Mutations in nuclear lamins or other proteins of the nuclear envelope are the root cause of a group of phenotypically diverse genetic disorders known as laminopathies, which have symptoms that range ...from muscular dystrophy to neuropathy to premature aging syndromes. Although precise disease mechanisms remain unclear, there has been substantial progress in our understanding of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant cell signaling. Building on these findings, small molecules are being discovered that may become effective therapeutic agents.
The phytohormone auxin plays crucial roles in nearly every aspect of plant growth and development. The auxin response factor (ARF) transcription factor family regulates auxin-responsive gene ...expression and exhibits nuclear localization in regions of high auxin responsiveness. Here we show that the ARF7 and ARF19 proteins accumulate in micron-sized assemblies within the cytoplasm of tissues with attenuated auxin responsiveness. We found that the intrinsically disordered middle region and the folded PB1 interaction domain of ARFs drive protein assembly formation. Mutation of a single lysine within the PB1 domain abrogates cytoplasmic assemblies, promotes ARF nuclear localization, and results in an altered transcriptome and morphological defects. Our data suggest a model in which ARF nucleo-cytoplasmic partitioning regulates auxin responsiveness, providing a mechanism for cellular competence for auxin signaling.
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•Condensation of transcription factors to attenuate hormone response•Mechanism for nucleo-cytoplasmic partitioning of transcription factors
ARF transcription factors mediate the activity of the phytohormone auxin, regulating every aspect of plant development. Powers et al. determine that some ARFs undergo phase transition to form large-order cytoplasmic protein assemblies that limit auxin responsiveness in a developmentally relevant context, illustrating a strong link between condensate formation and biological function.
Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer ...immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell- and natural killer cell-dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer.
Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts ...metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.
The extracellular domain of tumor necrosis factor receptors (TNFR) generally require assembly into a homotrimeric quaternary structure as a prerequisite for initiation of signaling via the ...cytoplasmic domains. TNF receptor homotrimers are natively activated by similarly homo-trimerized TNF ligands, but can also be activated by synthetic agonists including engineered antibodies and Fc-ligand fusion proteins. A large body of literature from pre-clinical models supports the hypothesis that synthetic agonists targeting a diverse range of TNF receptors (including 4-1BB, CD40, OX40, GITR, DR5, TNFRSF25, HVEM, LTβR, CD27, and CD30) could amplify immune responses to provide clinical benefit in patients with infectious diseases or cancer. Unfortunately, however, the pre-clinical attributes of synthetic TNF receptor agonists have not translated well in human clinical studies, and have instead raised fundamental questions regarding the intrinsic biology of TNF receptors. Clinical observations of bell-shaped dose response curves have led some to hypothesize that TNF receptor overstimulation is possible and can lead to anergy and/or activation induced cell death of target cells. Safety issues including liver toxicity and cytokine release syndrome have also been observed in humans, raising questions as to whether those toxicities are driven by overstimulation of the targeted TNF receptor, a non-TNF receptor related attribute of the synthetic agonist, or both. Together, these clinical findings have limited the development of many TNF receptor agonists, and may have prevented generation of clinical data which reflects the full potential of TNF receptor agonism. A number of recent studies have provided structural insights into how different TNF receptor agonists bind and cluster TNF receptors, and these insights aid in deconvoluting the intrinsic biology of TNF receptors with the mechanistic underpinnings of synthetic TNF receptor agonist therapeutics.
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•Novel technologies for autonomously controlling diabetes mellitus.•Interoperable single and bi-hormonal delivery systems for personalised treatment.•Complex control algorithms power ...and automate hybrid and closed-loop systems.•Smart insulin and glucagon delivery through stimuli responsive materials.•Encapsulation strategies and renewable cell sources for longevity of islet therapies.
Diabetes mellitus refers to a group of metabolic disorders which affect how the body uses glucose impacting approximately 9% of the population worldwide. This review covers the most recent technological advances envisioned to control and/or reverse Type 1 diabetes mellitus (T1DM), many of which will also prove effective in treating the other forms of diabetes mellitus. Current standard therapy for T1DM involves multiple daily glucose measurements and insulin injections. Advances in glucose monitors, hormone delivery systems, and control algorithms generate more autonomous and personalised treatments through hybrid and fully automated closed-loop systems, which significantly reduce hypo- and hyperglycaemic episodes and their subsequent complications. Bi-hormonal systems that co-deliver glucagon or amylin with insulin aim to reduce hypoglycaemic events or increase time spent in target glycaemic range, respectively. Stimuli responsive materials for the controlled delivery of insulin or glucagon are a promising alternative to glucose monitors and insulin pumps. By their self-regulated mechanism, these “smart” drugs modulate their potency, pharmacokinetics and dosing depending on patients’ glucose levels. Islet transplantation is a potential cure for T1DM as it restores endogenous insulin and glucagon production, but its use is not yet widespread due to limited islet sources and risks of chronic immunosuppression. New encapsulation strategies that promote angiogenesis and oxygen delivery while protecting islets from recipients’ immune response may overcome current limiting factors.
Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively ...termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors.
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high ...regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling. Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.
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•Somatic stem cells transiently activate mTORC1 signaling during tissue regeneration•Chronic mTORC1 activation leads to stem cell loss•Repeated regenerative episodes result in mTORC1-dependent loss of SCs•Long-term rapamycin exposure limits age-related SC loss in the tracheal epithelium
Studying flies and mice, Jasper and colleagues demonstrate that repeated regenerative episodes result in the loss of tissue stem cells (SCs) due to the transient activation of the growth regulator mTORC1 during SC activation. Pharmacological inhibition of mTORC1 can prevent this loss and limit the age-related decline in SC numbers.
Background
Recent research has convincingly shown that the ability to work mainly depends on the cognitive status in multiple sclerosis (MS). An international committee of experts recommended a brief ...neuropsychological battery to evaluate cognitive performance in MS. BICAMS comprises three tests, the Symbol Digit Modalities Test (SDMT), the learning trials of the California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R).
Objective
To validate BICAMS on a sample of German MS patients and healthy controls (HCs).
Methods
According to the international guidelines for validation, examiner’s instructions were standardized and translated into German. Due to the availability of better normative data for future applications in routine clinical care and classification of individual performance degree, the Rey Auditory Verbal Learning Test (RAVLT) (German version: Verbaler Lern- und Merkfähigkeits-Test, VLMT) was chosen instead of CVLT-II. 172 MS patients and 100 HCs entered the study. BICAMS was administered at baseline and retest (after 3–4 weeks).
Results
The groups did not differ in age, gender or education. Mean age of MS patients was 43.33 years (SD 11.64); 68% were female and 86.9% had relapsing-remitting MS. Patients performed significantly worse than HCs on the SDMT (
p
< 0.01) and on BVMT-R (
p
< 0.05) but not on VLMT. In addition, BICAMS was shown to be reliable over time:
r
= 0.71 for BVMT-R,
r
= 0.72 for VLMT and
r
= 0.85 for SDMT. SDMT
z
-score proved to be a good predictor for the ability to work in a full-time (
p
< 0.001) as well as in a part-time job (
p
< 0.001). VLMT
z
-score turned out to be a significant predictor only for the ability to work in a part-time job, while BVMT-R
z-
score showed no significant predictive value.
Conclusion
In this German validation study with the VLMT, the modified BICAMS (BICAMS-M) turned out to reliably detect cognitive problems in MS patients and to monitor cognitive performance over time. SDMT revealed the best predictive value for working ability. Moreover, only the SDMT was able to predict the ability to work in a part-time or full-time job. Following these results, application of the SDMT is recommended for medical statements on working ability of MS patients.
Fetal sex is independently associated with pregnancy complications and impacts neonatal outcomes. Evidence suggests that females have an advantage over males, with a better outcome in the perinatal ...period. In addition, fetal outcome in twin gestations is also related to the intrauterine position of the fetus, such as the first, the presenting or second twin. It has been demonstrated that the neonatal outcome of the second fetus is worse than that of the first fetus. This study aimed to examine the influence of fetal sex on obstetric outcomes in twin pregnancies based on the location of the fetus in the uterus.PURPOSEFetal sex is independently associated with pregnancy complications and impacts neonatal outcomes. Evidence suggests that females have an advantage over males, with a better outcome in the perinatal period. In addition, fetal outcome in twin gestations is also related to the intrauterine position of the fetus, such as the first, the presenting or second twin. It has been demonstrated that the neonatal outcome of the second fetus is worse than that of the first fetus. This study aimed to examine the influence of fetal sex on obstetric outcomes in twin pregnancies based on the location of the fetus in the uterus.Retrospective study. Maternal and obstetric outcomes were compared among three groups: male‒male, female‒female, and male‒female groups. Comparisons of neonatal outcomes were performed among the four groups: male A-male B, male A-female B, female A-male B, and female A-female B.METHODSRetrospective study. Maternal and obstetric outcomes were compared among three groups: male‒male, female‒female, and male‒female groups. Comparisons of neonatal outcomes were performed among the four groups: male A-male B, male A-female B, female A-male B, and female A-female B.A total of 1073 twin gestations were included, comprising 288 male‒male, 288 female‒female, and 497 male‒female gestations. A greater percentage of neonates admitted to the NICU was observed for male fetuses than for female fetuses. Adverse composite neonatal outcome was more common in the male‒male group than in the female‒male group and in the female‒female group.RESULTSA total of 1073 twin gestations were included, comprising 288 male‒male, 288 female‒female, and 497 male‒female gestations. A greater percentage of neonates admitted to the NICU was observed for male fetuses than for female fetuses. Adverse composite neonatal outcome was more common in the male‒male group than in the female‒male group and in the female‒female group.Twin gestation with a first twin male tends to have worse neonatal outcomes than does twin gestation with a first twin female. The presence of a male co-twin increases the risk of adverse outcomes.CONCLUSIONTwin gestation with a first twin male tends to have worse neonatal outcomes than does twin gestation with a first twin female. The presence of a male co-twin increases the risk of adverse outcomes.
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