existing biosurveillance frameworks. We used 2768 genome‐wide single nucleotide polymorphisms to compare invasive A. glabripennis populations in North America, using genomic variation to trace their sources of invasion and spread patterns, thereby refining our understanding of this species' invasion history. We found that most North American A. glabripennis infestations were distinct, resulting from multiple independent introductions from the native range. Following their introduction, all invasive populations experienced a genetic bottleneck which was followed by a population expansion, with a few also showing secondary spread to satellite infestations. Our study provides a foundation for a genome‐based biosurveillance tool that can be used to clarify the origin of intercepted individuals, allowing regulatory agencies to strengthen biosecurity measures against this invasive beetle.

Abstract To evaluate immune responses to COVID-19 vaccines in adults aged 50 years and older, spike protein (S)-specific antibody concentration, avidity, and function (via angiotensin-converting enzyme 2 (ACE2) inhibition surrogate neutralization and antibody dependent cellular phagocytosis (ADCP)), as well as S-specific T cells were quantified via activation induced marker (AIM) assay in response to two-dose series. Eighty-four adults were vaccinated with either: mRNA/mRNA (mRNA-1273 and/or BNT162b2); ChAdOx1-S/mRNA; or ChAdOx1-S/ChAdOx1-S. Anti-S IgG concentrations, ADCP scores and ACE2 inhibiting antibody concentrations were highest at one-month post-second dose and declined by four-months post-second dose for all groups. mRNA/mRNA and ChAdOx1-S/mRNA schedules had significantly higher antibody responses than ChAdOx1-S/ChAdOx1-S. CD8+ T-cell responses one-month post-second dose were associated with increased ACE2 surrogate neutralization. Antibody avidity (total relative avidity index) did not change between one-month and four-months post-second dose and did not significantly differ between groups by four-months post-second dose. In determining COVID-19 correlates of protection, a measure that considers both antibody concentration and avidity should be considered.

IntroductionBreast cancer (BC) is the most common cancer affecting women in the United States. Ductal carcinoma in situ (DCIS) is the earliest identifiable pre-invasive BC lesion. Estimates show that 14 to 50% of DCIS cases progress to invasive BC.MethodsOur objective was to identify nuclear matrix proteins (NMP) with specifically altered expression in DCIS and later stages of BC compared to non-diseased breast reduction mammoplasty and a contralateral breast explant culture using mass spectrometry and RNA sequencing to accurately identify aggressive DCIS.ResultsSixty NMPs were significantly differentially expressed between the DCIS and non-diseased breast epithelium in an isogenic contralateral pair of patient-derived extended explants. Ten of the sixty showed significant mRNA expression level differences that matched the protein expression. These 10 proteins were similarly expressed in non-diseased breast reduction cells. Three NMPs (RPL7A, RPL11, RPL31) were significantly upregulated in DCIS and all other BC stages compared to the matching contralateral breast culture and an unrelated non-diseased breast reduction culture. RNA sequencing analyses showed that these three genes were increasingly upregulated with BC progression. Finally, we identified three NMPs (AHNAK, CDC37 and DNAJB1) that were significantly downregulated in DCIS and all other BC stages compared to the isogenically matched contralateral culture and the non-diseased breast reduction culture using both proteomics and RNA sequencing techniques.DiscussionThese genes should form the basis of, or contribute to, a molecular diagnostic panel that could identify DCIS lesions likely to be indolent and therefore not requiring aggressive treatment.

Tropical climate conditions favor landscape evolution and the formation of highly weathered soils under different pedogenic processes due to certain differential properties. Traditional analysis coupled with VNIR-SWIR reflectance spectroscopy and X-ray diffractometry (XRD) analyses can reveal such characteristics. Several researchers cited throughout this study already discussed the possible applications of analyses in this field. All agree that integrated knowledge (holistic) can drive the future of the soil sciences. However, few refer to the potential of soil spectroscopy in deriving pedogenetic information. Thus, this paper aimed to assess pedomorphogeological relationships in a representative toposequence of the Brazilian Midwest using traditional analyses and geotechnologies. We performed landscape observations and soil sampling in the field. The laboratory’s physical, chemical, spectral, and mineralogical determinations supported the soil classification according to the World Reference Basis (WRB/FAO) system. Based on the analysis results, we divided five profiles into two soil groups (highly and slightly weathered soils) using Pearson’s correlation and hierarchical clustering analysis (HCA). Traditional analyses determined the diagnostic attributes. Spectroscopic readings from 0.35 to 2.5 µm wavelengths and XRD supported identifying soil attributes and properties. Finally, all soil classes were correlated according to correspondent reflectance spectra and primary pedological attributes. There was a strong correlation between spectral oxide features and X-ray diffraction peaks. The HCA based on oxide content and mineral composition validated the previous soil grouping. Thus, we could assess the pedomorphogeological relationships through VNIR-SWIR spectroscopy, XRD, and traditional analyses concerning pedogenic processes through their correlation with soil properties resulting from these processes. However, periodic measurements are required, making orbital sensing a continuous data source for soil monitoring.

MECP2 Duplication Syndrome (MDS) is a rare, severe neurodevelopmental disorder arising from duplications in the Xq28 region containing the MECP2 gene that predominantly affects males. We generated five human induced pluripotent stem cell (iPSC) lines from the fibroblasts of individuals carrying between 0.355 and 11.2 Mb size duplications in the chromosomal locus containing MECP2. All lines underwent extensive testing to confirm MECP2 duplication and iPSC-related features such as morphology, pluripotency markers, and trilineage differentiation potential. These lines are a valuable resource for molecular and functional studies of MDS as well as screening for a variety of therapeutic approaches.

Pedological maps in suitable scales are scarce in most countries due to the high costs involved in soil surveying. Therefore, methods for surveying and mapping must be developed to overpass the cartographic material obtention. In this sense, this work aims at assessing a digital soil map (DSM) built by multispectral data extrapolation from a source area to a target area using the ASTER time series modeling technique. For that process, eight representative toposequences were established in two contiguous micro-watersheds, with a total of 42 soil profiles for analyses and classification. We found Ferralsols, Plinthosols, Regosols, and a few Cambisols, Arenosols, Gleisols, and Histosols, typical of tropical regions. In the laboratory, surface soil samples were submitted to spectral readings from 0.40 µm to 2.50 µm. The soil spectra were morphologically interpreted, identifying shapes and main features typical of tropical soils. Soil texture grouped the curves by cluster analysis, forming a spectral library (SL). In parallel, an ASTER time series (2001, 2004, and 2006) was processed, generating a bare soil synthetic soil image (SySI) covering 39.7% of the target area. Multiple Endmember Spectral Mixture Analysis modeled the SL on the SySI generating DSM with 73% of Kappa index, in which identified about 77% is covered by rhodic Ferralsols. Besides the overestimation, the DSM represented the study area’s pedodiversity. Given the discussion raised, we consider including subsoil data and other features using other sensors in operations modeled by machine learning algorithms to improve results.

Purpose: To evaluate the patient-reported outcomes of primary direct visual internal urethrotomy (DVIU) and nontransecting bulbar urethroplasty techniques (NTBU) for the short segment (

Economic analysis of the tourism industry is a critical tool for local industries and governments to estimate, understand, and forecast the tourism potential and economic performance of a destination, especially amidst a crisis such as the COVID-19 pandemic. In this study, we take Macao as a case study, perform an analysis using an input-output framework. By constructing a tourism satellite account and a dynamic stochastic general equilibrium model, we estimate the contribution of the tourism industry to the economy of Macao and assess the ramifications of several government policies to mitigate the impact of COVID-19. Our findings provide the Macao government and local industrial stakeholders with critical information for pandemic mitigation and recovery strategies.

An electrically conductive metal typically transmits or absorbs a spin current. Here, we report on evidence that interfacing two metal thin films can suppress spin transmission and absorption. We examine spin pumping in spin-source/spacer/spin-sink heterostructures, where the spacer consists of metallic Cu and Cr thin films. The Cu/Cr spacer largely suppresses spin pumping—i.e., neither transmitting nor absorbing a significant amount of spin current—even though Cu or Cr alone transmits a sizable spin current. The antiferromagnetism of Cr is not essential for the suppression of spin pumping, as we observe similar suppression with Cu/V spacers with V as a nonmagnetic analog of Cr. We speculate that diverse combinations of spin-transparent metals may form interfaces that suppress spin pumping, although the underlying mechanism remains unclear. Our work may stimulate a new perspective on spin transport in metallic multilayers.

Abstract SMIFH2 is a small molecule inhibitor of the formin family of cytoskeletal regulators that was originally identified in a screen for suppression of actin polymerization induced by the mouse formin Diaphanous 1 (mDia1). Despite widespread use of this compound, it is unknown whether SMIFH2 inhibits all human formins. Additionally, the nature of protein/inhibitor interactions remains elusive. We assayed SMIFH2 against human formins representing six of the seven mammalian classes and found inhibitory activity against all formins tested. We synthesized a panel of SMIFH2 derivatives and found that, while many alterations disrupt SMIFH2 activity, substitution of an electron-donating methoxy group in place of the bromine along with halogenation of the furan ring increases potency by approximately five-fold. Similar to SMIFH2, the active derivatives are also pan-inhibitors for the formins tested. This result suggests that while potency can be improved, the goal of distinguishing between highly conserved FH2 domains may not be achievable using the SMIFH2 scaffold.

ObjectiveTo perform a systematic review assessing the impact of the different management options on health-related quality of life (HRQoL) of patients with localized renal masses or renal cell carcinomas (LRM/LRCC). Materials and MethodsSearches covering PubMed, Embase (Ovid), CENTRAL, PsycINFO (Ovid), CINAHL (EBSCO), and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for papers published up to 25 April 2021. Methods as per Cochrane Handbook were followed. “Modality” of treatment included radical nephrectomy (RN), nephron-sparing surgery (NSS), thermal ablation (TA), and active surveillance (AS). “Approach” was categorized as open incision and minimally invasive surgery (MIS). Risk of bias was assessed by ROBINS-I and Cochrane RoB 2 for observational studies and randomized controlled trials, respectively and certainty of the evidence by GRADE. ResultsSixteen observational studies and 1 randomized controlled trial (2.370 patients) met inclusion criteria. Fifteen different patient reported outcome measures (PROMs) were identified. Heterogeneity prevented quantitative analysis.Generic HRQoL decreases after RN and NSS, recovers within 6 to 12 months, and mostly overlaps with baseline values, irrespective of modality. Cancer-specific HRQoL improves faster after open-NSS than open-RN. The detrimental effect of RN may persist long-term in cross-evaluations. QoL scales significantly decrease after open surgery and MIS during the first weeks but improve faster after MIS. They are similar for both approaches at 1 year. Long-term cancer-specific QoL is similar for MIS and open procedures. Fear of recurrence is lower in older patients and affected by neither modality nor approach. ConclusionsLow quality evidence supports the use of MIS over the open approach when HRQoL is considered in the management of LRMs/LRCCs; data regarding the effect of the treatment modality of the LRM/LRCC show contradictory outcomes.

We present the tidal disruption event (TDE) AT2022lri, hosted in a nearby (≈144 Mpc) quiescent galaxy with a low-mass massive black hole (10 ^4 M _⊙ < M _BH < 10 ^6 M _⊙ ). AT2022lri belongs to the TDE-H+He subtype. More than 1 Ms of X-ray data were collected with NICER, Swift, and XMM-Newton from 187 to 672 days after peak. The X-ray luminosity gradually declined from 1.5 × 10 ^44 erg s ^−1 to 1.5 × 10 ^43 erg s ^−1 and remains much above the UV and optical luminosity, consistent with a super-Eddington accretion flow viewed face-on. Sporadic strong X-ray dips atop a long-term decline are observed, with a variability timescale of ≈0.5 hr–1 days and amplitude of ≈2–8. When fitted with simple continuum models, the X-ray spectrum is dominated by a thermal disk component with inner temperature going from ∼146 to ∼86 eV. However, there are residual features that peak around 1 keV, which, in some cases, cannot be reproduced by a single broad emission line. We analyzed a subset of time-resolved spectra with two physically motivated models describing a scenario either where ionized absorbers contribute extra absorption and emission lines or where disk reflection plays an important role. Both models provide good and statistically comparable fits, show that the X-ray dips are correlated with drops in the inner disk temperature, and require the existence of subrelativistic (0.1–0.3 c ) ionized outflows. We propose that the disk temperature fluctuation stems from episodic drops of the mass accretion rate triggered by magnetic instabilities or/and wobbling of the inner accretion disk along the black hole’s spin axis.

PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.

HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.

Introduction: Pelvic hypoperfusion caused by atherosclerosis has been proposed as a cause of lower urinary tract dysfunction including overactive bladder syndrome (OAB). Limited data indicate that OAB patients with concomitant diabetes or hypertension, known risk factors of atherosclerosis, may exhibit greater baseline OAB symptoms and slightly smaller therapeutic responses to treatment, but the impact of a combined presence of diabetes and hypertension has not been reported. Therefore, we have explored whether the combined presence of both comorbidities is associated with greater baseline OAB symptoms than that of either comorbidity alone. Secondary questions were exploration of the impact of either comorbidity on baseline symptoms, and of the impact of either comorbidity alone and their combination on therapeutic responses.Methods: Data from two non-interventional studies applying treatment with propiverine ER 30 or 45 mg/d for 12 weeks were analyzed.Results: Number of urgency episodes in the combination group was greater than with each comorbidity alone. The impact of comorbidities on baseline intensity of incontinence, frequency or nocturia or Patient Perception of Bladder Condition was less consistent or absent. Either comorbidity alone was associated with a smaller % improvement of symptoms, and their combination had a greater effect than either alone. However, all attenuations associated with comorbidity were small relative to the overall improvement. Conclusions: We conclude that comorbidities of diabetes and hypertension have detectable effects on OAB symptoms and treatment responses, but the small magnitude of these alterations does not justify changing existing paradigms for the clinical management of OAB.

Abstract A chronic Kidney Disease of unknown etiology (CKDu) has emerged with disproportionately high prevalence across dry lowland agricultural communities globally. Here we present the results of a prospective cohort of 293 patients with CKDu in the endemic region of Wilgamuwa, Sri Lanka, in whom we measured baseline kidney function and undertook quarterly follow up over 2 years. Well water was the primary historic drinking water source in the region, although a majority (68%) of participants reported switching to reverse osmosis water during study follow ups. Participants who reported ever drinking from well water had estimated glomerular filtration rates −6.7 (SD: 2.8) ml/min/1.73 m2 lower than participants who did not drink from well water historically (p = 0.0184) during the study period. Geospatial analysis identifies a cluster within the region where CKDu progression is significantly higher than the surrounding area. Samples of household wells (n = 262) indicated 68% had detectable agrochemical compounds with concentration above global water quality standards. It is expected that the detected contaminants compounds are indicators of poor water quality and that there is likely additional agrochemical exposure including commercial additives that may contribute to CKDu onset and/or progression. Thus, our study finds that well water exposure during a person’s lifetime in this region is associated with kidney function decline and identifies and quantifies putative nephrotoxic agrochemicals above safe drinking water concentrations in these wells.

IntroductionDespite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic. The mechanisms underlying osimertinib resistance are heterogenous. While genetic mutations within EGFR or other cancer driver pathways mediated mechanisms are well-documented, the role of tumor cell and tumor immune microenvironment in mediating the response to osimertinib remains elusive.Methods and resultsHere, using a syngeneic mouse model of EGFR-mutant lung cancer, we show that tumor regression elicited by osimertinib requires activation of CD8+ T cells. However, tumor-associated macrophages (TAMs) accumulated in advanced tumors inhibit CD8+ T cell activation and diminish the response to osimertinib. These results are corroborated by analyses of clinical data. Notably, reprogramming TAMs with a systemic STING agonist MSA-2 reinvigorates antitumor immunity and leads to durable tumor regression in mice when combined with osimertinib.DiscussionOur results reveal a new mechanism of EGFR-TKI resistance and suggest a new therapeutic strategy for the treatment of EGFR-mutant tumors.

Background Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.Methods PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.Results In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.Conclusions We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.

We conduct a systematic tidal disruption event (TDE) demographics analysis using the largest sample of optically selected TDEs. A flux-limited, spectroscopically complete sample of 33 TDEs is constructed using the Zwicky Transient Facility over 3 yr (from 2018 October to 2021 September). We infer the black hole (BH) mass ( M _BH ) with host galaxy scaling relations, showing that the sample M _BH ranges from 10 ^5.1 M _⊙ to 10 ^8.2 M _⊙ . We developed a survey efficiency corrected maximum volume method to infer the rates. The rest-frame g -band luminosity function can be well described by a broken power law of $\phi ({L}_{g})\propto {\left[{\left({L}_{g}/{L}_{\mathrm{bk}}\right)}^{0.3}+{\left({L}_{g}/{L}_{\mathrm{bk}}\right)}^{2.6}\right]}^{-1}$ , with L _bk = 10 ^43.1 erg s ^−1 . In the BH mass regime of 10 ^5.3 ≲ ( M _BH / M _⊙ ) ≲ 10 ^7.3 , the TDE mass function follows $\phi ({M}_{\mathrm{BH}})\propto {M}_{\mathrm{BH}}^{-0.25}$ , which favors a flat local BH mass function ( ${{dn}}_{\mathrm{BH}}/d\mathrm{log}{M}_{\mathrm{BH}}\approx \mathrm{constant}$ ). We confirm the significant rate suppression at the high-mass end ( M _BH ≳ 10 ^7.5 M _⊙ ), which is consistent with theoretical predictions considering direct capture of hydrogen-burning stars by the event horizon. At a host galaxy mass of M _gal ∼ 10 ^10 M _⊙ , the average optical TDE rate is ≈3.2 × 10 ^−5 galaxy ^−1 yr ^−1 . We constrain the optical TDE rate to be [3.7, 7.4, and 1.6] × 10 ^−5 galaxy ^−1 yr ^−1 in galaxies with red, green, and blue colors.

While animal studies have suggested an association between the presence of hypertension and the presence and/or severity of overactive bladder syndrome (OAB) symptoms, little clinical data is available. We have conducted a pre-specified secondary analysis of a non-interventional study involving 4450 OAB patients being treated with solifenacin to explore the existence of an association between OAB and hypertension using three parallel and overlapping definitions of hypertension to enhance robustness of analysis. Regardless of definition, patients with hypertension were older and had greater OAB symptom severity in univariate analyses. In multiple regression models including age as explanatory covariate, most relationships held up but effect sizes of concomitant hypertension on OAB severity were small (odds ratios

KLF4, OCT4, SOX2 and MYC cooperate to reorganize chromatin during somatic cell reprogramming. Here the authors show that KLF4 forms a liquid-like biomolecular condensate that recruits OCT4 and SOX2, and that condensation of the isolated KLF4 DNA binding domain with DNA is enhanced by CpG methylation

Abstract Background Quality of life outcomes have been used frequently in clinical trials of oral health interventions. This study assessed the effects of a randomized trial on oral health related quality of life comparing an individual-based oral hygiene intervention to a community-based intervention. Methods Participants were recruited from six low-income senior housing residences. Buildings were randomly assigned to receive the individual-based intervention followed by the community-based intervention or to receive the community-based intervention followed by the individual intervention. Participants’ oral hygiene was assessed at baseline (T0), one month after the first intervention (T1) and one month after the second intervention (T2) and six months after the T2 assessment (T3). Oral hygiene was measured by the Gingival Index (GI) and Plaque scores (PS). Surveys collected data on beliefs, attitudes, behaviors and self-reported health status at T0, T1 and T2. Only oral hygiene and quality of life, measured by the General Oral Health Assessment Index (GOHAI), was assessed at all time points. general linear mixed models (GLMM) were used to assess changes in GOHAI over time, the interaction of condition by time and the contribution of psychosocial, behavioral, health status and background variables to changes in GOHAI. Results 331 people completed T0 assessments; 306 completed T1; 285 completed T2 and 268 completed T3. Scores on GOHAI at T0 ranged from 10 to 48 with a mean of 39.7 (sd = 7.8) and a median of 42. At T1, mean GOHAI was 40.7 (sd = 8.2), at T2 mean GOHAI was 41.1 (sd = 7.8) and at T3, GOHAI was 42.3 (sd = 8.2). GLMM showed that GOHAI improved significantly from T0 to T3 (p = 0.01) but the time by intervention interaction was not significant indicating that both interventions were effective in improving GOHAI but one intervention was not better than the other. Ethnicity, health status, worries, self-efficacy, number of missing teeth and symptoms of dry mouth were related to improvements in GOHAI. Neither GI nor PS were related to GOHAI. Conclusions The participants reported relatively good oral health related quality of life which improved significantly over time. Improvement occurred among all participants regardless of condition, suggesting that either intervention would be effective in future studies. Trial Registry: Clinicaltrials.gov, Clinical Trials ID #NCT02419144; Title: A Bi-level Intervention to Improve Older Adult Oral Health Status; Registered 04/07/2015 URL: https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0005H9X&selectaction=Edit&uid=U0000KBK&ts=2&cx=-rajj5q

Public health emergencies like SARS, MERS, and COVID-19 have prioritized surveillance of zoonotic coronaviruses, resulting in extensive genomic characterization of coronavirus diversity in bats. Sequencing viral genomes directly from animal specimens remains a laboratory challenge, however, and most bat coronaviruses have been characterized solely by PCR amplification of small regions from the best-conserved gene. This has resulted in limited phylogenetic resolution and left viral genetic factors relevant to threat assessment undescribed. In this study, we evaluated whether a technique called hybridization probe capture can achieve more extensive genome recovery from surveillance specimens. Using a custom panel of 20,000 probes, we captured and sequenced coronavirus genomic material in 21 swab specimens collected from bats in the Democratic Republic of the Congo. For 15 of these specimens, probe capture recovered more genome sequence than had been previously generated with standard amplicon sequencing protocols, providing a median 6.1-fold improvement (ranging up to 69.1-fold). Probe capture data also identified five novel alpha- and betacoronaviruses in these specimens, and their full genomes were recovered with additional deep sequencing. Based on these experiences, we discuss how probe capture could be effectively operationalized alongside other sequencing technologies for high-throughput, genomics-based discovery and surveillance of bat coronaviruses.

Abstract The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110α, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110α activity, we followed development and growth of mice with heterozygous loss of p110α (Pik3ca +/−) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca +/− mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110α or pharmacological inhibition of p110α activity reduced neurosphere size, but not numbers, in vitro, suggesting that p110α activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects.

Abstract Background The control of lymphatic filariasis (LF) caused by Wuchereria bancrofti in the Central African Region has been hampered by the presence of Loa loa due to severe adverse events that arise in the treatment with ivermectin. The immunochromatographic test (ICT) cards used for mapping LF demonstrated cross-reactivity with L. loa and posed the problem of delineating the LF map. To verify LF endemicity in forest areas of Cameroon where mass drug administration (MDA) has not been ongoing, we used the recently developed strategy that combined serology, microscopy and molecular techniques. Methods This study was carried out in 124 communities in 31 health districts (HDs) where L. loa is present. At least 125 persons per site were screened. Diurnal blood samples were investigated for circulating filarial antigen (CFA) by FTS and for L. loa microfilariae (mf) using TBF. FTS positive individuals were further subjected to night blood collection for detecting W. bancrofti. qPCR was used to detect DNA of the parasites. Results Overall, 14,446 individuals took part in this study, 233 participants tested positive with FTS in 29 HDs, with positivity rates ranging from 0.0 to 8.2%. No W. bancrofti mf was found in the night blood of any individuals but L. loa mf were found in both day and night blood of participants who were FTS positive. Also, qPCR revealed that no W. bancrofti but L.loa DNA was found with dry bloodspot. Positive FTS results were strongly associated with high L. loa mf load. Similarly, a strong positive association was observed between FTS positivity and L loa prevalence. Conclusions Using a combination of parasitological and molecular tools, we were unable to find evidence of W. bancrofti presence in the 31 HDs, but L. loa instead. Therefore, LF is not endemic and LF MDA is not required in these districts.

Objectives Efforts to understand the factors influencing the uptake of reproductive, maternal, newborn, child health and nutrition (RMNCH&N) services in high disease burden low-resource settings have often focused on face-to-face surveys or direct observations of service delivery. Increasing access to mobile phones has led to growing interest in phone surveys as a rapid, low-cost alternatives to face-to-face surveys. We assess determinants of RMNCH&N knowledge among pregnant women with access to phones and examine the reliability of alternative modalities of survey delivery.Participants Women 5–7 months pregnant with access to a phone.Setting Four districts of Madhya Pradesh, India.Design Cross-sectional surveys administered face-to-face and within 2 weeks, the same surveys were repeated among two random subsamples of the original sample: face-to-face (n=205) and caller-attended telephone interviews (n=375). Bivariate analyses, multivariable linear regression, and prevalence and bias-adjusted kappa scores are presented.Results Knowledge scores were low across domains: 52% for maternal nutrition and pregnancy danger signs, 58% for family planning, 47% for essential newborn care, 56% infant and young child feeding, and 58% for infant and young child care. Higher knowledge (≥1 composite score) was associated with older age; higher levels of education and literacy; living in a nuclear family; primary health decision-making; greater attendance in antenatal care and satisfaction with accredited social health activist services. Survey questions had low inter-rater and intermodal reliability (kappa

In the Democratic Republic of Congo (DRC) which contains the greatest area of the second largest rainforest on Earth, people have long been connected to the forest for subsistence and livelihood from wild animals and bushmeat. This qualitative study sought to characterize the bushmeat movement-from hunting wild animals to market sale-and the roles of participants in the animal value chain, as well as their beliefs surrounding zoonotic disease and occupational risk. Actors in in eight bushmeat markets and two ports in Kinshasa, DRC completed semi-structured interviews between 2016 and 2018 in which they expressed belief in transmission of illness from domestic animals to humans, but not from wild animals to humans. Wild animals were viewed as pure and natural, in contrast to domestic animals which were considered tainted by human interference. Participants reported cutting themselves during the process of butchering yet did not consider butchering bushmeat to be a risky activity. Instead, they adopted safety practices learned over time from butchering experts and taught themselves how to butcher in a fashion that reduced the frequency of cutting. In general, butcherers rejected the idea of personal protective equipment use. Port markets were identified as important access points for meat coming from the Congo river and plane transport was identified as important for fresh and live meat coming from Équateur province. Most participants reported having heard about Ebola, but their mistrust in government messaging privileged a word-of-mouth story of witchcraft to be propagated about Ebola's origins. It is critical to better understand how public health messaging about outbreaks can successfully reach high risk communities, and to develop creative risk mitigation strategies for populations in regular contact with animal blood and body fluids. In this paper, we offer suggestions for formal and informal trusted channels through which health messages surrounding zoonotic risk could be conveyed to high-risk populations in Kinshasa.

Background: Young migrant workers working in the industrial zones (IZ) in low and middle-income countries are at risk for HIV and other sexually transmitted diseases. This study examines the sex-related risks of young women migrant workers in the IZ in Vietnam.Materials and Methods: This cross-sectional survey was conducted among 1,061 young migrant women working in the IZ park in Hanoi, Vietnam. Multivariate logistic regression analysis was used to identify factors associated with HIV testing and condom use at last sex.Results: A total of 1,061 young women migrant workers completed the survey in which 652 participants consented to take the initial rapid HIV test. All but one participant tested negative indicating a HIV prevalence of 150 (95% CI: 27–860) per 100,000 population among this population. There were no differences in sexual behavior, use of sexual and reproductive health services, HIV knowledge, perceived HIV risk or alcohol use between those who were HIV tested and those not tested. Single participants reported high rates of first sex while living in the IZ and high rates of condom use during the first-time sex, however, they had low levels of condom use at last sex. While the majority of married participants used the SRH/HIV services, nearly 80% of the single participants who reported having sex never used SRH/HIV services since living in the IZ. However, single participants were over 4 times more likely to use condoms at last sex compared to married participants (OR = 4.67; 95%CI = 2.96–7.85). Participants with vocational school or higher education was more likely to use condom (OR = 2.19; 95%CI = 1.05–4.57). Neither HIV knowledge or alcohol use were associated with condom use.Conclusions: Although HIV prevalence is very low among young women workers in the IZ in Vietnam, a significant number of them engaged in risky sexual behavior and low levels of condom use at last sex as well as low level of using SRH/HIV services highlights a need to develop interventions that provide tailored-made and cultural appropriate SRH education for unmarried female migrant workers to prevent risky sexual behaviors, sexually transmitted diseases and unwanted pregnancy.

We present observations of an extreme radio flare, VT J024345.70-284040.08, hereafter VT J0243, from the nucleus of a galaxy with evidence for historic Seyfert activity at redshift z = 0.074. Between NRAO Very Large Array (VLA) Sky Survey observations in 1993 to VLA Sky Survey observations in 2018, VT J0243 rose from a ∼ GHz radio luminosity of ν L _ν ≲ 10 ^38 erg s ^−1 to ν L _ν ∼ 10 ^40 erg s ^−1 , and still continues to brighten. The radio spectral energy distribution evolution is consistent with a nascent jet that has slowed over ∼3000 days with an average 0.1

Abstract Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain‐of‐function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti‐tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Cephalopods are ecologically and economically important marine groups in the world. Biodiversity description is essential for sustainable utilization of natural resources and to characterize biological entities for conservation. DNA barcoding is an effective tool used for identification of organisms at species level and is been widely used for delineate several ambiguity species. In this study, partial sequence of mitochondrial cytochrome c oxidase 1 (CO1) gene with a mean size of 680 bp was amplified by universal primers. Totally 13 individuals of Cephalopods comprising of three species, were barcoded and genetic variation was analysed. The maximum A+T content (67.60%) was recorded in Cistopus indicus and minimum (63.70%) in Sepioteuthis lessoniana. The maximum K2P distance (0.268) was found between the genus Cistopus and Sepioteuthis whereas the minimum distance (0.188) was observed between Uroteuthis and Sepia. The neighbour joining tree revealed three distinct clades represents Loligonidae, Sepiidae and Octopodidae with high boot strap values. However, Sepioteuthis lessoniana is showing a bifurcated branch and it may due to the co-occurring of cryptic species and till date this species is treated as Sepioteuthis lessoniana complex.

Coronaviruses play an important role as pathogens of humans and animals, and the emergence of epidemics like SARS, MERS and COVID-19 is closely linked to zoonotic transmission events primarily from wild animals. Bats have been found to be an important source of coronaviruses with some of them having the potential to infect humans, with other animals serving as intermediate or alternate hosts or reservoirs. Host diversity may be an important contributor to viral diversity and thus the potential for zoonotic events. To date, limited research has been done in Africa on this topic, in particular in the Congo Basin despite frequent contact between humans and wildlife in this region. We sampled and, using consensus coronavirus PCR-primers, tested 3,561 wild animals for coronavirus RNA. The focus was on bats (38%), rodents (38%), and primates (23%) that posed an elevated risk for contact with people, and we found coronavirus RNA in 121 animals, of which all but two were bats. Depending on the taxonomic family, bats were significantly more likely to be coronavirus RNA-positive when sampled either in the wet (Pteropodidae and Rhinolophidae) or dry season (Hipposideridae, Miniopteridae, Molossidae, and Vespertilionidae). The detected RNA sequences correspond to 15 alpha- and 6 betacoronaviruses, with some of them being very similar (>95% nucleotide identities) to known coronaviruses and others being more unique and potentially representing novel viruses. In seven of the bats, we detected RNA most closely related to sequences of the human common cold coronaviruses 229E or NL63 (>80% nucleotide identities). The findings highlight the potential for coronavirus spillover, especially in regions with a high diversity of bats and close human contact, and reinforces the need for ongoing surveillance.

With the expansion of maker programs in school and out-of-school settings, investigating the connections between making and learning is important for many reasons, not least to build the evidence base needed by educators committed to its practice. In this paper, we argue that, as a relatively new area of inquiry, studies of making can benefit from close dialogue between researchers and the practitioners who have pioneered and continue to develop the practice. We share how a research-practice partnership sought to amplify the voices of informal educators leading afterschool maker programs to address the research question: How can afterschool maker programs support student learning that is valued and relevant to the school day? We show how the research-practice partnership helped to refine a pedagogical framework describing learning dimensions of making and tinkering in ways that reflect the values and expert knowledge of informal educators committed to liberatory forms of education for young people, particularly those from socio-economically and racially marginalized communities.

Introduction: The COVID-19 pandemic has generated diverse reactions, but these have not yet been measured in the Latin American population.Objective: To determine the factors associated with the perception of fatalism in the face of COVID-19 infection in inhabitants of 20 cities in Peru.Material and Methods: A cross-sectional, multicenter study with a sample size of 2 466 people from 20 cities of Peru that measured fatalism during the COVID-19 pandemic was conducted through a validated survey (Cronbach´s alpha: 0,78) consisting of 7 items. Statistical analysis was conducted in terms of each city, and p < 0,05 was considered significant.Results: Of the 2 466 respondents, 36 % were depressed, 26 % thought that they might die, 17 % say that this was evidence of the end of the world, and 9 % could make a fatal decision. Women were more likely to engage in three of the fatalistic behaviors (becoming infected, p = 0,020; infecting others, p = 0,004, and becoming depressed, p = 0,020). At an older age there were 5 perceptions (infecting others, p = 0,007; becoming complicated, p < 0,001; becoming depressed, p < 0,001, thinking they would die, p < 0,001; or committing suicide, p = 0,014). Those at risk of complications of COVID-19 had 4 perceptions (infecting others, p = 0,024; becoming complicated, p = 0,002; thinking they would die, p < 0,001; and thinking that this is a sign of the end of the world, p = 0,039). Respondents who were agnostic exhibited a lower frequency in 5 perceptions, while atheist respondents showed a lower frequency in 2 perceptions.Conclusion: Many fatalistic ideas are found among the population in the face of the coronavirus pandemic.

Summary: The role of maternal and embryonic leucine zipper kinase (MELK) in cancer cell proliferation has been contentious, with recent studies arriving at disparate conclusions. We investigated the in vitro dependency of cancer cells on MELK under a range of assay conditions. Abrogation of MELK expression has little effect under common culture conditions, in which cells are seeded at high densities and reach confluence in 3–5 days. However, MELK dependency becomes clearly apparent in clonogenic growth assays using either RNAi or CRISPR technologies to modulate MELK expression. This dependency is in sharp contrast to that of essential genes, such as those encoding classic mitotic kinases, but is similar to that of other oncogenes including MYC and KRAS. Our study provides an example demonstrating some of the challenges encountered in cancer target validation, and reveals how subtle, but important, technical variations can ultimately lead to divergent outcomes and conclusions. : Techniques in Genetics; Technical Aspects of Cell Biology; Cancer Subject Areas: Techniques in Genetics, Technical Aspects of Cell Biology, Cancer

Abstract Urease enzyme (UE) has been reported to be a potent virulence factor for Helicobacter pylori (HP) bacteria indicated to be responsible for various gastrointestinal diseases. Therefore, the spread of HP, currently regarded by the World Health Organization as a class 1 carcinogen, could be better controlled by targeting UE. It is in this line that we have synthesized three new derivatives (2–4) of the naturally occurring olean-12-en-3-one (1), which was previously isolated from the figs of Ficus vallis-choudae Delile (Moraceae). Among the synthesized compounds, 3 and 4 contain an indole moiety. Their structures were unambiguously assigned by spectroscopic and spectrometric techniques (1D-NMR, 2D-NMR and MS). The starting material and the synthesized compounds were screened for UE inhibition activity, and showed significant activities with IC50 values ranging from 14.5 to 24.6 μM, with compound (1) being the most potent as compared to the positive control thiourea (IC50 = 21.6 μM). Amongst the synthetic derivatives, compound 4 was the most potent (IC50 = 17.9 μM), while the others showed activities close to that of the control. In addition, molecular docking study of target compounds 2–4 was performed in an attempt to explore their binding mode for the design of more potent UE inhibitors. Graphical Abstract

Abstract Background Nucleotide Excision Repair (NER) is a major pathway of mammalian DNA repair that is associated with drug resistance and has not been well characterized in acute lymphoblastic leukemia (ALL). The objective of this study was to explore the role of NER in relapsed ALL patients. We hypothesized that increased expression of NER genes was associated with drug resistance and relapse in ALL. Methods We performed secondary data analysis on two sets of pediatric ALL patients that all ultimately relapsed, and who had matched diagnosis-relapse gene expression microarray data (GSE28460 and GSE18497). GSE28460 included 49 precursor-B-ALL patients, and GSE18497 included 27 precursor-B-ALL and 14 T-ALL patients. Microarray data were processed using the Plier 16 algorithm and the 20 canonical NER genes were extracted. Comparisons were made between time of diagnosis and relapse, and between early and late relapsing subgroups. The Chi-square test was used to evaluate whether NER gene expression was altered at the level of the entire pathway and individual gene expression was compared using t-tests. Results We found that gene expression of the NER pathway was significantly increased upon relapse in patients that took 3 years or greater to relapse (late relapsers, P = .007), whereas no such change was evident in patients that relapsed in less than 3 years (early relapsers, P = .180). Moreover, at diagnosis, the NER gene expression of the early relapsing subpopulation was already significantly elevated over that of the late relapsing group (P

Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi005-A] and a non-demented control (NDC) patient [ASUi006-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and retained the ability to differentiate into cells representative of the three germ layers.Resource tableUnlabelled TableUnique stem cell lines identifierASUi005-AASUi006-AAlternative names of stem cell linesASU-161ASU-487InstitutionArizona State University; Tempe, AZ; USAContact information of distributorDavid Brafman, David.Brafman@asu.eduType of cell linesiPSCOriginHumanCell sourceHuman peripheral blood mononuclear cells (PBMCs)ClonalityClonalMethod of reprogrammingCytoTune®-iPS 2.0 Reprogramming SystemMultiline rationaleAge-matched Alzheimer's disease and non-demented control hiPSC lines homozygous for the APOE 4 risk factorGene modificationNoType of modificationN/AAssociated diseaseAlzheimer's diseaseGene/locusApolipoprotein E (APOE)Method of modificationN/AName of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock dateMarch 2018Cell line repository/bankNot applicableEthical approvalMayo Clinic Institutional Review Board; IRB # 15-008674

PURPOSE:We aimed to evaluate the genitourinary function and quality of life (QoL) following the ablation of different prostate segments with irreversible electroporation (IRE) for localized prostate cancer (PCa).METHODS:Sixty patients who received primary focal IRE for organ-confined PCa were recruited for this study. Patients were evaluated for genitourinary function and QoL per prostate segment treated (anterior vs. posterior, apex vs. base vs. apex-to-base, unilateral vs. bilateral). IRE system settings and patient characteristics were compared between patients with preserved vs. those with impaired erectile function and urinary continence. Data were prospectively collected at baseline, 3, 6, and 12 months using the expanded prostate cancer index composite, American Urological Association symptom score, SF-12 physical and mental component summary surveys. Difference over time within segments per questionnaire was evaluated using the Wilcoxon’s signed rank test. Outcome differences between segments were assessed using covariance models. Baseline measurements included questionnaire scores, age, and prostate volume.RESULTS:There were no statistically significant changes over time for overall urinary (P = 0.07–0.89), bowel (P = 0.06–0.79), physical (P = 0.18–0.71) and mental (P = 0.45–0.94) QoL scores within each segment. Deterioration of sexual function scores was observed at 6 months within each segment (P = 0.001–0.16). There were no statistically significant differences in QoL scores between prostate segments (P = 0.08–0.97). Older patients or those with poor baseline sexual function at time of treatment were associated with a greater risk of developing erectile dysfunction.CONCLUSION:IRE is a feasible modality for all prostate segments without any significantly different effect on the QoL outcomes. Older patients and those with poor sexual function need to be counseled regarding the risk of erectile dysfunction.

IntroductionThe goal of this project was to document the current state of a community-academic partnership, identifying early successes and lessons learned.MethodsWe employed qualitative methods, semi-structured interviews and document analysis, from 2 data sources to (1) show how the principles of community-based participatory research are enacted through the activities of Addressing Disparities in Asian Populations through Translational Research (ADAPT) and (2) elucidate the barriers and facilitators to adhering to those principles from the perspectives of the members themselves.ResultsIn addition to established community-based participatory research values, understanding individuals’ motivations for participation, the challenges aligning the priorities of community organizations and academic partners, and definitions of success are themes that emerged as key to the process of maintaining this partnership.ConclusionAs the emphasis on community-academic partnerships grows, there is potential for clinical and translational science awards to use community engagement to facilitate translational research beyond the traditional medical spheres of influence and to forge relationships with affected communities.

Tidal disruption events (TDEs) offer a unique way to study dormant black holes. While the number of observed TDEs has grown thanks to the emergence of wide-field surveys in the past few decades, questions regarding the nature of the observed optical, UV, and X-ray emission remain. We present a uniformly selected sample of 30 spectroscopically classified TDEs from the Zwicky Transient Facility Phase I survey operations with follow-up Swift UV and X-ray observations. Through our investigation into correlations between light-curve properties, we recover a shallow positive correlation between the peak bolometric luminosity and decay timescales. We introduce a new spectroscopic class of TDE, TDE-featureless, which are characterized by featureless optical spectra. The new TDE-featureless class shows larger peak bolometric luminosities, peak blackbody temperatures, and peak blackbody radii. We examine the differences between the X-ray bright and X-ray faint populations of TDEs in this sample, finding that X-ray bright TDEs show higher peak blackbody luminosities than the X-ray faint subsample. This sample of optically selected TDEs is the largest sample of TDEs from a single survey yet, and the systematic discovery, classification, and follow-up of this sample allows for robust characterization of TDE properties, an important stepping stone looking forward toward the Rubin era.

Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi003-A] and a non-demented control (NDC) patient [ASUi004-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and retained the ability to differentiate into cells representative of the three germ layers.

Vitamin D (VD) is a key factor in calcium-phosphorus metabolism. In addition, it has increasing popularity due to its pleiotropic effects: renal protection, antineoplastic properties, and diabetes mellitus and hypertension control. The VD axis is severely impaired in chronic kidney disease. The changes are present even in the earliest stages and progress as kidney function worsens. Significant changes in VD occur after successful kidney transplantation, as different factors interplay, leading to widespread VD insufficiency in kidney transplant recipients. The aim of our review is to demonstrate the changes in VD metabolism after kidney transplantation and to reveal their full impact on graft and patient survival in the post-transplant setting. Furthermore, current strategies for VD supplementation and their efficacy will be discussed.

The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110β inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110β activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.

Purpose – This paper aims to determine the essential “collective goods” which a foreign multinational enterprise (MNE) must have before production can start in a remote area of an emerging economy, and to consider the alternative governance modes available to procure or create these goods. Design/methodology/approach – This purpose is examined conceptually and theoretically. First, the concept of “collective goods” is presented, followed by a consideration of the traditional “buy, ally or make” contractual approaches available to obtain goods and services. These approaches are repositioned in the context of an “emerging economy” so that alternative “ordering systems” as well as “non-contractual” means of obtaining things have to be considered in the context of internalization and reciprocity theories. Findings – It is difficult to obtain collective goods in remote areas of emerging economies where private ordering prevails and even succeeds but at high transaction costs and with substantial government intervention. However, the use of non-contractual modes of exchange such as reciprocity is available to facilitate exchanges between market MNEs and nonmarket state offices and civil-society associations such as non-governmental organizations with which collaboration is necessary but which cannot be acquired or controlled by MNEs. However, market firms can use philanthropy and lobbying to obtain the help of these nonmarket actors who know how to operate under private and state-ordering systems. Research limitations/implications – Theoretical implications: Internalization theory explains why MNEs are able to obtain collective goods by providing them “in-house”, while reciprocity theory exemplifies how non-contractual modes of exchange can substitute for the traditional but contractual “buy, ally and/or make”. Practical implications – Managerial implications: In terms of the organizational structure of the subsidiary of an MNE operating in an emerging economy, it appears that the line functions of procurement, engineering and production may rely more on contractual exchanges with foreign suppliers, while the staff functions of public affairs, government relations and human resources may be more adept at using reciprocal exchange with local suppliers. Originality/value – The provisioning of the collective goods when a firm builds its facilities in a remote and underdeveloped part of an emerging economy has hardly received any research attention nor have the non-contractual ways – such as reciprocity – available in the context of private ordering to obtain these goods.