bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Correlates of Frailty Among Older People With and Without HIV in Rural Uganda
Authors: Mbabazi Phoebe , Chen Geoffrey , Ritchie Christine S. , Tsai Alexander C. , Reynolds Zahra , Paul Robert , Seeley Janet , Tong Yao , Hoeppner Susanne , Okello Samson , Nakasujja Noeline , Olivieri-Mui Brianne , Tanner Jeremy A. , Saylor Deanna , Asiimwe Stephen , Siedner Mark J. , Greene Meredith
Published: August 2024

Background:

The relationship between HIV and frailty, a predictor of poor outcomes in the face of stressors, remains unknown in older people in sub-Saharan Africa.

Methods:

We analyzed data from the Quality of Life and Ageing with HIV in Rural Uganda cohort study to estimate the prevalence and correlates of frailty among older people with HIV (PWH) on long-term antiretroviral therapy and among age- and sex-matched HIV-uninfected comparators. Frailty was defined as a self-report of 3 or 4 (and pre-frailty as 1 or 2) of the following phenotypic variables: weight loss, exhaustion, low activity, and slowness. We estimated the prevalence of frailty and prefrailty and fitted logistic regression models to estimate the association between HIV and frailty, adjusting for sociodemographic factors, depression, and other comorbidities.

Results:

We enrolled 599 participants (49% women) with a mean age of 58 years. PWH had a similar prevalence of frailty (8.1% vs. 10.9%, P = 0.24) but a lower prevalence of prefrailty (54.2% vs. 63.2%, P = 0.03) compared with their HIV-uninfected comparators. In multivariable regression models, people with depression [adjusted odds ratio (AOR) 7.52 (95% CI: 3.67 to 15.40), P < 0.001] and those with ≥1 comorbidities [AOR 3.15 (95% CI: 1.71 to 3.82), P < 0.001] were more likely to be frail. HIV serostatus was not significantly associated with frailty [AOR 0.71 (95% CI: 0.37 to 1.34), P = 0.29].

Conclusions:

Older PWH had a similar prevalence of frailty as those without HIV. These findings call for additional study of the factors that contribute to the robustness of older PWH in sub-Saharan Africa.
Brief Report: Antiretroviral Treatment Use Over Time Among Adolescents and Young Adults in the Rakai Community Cohort Study, 2011–2020
Authors: Kreniske Philip , Nalugoda Fred , Chen Ivy , Parate Neha , Wei Ying , Chang Larry W. , Ssekubugu Robert , Lutalo Tom , Kigozi Godfrey , Kagaayi Joseph , Sewankambo Nelson , Grabowski M. Kate , Nakigozi Gertrude , Serwadda David , Hoffman Susie , Santelli John
Published: August 2024

Background:

In sub-Saharan Africa, pediatric and adult treatment programs have not met the needs of youth living with HIV (15–24 years), whose enrollment in antiretroviral treatment (ART) programs is much lower than that of adults. To inform targeted interventions, we analyzed factors associated with ART use among youth in Uganda.

Methods:

Data were from 42 communities between 2011 and 2020 (5 survey rounds) from the Rakai Community Cohort Study, an open, population-based cohort. Among youth, we assessed trends in ART use over time and demographic characteristics and sexual behaviors associated with ART use.

Results:

Youth (N = 1518) contributed 2101 person-visits. ART coverage increased over time with 8% of men and 11% of women on ART in 2011–2013 and 45% and 68%, respectively, on ART in 2018–2020 (AORwomen vs. men=2.57; 95% CI: 1.72 to 3.84). Youth with 2 or more sexual partners compared with youth with 0–1 sexual partner were less likely to be on ART (men AOR = 0.40; 0.19–0.82; women AOR = 0.54; 0.41–0.72). Youth who reported consistent condom use were more likely to be on ART (men AOR = 2.94; 95% CI: 1.14 to 7.57; women AOR = 1.70; 95% CI: 1.00 to 2.88).

Conclusions:

In this longitudinal study, ART use among youth increased over time, yet at 63% remained well below UNAIDS 95-95-95 goals, thus depriving many of lifesaving treatment. Those engaging in fewer protective sexual behaviors had lower ART use, thus further increasing risk of future HIV transmission. Targeted efforts are needed to ensure rapid initiation of ART and continued engagement among this vulnerable population.
Factors Affecting Bone Fusion in Mandibular Reconstruction With Vascularized Free Fibula Flap
Authors: Palla Benjamin , Barawi Kaldoun , Burian Egon , Lenhart Nicolas , Moles Sarah Loren , Callahan Nicholas
Published: August 2024

Reconstruction of mandibular defects with free fibula flaps was described 3 decades ago. However, scant literature exists regarding their bony fusion. A retrospective cohort study was performed to determine what factors influence the amount of osseous fusion at various osteotomy sites (condyle, angle, body, parasymphysis, and midsagittal). A total of 30 patients (12 females and 18 males) with an average mean age of 49.7 years (SD: 22.1, range: 11–82) were included. There were 80 osteotomy locations, with 3 margins each, for 240 total fusion ratings and an average fusion of 3.70 (SD: 1.08) on a 1 to 5 scale. The amount of fusion at osteotomy sites was significantly association with sex (female 3.96 versus male 3.51, P = 0.001), age (r = −0.23, P < 0.001), postoperative (radiation therapy: 3.21 versus no-radiation therapy 3.76, P = 0.018), number of fibula segments (P < 0.001), etiology (P < 0.001), and mandibular defect classification (P < 0.001). No significant difference was identified between the amount of fusion and osteotomy type (fibula-fibula-fibula-mandible), location (P = 0.140), or margin (P = 0.612). These factors could be important predictors for nonunion and risk of postoperative fracture.
Digitally-assisted Design for Precise Mandibular Defect Repair Using Autogenous Bone
Authors: Yang Hongxuan , Wang Lin , Wang Xianzhu , Wu Guomin
Published: August 2024

This study introduces a novel surgical technique that leverages digital design for the precise repair of mandibular defects resulting from benign jaw tumors. The restoration of the mandibular defect is accomplished through autologous bone grafting from the mandible itself. This method significantly diminishes surgical complexity and risk, meeting the patient’s preference to avoid additional surgical sites. Notably, 15 months postsurgery, the patient’s mandible dimensions were suitable for dental implantation. Therefore, this technique has proven effective in repairing mandibular defects caused by the excision of benign tumors.
Handedness in Alzheimer Disease
Authors: Guido Giorgio , Bonato Alberto , Bonomi Samuele , Franceschini Simone , Morris John C.
Published: August 2024

Handedness has been a topic of scientific interest for many years. However, false and misleading ideas have dominated this field with a still limited amount of research into the association with clinical disorders like Alzheimer disease (AD). In accordance with PRISMA guidelines, PubMed, Embase, and Cochrane Library were searched for studies regarding the association of handedness and AD. Twelve articles were included. Case-control studies show that left-handedness is not a risk factor for late-onset AD (LOAD). However, nonright handedness was found to be more prevalent in patients with early-onset AD (EOAD). Moreover, handedness does not seem to affect neuropsychological performance. We also show that collapsing versus separating mixed and left-handedness may yield different results. Future research on the relation between handedness and AD may provide new insight into disease pathogenesis, improve rehabilitation, and help identify patients who will progress, aiding the design of prevention trials.
A Pilot Longitudinal Study to Evaluate the Efficacy, Safety, and Feasibility of Outpatient Parenteral Antimicrobial Therapy, and to Identify Real-World Barriers and Facilitators in a Resource-Limited Setting.
Authors: Kumar Amit , Panda Prasan Kumar , Kant Ravi , Bairwa Mukesh , Pai V.S. , Singh Darab , Das Nilanjana
Published: August 2024

Background: Outpatient Parenteral Antimicrobial Therapy (OPAT) offers a viable alternative to traditional hospitalization for intravenous antimicrobial treatment, especially in resource-limited settings. This pilot longitudinal study evaluates the efficacy, safety, and feasibility of OPAT, while identifying real-world barriers and facilitators in a resource-constrained environment. Methods: Conducted at AIIMS Rishikesh, this prospective observational study involved 20 patients who were systematically screened for OPAT eligibility using a predefined checklist. Patients were included if they met the criteria and demonstrated willingness for structured follow-up. Efficacy, safety, and feasibility were assessed through telephonic monitoring, patient feedback, and medical record review. Results: The cohort had a mean age of 37 years, comprising 12 males and 8 females. OPAT was administered at home, with 19 patients achieving afebrile status and clinical improvement. One patient was readmitted due to complications. Ceftriaxone was the most prescribed antimicrobial, with an average treatment duration of 14 days. OPAT reduced hospitalization by an average of 2 weeks, leading to decreased healthcare costs and enhanced patient satisfaction. Discussion: The study confirms OPAT's efficacy in managing diverse infections and its role in reducing hospital stay and costs. The favorable safety profile and positive patient feedback support OPAT as a patient-centered care option. Identified barriers and facilitators provide insights for optimizing OPAT in resource-limited settings. Conclusion: OPAT demonstrates 100% efficacy in ensuring patient safety and optimizing resource use. Further research and broader implementation are recommended, alongside dedicated training and adequate funding to address challenges and enhance outcomes. Keywords: Outpatient Parenteral Antimicrobial Therapy, OPAT, infection management, resource-limited settings, patient safety, healthcare resource optimization.
PrEP in the key population community: a qualitative study of perspectives on pre-exposure prophylaxis by men who have sex with men and female sex workers in Kigali, Rwanda
Authors: Ross Jonathan , Gasana Josephine , Zotova Natalia , Ndabakuranye Giovanni , Mabano Fabiola , Ingabire Charles , Adedimeji Adebola , Murenzi Gad , Patel Viraj V.
Published: August 2024

Background

Men who have sex with men (MSM) and female sex workers (FSW) are increasingly and disproportionately impacted by HIV in sub-Saharan Africa, yet current PrEP care models in this region are not optimized for these communities. Limited data exist describing experiences and preferences of MSM and FSW with respect to accessing and using PrEP.

Methods

We conducted qualitative, semi-structured interviews with MSM and FSW recruited from three health centers and seven community organizations in Kigali, Rwanda. Data were analyzed using a mixed deductive and inductive approach to describe key themes related to initiating and adhering to PrEP.

Results

Participants included 18 MSM and 14 FSW; 12 were using PrEP at the time of interview, 9 had previously used PrEP, and 11 had never used it. Participants highlighted the central role of their social networks as key sources of information about and support for PrEP use, and described a strong motivation to use PrEP as a way to protect both themselves and their communities from HIV. While stigma and discrimination were pervasive, these were experienced differently by MSM and FSW. Participants suggested community access points that allowed more discreet and less frequent contact with health care workers as important and desired strategies to improve engagement.

Conclusions

These findings suggest that leveraging community resources for disseminating information about HIV prevention and delivering PrEP could contribute to successful implementation of PrEP for MSM and FSW in Rwanda and other settings in SSA.
Class II Kinesin-12 facilitates cell plate formation by transporting cell plate materials in the phragmoplast
Authors: Yamada Moé , Matsuyama Hironori J.
Published: August 2024

Cell plate formation in plants is a complex process orchestrated by the targeted delivery of Golgi-derived and endosomal vesicles containing cell plate components to the phragmoplast midzone. It has long been hypothesised that vesicles are directionally transported along phragmoplast microtubules by motor proteins. However, the mechanisms governing the accumulation and immobilisation of vesicles at the phragmoplast midzone remain elusive, and the motor protein responsible has yet to be identified. Here, we show that the plant-specific class II Kinesin-12 (Kinesin12-II) functions as a motor protein that drives vesicle transport towards the phragmoplast midzone in the mossPhyscomitrium patens. Inkinesin12-IImutants, the directional movement of cell plate materials towards the midzone and their retention were abolished, resulting in delayed cell plate formation and phragmoplast disassembly. A macroscopic phenotype arising fromKinesin12-IIdisruption was the impediment to gametophore development. We showed that this defect was attributable to the production of aneuploid cells in the early gametophore, where chromosome missegregation occurred because of the incomplete disassembly of phragmoplast microtubules in the preceding cell cycle. These findings suggest that plant Kinesin-12 has evolved to acquire a unique and critical function that facilitates cell plate formation in the presence of phragmoplasts.
Neural Oscillation Features of ADHD Symptoms in Children: EEG Evidence from Resting State and Oddball Task
Authors: Zhang Siyuan , Yu Shuting , Cui Xiaobing , Li Xuebing
Published: August 2024

The current study examined resting-state and event-related neural oscillations associated with ADHD symptoms in children aged 6-12. 77 children were assessed using the Integrated Visual and Auditory Continuous Performance Test (IVA-CPT) and EEG during resting-state. A group of these children also completed a classic visual oddball task. Key findings include increased relative delta activity at left parietal electrodes during eyes-open and decreased relative theta activity at left posterior electrodes during eyes-closed, both associated with poor attention. Increased beta activity at right parieto-occipital electrodes during eyes-open and increased alpha activity at bilateral posterior electrodes during eyes-closed were associated with poor response control. In addition, the power of the P3 component was negatively correlated with attention across most frequency bands and conditions, except for delta power in the standard condition. Furthermore, combining multiple metrics, especially resting-state EEG oscillations, event-related oscillations, and parental ratings, provided a more robust prediction. The current study identified important brain regions and frequency bands related to ADHD symptoms, offering new insights for multi-metric prediction and clinical guidance.
Perturbation ofde novolipogenesis hinders MERS-CoV assembly and release, but not the biogenesis of viral replication organelles
Authors: Soultsioti M. , de Jong A.W.M. , Blomberg N. , Tas A. , Giera M. , Snijder E. J. , Barcena M.
Published: August 2024

Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive host endomembrane remodeling to generate viral replication organelles and exploit host membranes for assembly and budding of their enveloped progeny virions. Because of the overall significance of host membranes, we sought to gain insight into the role of host factors involved in lipid metabolism in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach in combination with pharmacological inhibitors, biochemical assays, lipidomics, light and electron microscopy. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), key host factors inde novofatty acid biosynthesis, led to pronounced inhibition of MERS-CoV particle release. Inhibition of ACC led to a profound metabolic switch in Huh7 cells, altering their lipidomic profile and inducing lipolysis. However, despite the extensive changes induced by the ACC inhibitor, the biogenesis of viral replication organelles remained unaffected. Instead, ACC inhibition appeared to affect the trafficking and post-translational modifications of the MERS-CoV envelope proteins. Electron microscopy revealed an accumulation of nucleocapsids in early budding stages, indicating that MERS-CoV assembly is adversely impacted by ACC inhibition. Notably, inhibition of palmitoylation resulted in similar effects, while supplementation of exogenous palmitic acid reversed the compound’s inhibitory effects, possibly reflecting a crucial need for palmitoylation of the MERS-CoV Spike and Envelope proteins for their role in virus particle assembly.

Importance

Middle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a zoonotic respiratory disease of limited transmissibility between humans. However, MERS-CoV is still considered a high-priority pathogen and is closely monitored by WHO due to its high lethality rate of around 35% of laboratory-confirmed infections. Like other positive-strand RNA viruses, MERS-CoV relies on the host cell’s endomembranes to support various stages of its replication cycle. However, in spite of this general reliance of MERS-CoV replication on host cell lipid metabolism, mechanistic insights are still very limited. In our study, we show that pharmacological inhibition of acetyl-CoA carboxylase (ACC), a key enzyme in the host cell’s fatty acid biosynthesis pathway, significantly disrupts MERS-CoV particle assembly without exerting a negative effect on the biogenesis of viral replication organelles. Furthermore, our study highlights the potential of ACC as a target for the development of host-directed antiviral therapeutics against coronaviruses.
Genotype dependence of virulence-associated genes in ESBL-producing Escherichia coli isolated from the blood of patients with urinary tract infections
Authors: Tanaka Mayuko , Hanawa Tomoko , Suda Tomoya , Tanji Yasunori , Le Minh Nhat , Kondo Kohei , Azame Aa Haeruman , Kiga Kotaro , Yonetani Shota , Yashiro Ryu , Omori Takuya , Matsuda Takeaki
Published: August 2024

Approximately 80% of urinary tract infections (UTIs) are caused by uropathogenic Escherichia coli (UPEC). The prevalence of extended-spectrum β-lactamase (ESBL)-producing E. coli in UPEC isolates belonging to specific multilocus sequence-type clones is a global concern. Relations between the pathogenicity of UPEC virulence factors and genotype have been discussed. However, the specific virulence factors and genotypes associated with a higher likelihood of causing UTIs remain unclear. This study analyzed the genotypes and virulence-associated genes of 46 ESBL-producing strains isolated from the blood of patients with UTIs who visited the Department of Emergency Medicine from 2017 to 2022 to elucidate the characteristics of UPEC strains associated with severe infections. Most phylogroups of clinical isolates were B2, except for D, found in three strains. The dominant multilocus sequence typing (MLST) was ST131, followed by ST73, ST95, and ST38, frequently observed in UPEC strains. ST131 strains were more resistant to levofloxacin (87.5%) than non-ST131 strains (50.0%) and caused fewer sepsis cases than non-ST131 strains. Based on in silico analysis, of 23 clinical isolates, the genes detected in all clinical strains could have important role in invasive UTIs. Clustering analysis highlighted the genotype MLST dependence of UPEC-specific virulence-associated genes. The absence of several UPEC-specific gene loci or the presence of ST38-specific indicated atypical repertories of virulence-associated genes in ST38 strains. Genes encoding secretion systems, which were found in enteropathogenic E. coli, were less detected in ST131 strains. These results suggested that the correlation of MLST and repertories should be considered to understand UPEC virulence.
Cell Geometry and Membrane Protein Crowding Constrain Growth Rate, Overflow Metabolism, Respiration, and Maintenance Energy
Authors: Carlson Ross P. , Beck Ashley E. , Benitez Mauricio Garcia , Harcombe William R. , Mahadevan Radhakrishnan , Gedeon Tomáš
Published: August 2024

A metabolic theory is presented for predicting maximum growth rate, overflow metabolism, respiration efficiency, and maintenance energy flux based on the intersection of cell geometry, membrane protein crowding, and metabolism. The importance of cytosolic macromolecular crowding on phenotype has been established in the literature but the importance of surface area has been largely overlooked due to incomplete knowledge of membrane properties. We demonstrate that the capacity of the membrane to host proteins increases with growth rate offsetting decreases in surface area-to-volume ratios (SA:V). This increase in membrane protein is hypothesized to be essential to competitiveEscherichia coliphenotypes. The presented membrane-centric theory uses biophysical properties and metabolic systems analysis to successfully predict the phenotypes ofE. coliK-12 strains, MG1655 and NCM3722, which are genetically similar but have SA:V ratios that differ up to 30%, maximum growth rates on glucose media that differ by 40%, and overflow phenotypes that start at growth rates that differ by 80%. These analyses did not consider cytosolic macromolecular crowding, highlighting the distinct properties of the presented theory. Cell geometry and membrane protein crowding are significant biophysical constraints on phenotype and provide a theoretical framework for improved understanding and control of cell biology.
Camp Dream. Speak. Live.: A Virtual Adaptation
Authors: Byrd Courtney T. , Coalson Geoffrey A. , Werle Danielle , Croft Robyn , Winters Katie L. , Young Megan M.
Published: August 2024

Purpose

The purpose of this study was to determine the efficacy of a virtual adaptation of the administration of Camp Dream. Speak. Live., an intensive, non-ableist manualized treatment program for children who stutter, with no indirect or direct fluency goals, in reducing the adverse impact of stuttering and increasing communication competence.

Methods

Sixty-one children who stutter participated in Virtual Camp Dream. Speak. Live. Pre- and post-treatment measures were identical to previous in-person administrations: (1) self- and caregiver-report of cognitive and affective impact of stuttering (Communication Attitude Test for Children who Stutter[KiddyCAT/CAT],Overall Assessment of Speaker’s Experience of Stuttering[OASES],PROMIS Pediatric Peer Relationship,andPROMIS Parent Proxy Relationships), and (2) unfamiliar clinician ratings of communication competence of impromptu presentations.

Results

Significant post-treatment gains were reported for theCAT,OASES, andPROMIS Peer Relationships Parent Proxy. Significant gains in post-treatment communication competence were observed. Pre-treatment stuttering frequency did not significantly predict changes in communication competence.

Conclusion

Findings from Virtual Camp Dream. Speak. Live. demonstrate that the administration of the adapted telepractice format of this manualized program yields comparable findings as when administered in-person, suggesting promising implications for use in locations for which in-person provision and/or access is not feasible.
Cross-modal Functional Plasticity after Cochlear-implantation
Authors: Esmaelpoor Jamal , Peng Tommy , Jelfs Beth , Mao Darren , Shader Maureen J. , McKay Colette M.
Published: August 2024

Objective

Despite evidence that cross-modal effects after hearing loss and cochlear implantation are primarily conveyed through synaptic gain and efficacy rather than reorganized fiber tracts, few studies have assessed cross-modal functional connectivity (CMFC) to evaluate plasticity. This study, inspired by the psychophysiological interactions (PPI) method, addresses its limitations and provides a robust approach to evaluating task-induced CMFC.

Design

Twenty-two post-lingually deafened, newly implanted adult cochlear implant (CI) recipients with severe hearing loss in the contralateral ear and 17 normal-hearing (NH) subjects participated. The experiment included audio-only and visual-only speech tasks, with resting-state FC as a baseline. Functional near-infrared spectroscopy (fNIRS) measured brain imaging data one month and one year post-implantation. CI users’ speech understanding performance was evaluated one year after implantation.

Results

A negative correlation was found between average contralateral task-induced CMFC and speech outcomes, particularly in links from the angular gyrus (AG), both one month and one year post-activation. Plastic changes showed higher task-induced CMFC in AG compared to the superior temporal gyrus (STG), aligning with neural efficiency principles. Task-induced CMFC remained elevated in CI users compared to NH cohorts even after one year.

Conclusion

Task-induced CMFC can serve as a significant marker of cross-modal plasticity and speech performance in CI recipients, indicating increased reliance on cross-modal processing in one year after implantation.
Sperm from infertile, oligozoospermic men have elevated mutation rates
Authors: Kunisaki Jason , Goldberg Michael E. , Lulla Suchita , Sasani Thomas , Hiatt Laurel , Nicholas Thomas J. , Liu Lihua , Torres-Arce Elizabeth , Guo Yixuan , James Emma , Horns Joshua J , Ramsay Joemy M , Chen Qi , Hotaling James M , Aston Kenneth I , Quinlan Aaron R.
Published: August 2024

Male infertility is associated with elevated rates of aneuploidy and DNA breaks in spermatozoa and germline precursors. This common condition is not well understood and is associated with poor individual and familial somatic health relative to fertile men. To further understand the extent and source of genome instability, we used error-corrected duplex DNA sequencing to test whether the impaired spermatogenesis and relatively poorer health of oligozoospermic men are linked to elevated single nucleotidede novomutation frequencies in their sperm and blood, respectively. We observed a significant 1.34 to 2.01-fold increase in age-adjusted sperm mutation frequencies in infertile, oligozoospermic men. Conversely, consistently elevated mutation frequencies in the blood of oligozoospermic men were not found. Gain-of-function mutations linked to clonal spermatogenesis and Mendelian disorders accumulate with age at a similar rate in normozoospermic and oligozoospermic men. These results implicate germline hypermutation as a hallmark feature of oligozoospermia and point to age-independent processes affecting spermatogonial stem cell biology that may underlie spermatogenic impairment before and after puberty. Our findings also underscore the importance of investigating tissue-specific mechanisms driving the association between reduced reproductive and somatic health in infertile men.
A randomized double-blind placebo-controlled clinical trial of Guanfacine Extended Release for aggression and self-injurious behavior associated with Prader-Willi Syndrome
Authors: Singh Deepan , Jacob Theresa , Silver Michael
Published: August 2024

Introduction: Prader-Willi Syndrome (PWS), a rare genetic disorder, affects development and behavior, frequently resulting in self-injury, aggression, hyperphagia, oppositional behavior, impulsivity and over-activity causing significant morbidity. Currently, limited therapeutic options are available to manage these neuropsychiatric manifestations. The aim of this clinical trial was to assess the efficacy of guanfacine-extended release (GXR) in reducing aggression and self-injury in individuals with PWS. Trial Design: Randomized, double-blind, placebo-controlled trial conducted under IRB approval. Methods: Subjects with a diagnosis of PWS, 6-35 years of age, with moderate to severe aggressive and/or self-injurious behavior as determined by the Clinical Global Impression (CGI)-Severity scale, were included in an 8-week double-blind, placebo-controlled, fixed-flexible dose clinical trial of GXR, that was followed by an 8-week open-label extension phase. Validated behavioral instruments and physician assessments measured the efficacy of GXR treatment, its safety and tolerability. Results: GXR was effective in reducing aggression/agitation and hyperactivity/noncompliance as measured by the Aberrant Behavior Checklist (ABC) scales (p=0.03). Overall aberrant behavior scores significantly reduced in the GXR arm. Aggression as measured by the Modified Overt Aggression Scale (MOAS) also showed a significant reduction. Skin-picking lesions as measured by the Self Injury Trauma (SIT) scale decreased in response to GXR. No serious adverse events were experienced by any of the study participants. Fatigue /sedation was the only adverse event significantly associated with GXR. The GXR group demonstrated significant overall clinical improvement as measured by the CGI-Improvement (CGI-I) scale. (p<0.01). Conclusion: Findings of this pragmatic trial strongly support the use of GXR for treatment of aggression, skin picking, and hyperactivity in children, adolescents, and adults with PWS. Trial Registration: ClinicalTrials.gov Identifier -NCT05657860
PLANES: Plausibility Analysis of Epidemiological Signals
Authors: Nagraj VP , Benefield Amy E. , Williams Desiree , Turner Stephen D.
Published: August 2024

Methods for reviewing epidemiological signals are necessary to building and maintaining data-driven public health capabilities. We have developed a novel approach for assessing the plausibility of infectious disease forecasts and surveillance data. The PLANES (PLausibilityANalysis ofEpidemiologicalSignals) methodology is designed to be multi-dimensional and flexible, yielding an overall score based on individual component assessments that can be applied at various temporal and spatial granularities. Here we describe PLANES, provide a demonstration analysis, and discuss how to use the open-source rplanes R package. PLANES aims to enable modelers and public health end-users to evaluate forecast plausibility and surveillance data integrity, ultimately improving early warning systems and informing evidence-based decision-making.
Using Repeated Lysis Steps Fractionates Between Heterotrophic and Cyanobacterial DNA Extracted from Xenic Cyanobacterial Cultures
Authors: Wagner Alexis D. , Ahmed Mohammed M. A. , Starks Victoria Aileen , Boudreau Paul Davis
Published: August 2024

Extracting DNA from cyanobacteria can be a challenge because of their diverse morphologies, challenging cellular structure, and the heterotrophic microbiome often present within cyanobacterial cultures. As such, even when our DNA yields are sufficient for sequencing, the percentage of reads coming from the cyanobacterial host can be low, leading to incomplete genomes spread across several scaffolds. In this research, we optimized a DNA isolation protocol using three iterative cell lysis steps to enrich the portion of DNA isolated coming from the cyanobacterial host rather than the heterotrophic microbiome. In order to utilize in-house nanopore sequencing, we faced a challenge in that our lysis protocol led to DNA shearing and a lower molecular weight DNA extract than is suitable for this sequencing technology. As such we used two bead-based size selection steps to remove shorter molecules of DNA before nanopore sequencing. EPI2ME analysis of the processed reads from the iterative lysis steps showed that in the first lysis the heterotrophic microbiome could make up more than half of all reads, but with each lysis the proportion of reads coming from these other species decreased. Using our iterative lysis protocol, we were able to sequence the genomes of two cyanobacteria isolated from fresh water sources around northern Mississippi, namely Leptolyngbya sp. BL-A-14 and Limnothrix sp. BL-A-16. The genomes of these isolates were assembled as closed chromosomes of 7.2 and 4.5 Mb for Leptolyngbya sp. BL-A-14 and Limnothrix sp. BL-A-16, respectively. Because some cyanobacteria have symbioses with their heterotrophic microbiome it is not always possible to prepare axenic cultures of these organisms, we hope our approach will be useful for sequencing xenic cultures of cyanobacteria, but we can also imagine applications in studying this microbiome specifically by focusing sequencing efforts on the first fraction.
Broadband high frequency Activity initializes Distractor Suppression
Authors: Schmid Paul , Reichert Christoph , Bartsch Mandy V. , Dürschmid Stefan
Published: August 2024

Selective attention requires fast and accurate distractor suppression. We investigated if broadband high-frequency activity (BHA; 80 – 150 Hz), indicative of local neuronal population dynamics in early sensory cortices, indexes rapid processing of distracting information. In the first experiment we tested whether BHA distinguishes targets from distracting information in a visual search paradigm using tilted gratings as targets and distractors. In the second experiment, we examined whether BHA distractor processing can be trained by statistical learning. In both experiments, BHA preceded the low-frequency target enhancement (NT) and distractor suppression (PD; 1-40 Hz) components and distinguished between targets and distractors. Only the BHA but not low-frequency component amplitude correlated with participants’ performance and was higher for lateral distractors versus lateral targets. Furthermore, BHA predicted the strength of the PD. These results indicate that BHA initiates stimulus discrimination via distractor suppression.

Significance Statement

Selective attention is the net result of successful target selection and distractor suppression, representing a key mechanism of human’s everyday life. Here, we shed light on the neural mechanisms of distractor processing by showing that the early occipital broadband high-frequency activity (BHA) is linked to successful distractor suppression. Specifically, the BHA predicted individual performance and PDstrength, a component associated with distractor suppression. We found the BHA and later the PDincreased in amplitude during implicit statistical learning indicative of a trainable distractor suppression mechanism. We demonstrate that the BHA serves as an early marker for a successful initiation of distractor suppression.
A developmental cell atlas of the human thyroid gland
Authors: Massalha Hassan , Trinh Mi K , Armingol Erick , Tuck Liz , Predeus Alexander , Mazin Pavel , Sancho-Serra Carmen , Oszlanczi Agnes , Wood Yvette , Parks Conor , Ogbonnah Toochi , Whitfield Holly J , Kelava Iva , Behjati Sam , Vento-Tormo Roser , Schoenmakers Nadia
Published: August 2024

The primary function of the thyroid gland is the synthesis and release of thyroid hormones, which are essential for health from embryogenesis to adulthood. Thyroid disorders occur frequently and include congenital hypothyroidism, which occurs due to aberrant thyroid development (thyroid dysgenesis) or impaired hormone synthesis and is particularly prevalent in trisomy 21 (T21). In contrast, thyroid carcinoma, an acquired disorder, is the most common endocrine malignancy in both paediatric and adult populations. Understanding the molecular basis of thyroid dysgenesis and paediatric thyroid carcinoma remains challenging, and requires an improved understanding of foetal thyroid development. To address this, we generated a comprehensive spatiotemporal atlas of the human thyroid during the first and second trimesters of pregnancy. Profiling over 200,000 cells with single-cell sequencing revealed key cell types involved in thyroid gland development, including the hormone-producing thyrocytes. We discovered that foetal thyroid follicular cells are heterogeneous epithelial populations consisting of two main functional subtypes (fTFC1, fTFC2), with fTFC2 expressing increased levels of PAX8, and spatial transcriptomics revealed subtype co-occurrence within individual follicles. While both fTFC1 and fTFC2 persist in adult thyroid, fTFC2 is a minor population amongst additional PAX8-positive follicular cell subsets. We observed thyroid dysgenesis in T21 age-matched specimens, and T21 thyrocytes showed transcriptional signatures of cytoskeletal disorganisation and altered interactions with the extracellular matrix, as well as compensatory activation of metabolic stress gene programs and upregulation of thyroid biosynthetic genes. In line with the altered proportions of fTFC2 in healthy foetal and adult thyroid, papillary thyroid cancer in children is transcriptionally enriched for the fTFC2 signature compared to that in adults. All together, these findings reveal thyrocyte heterogeneity across the lifespan and provide insights into thyroid development in health and disease, informing potential therapeutic interventions.
Restoring mechanophenotype reverts malignant properties of ECM-enriched vocal fold cancer
Authors: Kaivola Jasmin , Punovuori Karolina , Chastney Megan R. , Miroshnikova Yekaterina A. , Abdo Hind , Bertillot Fabien , Krautgasser Fabian , Franco Jasmin Di , Conway James R.W. , Follain Gautier , Hagström Jaana , Mäkitie Antti , Irjala Heikki , Ventelä Sami , Hamidi Hellyeh , Scita Giorgio , Cerbino Roberto , Wickström Sara A. , Ivaska Johanna
Published: August 2024

Increased extracellular matrix (ECM) and matrix stiffness promote solid tumor progression. However, mechanotransduction in cancers arising in mechanically active tissues remains underexplored. Here, we report upregulation of multiple ECM components accompanied by tissue stiffening in vocal fold cancer (VFC). We compare non-cancerous (NC) and patient- derived VFC cells – from early (mobile, T1) to advanced-stage (immobile, T3) cancers – revealing an association between VFC progression and cell-surface receptor heterogeneity, reduced laminin-binding integrin cell-cell junction localization and a flocking mode of collective cell motility. Mimicking physiological movement of healthy vocal fold tissue (stretching/vibration), decreases oncogenic nuclear β-catenin and YAP levels in VFC. Multiplex immunohistochemistry of VFC tumors uncovered a correlation between ECM content, nuclear YAP and patient survival, concordant with VFC sensitivity to YAP-TEAD inhibitors in vitro. Our findings present evidence that VFC is a mechanically sensitive malignancy and restoration of tumor mechanophenotype or YAP/TAZ targeting, represents a tractable anti-oncogenic therapeutic avenue for VFC.
Genomics-driven monitoring ofFraxinus latifolia(Oregon Ash) for conservation and EAB-resistance breeding
Authors: Melton Anthony E. , Faske Trevor M. , Sniezko Richard A. , Thibault Tim , Williams Wyatt , Parchman Thomas , Hamilton Jill A.
Published: August 2024

Understanding the evolutionary processes underlying range-wide genomic variation is critical to designing effective conservation and restoration strategies. Evaluating the influence of connectivity, demographic change, and environmental adaptation for threatened species can be invaluable to proactive conservation of evolutionary potential. In this study, we assessed genomic variation across the range ofFraxinus latifolia, a foundational riparian tree native to western North America recently exposed to the invasive emerald ash borer (Agrilus planipennis; EAB). Over 1,000 individuals from 61 populations were sequenced using reduced representation (ddRAD-seq) across the species’ range. Strong population structure was evident along a latitudinal gradient, with population connectivity largely maintained along central valley river systems, and a center of diversity coinciding with major river systems central to the species’ range. Despite evidence of connectivity, estimates of nucleotide diversity and effective population size were low across all populations, suggesting the patchy distribution ofF. latifoliapopulations may impact its long-term evolutionary potential. Range-wide estimates of genomic offset, which indicate genomic change required to adjust to future climate projections, were greatest in the eastern and lowest in the southern portions of the species’ range, suggesting the regional distribution of genomic variation may impact evolutionary potential longer-term. To preserve evolutionary capacity across populations needed for development of climate-resilient, EAB-resistant breeding programs, prioritizing conservation of range-wide genomic diversity will provide a foundation for species management long-term.
Epigenetic deprogramming driven by disruption of CIZ1-RNA nuclear assemblies in early-stage breast cancers
Authors: Coverley Dawn
Published: August 2024

CIZ1 is part of the large RNA-dependent supramolecular assemblies that form around the inactive X-chromosome (Xi) in female cells, and smaller assemblies throughout the nucleus in males and females. Here we show that CIZ1 C-terminal anchor domain (AD) is elevated in primary human breast tumour transcriptomes, even at stage I. Elevation of AD correlates with deprotection of chromatin, and up-regulation of lncRNA-containing gene clusters in approximately 10Mb regions that are enriched in cancer-associated genes. We modelled the effect of ectopic AD on endogenous CIZ1-Xi assemblies and observed dominant-negative interference with their re-formation after mitosis, leading to abnormal Xi assemblies similar to those in breast cancer cells, and depletion of histone modifications H2AK119ub1 and H3K27me3. Within days consistent alterations in gene expression were evident across the genome, showing that disruption of CIZ1-RNA assemblies has a destabilizing effect, likely by unscheduled exposure of underlying chromatin to modifying enzymes. Together the data argue for a dominant, potent and rapid effect of CIZ1 AD, that can deprogram established patterns of gene expression and which may predispose incipient tumours to epigenetic instability.
Replicator dynamics generalized for evolutionary matrix games under time constraints
Authors: Varga Tamas
Published: August 2024

One of the central results of evolutionary matrix games is that a state corresponding to an evolutionarily stable strategy (ESS) is an asymptotically stable equilibrium point of the standard replicator dynamics. This relationship is crucial because it simplifies the analysis of dynamic phenomena through static inequalities. Recently, as an extension of classical evolutionary matrix games, matrix games under time constraints have been introduced (Garay et al. 2017; Krivan and Cressman 2017). In this model, after an interaction, players do not only receive a payoff but must also wait a certain time depending on their strategy before engaging in another interaction. This waiting period can significantly impact evolutionary outcomes. We found that while the aforementioned classical relationship holds for two-dimensional strategies in this model, it generally does not apply for three-dimensional strategies (Varga and Garay 2024). To resolve this problem, we propose a generalization of the replicator dynamics that considers only individuals in active state, i.e., those not waiting, can interact and gain resources. We prove that using this generalized dynamics, the classical relationship holds true for matrix games under time constraints in any dimension: a state corresponding to an ESS is asymptotically stable. We believe this generalized replicator dynamics is more naturally aligned with the game theoretical model under time constraints than the classical form. It is important to note that this generalization reduces to the original replicator dynamics for classical matrix games.
Altered host pyruvate metabolism fuels and regulates fungal asexual reproduction
Authors: Lee Mi Yeon , Jaenisch Johan , McRae Amanda G. , Hirai-Adachi Chihiro , Louie Katherine , Silva Leslie P. , Bowen Benjamin P. , Northen Trent R. , Wildermuth Mary C.
Published: August 2024

Powdery mildew (PM) fungi are widespread pathogens impacting agricultural productivity. As obligate biotrophs, PMs get all nutrients from their host plant. Concurrent with asexual reproduction, the PM Golovinomyces orontii induces host lipid body accumulation in plant mesophyll cells underlying the epidermal cell that houses the fungal feeding structure. Herein, we show a PM-induced shift in plant primary metabolism, to bypass the pyruvate dehydrogenase complex (PDHc), acts in a dose-dependent manner to support host storage lipid production for PM acquisition. Not only are plant PDHc bypass-derived lipids incorporated into spore storage lipids, but they also act in a regulatory capacity to control the number of fungal reproductive structures per colony, ensuring the fitness of spores that are formed. Evolutionarily distant plant and animal obligate biotrophs manipulate host lipid metabolism for their own acquisition and we propose altered host pyruvate metabolism, bypassing the host PDHc bottleneck, as a common strategy to increase host source flux to acetate/acetyl-CoA for obligate microbial lipid acquisition.
Removal of the catalytic subunit of DNA-protein kinase in the proximal tubules promotes DNA and tubular damage during kidney injury
Authors: Swanson M. , Yun J. , Collier D.M. , Challagundla L. , Dogan M. , Kuscu C. , Garrett M.R. , Regner K.R. , Chung J. H. , Park F
Published: August 2024

Tubular epithelial cell damage can be repaired through a series of complex signaling pathways. An early event in many forms of tubular damage is the observation of DNA damage, which can be repaired by specific pathways depending upon the type of genomic alteration.. In this study, we report that the catalytic subunit of DNA protein kinase (DNA-PKcs), a central DNA repair enzyme involved in sensing DNA damage and performing double stranded DNA break repair, plays an important role in the extent of tubular epithelial cell damage following exposure to injurious acute and chronic stimuli. Selective loss of DNA-PKcs in the proximal tubules led to increased markers of kidney dysfunction, DNA damage, and tubular epithelial cell injury in multiple models of acute kidney injury, specifically bilateral renal ischemia-reperfusion injury and single dose of cisplatin (15 mg/kg IP). In contrast, in a mouse model of kidney fibrosis and chronic kidney disease (UUO),the protective effects of DNA-PKcs was not as obvious histologically from the tissue sections. In the absence of proximal tubular DNA-PKcs, there was reduced levels of fibrotic markers, α-SMA and fibronectin, which suggests that there may be a biphasic role of DNA-PKcs depending upon the conditions exerted upon the kidney. In conclusion, this study demonstrates that the catalytic subunit of DNA-PKcs plays a context-dependent role in the kidney to reduce DNA damage during exposure to various types of acute, but not chronic forms of injurious stimuli.
Terminal tracheal cells ofDrosophilaare immune privileged to maintain their Foxo-dependent structural plasticity
Authors: Bossen Judith , Raveendran Reshmi , He Jingjing , Roeder Thomas
Published: August 2024

Abstract

Respiratory organs fulfill several tasks, of which gas exchange is the most important. This function is also true for theDrosophilarespiratory organ, the tracheal system, in which the tracheal terminal cells (TTCs), the functional equivalents of the mammalian lung’s alveoli, are the structures where gas exchange occurs. To cope with the plethora of inhaled bacteria, fungi, and viruses, the trachea, like all airway organs, developed a sophisticated innate immune system to protect its large surface area. Bacterial infection of the Drosophila larval tracheal system induced a robust immune response throughout the entire airway epithelium, except for the TTCs that lacked this response. TTCs do not express the membrane-associated peptidoglycan recognition receptor PGRP-LC, which we assume protects these susceptible cells from Immune deficiency (Imd) pathway activation and JNK- mediated cell death. Thus, TTCs can be considered an immune-privileged cell type compared to the rest of the tracheal tissue. Targeted overexpression of PGRP-LCx in these cells led to a significant reduction in branching, cell damage, and ultimately cell death, which depletion of AP-1 or foxo could rescue. We hypothesize that the structural plasticity of TTCs in response to nutritional cues and hypoxia is incompatible with a potent immune function. Both reactions, the structural plasticity, and the immune response, require the transcription factor foxo, and we showed that it is essential for structural plasticity. Thus, the immune-privileged status of TTCs is (presumably) a mechanism that ensures normal TTC function.