Dual-Task Performance and Brain Morphologic Characteristics in Parkinson's Disease.

INTRODUCTION: Parkinson's disease (PD) reduces an individual's capacity for automaticity which limits their ability to perform two tasks simultaneously, negatively impacting daily function. Understanding the neural correlates of dual tasks (DTs) may pave the way for targeted therapies. To better understand automaticity in PD, we aimed to explore whether individuals with differing DT performances possessed differences in brain morphologic characteristics. METHODS: Data were obtained from 34 individuals with PD and 47 healthy older adults including (1) demographics (age, sex), (2) disease severity (Movement Disorder Society - Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Hoehn and Yahr, levodopa equivalent daily dose [LEDD]), (3) cognition (Montreal Cognitive Assessment), (4) LEDD, (5) single-task and DT performance during a DT-timed-up-and-go test utilizing a serial subtraction task, and (6) cortical thicknesses and subcortical volumes obtained from volumetric MRI. Participants were categorized as low or high DT performers if their combined DT effect was greater than the previously determined mean value for healthy older adults (µ = -74.2). Nonparametric testing using Quade's ANCOVA was conducted to compare cortical thicknesses and brain volumes between the highDT and lowDT groups while controlling for covariates: age, sex, MDS-UPDRS part III, LEDD, and intracranial volume. Secondarily, similar comparisons were made between the healthy older adult group and the highDT and lowDT groups. Lastly, a hierarchical linear regression model was conducted regressing combined DT effect on covariates (block one) and cortical thicknesses (block 2) in stepwise fashion. RESULTS: The highDT group had thicker cortices than the lowDT group in the right primary somatosensory cortex (p = 0.001), bilateral primary motor cortices (p ≤ 0.001, left; p = 0.002, right), bilateral supplementary motor areas (p = 0.001, left; p < 0.001, right), and mean of the bilateral hemispheres (p = 0.001, left; p < 0.001, right). Of note, left primary cortex thickness (p = 0.002), left prefrontal cortex thickness (p < 0.001), and right supplementary motor area thickness (p = 0.003) differed when adding a healthy comparison group. Additionally, the regression analysis found that the left paracentral lobule thickness explained 20.8% of the variability in combined DT effect (p = 0.011) beyond the influence of covariates. CONCLUSIONS: These results suggest regions underlying DT performance, specifically, a convergence of neural control relying on sensorimotor integration, motor planning, and motor activation to achieve higher levels of DT performance for individuals with PD.

Tandem gene amplification restores photosystem II accumulation in cytochrome b559 mutants of cyanobacteria.

Cytochrome (Cyt) b559 is a key component of the photosystem II complex (PSII) that is essential for its proper functioning and assembly. Site-directed mutants of the model cyanobacterium Synechocystis sp. PCC6803 with mutated heme axial ligands of Cyt b559 have little PSII and are therefore unable to grow photoautotrophically. Here we describe two types of Synechocystis autotrophic transformants that retained the same mutations in Cyt b559 but are able to accumulate PSII and grow photoautotrophically. Whole-genome sequencing revealed that all of these autotrophic transformants carried a variable number of tandem repeats (from 5 to 15) of chromosomal segments containing the psbEFLJ operon. RNA-seq analysis showed greatly increased transcript levels of the psbEFLJ operon in these autotrophic transformants. Multiple copies of the psbEFLJ operon in these transformants were only maintained during autotrophic growth, while its copy numbers gradually decreased under photoheterotrophic conditions. Two-dimensional PAGE analysis of membrane proteins revealed a strong deficiency in PSII complexes in the Cyt b559 mutants that was reversed in the autotrophic transformants. These results illustrate how tandem gene amplification restores PSII accumulation and photoautotrophic growth in Cyt b559 mutants of cyanobacteria, and may serve as an important adaptive mechanism for cyanobacterial survival.

A Structural Comparison of SARS-CoV-2 Main Protease and Animal Coronaviral Main Protease Reveals Species-Specific Ligand Binding and Dimerization Mechanism.

Animal coronaviruses (CoVs) have been identified to be the origin of Severe Acute Respiratory Syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and probably SARS-CoV-2 that cause severe to fatal diseases in humans. Variations of zoonotic coronaviruses pose potential threats to global human beings. To overcome this problem, we focused on the main protease (Mpro), which is an evolutionary conserved viral protein among different coronaviruses. The broad-spectrum anti-coronaviral drug, GC376, was repurposed to target canine coronavirus (CCoV), which causes gastrointestinal infections in dogs. We found that GC376 can efficiently block the protease activity of CCoV Mpro and can thermodynamically stabilize its folding. The structure of CCoV Mpro in complex with GC376 was subsequently determined at 2.75 Å. GC376 reacts with the catalytic residue C144 of CCoV Mpro and forms an (R)- or (S)-configuration of hemithioacetal. A structural comparison of CCoV Mpro and other animal CoV Mpros with SARS-CoV-2 Mpro revealed three important structural determinants in a substrate-binding pocket that dictate entry and release of substrates. As compared with the conserved A141 of the S1 site and P188 of the S4 site in animal coronaviral Mpros, SARS-CoV-2 Mpro contains N142 and Q189 at equivalent positions which are considered to be more catalytically compatible. Furthermore, the conserved loop with residues 46-49 in animal coronaviral Mpros has been replaced by a stable α-helix in SARS-CoV-2 Mpro. In addition, the species-specific dimerization interface also influences the catalytic efficiency of CoV Mpros. Conclusively, the structural information of this study provides mechanistic insights into the ligand binding and dimerization of CoV Mpros among different species.

Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression.

To improve the clinical outcome of tumor chemotherapy, more effective combination treatments against tumor metastasis and recurrence are required. Licochalcone A (LicA) is the root of Glycyrrhiza inflata and has been reported to possess anti-inflammatory, antimicrobial, and antitumor effects. Sorafenib (Sor), a multikinase inhibitor, is used to treat patients with solid tumors such as advanced hepatocellular carcinoma (HCC). However, the synergistic effects of LicA and Sor on the metastasis of human HCC cells have not been reported. We found that LicA and Sor did not have cytotoxic effects or arrest growth in human SK-Hep-1 and Huh-7 cells. In addition, treatment with LicA or Sor alone inhibited migration and invasion in human SK-Hep-1 and Huh-7 HCC cells. Furthermore, cotreatment with LicA and Sor synergistically inhibited the migration and invasion of HCC cells and significantly inhibited uPA protein expression. Notably, cotreatment of LicA and Sor synergistically and significantly downregulated MKK4-JNK expression. Through tail vein injection in nude mice, the aforementioned cotreatment synergistically suppressed SK-Hep-1 cell-mediated lung metastasis. These findings first revealed the synergistic effects of LicA and Sor cotreatment against human HCC cells, further suggesting that beneficial effects on tumor regression could be confirmed through prospective clinical trials.

Mutations of Cytochrome b559 and PsbJ on and near the QC Site in Photosystem II Influence the Regulation of Short-Term Light Response and Photosynthetic Growth of the Cyanobacterium Synechocystis sp. PCC 6803.

The characteristic features of two types of short-term light adaptations of the photosynthetic apparatus of the cyanobacterium Synechocystis sp. PCC 6803, state transition and blue-green light-induced fluorescence quenching, were compared in wild-type and cytochrome b559 and PsbJ mutant cells with mutations on and near the QC site in photosystem II (PSII). All mutant cells grew photoautotrophically and assembled stable PSII. Thermoluminescence emission experiments showed a decrease in the stability of the S3QB(-)/S2QB(-) charge pairs in the A16FJ, S28Aß, and V32Fß mutant cells. When dark-adapted wild-type and mutant cells were illuminated by medium-intensity blue light, the increase in the PSII fluorescence yield (indicating a transition to state 1) was more prominent in mutant than wild-type cells. Strong blue-light conditions induced a quenching of fluorescence corresponding to nonphotochemical fluorescence quenching (NPQ). The extension of NPQ decreased significantly in the mutants, and the kinetics appeared to be affected. When similar measures were repeated on an orange carotenoid protein (OCP)-deficient background, little or no quenching was observed, which confirms that the decrease in fluorescence under strong blue light corresponded to the OCP-dependent NPQ. Immunoblot results showed that the attenuated effect of blue light-induced NPQ in mutant cells was not due to a lack of OCP. Photosynthetic growth and biomass production were greater for A16FJ, S28Aß, and V32Fß mutant cells than for wild-type cells under normal growth conditions. Our results suggest that mutations of cytochrome b559 and PsbJ on and near the QC site of PSII may modulate the short-term light response in cyanobacteria.

Spectroscopic and functional characterization of cyanobacterium Synechocystis PCC 6803 mutants on the cytoplasmic-side of cytochrome b559 in photosystem II.

We performed spectroscopic and functional characterization on cyanobacterium Synechocystis PCC6803 with mutations of charged residues of the cytoplasmic side of cytochrome (Cyt) b559 in photosystem II (PSII). All of the mutant cells grew photoautotrophically and assembled stable PSII. However, R7Eα, R17Eα and R17Lß mutant cells grew significantly slower and were more susceptible to photoinhibition than wild-type cells. The adverse effects of the arginine mutations on the activity and the stability of PSII were in the following order (R17Lß>R7Eα>R17Eα and R17Aα). All these arginine mutants exhibited normal period-four oscillation in oxygen yield. Thermoluminescence characteristics indicated a slight decrease in the stability of the S3QB(-)/S2QB(-) charge pairs in the R7Eα and R17Lß mutant cells. R7Eα and R17Lß PSII core complexes contained predominantly the low potential form of Cyt b559. EPR results indicated the displacement of one of the two axial ligands to the heme of Cyt b559 in R7Eα and R17Lß mutant reaction centers. Our results demonstrate that the electrostatic interactions between these arginine residues and the heme propionates of Cyt b559 are important to the structure and redox properties of Cyt b559. In addition, the blue light-induced nonphotochemical quenching was significantly attenuated and its recovery was accelerated in the R7Lα and R17Lß mutant cells. Furthermore, ultra performance liquid chromatography-mass spectrometry results showed that the PQ pool was more reduced in the R7Eα and R17Lß mutant cells than wild-type cells in the dark. Our data support a functional role of Cyt b559 in protection of PSII under photoinhibition conditions in vivo.

Association between the hemodialysis eating index and risk factors of cardiovascular disease in hemodialysis patients.

OBJECTIVE: In this study, a Hemodialysis Eating Index (HDEI) suitable for hemodialysis (HD) patients in Taiwan was developed based on the dietary recommendations of the U.S. National Kidney Foundation for HD patients and the Taiwanese 2011 Daily Food Guide. The HDEI was used to explore HD-associated cardiovascular disease (CVD) risk factors. METHODS: In this prospective study, 108 HD patients from 2 HD centers in Taiwan were recruited as participants in 2010. All participants were older than 20 years. Patient CVD risk factor and 3-day dietary data were collected, and their HDEI scores were calculated. The HDEI scores comprise 12 food-related factors: the consumption of vegetables, fruits, total grains, whole grains, high-protein foods, high biological values, red and white meat, fish, oils, saturated fatty acids or trans fatty acids, nuts, and the duration of multivitamin use. The scores ranged from 5 to 100, and SAS software version 9.3 was used to perform statistical analyses. A P value less than .05 was considered statistically significant. RESULTS: The HDEI scores and serum albumin (Alb) levels were significantly and positively correlated. The participants were divided into 2 groups on the basis of the median HDEI score of 72.2. Two months after HDEI evaluation, the high-HDEI scoring group exhibited significantly decreased levels of serum total cholesterol and increased hemoglobin (Hb) levels. CONCLUSION: The HDEI can be used to reflect selected nutritional status markers, such as Alb and Hb levels and CVD risk factors, for HD patients. The HDEI can also serve as an eating index for HD patients in Taiwan to facilitate CVD prevention.

Dual-task gait has prognostic value for cognitive decline in Parkinson's disease.

INTRODUCTION: Cognitive decline frequently occurs in individuals with Parkinson's disease (PD), but the clinical methods to predict the onset of cognitive changes are limited. Given preliminary evidence of the link between gait and cognition, the purpose of this study was to determine if dual task (DT) gait was related to declines in cognition over two years in PD. METHODS: A retrospective two-year longitudinal study of 48 individuals with PD using data from the Parkinson's Progression Markers Initiative of the Michael J. Fox Foundation. The following data were extracted at baseline: spatiotemporal gait (during single and DT), demographics (age, sex), PD disease duration (time since diagnosis), motor function (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)), and cognition (Montreal Cognitive Assessment (MoCA)), with MoCA scores also extracted after two years. RESULTS: A binomial logistic regression was conducted, with all covariates (above) in block 1 and DT effect (DTE) of gait characteristics in block 2 entered in a stepwise fashion. The final model was statistically significant (χ2(6) = 23.20, p < 0.001) and correctly classified 78.7 % of participants by cognitive status after two years. Only DTE of arm swing asymmetry (ASA) (p = 0.030) was included in block 2 such that a 1 % decline in DTE resulted in 1.6 % increased odds of cognitive decline. CONCLUSIONS: Individuals with greater change in arm swing asymmetry from single to DT gait may be more likely to experience a decline in cognition within two years. These results suggested that reduced automaticity or poor utilization of attentional resources may be indicative of subtle changes in cognition and indicate that DT paradigms may hold promise as a marker of future cognitive decline.

New Structural and Mechanistic Insights Into Functional Roles of Cytochrome b 559 in Photosystem II.

Cytochrome (Cyt) b 559 is a key component of the photosystem II (PSII) complex for its assembly and proper function. Previous studies have suggested that Cytb 559 has functional roles in early assembly of PSII and in secondary electron transfer pathways that protect PSII against photoinhibition. In addition, the Cytb 559 in various PSII preparations exhibited multiple different redox potential forms. However, the precise functional roles of Cytb 559 in PSII remain unclear. Recent site-directed mutagenesis studies combined with functional genomics and biochemical analysis, as well as high-resolution x-ray crystallography and cryo-electron microscopy studies on native, inactive, and assembly intermediates of PSII have provided important new structural and mechanistic insights into the functional roles of Cytb 559. This mini-review gives an overview of new exciting results and their significance for understanding the structural and functional roles of Cytb 559 in PSII.

Spoken Word Recognition in Listeners with Mild Dementia Symptoms.

BACKGROUND: Difficulty understanding speech is a common complaint of older adults. In quiet, speech perception is often assumed to be relatively automatic. However, higher-level cognitive processes play a key role in successful communication in noise. Limited cognitive resources in adults with dementia may therefore hamper word recognition. OBJECTIVE: The goal of this study was to determine the impact of mild dementia on spoken word recognition in quiet and noise. METHODS: Participants were 53-86 years with (n = 16) or without (n = 32) dementia symptoms as classified by the Clinical Dementia Rating scale. Participants performed a word identification task with two levels of word difficulty (few and many similar sounding words) in quiet and in noise at two signal-to-noise ratios, +6 and +3 dB. Our hypothesis was that listeners with mild dementia symptoms would have more difficulty with speech perception in noise under conditions that tax cognitive resources. RESULTS: Listeners with mild dementia symptoms had poorer task accuracy in both quiet and noise, which held after accounting for differences in age and hearing level. Notably, even in quiet, adults with dementia symptoms correctly identified words only about 80% of the time. However, word difficulty was not a factor in task performance for either group. CONCLUSION: These results affirm the difficulty that listeners with mild dementia may have with spoken word recognition, both in quiet and in background noise, consistent with a role of cognitive resources in spoken word identification.

Crystal structure and functional implication of bacterial STING.

Mammalian innate immune sensor STING (STimulator of INterferon Gene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase (cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in ß-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2'3'-cGAMP-dependent signaling in eukaryotes.

Spectroscopic and functional characterizations of cyanobacterium Synechocystis PCC 6803 mutants on and near the heme axial ligand of cytochrome b559 in photosystem II.

The functional role of cytochrome (cyt) b(559) in photosystem II (PSII) was investigated in H22K alpha and Y18S alpha cyt b(559) mutants of the cyanobacterium Synechocystis sp. PCC6803. H22K alpha and Y18S alpha cyt b(559) mutant carries one amino acid substitution on and near one of heme axial ligands of cyt b(559) in PSII, respectively. Both mutants grew photoautotrophically, assembled stable PSII, and exhibited the normal period-four oscillation in oxygen yield. However, both mutants showed several distinct chlorophyll a fluorescence properties and were more susceptible to photoinhibition than wild type. EPR results indicated the displacement of one of the two axial ligands to the heme of cyt b(559) in H22K alpha mutant reaction centers, at least in isolated reaction centers. The maximum absorption of cyt b(559) in Y18S alpha mutant PSII core complexes was shifted to 561 nm. Y18S alpha and H22K alpha mutant PSII core complexes contained predominately the low potential form of cyt b(559). The findings lend support to the concept that the redox properties of cyt b(559) are strongly influenced by the hydrophobicity and ligation environment of the heme. When the cyt b(559) mutations placed in a D1-D170A genetic background that prevents assembly of the manganese cluster, accumulation of PSII is almost completely abolished. Overall, our data support a functional role of cyt b(559) in protection of PSII under photoinhibition conditions in vivo.

Exploring the Acoustic Perceptual Relationship of Speech in Parkinson's Disease.

Purpose Auditory perceptual judgments are commonly used to diagnose dysarthria and assess treatment progress. The purpose of the study was to examine the acoustic underpinnings of perceptual speech abnormalities in individuals with Parkinson's disease (PD). Method Auditory perceptual judgments were obtained from sentences produced by 13 speakers with PD and five healthy older adults. Twenty young listeners rated overall ease of understanding, articulatory precision, voice quality, and prosodic adequacy on a visual analog scale. Acoustic measures associated with the speech subsystems of articulation, phonation, and prosody were obtained, including second formant transitions, articulation rate, cepstral and spectral measures of voice, and pitch variations. Regression analyses were performed to assess the relationships between perceptual judgments and acoustic variables. Results Perceptual impressions of Parkinsonian speech were related to combinations of several acoustic variables. Approximately 36%-49% of the variance in the perceptual ratings were explained by the acoustic measures indicating a modest acoustic perceptual relationship. Conclusions The relationships between perceptual ratings and acoustic signals in Parkinsonian speech are multifactorial and involve a variety of acoustic features simultaneously. The modest acoustic perceptual relationships, however, suggest that future work is needed to further examine the acoustic bases of perceptual judgments in dysarthria.

Test-Retest Reliability of Audiometric Assessment in Individuals With Mild Dementia.

Importance: Accurate assessment of hearing is critically important regardless of a person's cognitive ability. The degree to which hearing can be reliably measured in adults with mild dementia has not been determined. Objective: To obtain quantitative measures of reliability to evaluate the degree to which audiologic testing can be accurately conducted in older adults with mild dementia. Design, Setting, and Participants: This repeated-measures cross-sectional study consisted of a comprehensive audiologic assessment on 2 occasions separated by 1 to 2 weeks performed in the department of otolaryngology at the Washington University School of Medicine from December 3, 2018, to March 4, 2020. Participants were 15 older adults with a verified diagnosis of mild dementia and 32 older adults without a verified diagnosis of mild dementia who were recruited from the Knight Alzheimer Disease Research Center at Washington University in St Louis. Main Outcomes and Measures: Test-retest reliability was assessed for tympanometry, acoustic reflex thresholds, otoacoustic emissions, hearing sensitivity, speech reception threshold, speech perception in noise, and hearing handicap, using standard clinical audiology measures. Results: A total of 47 older adults (26 women; mean [SD] age, 74.8 [6.0] years [range, 53-87 years]), including 32 with normal cognitive function and 15 with very mild or mild dementia, completed the study protocol. For participants with mild dementia, high test-retest reliability (Spearman ρ > 0.80) was found for most measures typically included in a comprehensive audiometric evaluation. For acoustic reflex thresholds, agreement was moderate to high, averaging approximately 83% across frequencies for both groups. Scores for the screening Hearing Handicap Inventory for the Elderly at time 1 and time 2 were highly correlated for the group with normal cognitive function (r = 0.84 [95% CI, 0.70-0.93]) and for the group with mild dementia (r = 0.96 [95% CI, 0.88-0.99]). For hearing thresholds, all rank-order correlations were above 0.80 with 95% CIs at or below 15% in width, with the exception of a moderate correlation of bone conduction thresholds at 500 Hz for the group with normal cognitive function (r = 0.69 [95% CI, 0.50-0.84]) and slightly wider 95% CIs for low-frequency bone conduction thresholds for both groups. For speech reception thresholds, correlations were high for groups with normal cognitive function (r = 0.91 [95% CI, 0.84-0.95]) and mild dementia (r = 0.83 [95% CI, 0.63-0.94]). Conclusions and Relevance: Test-retest reliability for hearing measures obtained from participants with mild dementia was comparable to that obtained from cognitively normal participants. These findings suggest that mild cognitive impairment does not preclude accurate audiologic assessment.

Gelatin/Chitosan Bilayer Patches Loaded with Cortex Phellodendron amurense/Centella asiatica Extracts for Anti-Acne Application.

Acne is a chronic inflammatory skin disease that often occurs with anaerobic Propionibacterium acnes (P. acnes). Anti-acne patches, made of hydrocolloid or hydrogel, have become a popular way of topical treatment. The outer water-impermeable layer of commercial patches might create hypoxic conditions and promote P. acnes growth. In this study, gelatin/chitosan (GC) bilayer patches were prepared at different temperatures that included room temperature (RT), -20 °C/RT, and -80 °C/RT. The most promising GC bilayer patch (-80 °C /RT) contained a dense upper layer for protection from bacteria and infection and a porous lower layer for absorbing pus and fluids from pimples. The anti-acne bilayer patch was loaded with Cortex Phellodendri amurensis (PA) and Centella asiatica (CA) extracts. PA extract could inhibit the growth of P. acnes and CA extract was reported to improve wound healing and reduce scar formation. Moreover, the water retention rate, weight loss rate, antibacterial activity, and in vitro cytotoxicity of the patches were investigated. The porous structure of the patches promoted water retention and contributed to absorbing the exudate when used on open acne wounds. The GC bilayer patches loaded with PA/CA extracts were demonstrated to inhibit the growth of P. acnes, and accelerate the skin fibroblast cell viability. Based on their activities and characteristics, the GC bilayer patches with PA/CA extract prepared at -80 °C/RT obtain the potential for the application of acne spot treatment.

Screening strategy of TMPRSS2 inhibitors by FRET-based enzymatic activity for TMPRSS2-based cancer and COVID-19 treatment.

Transmembrane serine protease (TMPRSS2) plays an oncogenic role in prostate cancer as the fusion gene with ERG, and has also been demonstrated to be essential for the cellular entry of severe acute respiratory syndrome coronaviruses (SARS-CoV). Thus, targeting TMPRSS2 is a promising strategy for therapies against both prostate cancer and coronavirus infection. Although Nafamostat and Camostat have been identified as TMPRSS2 inhibitors, severe side effects such as cerebral hemorrhage, anaphylactoid reaction, and cardiac arrest shock greatly hamper their clinical use. Therefore, more potent and safer drugs against this serine protease should be further developed. In this study, we developed a fluorescence resonance energy transfer (FRET)-based platform for effectively screening of inhibitors against TMPRSS2 protease activity. The disruption of FRET between green and red fluorescent proteins conjugated with the substrate peptide, which corresponds to the cleavage site of SARS-CoV-2 Spike protein, was measured to determine the enzymatic activity of TMPRSS2. Through an initiate pilot screening with around 100 compounds, Flupirtine, a selective neuronal potassium channel opener, was identified as a potential TMPRSS2 inhibitor from an FDA-approved drug library by using this screening platform, and showed inhibitory effect on the TMPRSS-dependent infection of SARS-CoV-2 Spike-pseudotyped lentiviral particles. This study describes a platform proven effective for rapidly screening of TMPRSS2 inhibitors, and suggests that Flupirtine may be worthy of further consideration of repurposing to treat COVID-19 patients.

Identification and characterization of a cytochrome b559 Synechocystis 6803 mutant spontaneously generated from DCMU-inhibited photoheterotrophical growth conditions.

We identified a spontaneously generated mutant from Synechocystis sp. PCC6803 wild-type cells grown in BG-11 agar plates containing 5 mM Glu and 10 microM DCMU. This mutant carries an R7L mutation on the alpha-subunit of cyt b559 in photosystem II (PSII). In the recent 2.9 A PSII crystal structural model, the side chain of this arginine residue is in close contact with the heme propionates of cyt b559. We called this mutant WR7Lalpha cyt b559. This mutant grew at about the same rate as wild-type cells under photoautotrophical conditions but grew faster than wild-type cells under photoheterotrophical conditions. In addition, 77 K fluorescence and 295 K chlorophyll a fluorescence spectral results indicated that the energy delivery from phycobilisomes to PSII reaction centers was partially inhibited or uncoupled in this mutant. Moreover, WR7Lalpha cyt b559 mutant cells were more susceptible to photoinhibition than wild-type cells under high light conditions. Furthermore, our EPR results indicated that in a significant fraction of mutant reaction centers, the R7Lalpha cyt b559 mutation induced the displacement of one of the axial histidine ligands to the heme of cyt b559. On the basis of these results, we propose that the Arg7Leu mutation on the alpha-subunit of cyt b559 alters the interaction between the APC core complex and PSII reaction centers, which reduces energy delivery from the antenna to the reaction center and thus protects mutant cells from DCMU-induced photo-oxidative stress.

Predicting Intelligibility Deficits in Parkinson's Disease With Perceptual Speech Ratings.

Purpose This study investigated whether perceptual ratings of speech parameters were predictive of transcription intelligibility in quiet and in noise for speakers with Parkinson's disease (PD). Method Ten speakers with PD and five healthy controls read 56 sentences. One group of 60 listeners orthographically transcribed the sentences in quiet, and another group of 60 listeners transcribed in noise. An additional 23 listeners judged a variety of speech parameters, including articulation, prosody, resonance, voice quality, and ease of understanding on a visual analog scale. Scores of the visual analog scale ratings were regressed against transcription intelligibility in quiet and in noise. Results Perceptual ratings of all the speech parameters were lower for speakers with PD. Global speech understanding, indexed by ease of understanding ratings, was associated with transcription intelligibility in quiet and in noise with a stronger effect in noise. Among the rated speech parameters, ease of understanding and voice quality ratings were significant predictors of speech intelligibility in noise. Conclusions Speech in individuals with PD was more difficult for listeners to understand and was characterized by deficits in articulation, prosody, resonance, and voice quality compared to normal speech produced by healthy older adults. Ease of understanding ratings, even when performed in quiet, predicted intelligibility in noise. Poor voice quality ratings in PD, a sign of phonatory deficit, had a negative impact on intelligibility in noise for speakers with PD.

Comparative Genomic Analysis of a Novel Strain of Taiwan Hot-Spring Cyanobacterium Thermosynechococcus sp. CL-1.

Thermosynechococcus is a genus of thermophilic unicellular cyanobacteria that are dominant in microbial mats at about 50-65°C in alkaline hot springs of eastern Asia. We used PacBio SMRT Sequencing to sequence the complete genome of a novel strain of thermophilic cyanobacterium, Thermosynechococcus sp. CL-1, isolated from the Chin-Lun hot spring (pH 9.3, 62°C) in Taiwan. Genome-scale phylogenetic analysis and average nucleotide identity (ANI) results suggested that CL-1 is a new species in the genus Thermosynechococcus. Comparative genome analysis revealed divergent genome structures of Thermosynechococcus strains. In addition, the distinct genetic differences between CL-1 and the other Thermosynechococcus strains are related to photosynthesis, transporters, signal transduction, the chaperone/usher system, nitric oxide protection, antibiotic resistance, prokaryotic immunity systems, and other physiological processes. This study suggests that Thermosynechococcus strains have actively acquired many putative horizontally transferred genes from other bacteria that enabled them to adapt to different ecological niches and stressful conditions in hot springs.

Relationship Between F2 Slope and Intelligibility in Parkinson's Disease: Lexical Effects and Listening Environment.

Purpose There is a complex relationship between speech production and intelligibility of speech. The current study sought to evaluate the interaction of the factors of lexical characteristics, listening environment, and the 2nd formant transition (F2 slope) on intelligibility of speakers with Parkinson's disease (PD). Method Twelve speakers with PD and 12 healthy controls read sentences that included words with the diphthongs /aɪ/, /ɔɪ/, and /aʊ/. The F2 slope of the diphthong transition was measured and averaged across the 3 diphthongs for each speaker. Young adult listeners transcribed the sentences to assess intelligibility of words with high and low word frequency and high and low neighborhood density in quiet and noisy listening conditions. The average F2 slope and intelligibility scores were entered into regression models to examine their relationship. Results F2 slope was positively related to intelligibility in speakers with PD in both listening conditions with a stronger relationship in noise than in quiet. There was no significant relationship between F2 slope and intelligibility of healthy speakers. In the quiet condition, F2 slope was only correlated with intelligibility in less-frequent words produced by the PD group. In the noise condition, F2 slope was related to intelligibility in high- and low-frequency words and high-density words in PD. Conclusions The relationship between F2 slope and intelligibility in PD was affected by lexical factors and listening conditions. F2 slope was more strongly related to intelligibility in noise than in quiet for speakers with PD. This relationship was absent in highly frequent words presented in quiet and those with fewer lexical neighbors.