Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapeutic antisense oligonucleotides for movement disorders

Movement disorders are a group of neurological conditions characterized by abnormalities of movement and posture. They are broadly divided into akinetic and hyperkinetic syndromes. Until now, no effective symptomatic or disease‐modifying therapies have been available. However, since many of these disorders are monogenic or have some well‐defined genetic component, they represent strong candidates for antisense oligonucleotide (ASO) therapies. ASO therapies are based on the use of short synthetic single‐stranded ASOs that bind to disease‐related target RNAs via Watson–Crick base‐pairing and pleiotropically modulate their function. With information arising from the RNA sequence alone, it is possible to design ASOs that not only alter the expression levels but also the splicing defects of any protein, far exceeding the intervention repertoire of traditional small molecule approaches. Following the regulatory approval of ASO therapies for spinal muscular atrophy and Duchenne muscular dystrophy in 2016, there has been tremendous momentum in testing such therapies for other neurological disorders. This review article initially focuses on the chemical modifications aimed at improving ASO effectiveness, the mechanisms by which ASOs can interfere with RNA function, delivery systems and pharmacokinetics, and the common set of toxicities associated with their application. It, then, describes the pathophysiology and the latest information on preclinical and clinical trials utilizing ASOs for the treatment of Parkinson′s disease, Huntington′s disease, and ataxias 1, 2, 3, and 7. It concludes with issues that require special attention to realize the full potential of ASO‐based therapies.
Practical implications for providing physical activity counseling for the older adult: An integrative review.

BACKGROUND Physical inactivity in the older adult is associated with functional decline, increased fall risk, and threatens the ability of the older adult to live independently. Nurse practitioners, with their expertise in health promotion and chronic disease management, are well positioned to provide physical activity (PA) counseling. However, there is a gap in the literature describing a practical formula for providing PA counseling and PA prescriptions for clinical practice. OBJECTIVE The objective of this integrative review was to synthesize the literature related to counseling interventions designed to increase PA among older adults and provide practical recommendations for incorporating recommendations into practice. DATA SOURCES Five different databases were searched along with ancestry searching of relevant articles. Eligible studies tested methods of recommending PA for adults age ≥65 years, including in-person counseling, phone calls, written information, and exercise prescriptions. CONCLUSIONS Health care providers are able to motivate older adults to increase PA in the short term. Diverse health care disciplines are efficacious at motivating older adults to increase PA. Various counseling interventions can be used with varying amounts of time investment. IMPLICATIONS FOR PRACTICE Physical activity counseling is an underused but effective intervention for increasing PA in older adults. Older adults respond well to advice to increase their PA especially with the addition of a written exercise prescription. Basing PA counseling interventions on a theoretical construct such as social cognitive theory or transtheoretical stages of change theory improves the efficacy of the interventions.
Endothelium-Macrophage Crosstalk Mediates Blood-Brain Barrier Dysfunction in Hypertension

Supplemental Digital Content is available in the text. Hypertension is a leading cause of stroke and dementia, effects attributed to disrupting delivery of blood flow to the brain. Hypertension also alters the blood-brain barrier (BBB), a critical component of brain health. Although endothelial cells are ultimately responsible for the BBB, the development and maintenance of the barrier properties depend on the interaction with other vascular-associated cells. However, it remains unclear if BBB disruption in hypertension requires cooperative interaction with other cells. Perivascular macrophages (PVM), innate immune cells closely associated with cerebral microvessels, have emerged as major contributors to neurovascular dysfunction. Using 2-photon microscopy in vivo and electron microscopy in a mouse model of Ang II (angiotensin II) hypertension, we found that the vascular segments most susceptible to increased BBB permeability are arterioles and venules >10 µm and not capillaries. Brain macrophage depletion with clodronate attenuates, but does not abolish, the increased BBB permeability in these arterioles where PVM are located. Deletion of AT1R (Ang II type-1 receptors) in PVM using bone marrow chimeras partially attenuated the BBB dysfunction through the free radical-producing enzyme Nox2. In contrast, downregulation of AT1R in cerebral endothelial cells using a viral gene transfer-based approach prevented the BBB disruption completely. The results indicate that while endothelial AT1R, mainly in arterioles and venules, initiate the BBB disruption in hypertension, PVM are required for the full expression of the dysfunction. The findings unveil a previously unappreciated contribution of resident brain macrophages to increased BBB permeability of hypertension and identify PVM as a putative therapeutic target in diseases associated with BBB dysfunction.
Carbon import into barley roots: stimulation by galactose

Galactose was applied to one-half of a split root system of barley. It stimulated import of photoassimilate labelled with C-11 from leaf 2 into that root half at concentrations from 0.2-50 mol m -3 . The lag before an increase in import was detected decreased from >60 to <30 min as concentration of galactose was increased across this range. In the presence of 10 mol m -3 glucose, 2 mol m -3 galactose did not increase import of C-11. Whilst 2 and 50 mol m -3 galactose had no effect on respiratory oxygen uptake of roots, they caused a rise in the rate of evolution of 11 CO 2 in <5 min
Inactivation of the dimeric RappLS20 anti-repressor of the conjugation operon is mediated by peptide-induced tetramerization

Abstract Quorum sensing allows bacterial cells to communicate through the release of soluble signaling molecules into the surrounding medium. It plays a pivotal role in controlling bacterial conjugation in Gram-positive cells, a process that has tremendous impact on health. Intracellular regulatory proteins of the RRNPP family are common targets of these signaling molecules. The RRNPP family of gene regulators bind signaling molecules at their C-terminal domain (CTD), but have highly divergent functionalities at their N-terminal effector domains (NTD). This divergence is also reflected in the functional states of the proteins, and is highly interesting from an evolutionary perspective. RappLS20 is an RRNPP encoded on the Bacillus subtilis plasmid pLS20. It relieves the gene repression effectuated by RcopLS20 in the absence of the mature pLS20 signaling peptide Phr*pLS20. We report here an in-depth structural study of apo and Phr*pLS20-bound states of RappLS20 at various levels of atomic detail. We show that apo-RappLS20 is dimeric and that Phr*pLS20-bound Rap forms NTD-mediated tetramers. In addition, we show that RappLS20 binds RcopLS20 directly in the absence of Phr*pLS20 and that addition of Phr*pLS20 releases RcopLS20 from RappLS20. This allows RcopLS20 to bind the promotor region of crucial conjugation genes blocking their expression.
FORMATION OF FLOWERHEAD GALLS BY THE CANADA THISTLE GALL-FLY, UROPHORA CARDUI (DIPTERA: TEPHRITIDAE), UNDER CAGE CONDITIONS

Abstract Normally, Urophora cardui (L.) induces galls on the stems of Cirsium arvense (L.) Scop. (Canada thistle). However, six galls were found in flowerheads when flies were cultured in growth chambers. All flowerhead galls developed from receptacle tissues of male thistle capitula and were structurally similar to those induced from stem tissues. The appearance of these atypical galls contributes to our understanding of organ specificity of gall-inducing insects. Résumé Normalement Urophora cardui (L.) induit des galles sur les tiges du Cirsium arvense (L.) Scop. (le chardon des champs). Cependant, six galles trouvées sur des capitules ont été induites par des mouches élevées en chambres de croissance. Les galles sur capitules se sont dévelopées sur les tissus du réceptacle de capitules mâles et elles étaient de structure similaire à celles induites sur les tissus de la tige. L’apparence de ces galles anormales ajoute à notre compréhension de la spécificité de l’organe chez les insectes cécidogènes.
Antibody-drug conjugates in breast cancer: the chemotherapy of the future?

PURPOSE OF REVIEW Antibody-drug conjugates (ADCs) represent an interesting new class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies. The aim of this article is to review the efficacy and safety of ADCs in breast cancer. RECENT FINDINGS Following the approval of T-DM1 both in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel anti-HER2 ADCs have been investigated. Some of these compounds, such as the recently FDA-approved trastuzumab deruxtecan, have shown relevant activity in T-DM1-pretreated patients, possibly thanks to the so-called bystander effect, namely the ability to exert cytotoxic activity also against antigen-negative cells. Such feature allows to overcome the HER2 intratumoral heterogeneity in breast cancer and could explain in the preliminary activity demonstrated also in HER2-low breast cancers. However, several ADCs targeting other cancer-associated antigens than HER2 are under development, representing a promising strategy for the treatment of triple-negative tumors, exemplified by the encouraging results of sacituzumab govitecan. SUMMARY ADCs are innovative and effective therapeutic drugs in breast cancer. Research efforts are ongoing to identify novel targets and combination with other treatment modalities, particularly with immunotherapy, to further improve patients' outcomes.
Environmental modulation of mucosal immunity. Opportunities in respiratory viral infections

The exact cause of severe disease in children during primary RSV infections is not completely clear. There is a link with viral load, but differences virus strains do not seem to be the major reason why in some children the disease manifests as a mild cold while others suffer from a severe lower respiratory tract disease. The prevalence of severe lower respiratory tract infection due to RSV is high in the neonatal period. The immune response in this age group is characterized by suppressed innate immune responses and a Th2 bias, reasons for poorly effective immune responses to infection and vaccination. During the neonatal period maternally derived antibodies and maturation of neonatal immunity via microbial colonization of mucosal surfaces are both important factors to protect the newborn against pathogens upon the first encounter. However, the presentation of antibody opsonized virus to various cell types alters the innate pathogen recognition pathways, affecting the onset of subsequent immune responses evoked by these cells and subsequently the ability to respond to RSV infections. Furthermore, altered mucosal colonization due to antibiotic treatment, environmental challenges or pharmaceutical components might affect the development of neonatal immunity. In this thesis we investigate the possible influence of (maternally derived) RSV specific antibodies and microbiome manipulation via specific prebiotic oligosaccharides and broad spectrum antibiotics on immunity against RSV. We show in our studies that the use of highly neutralising antibodies or antibiotics in new-borns should carefully be evaluated for their potential to alter innate immune responses and the development of adaptive immunity to RSV and certainly also other pathogens. Extrapolation from our mouse model suggests that antibiotics used in the neonatal period might increase the risk of developing severe RSV bronchiolitis and susceptibility to develop allergic disease in later life. A better understanding of the mechanism by which vaccine induced immune responses can be amplified or altered by microbiome manipulation, might in the future lead to promising options whereby dietary manipulation support neonatal immune development and vaccine efficacy.
Transgenic canola plants over-expressing bacterial catalase exhibit enhanced resistance to Peronospora parasitica and Erysiphe polygoni

Transgenic canola (Brassica napus.L) plants express ing the bacterial catalase katE in the chloroplasts were obtained by the Agrobacterium-med iated transformation method. Resistance and susceptibility of the transgenic canola plants were evaluated against the airborne pathogenic fungi, Peronospora parasitica causing downy mildew and Ery siphe polygon causing powdery mildew under artificial infection in the greenhouse. The b ioassays of the transgenic plants demonstrated that the growth of both fungi and the development o f disease incidence were significantly inhibited in the leaves of the transgenic canola plants compa red to controls. Chemical analyses of the transgenic plants revealed constitutive expression of the enzymes catalase, peroxidase and polyphenoloxidase as well as higher levels of free polyamines i. e. putrescine, spermidine and spermine compared with the control plants. Together , these data indicate an enhanced resistance of the transgenic canola plants expressing the bacteri al catalase to the downy mildew and powdery mildew pathogens.
Not seeing the forest for the trees: a systematic review of comprehensive distress management programs and implementation strategies.

PURPOSE OF REVIEW Clinically significant distress is common in patients with cancer and if untreated can be associated with adverse outcomes. This article offers a review of current approaches to implementing and reporting the minimum components of distress screening and management interventions in cancer services. RECENT FINDINGS Twenty-two relevant published articles were identified from January 2018 to February 2020. The reporting of recommended minimum components of distress screening and management interventions in these articles was not consistent. The majority of studies used validated tools to conduct initial screening. However, recommendations were either not reported or not followed regarding subsequent pathway components, secondary assessment, referral pathways linked to screening results and rescreening. The majority of studies did not include a description of the implementation of the distress screening program. A small number of studies described a comprehensive set of implementation strategies. SUMMARY Distress screening and management interventions in cancer are an important component of comprehensive cancer care. To improve patient outcomes and guide researchers and services to identify effective models, studies must include and evaluate minimum recommended components and implementation strategies. Addressing these limitations with high-quality, robust interventions is vital for advancing the implementation of effective distress management.
Heterozygosity and fitness benefits of extrapair mate choice in White-rumped Swallows (Tachycineta leucorrhoa)

Female birds that engage in extrapair mating may choose extrapair mates that are genetically compatible, increasing their fitness through genetic benefits, such as increased heterozygosity, to their offspring; or choose mates that are heterozygous at one or more loci. Here, we describe the extrapair mating system, explore the fitness benefits of extrapair mating and test the heterozygosity hypothesis in White-rumped Swallows (Tachycineta leucorrhoa) breeding in Argentina using a panel of microsatellite loci. Extrapair offspring accounted for 56% of the nestlings and 77% of the broods in our population. Within broods, 1--4 males fathered extrapair offspring, and in 29% of nests, all offspring were from extrapair sires. We found that broods with extrapair offspring fledged overall more young than broods with no extrapair offspring but that the young that died were more heterozygous than the ones that fledged. Although extrapair offspring had a higher probability of surviving than within-pair offspring, these 2 groups did not differ in their level of heterozygosity. Neither the heterozygosity of the social mate nor the genetic similarity of the social pair predicted the presence of extrapair young. Instead, females chose social mates that were significantly less genetically similar to them. Our results do not support the heterozygosity hypothesis and contradict 2 of its main predictions. Copyright 2011, Oxford University Press.
Continuous developmental change can explain discontinuities in word learning

Cognitive development is often characterized in terms of discontinuities, but these discontinuities can sometimes be apparent rather than actual and can arise from continuous developmental change. To explore this idea, we use as a case study the finding by Stager and Werker (1997) that children's early ability to distinguish similar sounds does not automatically translate into word learning skills. Early explanations proposed that children may not be able to encode subtle phonetic contrasts when learning novel word meanings, thus suggesting a discontinuous/stage-like pattern of development. However, later work has revealed (e.g., through using more precise testing methods) that children do encode such contrasts, thus favoring a continuous pattern of development. Here we propose a probabilistic model that represents word knowledge in a graded fashion and characterizes developmental change as improvement in the precision of this graded knowledge. Our model explained previous findings in the literature and provided a new prediction - the referents' visual similarity modulates word learning accuracy. The models' predictions were corroborated by human data collected from both preschool children and adults. The broader impact of this work is to show that computational models, such as ours, can help us explore the extent to which episodes of cognitive development that are typically thought of as discontinuities may emerge from simpler, continuous mechanisms.
Cell‐based and antibody‐mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

Despite new insights in molecular features of leukemic cells and the availability of novel treatment approaches and drugs, acute myeloid leukemia (AML) remains a major clinical challenge. In fact, many patients with AML relapse after standard therapy and eventually die from progressive disease. The basic concept of leukemic stem cells (LSC) has been coined with the goal to decipher clonal architectures in various leukemia‐models and to develop curative drug therapies by eliminating LSC. Indeed, during the past few years, various immunotherapies have been tested in AML, and several of these therapies follow the strategy to eliminate relevant leukemic subclones by introducing LSC‐targeting antibodies or LSC‐targeting immune cells. These therapies include, among others, new generations of LSC‐eliminating antibody‐constructs, checkpoint‐targeting antibodies, bi‐specific antibodies, and CAR‐T or CAR‐NK cell‐based strategies. However, responses are often limited and/or transient which may be due to LSC resistance. Indeed, AML LSC exhibit multiple forms of resistance against various drugs and immunotherapies. An additional problems are treatment‐induced myelotoxicity and other side effects. The current article provides a short overview of immunological targets expressed on LSC in AML. Moreover, cell‐based therapies and immunotherapies tested in AML are discussed. Finally, the article provides an overview about LSC resistance and strategies to overcome resistance.
Effects of Evening Exposure to Light from Organic Light-Emitting Diodes on Melatonin and Sleep

Background and Purpose Organic light-emitting diodes (OLEDs) emit less blue light than traditional light-emitting diodes (LEDs), but the effects of OLED light exposure (LE) on melatonin and sleep have not been evaluated. Methods Twenty-four healthy subjects (age 26.9±5.7 years; including 18 females) with the intermediate chronotype were exposed to three different light conditions [4,000 K 150 lux OLED LE, 4,000 K 150 lux LED LE, and dim light (DL) at <10 lux] for 6.5 h from 17:30 to 24:00, in a random order and with a 1-week interval. Participants entered the unit for the experiment at 16:00, and their daylight was measured by actigraphy from 8:00 to 16:00 during each session. Saliva samples for melatonin were taken every hour from 18:00 to 24:00. Sleep was monitored by polysomnography, and vigilance was evaluated by psychomotor vigilance test upon awakening. Results Melatonin onset occurred at 21:11±01:24, 21:20±01:19, and 21:36±01:16 in the DL, OLED, and LED conditions, respectively. Melatonin onset was significantly delayed under LED LE compared to DL (p=0.007) but did not differ under OLED LE (p=0.245). Melatonin suppression, sleep parameters, and vigilance were similar among the three light conditions. The accumulated amount of daytime light in each session was negatively correlated with the melatonin onset time under the DL (rho=−0.634, p=0.002) and OLED (rho=−0.447, p=0.029) conditions, not under the LED condition (p=0.129). Conclusions Melatonin onset under OLED LE was not significantly delayed compared to DL. Exposure to sufficient daylight may advance melatonin onset even when a subject is exposed to OLED LE in the evening.
Nouvelles analyses des crises alimentaires en Afrique de l'Ouest

La question des crises est un element central de debat et un enjeu strategique pour l’ensemble des protagonistes en Afrique de l’Ouest. Les crises alimentaires et nutritionnelles y possedent une recurrence, une intensite et une variabilite fortes qui constituent des defis renouveles. Leur definition, leur delimitation et leur gestion constituent aussi un champ professionnel structure et ancien d’intervention. Differentes approches peuvent etre mobilisees afin de rendre compte de la diversite et de la complexite des crises alimentaires et nutritionnelles. Certaines, davantage descriptives, enumerent leurs causes et leurs manifestations tandis que d’autres insistent sur leur caractere construit, leurs dynamiques propres liees aux interactions entre phenomenes. Les differents acteurs institutionnels impliques, nationaux comme internationaux, ont, jusqu’a present, surtout favorise l’amelioration progressive de systemes experts apportant des reponses techniques de court terme. En parallele, cette evolution a conduit a une harmonisation des cadres de pensee prejudiciable a la prise en compte de la diversite des questionnements et a l’integration des acteurs non-institutionnels. Ce sont ces frontieres et ces limites que cet article entend questionner afin de rappeler la dimension politique de la gestion des crises alimentaires (et de leur eventuelle resolution).