Abstract
Purpose
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of beta cells, resulting in a loss of insulin production. Patients with T1D carry a substantial ...disease burden as well as substantial short-term and long-term risks associated with inadequate glycemic control. Currently, treatment mainly consists of insulin, which only treats the symptoms of T1D and not the root cause. Thus, disease-modifying agents such as anti-CD3 monoclonal antibodies (mAbs) that target the autoimmune destruction of beta cells in T1D would provide significant relief and health benefits for patients with T1D. This review summarizes the clinical evidence regarding the safety and efficacy of anti-CD3 mAbs in the prevention and treatment of T1D.
Summary
A total of 27 studies reporting or evaluating data from clinical trials involving otelixizumab and teplizumab were included in the review. Anti-CD3 mAbs have shown significant benefits in both patients at high risk for T1D and those with recent-onset T1D. In high-risk populations, anti-CD3 mAbs delayed time to diagnosis, preserved C-peptide levels, and improved metabolic parameters. In recent-onset T1D, anti-CD3 mAbs preserved C-peptide levels and reduced insulin needs for extended periods. Anti-CD3 mAb therapy appears to be safe, with primarily transient and self-limiting adverse effects and no negative long-term effects.
Conclusion
Anti-CD3 mAbs are promising disease-modifying treatments for T1D. Their role in T1D may introduce short-term and long-term benefits with the potential to mitigate the significant disease burden; however, more evidence is required for an accurate assessment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The seasonal variability of the carbonate system in the eastern Mediterranean Sea (EMed) was investigated based on discrete total alkalinity (A
T
), total dissolved inorganic carbon (C
T
), and pH ...measurements collected during three cruises around Crete between June 2018 and March 2019. This study presents a detailed description of this new carbonate chemistry dataset in the eastern Mediterranean Sea. We show that the North Western Levantine Basin (NWLB) is unique in terms of range of A
T
variation vs. C
T
variation in the upper water column over an annual cycle. The reasons for this singularity of the NWLB can be explained by the interplay between strong evaporation and the concomitant consumption of C
T
by autotrophic processes. The high range of A
T
variations, combined to temperature changes, has a strong impact on the variability of the seawater
p
CO
2
(
p
CO
2
S
W
). Based on Argo float data, an entire annual cycle for
p
CO
2
S
W
in the NWLB has been reconstructed in order to estimate the temporal sequence of the potential “source” and “sink” of atmospheric CO
2
. By combining this dataset with previous observations in the NWLB, this study shows a significant ocean acidification and a decrease in the oceanic surface pH
T
25
of −0.0024 ± 0.0004 pH
T
25
units.a
–1
. The changes in the carbonate system are driven by the increase of atmospheric CO
2
but also by unexplained temporal changes in the surface A
T
content. If we consider that the EMed will, in the future, encounter longer, more intense and warmer summer seasons, this study proposes some perspectives on the carbonate system functioning of the “future” EMed.
Chronological aging of yeast cells is commonly used as a model for aging of human post-mitotic cells. The yeast Saccharomyces cerevisiae grown on glucose in the presence of ammonium sulphate is ...mainly used in yeast aging research. We have analyzed chronological aging of the yeast Hansenula polymorpha grown at conditions that require primary peroxisome metabolism for growth.
The chronological lifespan of H. polymorpha is strongly enhanced when cells are grown on methanol or ethanol, metabolized by peroxisome enzymes, relative to growth on glucose that does not require peroxisomes. The short lifespan of H. polymorpha on glucose is mainly due to medium acidification, whereas most likely ROS do not play an important role. Growth of cells on methanol/methylamine instead of methanol/ammonium sulphate resulted in further lifespan enhancement. This was unrelated to medium acidification. We show that oxidation of methylamine by peroxisomal amine oxidase at carbon starvation conditions is responsible for lifespan extension. The methylamine oxidation product formaldehyde is further oxidized resulting in NADH generation, which contributes to increased ATP generation and reduction of ROS levels in the stationary phase.
We conclude that primary peroxisome metabolism enhanced chronological lifespan of H. polymorpha. Moreover, the possibility to generate NADH at carbon starvation conditions by an organic nitrogen source supports further extension of the lifespan of the cell. Consequently, the interpretation of CLS analyses in yeast should include possible effects on the energy status of the cell.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During the winter 2013, an intense observation and monitoring was performed in the north‐western Mediterranean Sea to study deep water formation process that drives thermohaline circulation and ...biogeochemical processes (HYMEX SOP2 and DEWEX projects). To observe intensively and continuously the impact of deep convection on oxygen (O2) ventilation, an observation strategy was based on the enhancement of the Argo‐O2 floats to monitor the offshore dense water formation area (DWF) in the Gulf of Lion prior to and at the end of the convective period (December 2012 to April 2013). The intense O2 measurements performed through shipborne CTD casts and Argo‐O2 floats deployment revealed an O2 inventory rapidly impacted by mixed layer (ML) deepening on the month scale. The open‐sea convection in winter 2013 ventilated the deep waters from mid‐February to the end of May 2013. The newly ventilated dense water volume, based on an Apparent Oxygen Utilization (AOU) threshold, was estimated to be about 1.5 × 1013 m3 during the DWF episode, increasing the deep O2 concentrations from 196 to 205 µmol kg−1 in the north‐western basin.
Key Points
Intense oxygen measurements were performed through Argo‐O2 floats in the north‐western Mediterranean Sea during convection events
Ventilated dense water volume was estimated around 1.5 × 1013 m3 during the open‐sea convection process in winter 2013
Deep oxygen ventilation started in mid‐February and ended at the end of May 2013
The estimation of arterial blood gas and lactate from central venous blood analysis and pulse oximetry (SpO2) readings has not yet been extensively validated.
In this multicentre, prospective study ...performed in 590 patients with acute circulatory failure, we measured blood gases and lactate in simultaneous central venous and arterial blood samples at 6 h intervals during the first 24 h after insertion of central venous and arterial catheters. The study population was randomly divided in a 2:1 ratio into model derivation and validation sets. We derived predictive models of arterial pH, carbon dioxide partial pressure, oxygen saturation, and lactate, using clinical characteristics, SpO2, and central venous blood gas values as predictors, and then tested their performance in the validation set.
In the validation set, the agreement intervals between predicted and actual values were −0.078/+0.084 units for arterial pH, −1.32/+1.36 kPa for arterial carbon dioxide partial pressure, −5.15/+4.47% for arterial oxygen saturation, and −1.07/+1.05 mmol litre−1 for arterial lactate (i.e. around two times our predefined clinically tolerable intervals for all variables). This led to ∼5% (or less) of extreme-to-extreme misclassifications, thus giving our predictive models only marginal agreement. Thresholds of predicted variables (as determined from the derivation set) showed high predictive values (consistently >94%), to exclude abnormal arterial values in the validation set.
Using clinical characteristics, SpO2, and central venous blood analysis, we predicted arterial blood gas and lactate values with marginal accuracy in patients with circulatory failure. Further studies are required to establish whether the developed models can be used with acceptable safety.
The long-term monitoring of basic hydrological parameters (temperature and salinity), collected as time series with adequate temporal resolution (i.e. with a sampling interval allowing the resolution ...of all important timescales) in key places of the Mediterranean Sea (straits and channels, zones of dense water formation, deep parts of the basins), constitute a priority in the context of global changes. This led CIESM (The Mediterranean Science Commission) to support, since 2002, the HYDROCHANGES programme (http//www.ciesm.org/marine/programs/hydrochanges.htm), a network of autonomous conductivity, temperature, and depth (CTD) sensors, deployed on mainly short and easily manageable subsurface moorings, within the core of a certain water mass. The HYDROCHANGES strategy is twofold and develops on different scales. To get information about long-term changes of hydrological characteristics, long time series are needed. But before these series are long enough they allow the detection of links between them at shorter timescales that may provide extremely valuable information about the functioning of the Mediterranean Sea. The aim of this paper is to present the history of the programme and the current set-up of the network (monitored sites, involved groups) as well as to provide for the first time an overview of all the time series collected under the HYDROCHANGES umbrella, discussing the results obtained thanks to the programme.
L'organisation de l'espace mauricien, insulaire et exigu (1 865 km2), est quelque peu dichotomique. La région urbaine centrale qui prend appui sur Port-Louis, la capitale portuaire, bénéficie des ...externalités qui fondent de nos jours les avantages comparatifs des régions : elle concentre plus de la moitié de la population et plus de 80 % des industries et des services. La région rurale périphérique est sans doute éminemment agricole (canne à sucre et secondairement thé sur les « hautes terres ») mais son littoral a été bien souvent aménagé pour le tourisme balnéaire. Cette structure spatiale est polygénique. Elle se compose d'éléments dont les uns sont hérités du passé et les autres sont le fruit de la politique d'indépendance. Du passé colonial subsiste la quasi-monoculture de la canne à sucre et une société pluri-ethnique composée d'apports européens (Franco-Mauriciens), afro-malgaches et asiatiques où domine la population indienne et cloisonnée en communautés. L'indépendance a eu pour effet social un accroissement démographique rapide en passe d'être jugulé et pour effet économique le développement d'activités nouvelles, tourisme international et industries d'exportation de la zone franche. Une telle orientation intègre davantage l'île à l'Europe qu'à son propre environnement géographique. Bien que le produit intérieur brut augmente plus vite que la population, la croissance de la consommation est supérieure à celle de ce produit et la dépendance externe s'accroît d'autant. The organization of space in Mauritius, a small island of 1 865 km2 (1 164 square miles), is somewhat dichotomic. The central urban region, organized around Port-Louis, the harbour capital, benefits from externalities, upon which comparative advantages of regions are founded nowadays : it concentrates more than half of the population and more than 80 % of industries and services. The outlying rural region is essentially agricultural indeed — sugar cane and, secondarily, tea on the " high lands " — but its coastline has quite often been developed into sea resorts. Such a structure of space is polygenic. It is composed of elements among which some have been inherited from the past and others are the result of a policy of independence. From colonial past there remains the quasi-monoculture of sugar cane and a pluri-ethnical society originated from Europeans (French Mauritians), Afro-Malagasy, and Asians among whom the Indian population, partitioned into communities, prevails. Independence has had the social effect of a swift demographic increase in a fair way to being jugulated, and the economical effect of a development of new activites, international tourism and export industries in the free zone. Such an orientation integrates the island into Europe rather than its own geographical environment. Though the gross national product grows faster than population, the increase of consumption is larger than the increase of that product, and external dependence grows in proportion.
The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report ...multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre–ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis.
•Biallelic variants in HEATR3 are associated with DBA and other clinical features in humans.•HEATR3 variants destabilize the protein, resulting in a reduction of nuclear uL18 and impaired ribosome biogenesis.
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To investigate the effects of episodic occurrence of dissolved organic carbon (DOC) in the natural environment, bacterial degradation of labile DOC was studied under laboratory- controlled conditions ...followed by modelling. A single labile DOC compound was periodically added to the experimental culture and its degradation by a monospecific marine bacterial strain was followed. The measured variables were DOC and bacterial biomass determined from the particulate organic carbon values. Experimental dynamics showed a repetition of 2 successive patterns after each DOC pulse: (1) substrate consumption and bacterial growth in the first few hours after substrate addition, followed by (2) bacterial reduction (organic carbon-related) and associated non-labile DOC release within the next few hours. Based on these experimental results, the Dynamic Energy Budget theory was applied for the first time to such conditions to develop a mechanistic model that comprised 7 parameters and 4 state variables in which bacterial biomass was fractionated into reserve and structure compartments. The model was constructed by accounting for a constant specific maintenance rate and comprised 2 different cell maintenance fluxes, one fuelled from cell reserves when substrate was abundant and one from reserves and cell structures when starvation occurred. This new model of bacterial degradation adequately matched experimental measurements and accurately reproduced the accumulation of non-labile DOC in the culture during the experiment. This model can easily be implemented in an aquatic biogeochemical model and could provide better understanding of the role of bacteria in carbon cycling in fluctuating environments.
Le vieillissement et l’obésité sont devenus des enjeux majeurs dans le domaine de la santé publique. L’activité physique et la nutrition jouent un rôle important dans la prévention des effets de ...santé adverses liés au vieillissement et permettent donc de maintenir un vieillissement en santé. Il a été démontré qu’un entraînement high intensity interval training (HIIT) combiné à une supplémentation en citrulline (CIT) peut améliorer les performances physiques et fonctionnelles. Il serait donc intéressant de découvrir les paramètres moléculaires cachés derrière ces adaptations physiologiques à travers les analyses métabolomiques. L’objectif de cette étude est d’évaluer l’adaptation du profil sanguin métabolomique suite à 12 semaines d’entraînement HIIT combiné à une supplémentation en CIT chez des adultes âgés obèses. Ceci permettrait de dévoiler de nouveaux biomarqueurs liés à la nutrition et à l’activité physique chez les adultes âgés obèses.
Soixante et onze hommes et femmes âgés obèses et sédentaires ont participé à cette étude interventionnelle randomisée en double aveugle : un programme d’entraînement HIIT sur 12 semaines avec une supplémentation en CIT (10g/jour) ou placebo (PLA). Des échantillons de plasma ont été prélevés avant et après l’intervention afin d’obtenir le profile métabolomique à travers 4 spectromètres :
– UHPLC/q-Exactive (Thermo Scientific) ;
– LC/QTRAP 6500+ (AB Sciex) ;
– LC/QQQ 6410 (Agilent) ;
– GC/7000C (Agilent) couplés à différentes méthodes de chromatographie en phases liquides ou gazeuses.
Au total, 364 métabolites et ratios de métabolites ont été obtenus. Parmi les 44 métabolites montrant des variations significatives, un effet HIIT a été observé pour 34 (14 ont diminué et 20 ont augmenté suite au HIIT) et un effet combiné HIIT×supplémentation pour 10 (en comparant au groupe PLA, 8 ont augmenté et 2 ont diminué dans le groupe CIT).
Les analyses métabolomiques suite à un entraînement HIIT combiné à une supplémentation en citrulline ont révélé des adaptations intéressantes au niveau du profil métabolomique sanguin chez les adultes âgés obèses. Il serait intéressant de corréler ces métabolites à des mesures cliniques afin d’identifier des biomarqueurs utiles au domaine de la gériatrie et au suivi des individus âgés obèses.
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