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  1. Smith SM, Beaver RA, Cognato AI
    Zookeys, 2020;983:1-442.
    PMID: 33244289 DOI: 10.3897/zookeys.983.52630
    The Southeast Asian xyleborine ambrosia beetle fauna is reviewed for the first time. Thirty-four genera and 315 species are reviewed, illustrated, and keyed to genera and species. Sixty-three new species are described: Amasa cycloxyster sp. nov., Amasa galeoderma sp. nov., Amasa gibbosa sp. nov., Amasa lini sp. nov., Amasa tropidacron sp. nov., Amasa youlii sp. nov., Ambrosiophilus caliginestris sp. nov., Ambrosiophilus indicus sp. nov., Ambrosiophilus lannaensis sp. nov., Ambrosiophilus papilliferus sp. nov., Ambrosiophilus wantaneeae sp. nov., Anisandrus achaete sp. nov., Anisandrus auco sp. nov., Anisandrus auratipilus sp. nov., Anisandrus congruens sp. nov., Anisandrus cryphaloides sp. nov., Anisandrus feronia sp. nov., Anisandrus hera sp. nov., Anisandrus paragogus sp. nov., Anisandrus sinivali sp. nov., Anisandrus venustus sp. nov., Anisandrus xuannu sp. nov., Arixyleborus crassior sp. nov., Arixyleborus phiaoacensis sp. nov., Arixyleborus setosus sp. nov., Arixyleborus silvanus sp. nov., Arixyleborus sittichayai sp. nov., Arixyleborus titanus sp. nov., Coptodryas amydra sp. nov., Coptodryas carinata sp. nov., Coptodryas inornata sp. nov., Cyclorhipidion amasoides sp. nov., Cyclorhipidion amputatum sp. nov., Cyclorhipidion denticauda sp. nov., Cyclorhipidion muticum sp. nov., Cyclorhipidion obesulum sp. nov., Cyclorhipidion petrosum sp. nov., Cyclorhipidion truncaudinum sp. nov., Cyclorhipidion xeniolum sp. nov., Euwallacea geminus sp. nov., Euwallacea neptis sp. nov., Euwallacea subalpinus sp. nov., Euwallacea testudinatus sp. nov., Heteroborips fastigatus sp. nov., Heteroborips indicus sp. nov., Microperus latesalebrinus sp. nov., Microperus minax sp. nov., Microperus sagmatus sp. nov., Streptocranus petilus sp. nov., Truncaudum bullatum sp. nov., Xyleborinus cuneatus sp. nov., Xyleborinus disgregus sp. nov., Xyleborinus echinopterus sp. nov., Xyleborinus ephialtodes sp. nov., Xyleborinus huifenyinae sp. nov., Xyleborinus jianghuansuni sp. nov., Xyleborinus thaiphami sp. nov., Xyleborinus tritus sp. nov., Xyleborus opacus sp. nov., Xyleborus sunisae sp. nov., Xyleborus yunnanensis sp. nov., Xylosandrus bellinsulanus sp. nov., Xylosandrus spinifer sp. nov.. Thirteen new combinations are given: Ambrosiophilus consimilis (Eggers) comb. nov., Anisandrus carinensis (Eggers) comb. nov., Anisandrus cristatus (Hagedorn) comb. nov., Anisandrus klapperichi (Schedl) comb. nov., Anisandrus percristatus (Eggers) comb. nov., Arixyleborus resecans (Eggers) comb. nov., Cyclorhipidion armiger (Schedl) comb. nov., Debus quadrispinus (Motschulsky) comb. nov., Heteroborips tristis (Eggers) comb. nov., Leptoxyleborus machili (Niisima) comb. nov., Microperus cruralis (Schedl) comb. nov., Planiculus shiva (Maiti & Saha) comb. nov., Xylosandrus formosae (Wood) comb. nov. Twenty-four new synonyms are proposed: Ambrosiophilus osumiensis (Murayama, 1934) (= Xyleborus nodulosus Eggers, 1941 syn. nov.); Ambrosiophilus subnepotulus (Eggers, 1930) (= Xyleborus cristatuloides Schedl, 1971 syn. nov.); Ambrosiophilus sulcatus (Eggers, 1930) (= Xyleborus sinensis Eggers, 1941 syn. nov.; = Xyleborus sulcatulus Eggers, 1939 syn. nov.); Anisandrus hirtus (Hagedorn, 1904) (= Xyleborus hirtipes Schedl, 1969 syn. nov.); Cnestus protensus (Eggers, 1930) (= Cnestus rostratus Schedl, 1977 syn. nov.); Cyclorhipidion bodoanum (Reitter, 1913) (= Xyleborus misatoensis Nobuchi, 1981 syn. nov.); Cyclorhipidion distinguendum (Eggers, 1930) (= Xyleborus fukiensis Eggers, 1941 syn. nov.; = Xyleborus ganshoensis Murayama, 1952 syn. nov.); Cyclorhipidion inarmatum (Eggers, 1923) (= Xyleborus vagans Schedl, 1977 syn. nov.); Debus quadrispinus (Motschulsky, 1863) (= Xyleborus fallax Eichhoff, 1878 syn. nov.); Euwallacea gravelyi (Wichmann, 1914) (= Xyleborus barbatomorphus Schedl, 1951 syn. nov.); Euwallacea perbrevis (Schedl, 1951) (= Xyleborus molestulus Wood, 1975 syn. nov.; Euwallacea semirudis (Blandford, 1896) (= Xyleborus neohybridus Schedl, 1942 syn. nov.); Euwallacea sibsagaricus (Eggers, 1930) (= Xyleborus tonkinensis Schedl, 1934 syn. nov.); Euwallacea velatus (Sampson, 1913) (= Xyleborus rudis Eggers, 1930 syn. nov.); Microperus kadoyamaensis (Murayama, 1934) (= Xyleborus pubipennis Schedl, 1974 syn. nov.; =Xyleborus denseseriatus Eggers, 1941 syn. nov.); Stictodex dimidiatus (Eggers, 1927) (=Xyleborus dorsosulcatus Beeson, 1930 syn. nov.); Webbia trigintispinata Sampson, 1922 (= Webbia mucronatus Eggers, 1927 syn. nov.); Xyleborinus artestriatus (Eichhoff, 1878) (= Xyelborus angustior [sic] Eggers, 1925 syn. nov.; = Xyleborus undatus Schedl, 1974 syn. nov.); Xyleborinus exiguus (Walker, 1859) (= Xyleborus diversus Schedl, 1954 syn. nov.); Xyleborus muticus Blandford, 1894 (= Xyleborus conditus Schedl, 1971 syn. nov.; = Xyleborus lignographus Schedl, 1953 syn. nov.). Seven species are removed from synonymy and reinstated as valid species: Anisandrus cristatus (Hagedorn, 1908), Cyclorhipidion tenuigraphum (Schedl, 1953), Diuncus ciliatoformis (Schedl, 1953), Euwallacea gravelyi (Wichmann, 1914), Euwallacea semirudis (Blandford, 1896), Microperus fulvulus (Schedl, 1942), Xyleborinus subspinosus (Eggers, 1930).
  2. Smith SM, Beaver RA, Pham TH, Cognato AI
    Zootaxa, 2022 Nov 15;5209(1):1-33.
    PMID: 37045407 DOI: 10.11646/zootaxa.5209.1.1
    Eighteen xyleborine ambrosia beetles are described and illustrated: Anisandrus proscissus Smith, Beaver, Pham & Cognato sp. nov. (Vietnam), Anisandrus simplex Smith, Beaver & Cognato sp. nov. (Nepal), Arixyleborus belalongi Smith, Beaver & Cognato sp. nov. (Brunei Darussalam), Beaverium brevicaudatus Smith, Beaver & Cognato sp. nov. (Indonesia), Cnestus luculentus Smith, Beaver & Cognato sp. nov. (India), Cyclorhipidion achlys Smith, Beaver, Pham & Cognato sp. nov. (Vietnam), Cyclorhipidion conidentatus Smith, Beaver & Cognato sp. nov. (Indonesia), Cyclorhipidion gladigerum Smith, Beaver & Cognato sp. nov. (Thailand), Cyclorhipidion lapilliferum Smith, Beaver, Pham & Cognato sp. nov. (Vietnam), Cyclorhipidion nepalense Smith, Beaver & Cognato sp. nov. (Nepal), Cyclorhipidion taedulum Smith, Beaver, Pham & Cognato sp. nov. (Vietnam), Cyclorhipidion titorum Smith, Beaver, Pham & Cognato sp. nov. (Vietnam), Euwallacea alastos Smith, Beaver & Cognato sp. nov. (Japan), Leptoxyleborus regina Smith, Beaver & Cognato sp. nov. (Papua New Guinea), Tricosa hipparion Smith, Beaver & Cognato sp. nov. (Malaysia), Xyleborinus acanthopteron Smith, Beaver & Cognato sp. nov. (Thailand), Xyleborinus dumosus Smith, Beaver, Pham & Cognato sp. nov. (Vietnam), Xyleborinus nobuchii Smith, Beaver & Cognato sp. nov. (Japan). New distribution records are reported for 67 Asian species. Cyclorhipidion nemesis Smith & Cognato, described from U. S. A., is reported from Asia (China), its hypothesized native continent, for the first time. Its identity is confirmed with COI and CAD DNA within a phylogenetic analysis including other Cyclorhipidion species.
  3. Tindall SM, Vallières C, Lakhani DH, Islahudin F, Ting KN, Avery SV
    Sci Rep, 2018 02 06;8(1):2464.
    PMID: 29410428 DOI: 10.1038/s41598-018-20816-0
    Antimalarial drug resistance hampers effective malaria treatment. Critical SNPs in a particular, putative amino acid transporter were recently linked to chloroquine (CQ) resistance in malaria parasites. Here, we show that this conserved protein (PF3D7_0629500 in Plasmodium falciparum; AAT1 in P. chabaudi) is a structural homologue of the yeast amino acid transporter Tat2p, which is known to mediate quinine uptake and toxicity. Heterologous expression of PF3D7_0629500 in yeast produced CQ hypersensitivity, coincident with increased CQ uptake. PF3D7_0629500-expressing cultures were also sensitized to related antimalarials; amodiaquine, mefloquine and particularly quinine. Drug sensitivity was reversed by introducing a SNP linked to CQ resistance in the parasite. Like Tat2p, PF3D7_0629500-dependent quinine hypersensitivity was suppressible with tryptophan, consistent with a common transport mechanism. A four-fold increase in quinine uptake by PF3D7_0629500 expressing cells was abolished by the resistance SNP. The parasite protein localised primarily to the yeast plasma membrane. Its expression varied between cells and this heterogeneity was used to show that high-expressing cell subpopulations were the most drug sensitive. The results reveal that the PF3D7_0629500 protein can determine the level of sensitivity to several major quinine-related antimalarials through an amino acid-inhibitable drug transport function. The potential clinical relevance is discussed.
  4. Alamri RD, Elmeligy MA, Albalawi GA, Alquayr SM, Alsubhi SS, El-Ghaiesh SH
    Int Immunopharmacol, 2021 Apr;93:107398.
    PMID: 33571819 DOI: 10.1016/j.intimp.2021.107398
    Leflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH is a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step in the de novo synthesis of the pyrimidine nucleotides. LF produces cellular depletion of pyrimidine nucleotides required for cell growth and proliferation. Based on the affected cells the outcome can be attainable as immunosuppression, antiproliferative, and/or the recently gained attention of the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is an additional mechanistic benefit of LF, which inhibits immunological events such as cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is approved for the treatment of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been used off-label for the treatment of relapsing-remitting multiple sclerosis. However, LF antiviral activity is repurposed and under investigation with related compounds under a phase-I trial as a SARS CoV-2 antiviral in cases with COVID-19. Despite success in improving patients' mobility and reducing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF should not be used in patients with hepatic impairment or in combination with drugs elaborating a burden on the liver without regular monitoring of liver enzymes and serum bilirubin as safety biomarkers. This study aims to review the pharmacological and safety profile of LF with a focus on the LF-induced hepatic injury from the perspective of pathophysiology and possible protective agents.
  5. Chilenski SM, Ang PM, Greenberg MT, Feinberg ME, Spoth R
    Prev Sci, 2014 Apr;15(2):125-137.
    PMID: 23404665 DOI: 10.1007/s11121-012-0347-5
    The current study examined the impact of the PROSPER delivery system for evidence-based prevention programs on multiple indicators of social capital in a rural and semi-rural community sample. Utilizing a randomized blocked design, 317 individuals in 28 communities across two states were interviewed at three time points over the course of 2.5 years. Bridging, linking, and the public life skills forms of social capital were assessed via community members' and leaders' reports on the perceptions of school functioning and the Cooperative Extension System, collaboration among organizations, communication and collaboration around youth problems, and other measures. Longitudinal mixed model results indicate significant improvements in some aspects of bridging and linking social capital in PROSPER intervention communities. Given the strength of the longitudinal and randomized research design, results advance prevention science by suggesting that community collaborative prevention initiatives can significantly impact community social capital in a rural and semi-rural sample. Future research should further investigate changes in social capital in different contexts and how changes in social capital relate to other intervention effects.
  6. Ross H, Husain MJ, Kostova D, Xu X, Edwards SM, Chaloupka FJ, et al.
    MMWR Morb Mortal Wkly Rep, 2015 May 29;64(20):547-50.
    PMID: 26020137
    An estimated 11.6% of the world cigarette market is illicit, representing more than 650 billion cigarettes a year and $40.5 billion in lost revenue. Illicit tobacco trade refers to any practice related to distributing, selling, or buying tobacco products that is prohibited by law, including tax evasion (sale of tobacco products without payment of applicable taxes), counterfeiting, disguising the origin of products, and smuggling. Illicit trade undermines tobacco prevention and control initiatives by increasing the accessibility and affordability of tobacco products, and reduces government tax revenue streams. The World Health Organization (WHO) Protocol to Eliminate Illicit Trade in Tobacco Products, signed by 54 countries, provides tools for addressing illicit trade through a package of regulatory and governing principles. As of May 2015, only eight countries had ratified or acceded to the illicit trade protocol, with an additional 32 needed for it to become international law (i.e., legally binding). Data from multiple international sources were analyzed to evaluate the 10 most commonly used approaches for addressing illicit trade and to summarize differences in implementation across select countries and the European Union (EU). Although the WHO illicit trade protocol defines shared global standards for addressing illicit trade, countries are guided by their own legal and enforcement frameworks, leading to a diversity of approaches employed across countries. Continued adoption of the methods outlined in the WHO illicit trade protocol might improve the global capacity to reduce illicit trade in tobacco products.
  7. Islahudin F, Tindall SM, Mellor IR, Swift K, Christensen HE, Fone KC, et al.
    Sci Rep, 2014 Jan 09;4:3618.
    PMID: 24402577 DOI: 10.1038/srep03618
    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.
  8. Hyde PN, Sapper TN, LaFountain RA, Kackley ML, Buga A, Fell B, et al.
    Nutrients, 2021 Jun 05;13(6).
    PMID: 34198888 DOI: 10.3390/nu13061944
    BACKGROUND: Foods rich in saturated fatty acids (SFAs) have been discouraged by virtue of their cholesterol-raising potential, but this effect is modulated by the food source and background level of carbohydrate.

    OBJECTIVE: We aimed to compare the consumption of palm stearin (PS) versus butter on circulating cholesterol responses in the setting of both a low-carbohydrate/high-fat (LC/HF) and high-carbohydrate/low-fat (HC/LF) diet in healthy subjects. We also explored effects on plasma lipoprotein particle distribution and fatty acid composition.

    METHODS: We performed a randomized, controlled-feeding, cross-over study that compared a PS- versus a Butter-based diet in a group of normocholesterolemic, non-obese adults. A controlled canola oil-based 'Run-In' diet preceded the experimental PS and Butter diets. All diets were eucaloric, provided for 3-weeks, and had the same macronutrient distribution but varied in primary fat source (40% of the total fat). The same Run-In and cross-over experiments were done in two separate groups who self-selected to either a LC/HF (n = 12) or a HC/LF (n = 12) diet track. The primary outcomes were low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL)-C, triglycerides, and LDL particle distribution.

    RESULTS: Compared to PS, Butter resulted in higher LDL-C in both the LC/HF (13.4%, p = 0.003) and HC/LF (10.8%, p = 0.002) groups, which was primarily attributed to large LDL I and LDL IIa particles. There were no differences between PS and Butter in HDL-C, triglycerides, or small LDL particles. Oxidized LDL was lower after PS than Butter in LC/HF (p = 0.011), but not the HC/LF group.

    CONCLUSIONS: These results demonstrate that Butter raises LDL-C relative to PS in healthy normocholesterolemic adults regardless of background variations in carbohydrate and fat, an effect primarily attributed to larger cholesterol-rich LDL particles.

  9. Mohd-Zin SW, Abdullah NL, Abdullah A, Greene ND, Cheah PS, Ling KH, et al.
    Genome, 2016 Jul;59(7):439-48.
    PMID: 27373307 DOI: 10.1139/gen-2015-0142
    The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4(rb-2J/rb-2J), is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or "hopping gait" phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4(rb-2J) corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4(rb-2J) allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein-protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.
  10. Siti Sarah M, Nor Aini U, Nurismah MI, Hafiza A, Khalidah M, Mokhtar AB, et al.
    Clin Ter, 2014;165(1):35-9.
    PMID: 24589949 DOI: 10.7471/CT.2014.1659
    Paraproteinemia is one of the diagnostic features of multiple myeloma. A commonly used method is the detection of paraprotein by agarose gel electrophoresis (AGE) followed by by immunofixation electrophoresis (IFE) to confirm monoclonality. Due to their smaller size, immunoglobulin A (IgA) and light chain only paraproteins may appear at the beta or even alpha 2 protein fractions. Here, we discuss a case report of a 47-year-old man who presented with pathological fracture of third thoracic (T3) vertebra. Serum protein electrophoresis (SPE) was initially reported as no paraprotein detected. However, a bone biopsy was reported to show plasma cell proliferation with light chain restriction. A repeat sample for protein electrophoresis together with IFE revealed lambda light chain paraprotein co-migrating at the beta region. The beta band plus paraprotein was quantitated as 4.3 g/L (7.0%), which was within normal limits of the beta protein fraction. Hence, it has to be remembered that if the SPE is negative, it does not necessarily mean that the paraprotein is absent in cases which are highly suspicious.
  11. Rehman AU, Khattak M, Mushtaq U, Latif M, Ahmad I, Rasool MF, et al.
    Front Public Health, 2023;11:1244450.
    PMID: 38074769 DOI: 10.3389/fpubh.2023.1244450
    BACKGROUND: The existence of Type 2 Diabetes Mellitus (DM) in tuberculosis (TB) patients is very dangerous for the health of patients. One of the major concerns is the emergence of MDR-TB in such patients. It is suspected that the development of MDR-TB further worsens the treatment outcomes of TB such as treatment failure and thus, causes disease progression.

    AIM: To investigate the impact of DM on the Emergence of MDR-TB and Treatment Failure in TB-DM comorbid patients.

    METHODOLOGY: The PubMed database was systematically searched until April 03, 2022 (date last searched). Thirty studies met the inclusion criteria and were included in this study after a proper selection process.

    RESULTS: Tuberculosis-Diabetes Mellitus patients were at higher risk to develop MDR-TB as compared to TB-non-DM patients (HR 0.81, 95% CI: 0.60-0.96, p 

  12. Sarah M, Anahita DC, Zachary WEY, Thanh DL, Hiep NC, Kenichi H, et al.
    J Leukoc Biol, 2024 Feb 20.
    PMID: 38374693 DOI: 10.1093/jleuko/qiae034
    A well-documented Achilles heel of current cancer immunotherapy approaches is T cell exhaustion within solid tumor tissues. The pro-inflammatory cytokine interleukin-23 (IL-23) has been utilised to augment chimeric antigen receptor (CAR)-T cells survival and tumor immunity. However, in-depth interrogation of molecular events downstream of IL-23/IL23R signaling is hampered by a paucity of suitable cell models. The current study investigates the differential contribution of IL-2 and IL-23 to the maintenance and differentiation of the IL-23 responsive Kit225 T-cell line. We observed that IL-23 enhanced cellular fitness and survival but was insufficient to drive proliferation. IL-23 rapidly induced phosphorylation of STAT1, 3 and 4, and mRNA expression of IL17A, the archetypal effector cytokine of Th17 cells, but not their lineage markers RORC and NCR1. These observations suggest that IL-23 endowed Th17/ILC3-like effector function but did not promote their differentiation. In contrast, spontaneous differentiation of Kit225 cells towards a Th17/ILC3-like phenotype was induced by prolonged IL-2 withdrawal. This was marked by strongly elevated basal IL17A and IL17F expression and the secretion of IL-17. Together, our data present Kit225 cells as a valuable model for studying the interplay between cytokines and their contribution to T cell survival, proliferation, and differentiation.
  13. Searchfield GD, Zhang J, Biswas R, De Ridder D, Deutsch B, Hall DA, et al.
    PMID: 34291436 DOI: 10.1007/7854_2021_230
  14. Searchfield GD, Zhang J, Biswas R, De Ridder D, Deutsch B, Hall DA, et al.
    Curr Top Behav Neurosci, 2021;51:461-483.
    PMID: 33665781 DOI: 10.1007/7854_2020_217
    This volume has highlighted the many recent advances in tinnitus theory, models, diagnostics, therapies, and therapeutics. But tinnitus knowledge is far from complete. In this chapter, contributors to the Behavioral Neuroscience of Tinnitus consider emerging topics and areas of research needed in light of recent findings. New research avenues and methods to explore are discussed. Issues pertaining to current assessment, treatment, and research methods are outlined, along with recommendations on new avenues to explore with research.
  15. Kotlarz D, Marquardt B, Barøy T, Lee WS, Konnikova L, Hollizeck S, et al.
    Nat Genet, 2018 Mar;50(3):344-348.
    PMID: 29483653 DOI: 10.1038/s41588-018-0063-6
    Transforming growth factor (TGF)-β1 (encoded by TGFB1) is the prototypic member of the TGF-β family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-β1-LAP complex, which is suggestive of perturbed bioavailability of TGF-β1. Our study shows that TGF-β1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.
  16. Ripple WJ, Chapron G, López-Bao JV, Durant SM, Macdonald DW, Lindsey PA, et al.
    Bioscience, 2016 Oct 01;66(10):807-812.
    PMID: 28533560 DOI: 10.1093/biosci/biw092
  17. Pavlov YG, Adamian N, Appelhoff S, Arvaneh M, Benwell CSY, Beste C, et al.
    Cortex, 2021 11;144:213-229.
    PMID: 33965167 DOI: 10.1016/j.cortex.2021.03.013
    There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.
  18. Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, et al.
    J Clin Oncol, 2020 03 01;38(7):674-685.
    PMID: 31841383 DOI: 10.1200/JCO.19.01907
    PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.

    METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.

    RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.

    CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

  19. Lecarpentier J, Silvestri V, Kuchenbaecker KB, Barrowdale D, Dennis J, McGuffog L, et al.
    J Clin Oncol, 2017 Jul 10;35(20):2240-2250.
    PMID: 28448241 DOI: 10.1200/JCO.2016.69.4935
    Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
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