Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation

Post‐translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA‐binding protein TAR DNA‐binding protein (TDP‐43), is hyperphosphorylated in disease on several C‐terminal serine residues, a process generally believed to promote TDP‐43 aggregation. Here, we however find that Casein kinase 1δ‐mediated TDP‐43 hyperphosphorylation or C‐terminal phosphomimetic mutations reduce TDP‐43 phase separation and aggregation, and instead render TDP‐43 condensates more liquid‐like and dynamic. Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP‐43, but suppress accumulation of TDP‐43 in membrane‐less organelles and promote its solubility in neurons. We speculate that TDP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP‐43 aggregation.     

K2P18.1 translates T cell receptor signals into thymic regulatory T cell development

It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that driv...     

Pathways governing G1/S transition and their response to DNA damage

The ability to self-replicate is a fundamental feature of life, reflected at the cellular level by a highly regulated process initiated in G1 phase via commitment to a round of DNA replication and cell division. Here we briefly highlight recent advances in understanding the molecular pathways which govern the decision of mammalian somatic cells to enter S phase, and the so-called cell cycle checkpoints which guard the G1/S transition and S phase progression against potentially deleterious effects of genotoxic stress. Particular emphasis is put on the emerging parallel yet cooperative pathways of retinoblastoma protein (pRB)–E2F and Myc, their convergence to control the activity of the cyclin-dependent kinase 2 (Cdk2) at the G1/S boundary, as well as the two waves of checkpoint responses at G1/S: the rapid pathway(s) leading to Cdc25A degradation, and the delayed p53–p21 cascade, both silencing the Cdk2 activity upon DNA damage.     

Cuticular wax profiles of leaves of some traditionally used African Bignoniaceae

Bignoniaceae, Newbouldia laevis, Markhamia acuminata, Spathodea campanulata and Kigelia africana were analysed by GC-MS. The principal constituents were represented by a homologous series of n-alkanes (C23-C33), n-alcohols (C18-C30) and related carboxylic acids (C16-C36). For N. laevis and M. acuminata, ursolic and oleanolic acid were the most abundant wax components (52 and 60%, respectively), followed by the C29, the C31 and the C33 n-alkanes. The predominant components of S. campanulata were n-alcohols (35%), with octacosanol and triacontanol as the most abundant ones, while K. africana is distinguished from these three members by the conspicuous absence of triterpenoic acids and the predominance of n-alkanes (70%) with hentriacontane and tritriacontane as the main representatives. Other notable constituents were sterols, albeit present in trace amounts. The wax profiles are discussed in terms of taxonomic characters.     

Public, private and non-specific antibodies induced by non-cytopathic viral infections

Lymphocytic choriomeningitis virus (LCMV) represents a useful experimental model of murine infection with a non-cytopathic virus, bearing resemblance to HIV and hepatitis C virus (HCV) infections in humans. Recent data from the LCMV model indicate that the humoral immune response that is induced by non-cytopathic viruses is far more complex than previously appreciated. LCMV-induced IgG production is largely polyclonal, with more than 90% of the antibody repertoire constituting non-relevant specificities. A delayed virus-neutralizing antibody response is induced, including specificities directed not only against the parental LCMV-strain present in the host but also cross-specifically against LCMV-variants isolated from other hosts. These findings provide novel insights to aid our understanding of clinically relevant observations that are recorded following human infection with HIV, HCV and dengue viruses.     

Multimodal pressure-flow method to assess dynamics of cerebral autoregulation in stroke and hypertension

Background

This study evaluated the effects of stroke on regulation of cerebral blood flow in response to fluctuations in systemic blood pressure (BP). The autoregulatory dynamics are difficult to assess because of the nonstationarity and nonlinearity of the component signals.

Methods

We studied 15 normotensive, 20 hypertensive and 15 minor stroke subjects (48.0 ± 1.3 years). BP and blood flow velocities (BFV) from middle cerebral arteries (MCA) were measured during the Valsalva maneuver (VM) using transcranial Doppler ultrasound.

Results

A new technique, multimodal pressure-flow analysis (MMPF), was implemented to analyze these short, nonstationary signals. MMPF analysis decomposes complex BP and BFV signals into multiple empirical modes, representing their instantaneous frequency-amplitude modulation. The empirical mode corresponding to the VM BP profile was used to construct the continuous phase diagram and to identify the minimum and maximum values from the residual BP (BP_R) and BFV (BFV_R) signals. The BP-BFV phase shift was calculated as the difference between the phase corresponding to the BP_R and BFV_R minimum (maximum) values. BP-BFV phase shifts were significantly different between groups. In the normotensive group, the BFV_R minimum and maximum preceded the BP_R minimum and maximum, respectively, leading to large positive values of BP-BFV shifts.

Conclusion

In the stroke and hypertensive groups, the resulting BP-BFV phase shift was significantly smaller compared to the normotensive group. A standard autoregulation index did not differentiate the groups. The MMPF method enables evaluation of autoregulatory dynamics based on instantaneous BP-BFV phase analysis. Regulation of BP-BFV dynamics is altered with hypertension and after stroke, rendering blood flow dependent on blood pressure.