Role of the Fas/Fas ligand system in female reproductive organs: survival and apoptosis

For centuries, the question of "whether there is life after death" has intrigued the mind of philosophers and the same question fascinates researchers in the field of apoptosis today. The death of a cell is by no means the end of the story. On the contrary, growing evidence suggests that the clearance of apoptotic bodies by macrophages is an important regulatory component in tissue renewal. Without death by apoptosis, the life of reproductive tissues and their function would not be possible. The survival signals that counteract cell death also prepare the cells for apoptosis, and dead cells are important stimuli for tissue survival. The Fas/Fas ligand system is an important mediator of apoptosis and is an excellent example of this apparently contradictory phenomenon.     

A BRCA1 founder mutation, identified with haplotype analysis, allowing genotype/phenotype determination and predictive testing

We searched for a founder mutation in a population from one geographic region of Norway with prevalent breast/ovarian cancer families. We sampled 33 breast/ovarian cancer families and determined haplotypes of four markers linked to the BRCA1 region. Of the affected 33 index women, 13 (39.4%) shared one haplotype. In five (15% of total), an identical mutation was indicated by an abnormal truncated protein test (PTT) of exon 11 and shown to represent a 1675delA mutation. In the other index women, PTT of exon 11 showed no abnormality. No other BRCA1 founder mutation of this prevalence is likely because no other haplotype was more frequent in affecteds than in controls. All families with the 1675delA mutation in this geographic region may be considered as part of one large kindred. This allows a genotype–phenotype correlation to be precisely determined and used in genetic counselling for predictive testing within this kindred. Identification of identical haplotypes between unrelated affected individuals may be used to estimate the extent of founder effects for any mapped disease, without knowledge of the specific founder mutation.     

Physiological relevance of aquaporins: luxury or necessity?

Aquaporins are members of a large family of pore-forming intrinsic membrane proteins, the MIP family. Based on their permeability properties they are now further subdivided into aquaporins, with real water-selective pores, and aquaglyceroporins with slightly less selective pores. Aquaporins are expressed in a large variety of tissues throughout the body but in most situations it is not clear whether their presence is necessary for the proper physiological function of these tissues. This review focuses on recent insight into the physiological relevance of aquaporins gained from studying aquaporin knockout mouse models and from diseases, on new surprising findings related to gating and selectivity, and on the consequences of tetramerization for routing and the genetics of nephrogenic diabetes insipidus. The active fluid transport in proximal tubules and in salivary glands is seriously compromised by aquaporin deletion. This is in contrast to lung, airways and stomach, where active fluid transport proceeds unhindered in the face of greatly reduced water permeabilities due to aquaporin deletion. Therefore, aquaporins seem to be a necessity at extreme high rates of active fluid transport but appear to be more of a luxury at medium or low fluid transport rates.     

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium

Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca²⁺ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations suggested that the pathomechanisms by which the variants cause muscle disease include disruption of the binding sites for Ca²⁺ and for troponin I. In line with these findings, physiological studies in myofibers isolated from patients’ biopsies revealed a markedly reduced force response of the sarcomeres to [Ca²⁺]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC. Finally, we tested the therapeutic potential of the fast skeletal muscle troponin activator tirasemtiv in patients’ myofibers and showed that the contractile dysfunction was repaired. Thus, our data reveal that pathogenic variants in TNNC2 cause congenital muscle disease, and they provide therapeutic angles to repair muscle contractility.     

Functional recovery after destruction of dopamine systems in the nucleus accumbens of rats. II. Facilitation by the ACTH-(4-9) analog ORG 2766

Functional recovery from motor hypoactivity of rats with 6-OHDA lesions in the nucleus accumbens is accelerated by intra-accumbal or subcutaneous treatment with the ACTH-(4-9) analog ORG 2766. The spontaneous recovery period of 3 weeks is shortened to 7 days by daily treatment with this peptide during the first 6 days after the lesion. The 6-OHDA lesion induced a decrease of about 30-40% in the levels of dopamine, HVA and DOPAC as well as in the uptake of [3H]dopamine in nucleus accumbens tissue in vitro. Treatment with ORG 2766 during the first 6 days following the lesion did not affect the lesion-induced changes in these biochemical parameters. Binding studies with [3H]haloperidol in nucleus accumbens tissue of placebo or ORG 2766-treated sham-lesioned rats revealed a linear Scatchard plot 7 days after the sham lesion. In tissue of placebo-treated 6-OHDA lesioned animals a similar linear Scatchard plot was found but in tissue of ORG 2766-treated 6-OHDA-lesioned rats the Scatchard plot was curvilinear in shape indicating two types of binding sites. In the 6-OHDA-lesioned rats treated with ORG 2766 the behavioral response upon apomorphine challenge was enhanced suggesting the existence of functional supersensitivity of the DA system. Similar changes in Scatchard plots and apomorphine-induced behavioral changes have been previously reported after spontaneous recovery. The present study indicates that ORG 2766 accelerates the process of functional recovery from impaired motor behavior of rats with 6-OHDA lesions in the nucleus accumbens, which may be due to development of denervation supersensitivity.     

Individual and Joint Expert Judgments as Reference Standards in Artifact Detection

Objective

To investigate the agreement among clinical experts in their judgments of monitoring data with respect to artifacts, and to examine the effect of reference standards that consist of individual and joint expert judgments on the performance of artifact filters.

Design

Individual judgments of four physicians, a majority vote judgment, and a consensus judgment were obtained for 30 time series of three monitoring variables: mean arterial blood pressure (ABPm), central venous pressure (CVP), and heart rate (HR). The individual and joint judgments were used to tune three existing automated filtering methods and to evaluate the performance of the resulting filters.

Measurements

The interrater agreement was calculated in terms of positive specific agreement (PSA). The performance of the artifact filters was quantified in terms of sensitivity and positive predictive value (PPV).

Results

PSA values between 0.33 and 0.85 were observed among clinical experts in their selection of artifacts, with relatively high values for CVP data. Artifact filters developed using judgments of individual experts were found to moderately generalize to new time series and other experts; sensitivity values ranged from 0.40 to 0.60 for ABPm and HR filters (PPV: 0.57–0.84), and from 0.63 to 0.80 for CVP filters (PPV: 0.71–0.86). A higher performance value for the filters was found for the three variable types when joint judgments were used for tuning the filtering methods.

Conclusion

Given the disagreement among experts in their individual judgment of monitoring data with respect to artifacts, the use of joint reference standards obtained from multiple experts is recommended for development of automatic artifact filters.     

KIF16B is a candidate gene for a novel autosomal‐recessive intellectual disability syndrome

Intellectual disability (ID) and global developmental delay are closely related; the latter is reserved for children under the age of 5 years as it is challenging to reliably assess clinical severity in this population. ID is a common condition, with up to 1%–3% of the population being affected and leading to a huge social and economic impact. ID is attributed to genetic abnormalities most of the time; however, the exact role of genetic involvement in ID is yet to be determined. Whole exome sequencing (WES) has gained popularity in the workup for ID, and multiple studies have been published examining the diagnostic yield in identification of the disease‐causing variant (16%–55%), with the genetic involvement increasing as intelligence quotient decreases. WES has also accelerated novel disease gene discovery in this field. We identified a novel biallelic variant in the KIF16B gene (NM_024704.4:c.3611T > G) in two brothers that may be the cause of their phenotype.     

Metabolic impacts of high dietary exposure to persistent organic pollutants in mice

Persistent organic pollutants (POPs) have been linked to metabolic diseases. Yet, the effects of high exposure to dietary POPs remain unclear. We therefore investigated whether elevated exposure to POPs provided by whale meat supplementation could contribute to insulin resistance.     

Type 2 helper T-cell cytokines induce morphologic and molecular characteristics of atopic dermatitis in human skin equivalent

Both the immune system and the epidermis likely have an important role in the pathogenesis of atopic dermatitis (AD). The objective of the present study was to develop a human skin equivalent model exhibiting morphologic and molecular characteristics of AD in a controlled manner. Skin equivalents generated from normal adult human keratinocytes were stimulated with type 2 T-helper cell (Th2) cytokines IL-4 and IL-13, and morphologic features and gene expression of the epidermis were studied. Th2 cytokines induced intercellular edema similar to spongiotic changes observed in lesional AD as assessed at histopathologic analysis and electron microscopy. Furthermore, genes known to be specifically expressed in epidermis of patients with AD such as CAII and NELL2 were induced. In contrast, expression of psoriasis-associated genes such as elafin and hBD2 was not changed. Th2 cytokines caused DNA fragmentation in the keratinocytes, which could be inhibited by the caspase inhibitor Z-VAD, which suggests that apoptosis was induced. In addition, up-regulation of the death receptor Fas was observed in keratinocytes after Th2 cytokine stimulation. IL-4 and IL-13 induced phosphorylation of the signaling molecule STAT6. It was concluded that the skin equivalent model described herein may be useful in investigation of the epidermal aspects of AD and for study of drugs that act at the level of keratinocyte biology.