Electric field and strain induced Rashba effect in hybrid halide perovskites

Using first principles density functional theory calculations, we show how Rashba-type energy band splitting in the hybrid organic-inorganic halide perovskites APbX$_3$ (A=CH$_3$NH$_3^+$, CH(NH$_2$)$_2^+$, Cs$^+$ and X=I, Br) can be tuned and enhanced with electric fields and anisotropic strain. In particular, we demonstrate that the magnitude of the Rashba splitting of tetragonal (CH$_3$NH$_3$)PbI$_3$ grows with increasing macroscopic alignment of the organic cations and electric polarization, indicating appreciable tunability with experimentally-feasible applied fields, even at room temperature. Further, we quantify the degree to which this effect can be tuned via chemical substitution at the A and X sites, which alters amplitudes of different polar distortion patterns of the inorganic PbX$_3$ cage that directly impact Rashba splitting. In addition, we predict that polar phases of CsPbI$_3$ and (CH$_3$NH$_3$)PbI$_3$ with $R3c$ symmetry possessing considerable Rashba splitting might be accessible at room temperature via anisotropic strain induced by epitaxy, even in the absence of electric fields

Molecular basis for chaperone activities of the BRICHOS domain against different types of clumpy clients : a route to prevent amyloid toxicity

Protein aggregation is a hallmark of a wide range of human disorders, including Alzheimer’s disease and type II diabetes, and are often associated with imbalances in the cellular protein homeostasis. Molecular chaperones play an important role in modulating proteostasis and thereby counteract toxic consequences of misfolded or aggregated proteins. In this thesis, we investigated the molecular chaperone functions of several isolated BRICHOS domains against amyloid fibril formation and non-fibrillar protein aggregation. We propose that the ability of the BRICHOS domain to chaperone substrates with structurally distinct aggregation pathways is encoded in its ability to form different assembly states. BRICHOS domains are found in about ten distantly related protein families. It was proposed that they have an intramolecular chaperone-like function, preventing misfolding of a b-sheet prone region within their respective precursor proteins. Surprisingly, the activity of the Bri2 BRICHOS and proSP-C BRICHOS domain can extend to other aggregation-prone peptides and proteins. However, the molecular mechanisms of this diverse substrate spectrum remained unclear. Here we show that the Bri2 BRICHOS domain forms polydisperse assembly states ranging from monomers, that efficiently reduce amyloid-associated neurotoxicity in hippocampal mouse brain slices, to large oligomers that exclusively exhibit activities against non-fibrillar protein aggregation (paper I). Based on these findings, we designed a stable Bri2 BRICHOS monomer mutant that specifically blocks the formation of toxic species during amyloid fibril formation and partly disassembles wild-type Bri2 BRICHOS oligomers into monomers (paper II). Furthermore, we show that the conversion from Bri2 BRICHOS monomers towards large oligomers and hence the generation of activities against non-fibrillar protein aggregation is triggered by reducing conditions and is mediated through distinct thiol reactivities (paper III). The ability to adopt polydisperse assembly states together with activities against fibrillar and non-fibrillar protein aggregation are not only limited to Bri2 BRICHOS but similarly apply to Bri3 BRICHOS (paper IV). In contrast to Bri2 BRICHOS and Bri3 BRICHOS, proSP-C BRICHOS exists mostly as trimers in solution but a mutation at the homologous position in Bri2 BRICHOS (as shown in paper II) similarly resulted in a stable proSP-C BRICHOS monomer variant. This monomer mutant enabled us to investigate in detail the binding spectrum of the proSP-C BRICHOS domain towards different aggregates during amyloid fibril formation (paper V). This thesis gives new insights into the structure and function relationship of the molecular chaperone domain BRICHOS

Patient with disseminated renal cell cancer with severe bone and neuropathic pain syndrome and social problems - a case report

A 72-years-old woman diagnosed with renal cell carcinoma and metastases to pelvic bones that caused severe bone and neuropathic pain was depicted. Apart from difficulties in pain management social problems connected with the care for a patient’s spouse who also needed palliative care due to disseminated prostate cancer and died during the care for the patient were discussed. This patient’s case indicates the need for holistic approach to patients in palliative care with the provision of effective symptomatic treatment along with comprehensive psychosocial and spiritual support.A 72-years-old woman diagnosed with renal cell carcinoma and metastases to pelvic bones that caused severe bone and neuropathic pain was depicted. Apart from difficulties in pain management social problems connected with the care for a patient’s spouse who also needed palliative care due to disseminated prostate cancer and died during the care for the patient were discussed. This patient’s case indicates the need for holistic approach to patients in palliative care with the provision of effective symptomatic treatment along with comprehensive psychosocial and spiritual support

The role of naldemedine in the treatment of patients with opioid-induced constipation

Opioid-induced bowel dysfunction (OIBD) and opioid-induced constipation (OIC) significantly decrease patients’ quality of life (QoL), lead to complications and opioid non-compliance resulting in pain exacerbation. Traditional laxatives are first-line preventive and therapeutic measures, although they display limited efficacy and several adverse effects (AE). Non-pharmacology measures, prokinetics, opioid switch, all have little evidence and do not target OIBD and OIC pathophysiology both associated with activation of predominantly μ-opioid receptors mostly peripherally in the gastrointestinal (GI) tract. A combination of prolonged-release (PR) oxycodone with PR naloxone in one tablet with a ratio of 2:1 is available, although limitations include maximal daily dose of 160 mg/80 mg, respectively, and normal liver function. Peripherally acting μ-opioid receptor antagonists (PAMORA) block opioid receptors in the GI tract without compromising analgesia as they do not cross the blood–brain barrier. Currently three drugs are available: methylnaltrexone, naloxegol and naldemedine. Naldemedine has proven efficacy superior to placebo in the treatment of OIC in both cancer and non-cancer patients while improving patient-reported constipation symptoms and patients’ QoL. It is well tolerated with mostly mild to moderate intensity GI adverse effects such as abdominal, pain, nausea, and diarrhea, without compromising analgesia. Naldemedine dosing is convenient as it is administered once daily by an oral route. Moreover, naldemedine may be safely used in patients with renal failure and mild to moderate hepatic impairment. Effective prevention and treatment of OIC is of paramount importance in patients receiving long-term opioid therapy. Palliat Med Pract 2019; 13, 3: 113–12