Molecular insights into the interaction between a disordered protein and a folded RNA.

Intrinsically disordered protein regions (IDRs) are well-established as contributors to intermolecular interactions and the formation of biomolecular condensates. In particular, RNA-binding proteins (RBPs) often harbor IDRs in addition to folded RNA-binding domains that contribute to RBP function. To understand the dynamic interactions of an IDR-RNA complex, we characterized the RNA-binding features of a small (68 residues), positively charged IDR-containing protein, SERF. At high concentrations, SERF and RNA undergo charge-driven associative phase separation to form a protein- and RNA-rich dense phase. A key advantage of this model system is that this threshold for demixing is sufficiently high that we could use solution-state biophysical methods to interrogate the stoichiometric complexes of SERF with RNA in the one-phase regime. Herein, we describe our comprehensive characterization of SERF alone and in complex with a small fragment of the HIV-1 TAR RNA (TAR) with complementary biophysical methods and molecular simulations. We find that this binding event is not accompanied by the acquisition of structure by either molecule; however, we see evidence for a modest global compaction of the SERF ensemble when bound to RNA. This behavior likely reflects attenuated charge repulsion within SERF via binding to the polyanionic RNA and provides a rationale for the higher-order assembly of SERF in the context of RNA. We envision that the SERF-RNA system will lower the barrier to accessing the details that support IDR-RNA interactions and likewise deepen our understanding of the role of IDR-RNA contacts in complex formation and liquid-liquid phase separation.

Serum Lipoprotein(a) Is Not Associated with Graves' Ophthalmopathy.

Aim: To investigate the relationship of serum lipoprotein(a) [Lp(a)] and other serum lipids with presence of Graves' ophthalmopathy (GO). Methods: A total of 99 consecutive patients diagnosed with Graves' disease (GD), aged 18-65 years, who had not received prior treatment for GO, thyroid surgery, or radioactive iodine therapy, were recruited between June 2020 and July 2022. In addition, 56 healthy controls (HCs) were included as the control group. All patients underwent an ophthalmological examination, and were classified based on the presence of GO into the GO group (n = 45) and no GO group (n = 54). Fasting blood samples were collected from all participants to analyze serum lipid parameters, including Lp(a), total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: The median serum levels of Lp(a) were 5.7 [4.3-9.2] in the GO group, 6.7 [3.7-9.9] in the no GO group, and 4.7 [3-7.6] in the HC group. The intergroup comparisons of serum Lp(a) levels showed no significant result. The serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were also similar between the groups (P > 0.05 for all). However, when analyzing only euthyroid GD patients and the control group, the serum LDL cholesterol levels were found to be significantly higher in the euthyroid GO group [median: 132 interquartile range (IQR) (110-148) mg/dL] than in the HCs [median: 96 IQR (94-118) mg/dL] (P = 0.002). Conclusion: The findings of our study did not support the association between serum Lp(a) levels and GO.

Multivalent Dynamic Colocalization of Avian Influenza Polymerase and Nucleoprotein by Intrinsically Disordered ANP32A Reveals the Molecular Basis of Human Adaptation.

Adaptation of avian influenza RNA polymerase (FluPol) to human cells requires mutations on the 627-NLS domains of the PB2 subunit. The E627K adaptive mutation compensates a 33-amino-acid deletion in the acidic intrinsically disordered domain of the host transcription regulator ANP32A, a deletion that restricts FluPol activity in mammalian cells. The function of ANP32A in the replication transcription complex and in particular its role in host restriction remains poorly understood. Here we characterize ternary complexes formed between ANP32A, FluPol, and the viral nucleoprotein, NP, supporting the putative role of ANP32A in shuttling NP to the replicase complex. We demonstrate that while FluPol and NP can simultaneously bind distinct linear motifs on avian ANP32A, the deletion in the shorter human ANP32A blocks this mode of colocalization. NMR reveals that NP and human-adapted FluPol, containing the E627 K mutation, simultaneously bind the identical extended linear motif on human ANP32A in an electrostatically driven, highly dynamic and multivalent ternary complex. This study reveals a probable molecular mechanism underlying host adaptation, whereby E627K, which enhances the basic surface of the 627 domain, is selected to confer the necessary multivalent properties to allow ANP32A to colocalize NP and FluPol in human cells.

Endocrinological Follow-Up Characteristics of People Diagnosed with Gender Dysphoria in Turkey.

Purpose: Various problems related to the gender-affirming therapy (GAT) can adversely affect both the physical and mental health of people diagnosed with gender dysphoria (GD). In this study, we aimed to highlight the reasons for loss to follow-up during the gender-affirming hormone therapy (GAHT), which is an important component of GAT. Methods: People diagnosed with GD who were followed for GAHT between January 2014 and June 2019 (female-to-male: 349; male-to-female: 89) were enrolled. The prepared questionnaire was administered to participants at routine follow-up visits. We arranged tele-interviews for those who did not attend the follow-up visits. Results: During GAHT process, the health problems most frequently reported by people diagnosed with GD were related to mental health. The most important factors in regular follow-up were the completion of legal procedures in Turkey required for GAT and citizenship alteration, financial barriers, lack of time for clinical visits, and dissatisfaction with health care setting. In addition, we found that the frequency of desire for supervised GAHT and family support were higher in regularly followed people diagnosed with GD. On the contrary, self-initiation of GAHT and mental disorders were more common in people diagnosed with GD lost to follow-up. Conclusion: The present study provides important information regarding the reasons for loss to follow-up during GAT in Turkey. Elucidation of reasons for loss to follow-up can aid in identifying the gaps in medical care, improve compliance, and outcomes of people diagnosed with GD.

Can "VAI" Better Indicate Metabolic Syndrome Compared with Other Metabolic Syndrome-Related Parameters in Patients with Thyroid Nodules? A Study from Turkey.

Background: To investigate the relationship between visceral adiposity index (VAI) and other metabolic syndrome (MetS)-related parameters, and thyroid nodules. Methods: This single-center, prospective, case-control study included 67 patients with thyroid nodules and 48 healthy volunteers with similar age, sex, and body mass index (BMI). Biochemical parameters were obtained from medical charts. Anthropometric measurements and total body composition analysis were performed to calculate VAI and other MetS parameters. The parenchymal structure was evaluated according to VESINC (Volume, Echogenicity, Sonographic texture, Infiltration of pseudonodular Nodules, Cysts) system on thyroid ultrasound and nodule characteristics were also detected. MetS was defined according to International Diabetes Federation criteria. Results: We examined a total of 67 patients with thyroid nodule and 48 healthy volunteers. Sixty-one (91%) were female in the patient group; and 43 (90%) were female in the control group. The mean age was 48.5 ± 11.6 years in the patient group; 47.2 ± 9.5 years in the control. The median VAI was significantly higher in the patient group than the control group [4.1 interquartile range (IQR: 2.6-5.9) vs. 3 (IQR: 2-4.3), P = 0.024]. There was a positive correlation between VAI and BMI, waist/hip ratio (WHpR), waist/height ratio (WHtR), and homeostasis of model assessment of insulin resistance (HOMA-IR). On the other hand, there was no significant correlation between VAI and thyroid function tests and autoantibodies and thyroid volume. Conclusions: In conclusion, we demonstrated that MetS was more common in patients with thyroid nodules. Although VAI and HOMA-IR levels were significantly different between the two groups, we found no significant difference in terms of waist circumference, WHpR, and WHtR. This might suggest that VAI compared with these parameters, better predicts the risk of MetS in patients with thyroid nodules.

Simultaneous use of FDG-18 and 68Ga-citrate PET/CT for the differential diagnosis of sarcoidosis and malignant disease.

A 67-year-old male presented with cutaneous rash, lassitude and fatigue of three weeks. Personal history included psoriasis and sarcoidosis. Physical examination revealed macular rash on the anterior chest wall. Laboratory results were within normal limits. Chest X-ray showed normal findings. Pulmonary function tests demonstrated a mild obstructive pattern and a mild decrease in DLCO/VA. Thorax CT revealed two nodules in the right upper and middle lobe. 68Ga-citrate PET/CT did not demonstrate any active inflammatory reaction associated with sarcoidosis while 18F-FDG PET/CT revealed increased FDG uptake in the right middle lobe, upper division bronchus and in the left lower abdominal quadrant. Histopathologic examination of the colon biopsy was compatible with adenocarcinoma and bronchoscopic biopsy of the lung lesions revealed nonspecific granulomatous inflammation. BAL cytology was normal while BAL culture did not grow any pathologic organisms. Simultaneous use of 18F-FDG and 68Ga-citrate PET/CT was the hallmark for the final diagnosis in our patient. While FDG/PET has detected the pulmonary and colonic malignant foci in our patient, 68Ga-citrate PET/CT excluded the presence of active granulomatous inflammation of sarcoidosis. Simultaneous utility of these two imaging modalities in patients with sarcoidosis is of great importance in terms of guiding the clinician towards the accurate diagnostic pathway which is the hallmark for final diagnosis, especially in the presence of concomitant malignant disease.