Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

Genomic analyses correspond with deep persistence of peoples of Blackfoot Confederacy from glacial times.

Mutually beneficial partnerships between genomics researchers and North American Indigenous Nations are rare yet becoming more common. Here, we present one such partnership that provides insight into the peopling of the Americas and furnishes another line of evidence that can be used to further treaty and Indigenous rights. We show that the genomics of sampled individuals from the Blackfoot Confederacy belong to a previously undescribed ancient lineage that diverged from other genomic lineages in the Americas in Late Pleistocene times. Using multiple complementary forms of knowledge, we provide a scenario for Blackfoot population history that fits with oral tradition and provides a plausible model for the evolutionary process of the peopling of the Americas.

CT pulmonary arteriogram diagnosis of macroscopic fat embolism to the lung.

Pulmonary fat embolism (PFE) is a recognised complication of long bone fractures. The majority of cases represent microscopic embolism and are not detectable at CT pulmonary arteriography (CTPA). CT can be used to detect macroscopic fat based on Hounsfield attenuation. This case describes a case of macroscopic fat embolism to the pulmonary arteries which was confidently diagnosed at CTPA. Distinction from thromboembolism is important as treatment is supportive and may avoid risks of anticoagulation.

ERS/EBMT clinical practice guidelines on treatment of pulmonary chronic graft-versus-host disease in adults.

Chronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available. The purpose of this joint European Respiratory Society (ERS) and European Society for Blood and Marrow Transplantation task force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine and methodology, as well as patient advocates, formulated eight PICO (patient, intervention, comparison, outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the Grading of Recommendations Assessment, Development and Evaluation approach to develop recommendations. The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes.

Survey of European Blood and Marrow Transplant (EBMT) nurses to explore the current topical skin management of chronic cutaneous graft versus host disease in the real-world clinical environment.

PURPOSE: To understand the current practice in relation to the management of topical therapy for cutaneous chronic Graft versus Host Disease (ccGvHD) and access to extracorporeal photopheresis (ECP) within European allogeneic haematopoietic cell transplantation centres by a survey of nurses. METHOD: This was a multicentre cross-national study at eligible European Blood and Marrow Transplant centres. Eligibility required more than 30% of treated patients having allogeneic haematopoietic cell transplant. Centres performing only autologous stem cell transplants were excluded from the study. RESULTS: 12% of respondents were unaware of whether their centre had a policy or not for monitoring chronic cutaneous graft versus host disease. Over half had the affiliation of a dermatologist for referral, but only 19% had access to a specialist nurse. Patient education was routinely provided in most of the centres (86%). Results suggested as the severity of a patient's chronic cutaneous graft versus host disease increased, there was a reduction in the amount of topical emollients and steroids employed. Following topical therapies, systemic treatments, and other modalities such as ECP were employed with less focus directed towards topical care. CONCLUSIONS: Topical treatment is the backbone of any treatment paradigm for chronic cutaneous graft versus host disease, however, there is no universally agreed algorithm. Improved skin care may lead to a reduction in the amount of systemic therapy required, thus increasing patients' quality of life. There is little standardisation in the topical management of chronic cutaneous graft versus host disease, despite skin being the most cited organ affected by chronic graft versus host disease, this should be addressed.

Preliminary Results from Retrospective Correlation of Circulating Tumor DNA (ct-DNA) with Imaging for HPV-positive Oropharyngeal Squamous Cell Carcinoma.

The role of molecular markers is increasingly being recognized for head and neck tumors ranging from benign lesions like paragangliomas to malignancies like squamous cell carcinomas (SCCa). Multiple studies have recently validated blood tests for circulating tumor tissue modified viral- human papillomavirus DNA (HPV ct-DNA) (NavDx, Naveris Laboratories) for posttreatment surveillance of HPV-driven oropharyngeal SCCa. This technology quantifies fragments of circulating DNA that are shed into the blood stream with very high (>95%) positive and negative predictive values and are also highly sensitive in distinguishing tumor HPV-DNA from a non-cancerous source. This study has a cohort of 34 patients with HPV-driven oropharyngeal SCCa, having at least three sequential imaging studies and ct-DNA values. The study showed a strong positive correlation between the imaging findings and ct-DNA level in recurrent HPV positive oropharyngeal SCCa. Findings also include 100% negative predictive value of HPV ct-DNA tests to rule out tumor recurrence. At our institution, we are now routinely performing the ct-DNA assay for surveillance of treated HPV-oropharyngeal SCCa. Correlation between clinical, radiological, and biomarker findings are now part of routine discussions during the multidisciplinary tumor boards.ABBREVIATIONS: ct-DNA=circulating tumor deoxyribonucleic acid; HPV=Human Papilloma virus;OPC=Oropharyngeal SCCa=Squamous cell carcinomas; PCR= Polymerase chain reaction.

Radiologic Classification of Hippocampal Sclerosis in Epilepsy.

Temporal lobe epilepsy is a common form of epilepsy that is often associated with hippocampal sclerosis (HS). Although HS is commonly considered a binary assessment in radiological evaluation, it is known that histopathological changes occur in distinct clusters. Some subtypes of HS only affect certain subfields, resulting in minimal changes to the overall volume of the hippocampus. This is likely a major reason why whole hippocampal volumetrics have underperformed versus expert readers. With recent advancements in MRI technology, it is now possible to characterize the substructure of the hippocampus more accurately. However, this is not consistently addressed in radiographic evaluations. The histological subtype of HS is critical for prognosis and treatment decision making, necessitating improved radiological classification of HS. The International League Against Epilepsy (ILAE) has issued a consensus classification scheme for subtyping HS histopathological changes. This review aims to explore how the ILAE subtypes of HS correlate with radiographic findings, introduce a grading system that integrates radiological and pathological reporting in HS, and outline an approach to detecting HS subtypes using MRI. This framework will not only benefit current clinical evaluations, but also enhance future studies involving high-resolution MRI in temporal lobe epilepsy.ABBREVIATIONS: CA = cornu ammonis; DG = dentate gyrus; HS = hippocampal sclerosis; ILAE = International League Against Epilepsy; SRLM = strata radiatum, lacunosum, and moleculare layers; TLE = temporal lobe epilepsy.

On the stability of canonical correlation analysis and partial least squares with application to brain-behavior associations.

Associations between datasets can be discovered through multivariate methods like Canonical Correlation Analysis (CCA) or Partial Least Squares (PLS). A requisite property for interpretability and generalizability of CCA/PLS associations is stability of their feature patterns. However, stability of CCA/PLS in high-dimensional datasets is questionable, as found in empirical characterizations. To study these issues systematically, we developed a generative modeling framework to simulate synthetic datasets. We found that when sample size is relatively small, but comparable to typical studies, CCA/PLS associations are highly unstable and inaccurate; both in their magnitude and importantly in the feature pattern underlying the association. We confirmed these trends across two neuroimaging modalities and in independent datasets with n ≈ 1000 and n = 20,000, and found that only the latter comprised sufficient observations for stable mappings between imaging-derived and behavioral features. We further developed a power calculator to provide sample sizes required for stability and reliability of multivariate analyses. Collectively, we characterize how to limit detrimental effects of overfitting on CCA/PLS stability, and provide recommendations for future studies.

Dynamic regulation of hepatic lipid metabolism by torsinA and its activators.

Depletion of torsinA from hepatocytes leads to reduced liver triglyceride secretion and marked hepatic steatosis. TorsinA is an atypical ATPase that lacks intrinsic activity unless it is bound to its activator, lamina-associated polypeptide 1 (LAP1) or luminal domain-like LAP1 (LULL1). We previously demonstrated that depletion of LAP1 from hepatocytes has more modest effects on liver triglyceride secretion and steatosis development than depletion of torsinA. We now show that depletion of LULL1 alone does not significantly decrease triglyceride secretion or cause steatosis. However, simultaneous depletion of both LAP1 and LULL1 leads to defective triglyceride secretion and marked steatosis similar to that observed with depletion of torsinA. Depletion of both LAP1 and torsinA from hepatocytes generated phenotypes similar to those observed with only torsinA depletion, implying that the 2 proteins act in the same pathway in liver lipid metabolism. Our results demonstrate that torsinA and its activators dynamically regulate hepatic lipid metabolism.

The initiation and early development of the tubulin-containing cytoskeleton in the human parasite Toxoplasma gondii.

The tubulin-containing cytoskeleton of the human parasite Toxoplasma gondii includes several distinct structures: the conoid, formed of 14 ribbon-like tubulin polymers, and the array of 22 cortical microtubules (MTs) rooted in the apical polar ring. Here we analyze the structure of developing daughter parasites using both 3D-SIM and expansion microscopy. Cortical MTs and the conoid start to develop almost simultaneously, but from distinct precursors near the centrioles. Cortical MTs are initiated in a fixed sequence, starting around the periphery of a short arc that extends to become a complete circle. The conoid also develops from an open arc into a full circle, with a fixed spatial relationship to the centrioles. The patterning of the MT array starts from a "blueprint" with ∼five-fold symmetry, switching to 22-fold rotational symmetry in the final product, revealing a major structural rearrangement during daughter growth. The number of MT is essentially invariant in the wild-type array, but is perturbed by the loss of some structural components of the apical polar ring. This study provides insights into the development of tubulin-containing structures that diverge from conventional models, insights that are critical for understanding the evolutionary paths leading to construction and divergence of cytoskeletal frameworks.

7 T Lesion-Attenuated Magnetization-Prepared Gradient Echo Acquisition for Detection of Posterior Fossa Demyelinating Lesions in Multiple Sclerosis.

OBJECTIVES: Detection of infratentorial demyelinating lesions in multiple sclerosis (MS) presents a challenge in magnetic resonance imaging (MRI), a difficulty that is further heightened in 7 T MRI. This study aimed to assess the efficacy of a novel MRI approach, lesion-attenuated magnetization-prepared gradient echo acquisition (LAMA), for detecting demyelinating lesions within the posterior fossa and upper cervical spine on 7 T MRI and contrast its performance with conventional double-inversion recovery (DIR) and T2-weighted turbo spin echo sequences. MATERIALS AND METHODS: We conducted a retrospective cross-sectional study in 42 patients with a confirmed diagnosis of MS. All patients had 7 T MRI that incorporated LAMA, 3D DIR, and 2D T2-weighted turbo spin echo sequences. Three readers assessed lesion count in the brainstem, cerebellum, and upper cervical spinal cord using both DIR and T2-weighted images in one session. In a separate session, LAMA was analyzed alone. Contrast-to-noise ratio was also compared between LAMA and the conventional sequences. Lesion counts between methods were assessed using nonparametric Wilcoxon signed rank test. Interrater agreement in lesion detection was estimated by intraclass correlation coefficients. RESULTS: LAMA identified a significantly greater number of lesions than DIR + T2 (mean 6.4 vs 3.0; P < 0.001). LAMA also exhibited better interrater agreement (intraclass correlation coefficient [95% confidence interval], 0.75 [0.41-0.88] vs 0.61 [0.35-0.78]). The contrast-to-noise ratio for LAMA (3.7 ± 0.9) significantly exceeded that of DIR (1.94 ± 0.7) and T2 (1.2 ± 0.7) (all P's < 0.001). In cases with no lesions detected using DIR + T2, at least 1 lesion was identified in 83.3% with LAMA. Across all analyzed brain regions, LAMA consistently detected more lesions than DIR + T2. CONCLUSIONS: LAMA significantly improves the detection of infratentorial demyelinating lesions in MS patients compared with traditional methods. Integrating LAMA with standard magnetization-prepared 2 rapid acquisition gradient echo acquisition provides a valuable tool for accurately characterizing the extent of MS disease.

SARS-CoV-2 Delta and Omicron community transmission networks as added value to contact tracing.

OBJECTIVES: Calculations of SARS-CoV-2 transmission networks at a population level have been limited. Networks that estimate infections between individuals and whether this results in a mutation, can be a way to evaluate fitness of a mutational clone by how much it expands in number as well as determining the likelihood a transmission results in a new variant. METHODS: Australian Delta and Omicron SARS-CoV-2 sequences were downloaded from GISAID. Transmission networks of infection between individuals were estimated using a novel mathematical method. RESULTS: Many of the sequences were identical, with clone sizes following power law distributions driven by negative binomial probability distributions for both the number of infections per individual and the number of mutations per transmission (median 0.74 nucleotide changes for Delta and 0.71 for Omicron). Using these distributions, an agent-based model was able to replicate the observed clonal network structure, providing a basis for more detailed COVID-19 modelling. Possible recombination events, tracked by insertion/deletion (indel) patterns, were identified for each variant in these outbreaks. CONCLUSIONS: This modelling approach reveals key transmission characteristics of SARS-CoV-2 and may complement traditional contact tracing. This methodology can also be applied to other diseases as genetic sequencing of viruses becomes more commonplace.

A spatiotemporally resolved atlas of mRNA decay in the C. elegans embryo reveals differential regulation of mRNA stability across stages and cell types.

During embryonic development, cells undergo dynamic changes in gene expression that are required for appropriate cell fate specification. Although both transcription and mRNA degradation contribute to gene expression dynamics, patterns of mRNA decay are less well-understood. Here we directly measured spatiotemporally resolved mRNA decay rates transcriptome-wide throughout C. elegans embryogenesis by transcription inhibition followed by bulk and single-cell RNA-sequencing. This allowed us to calculate mRNA half-lives within specific cell types and developmental stages and identify differentially regulated mRNA decay throughout embryonic development. We identified transcript features that are correlated with mRNA stability and found that mRNA decay rates are associated with distinct peaks in gene expression over time. Moreover, we provide evidence that, on average, mRNA is more stable in the germline compared to in the soma and in later embryonic stages compared to in earlier stages. This work suggests that differential mRNA decay across cell states and time helps to shape developmental gene expression, and it provides a valuable resource for studies of mRNA turnover regulatory mechanisms.

A gap analysis of midwifery competency, pre- and in-service education for reproductive, maternal, newborn, child and, adolescent health in Lao People's Democratic Republic.

Background: Ensuring midwives deliver quality essential services requires systematic and timely updates to midwifery education based on constantly evolving global evidence and local needs. However, midwifery curricula are often not updated to incorporate new evidence, consistent with national standards. This study supported the Ministry of Health of Lao People's Democratic Republic to identify gaps in the midwifery competency framework and training packages. Methods: Stakeholder consultations and a document review were conducted to define a core package of RMNCAH interventions and care tasks that midwives should provide based on the national Essential Health Service Package (EHSP). Nationally defined midwifery competencies, the higher diploma midwifery curriculum, and in-service training packages were mapped against required interventions and care tasks. Data were used to revise midwifery education standards. Findings: Midwives were expected to provide 47 RMNCAH interventions based on the EHSP. At baseline, 7 (14.9%), 11 (23.4%) and 35 (74.5%) of the 47 interventions were included in the midwifery competency, higher diploma in midwifery curriculum, and in-service training materials, respectively. After revision, the midwifery competency framework included 42 of 47 interventions (89.4%). The data are currently being used to review and update the national midwifery pre-service diploma curriculum. Interpretation: This analysis enabled the Ministry to identify RMNCAH content gaps in national midwifery education standards and align them with the EHSP. Regular use of a quantitative approach to review educational content is essential to ensure standards are consistent with changing evidence. The approach has potential application to other service areas, cadres, and countries. Funding: Korea Foundation for International Healthcare (KOFIH) supported research operation.

A regulatory gap analysis of midwifery to deliver essential reproductive, maternal, newborn, child and adolescent health services in Lao People's Democratic Republic.

Background: In Lao Peoples Democratic Republic, midwives are the main providers of primary reproductive, maternal, newborn, child and adolescent (RMNCAH) services. We analyzed to what extent practice regulations allow midwives to provide nationally defined essential RMNCAH services. Methods: Stakeholder consultations and document reviews were conducted to identify the essential RMNCAH interventions and care tasks midwives are expected to provide without physicians. These were defined in: 1) the Essential Health Service Package (EHSP) and 2) 18 national standards and guidelines. We then mapped whether midwifery regulations, which provide the legal framework for clinical service provision, supported delivery of these standards to identify regulatory gaps. Data were used to update regulations. Findings: Midwives were expected to provide 39 RMNCAH interventions without physicians, representing 1100 care tasks. Midwifery practice regulations allowed eight of 39 interventions (20.5%) and 705 of 1100 care tasks (64.1%) at baseline. Of the 31 interventions not allowed for provision by midwives, 83.9% (26) required prescribing and giving medicines, 51.6% (16) ordering and conducting diagnostics, 38.7% (12) making a clinical diagnosis, and 22.6% (7) use of non-pharmacological interventions. The Ministry of Health convened a multi-stakeholder group to revise the midwifery practice regulations, which increased the legally supported interventions and care tasks to 37 (94.9%) and 1081 (98.3%), respectively. Interpretation: This novel methodology enabled systematic identification and quantification of regulatory gaps in midwifery practice and data-driven revisions. Consequently, regulatory support for delivery of primary RMNCAH interventions vastly improved. The approach can be applied to other clinical cadres, service areas and countries. Funding: Korea Foundation for International Health Care (KOFIH) supported research operation.

Engraftment and injury repair in regionally conditioned rat lung in vivo by lung progenitors derived from human pluripotent stem cells.

Although lung disease is a major cause of mortality, the mechanisms involved in human lung regeneration are unclear because of the lack of experimental models. Here we report a novel model where human pluripotent stem cell-derived expandable cell lines sharing features of airway secretory and basal cells engraft in the distal rat lung after conditioning by locoregional de-epithelialization followed by irradiation and immunosuppression. The engrafting cells, which we named distal lung epithelial progenitors (DLEPs), contributed to alveolar epithelial cells and generated 'KRT5-pods', structures involved in distal lung repair after severe injury, but only rarely to distal airways. Most strikingly, however, injury induced by the conditioning regimen was largely prevented by the engrafting DLEPs. The approach described here provides a model to study mechanisms involved in human lung regeneration, and potentially lays the foundation for the preclinical development of cell therapy to treat lung injury and disease.

Benefits and harms of cervical screening, triage and treatment strategies in women living with HIV.

To support a strategy to eliminate cervical cancer as a public health problem, the World Health Organisation (WHO) reviewed its guidelines for screening and treatment of cervical pre-cancerous lesions in 2021. Women living with HIV have 6-times the risk of cervical cancer compared to women in the general population, and we harnessed a model platform ('Policy1-Cervix-HIV') to evaluate the benefits and harms of a range of screening strategies for women living with HIV in Tanzania, a country with endemic HIV. Assuming 70% coverage, we found that 3-yearly primary HPV screening without triage would reduce age-standardised cervical cancer mortality rates by 72%, with a number needed to treat (NNT) of 38.7, to prevent a cervical cancer death. Triaging HPV positive women before treatment resulted in minimal loss of effectiveness and had more favorable NNTs (19.7-33.0). Screening using visual inspection with acetic acid (VIA) or cytology was less effective than primary HPV and, in the case of VIA, generated a far higher NNT of 107.5. These findings support the WHO 2021 recommendation that women living with HIV are screened with primary HPV testing in a screen-triage-and-treat approach starting at 25 years, with regular screening every 3-5 years.

ENTRAIN: integrating trajectory inference and gene regulatory networks with spatial data to co-localize the receptor-ligand interactions that specify cell fate.

MOTIVATION: Cell fate is commonly studied by profiling the gene expression of single cells to infer developmental trajectories based on expression similarity, RNA velocity, or statistical mechanical properties. However, current approaches do not recover microenvironmental signals from the cellular niche that drive a differentiation trajectory. RESULTS: We resolve this with environment-aware trajectory inference (ENTRAIN), a computational method that integrates trajectory inference methods with ligand-receptor pair gene regulatory networks to identify extracellular signals and evaluate their relative contribution towards a differentiation trajectory. The output from ENTRAIN can be superimposed on spatial data to co-localize cells and molecules in space and time to map cell fate potentials to cell-cell interactions. We validate and benchmark our approach on single-cell bone marrow and spatially resolved embryonic neurogenesis datasets to identify known and novel environmental drivers of cellular differentiation. AVAILABILITY AND IMPLEMENTATION: ENTRAIN is available as a public package at https://github.com/theimagelab/entrain and can be used on both single-cell and spatially resolved datasets.

Static and dynamic fMRI-derived functional connectomes represent largely similar information.

Functional connectivity (FC) of blood oxygen level-dependent (BOLD) fMRI time series can be estimated using methods that differ in sensitivity to the temporal order of time points (static vs. dynamic) and the number of regions considered in estimating a single edge (bivariate vs. multivariate). Previous research suggests that dynamic FC explains variability in FC fluctuations and behavior beyond static FC. Our aim was to systematically compare methods on both dimensions. We compared five FC methods: Pearson's/full correlation (static, bivariate), lagged correlation (dynamic, bivariate), partial correlation (static, multivariate), and multivariate AR model with and without self-connections (dynamic, multivariate). We compared these methods by (i) assessing similarities between FC matrices, (ii) by comparing node centrality measures, and (iii) by comparing the patterns of brain-behavior associations. Although FC estimates did not differ as a function of sensitivity to temporal order, we observed differences between the multivariate and bivariate FC methods. The dynamic FC estimates were highly correlated with the static FC estimates, especially when comparing group-level FC matrices. Similarly, there were high correlations between the patterns of brain-behavior associations obtained using the dynamic and static FC methods. We conclude that the dynamic FC estimates represent information largely similar to that of the static FC.

The initiation and early development of the tubulin-containing cytoskeleton in the human parasite Toxoplasma gondii.

The tubulin-containing cytoskeleton of the human parasite Toxoplasma gondii includes several distinct structures: the conoid, formed of 14 ribbon-like tubulin polymers, and the array of 22 cortical microtubules (MTs) rooted in the apical polar ring. Here we analyze the structure of developing daughter parasites using both 3D-SIM and expansion microscopy. Cortical MTs and the conoid start to develop almost simultaneously, but from distinct precursors near the centrioles. Cortical MTs are initiated in a fixed sequence, starting around the periphery of a short arc that extends to become a complete circle. The conoid also develops from an open arc into a full circle, with a fixed spatial relationship to the centrioles. The patterning of the MT array starts from a "blueprint" with ∼ 5-fold symmetry, switching to 22-fold rotational symmetry in the final product, revealing a major structural rearrangement during daughter growth. The number of MT is essentially invariant in the wild-type array, but is perturbed by the loss of some structural components of the apical polar ring. This study provides insights into the development of tubulin-containing structures that diverge from conventional models, insights that are critical for understanding the evolutionary paths leading to construction and divergence of cytoskeletal frameworks.