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The lateral prefrontal cortex (LPFC) is an evolutionarily expanded region in humans that is critical for numerous complex functions, many of which are largely hominoid-specific. While recent work shows that the presence or absence of specific sulci in anterior LPFC is associated with cognitive performance across age groups, it is unknown whether the presence of these structures relates to individual differences in the functional organization of LPFC. To fill this gap in knowledge, we leveraged multimodal neuroimaging data from 72 young adult humans aged 22-36 and show that dorsal and ventral components of the paraintermediate frontal sulcus (pimfs) present distinct morphological (surface area), architectural (thickness and myelination), and functional (resting-state connectivity networks) properties. We further contextualize the pimfs components within classic and modern cortical parcellations. Taken together, the dorsal and ventral pimfs components mark transitions in anatomy and function in LPFC, across metrics and parcellations. These results emphasize that the pimfs is a critical structure to consider when examining individual differences in the anatomical and functional organization of LPFC and highlight the importance of considering individual anatomy when investigating structural and functional features of the cortex.

Superficial white matter (SWM) represents a significantly understudied part of the human brain, despite comprising a large portion of brain volume and making up a majority of cortico-cortical white matter connections. Using multiple, high-quality datasets with large sample sizes (N = 2421, age range 5–100) in combination with methodological advances in tractography, we quantified features of SWM volume and thickness across the brain and across development, young adulthood, and aging. We had four primary aims: (1) characterize SWM thickness across brain regions (2) describe associations between SWM volume and age (3) describe associations between SWM thickness and age, and (4) quantify relationships between SWM thickness and cortical features. Our main findings are that (1) SWM thickness varies across the brain, with patterns robust across individuals and across the population at the region-level and vertex-level; (2) SWM volume shows unique volumetric trajectories with age that are distinct from gray matter and other white matter trajectories; (3) SWM thickness shows nonlinear cross-sectional changes across the lifespan that vary across regions; and (4) SWM thickness is associated with features of cortical thickness and curvature. For the first time, we show that SWM volume follows a similar trend as overall white matter volume, peaking at a similar time in adolescence, leveling off throughout adulthood, and decreasing with age thereafter. Notably, the relative fraction of total brain volume of SWM continuously increases with age, and consequently takes up a larger proportion of total white matter volume, unlike the other tissue types that decrease with respect to total brain volume. This study represents the first characterization of SWM features across the large portion of the lifespan and provides the background for characterizing normal aging and insight into the mechanisms associated with SWM development and decline.

Central nervous system (CNS) malignancies are rare, but commonly fatal and glioblastoma (GBM) is the most common of the primary brain tumors. In contrast to metastatic malignancies involving the CNS, which have external blood supplies that develop when the malignant cells penetrate the blood-brain-barrier (BBB), GBM generates its own intracerebral neovascular support system. Thus, the therapeutic issues as discussed herein review the development of drugs and therapeutics that will penetrate the BBB and are cytotoxic to GBM and other brain tumors. Since GBM is a CNS malignancy with minimal effective therapeutic options available, designing drugs and therapeutics as treatment for this malignancy that penetrate, but do not disrupt the BBB is the goal of this chapter. 4-Demethylcholesteryl-4-penclomedine (DM-CHOC-PEN) was designed and developed because of its lipophilic properties that would potentiate crossing the BBB and penetrate brain tumors. The drug has now completed Phase I/II clinical trial in humans with primary brain malignancies demonstrating objective responses in GBM. In addition, preliminary experiences with naturally occurring polyphenols—curcumin, quercetin, catechins and phloretin and derivatives—are reviewed as potential naturally occurring anti-glioblastoma agents.

Transcriptomic contributions to the anatomical, functional, and network layout of the human cerebral cortex (HCC) has become a major interest in cognitive and systems neuroscience. Here, we tested if transcriptomic differences support a modern, algorithmic cytoarchitectonic parcellation of HCC. Using a data-driven approach, we identified a sparse subset of genes that differentially contributed to the cytoarchitectonic parcellation of HCC. A novel metric (cortical thickness/myelination ratio; CT/M ratio), as well as cell density, correlated with gene expression. Enrichment analyses showed that genes specific to the cytoarchitectonic parcellation of the HCC were related to molecular functions such as transmembrane transport and ion channel activity. Together, the novel relationship between transcriptomics and the CT/M ratio bridges the gap among i) gradients at the macroscale, ii) areas at the meso-scale, and iii) cell density at the microscale, as well as supports the recently proposed cortical spectrum theory.

The aim of this study is to use tibial Hounsfield unit measurements from preoperative computed tomography scans of ankle fractures to predict delayed union and nonunion. We hypothesize that patients with lower Hounsfield unit averages, an indirect measure of lower bone mineral density, in the distal tibia are more likely to develop delayed union and nonunion complications after ankle fracture surgery. Patient data from January 2010 to January 2020 were retrospectively analyzed from 2 institutions. Exposure cases of delayed union or nonunion that had preoperative computed tomography were compared to 5 controls matched for sex, age, and classification. 3 measurements were taken from the tibia on axial computed tomography and averaged to create a summative measure for overall bone health. Statistical analysis was used to analyze the relationship between the groups. 19 exposure patients were compared to 95 control patients. There were 16 females and 3 males in the exposure group aged from 30 to 88 years. Average follow-up was 1.6 years. The average exposure and control Hounsfield measurements were 186 (161-210) and 258 (248-269), respectively. Significant differences were found for all measured averages. This is the first study to our knowledge relating preoperative tibial Hounsfield measurements to healing rates of ankle fractures. Measurements taken from any of the 3 sites or the average could be an indicator of overall bone health. Using this technique on preoperative imaging will help surgeons adjust their perioperative planning for patients at higher risk for delayed union and nonunion.

Identifying structural-functional correspondences is a major goal among biologists. In neurobiology, recent findings identify relationships between performance on cognitive tasks and the presence or absence of small, shallow indentations, or sulci, of the human brain. Here, we tested if the presence or absence of one such sulcus, the paraintermediate frontal sulcus (pimfs-v) in lateral prefrontal cortex, was related to relational reasoning in young adults from the Human Connectome Project (ages 22-36). After manually identifying 2,877 sulci across 144 hemispheres, our results indicate that the presence of the pimfs-v in the left hemisphere was associated with a 21-34% higher performance on a relational reasoning task. These findings have direct developmental and evolutionary relevance as recent work shows that the presence or absence of the pimfs-v is also related to reasoning performance in a pediatric cohort, and that the pimfs-v is exceedingly rare in chimpanzees. Thus, the pimfs-v is a novel developmental, cognitive, and evolutionarily relevant feature that should be considered in future studies examining how the complex relationships among multiscale anatomical and functional features of the brain give rise to abstract thought.

Objective Hypoglossal nerve stimulation (HNS) implantation in the US requires preoperative drug-induced sleep endoscopy (DISE) screening for complete concentric palatal collapse (CCC) to establish treatment candidacy. We hypothesized that supine pharyngeal width (SPW) in awake patients is associated with CCC and HNS therapy outcomes. Methods Adults with moderate to severe obstructive sleep apnea underwent awake measurement of SPW followed by DISE screening for CCC. Eligible patients electing for HNS implantation underwent postoperative polysomnography per standard of care. Results SPW was measured in 73 patients. For SPW >20 mm, the positive likelihood ratio for absence of CCC was 6.67 with pre- and post-test odds of 6.3 and 42.0, respectively. Postoperative PSG data were available from 31 of 44 (70.5%) patients subsequently implanted with HNS. Patients with SPW >20 mm had a greater rate of HNS response than those with SPW ≤20 (62 vs 30%; P < .05). Only SPW and BMI were significantly associated with CCC and HNS response in regression models. Conclusion In a retrospective cohort study, SPW was significantly associated with CCC and postoperative apnea-hypopnea index following HNS implantation. SPW may be a viable screening tool for HNS candidacy.

Younger breast cancer survivors (YBCS) consistently report poorer quality of life (QOL) than older survivors. Increasing physical activity (PA) may improve QOL, but this has been understudied in YBCS. This single arm pilot study evaluated the feasibility and acceptability of a 3-month, peer-delivered, remote intervention to increase PA and improve QOL in YBCS. Data were collected from October 2019 – July 2020. Participants (n = 34, 43.1 ± 5.5 years old, 46 ± 34.4 months post-diagnosis, BMI = 30.2 ± 7.4 kg/m2) completed six video sessions with a trained peer mentor; self-monitored PA with a Fitbit activity tracker; and interacted with a private Fitbit Community for social support. At baseline, 3-and 6-months, participants completed QOL questionnaires and PA was measured through accelerometer (moderate-to-vigorous PA [MVPA]) and self-report (strength and flexibility). A parallel mixed-methods approach (qualitative interviews and quantitative satisfaction survey at 3-months) explored intervention feasibility and acceptability. One-way repeated-measures ANOVAs examined impacts on PA and QOL at 3-and 6-months. The intervention was feasible as evidenced by efficient recruitment, high retention, and adherence to intervention components. Remote delivery, working with a peer mentor, and using Fitbit tools were highly acceptable. From baseline to 3-months, participants increased time spent in objectively measured MVPA, strength, and flexibility exercises, and reported meaningful improvements to body image, fatigue, anxiety, and emotional support. A fully remote, peer-to-peer intervention is an acceptable and promising strategy to increase PA and improve QOL in YBCS. Refinements to the intervention and its delivery should be further assessed in future studies, toward the goal of disseminating an evidence-based, scalable intervention to the growing number of YBCS.Trial registration Prospectively registered as NCT04064892.

Gene expression gradients radiating from regions of primary sensory cortices have recently been described and are thought to underlie the large-scale organization of the human cerebral cortex. However, the role of transcription in the functional layout of a single region within the adult brain has yet to be clarified, likely owing to the difficulty of identifying a brain region anatomically consistent enough across individuals with dense enough tissue sampling. Overcoming these hurdles in human primary visual cortex (V1), we show a relationship between differential gene expression and the cortical layout of eccentricity in human V1. Interestingly, these genes are unique from those previously identified that contribute to the positioning of cortical areas in the visual processing hierarchy. Enrichment analyses show that a subset of the identified genes encode for structures related to inhibitory interneurons, ion channels, as well as cellular projections, and are expressed more in foveal compared to peripheral portions of human V1. These findings predict that tissue density should be higher in foveal compared to peripheral V1. Using a histological pipeline, we validate this prediction using Nissl-stained sections of postmortem occipital cortex. We discuss these findings relative to previous studies in non-human primates, as well as in the context of an organizational pattern in which the adult human brain employs transcription gradients at multiple spatial scales: across the cerebral cortex, across areas within processing hierarchies, and within single cortical areas.

Posterior malleolar fractures are often part of complex ankle fracture patterns. Radiographs and computed tomography are often obtained in the preoperative setting. In this study, we compared measurements from lateral ankle radiographs with measurements on axial computed tomography. We hypothesize that there is an association between measurements taken on lateral XR and certain fracture morphology such as medial extension and that measurements taken on lateral XR can be used to predict likelihood of medial extension type fractures. A multi-center retrospective analysis was performed involving patients with trimalleolar ankle fractures treated at two large urban healthcare systems ranging from January 1, 2010 to November 1, 2019. A total of 279 patients met criteria including 186 females and 93 males aged 18 to 90 with an average age 55. Four reviewers measured continuous variables on lateral radiograph and axial computed tomography: posterior malleolus fracture height, articular surface length, medial-lateral width, and anterior-posterior depth and then agreement was assessed via intraclass correlation coefficient. Pearson correlations were calculated for all pairwise combinations of measurements. Two fracture classification systems were then evaluated for association with the continuous variables. Lateral height was divided into quartiles and analyzed for the degree of association. Positive correlation was found between lateral height and axial depth/axial width. Taller lateral height values were statistically associated with medial extension type fractures. Lateral height 24.5mm-29.5mm is 3.1x higher, and lateral height29.5mm is 8.6x more likely to have medial extension when compared to shorter lateral heights(20.5mm). Based on these findings we suggest increased usage of pre-operative CT and evaluation for the use of posteromedial approaches in the setting of taller lateral height fracture patterns(24.5mm) as seen on lateral XR.

Previous findings show that the morphology of folds (sulci) of the human cerebral cortex flatten during postnatal development. However, previous studies did not consider the relationship between sulcal morphology and cognitive development in individual participants. Here, we fill this gap in knowledge by leveraging cross-sectional morphological neuroimaging data in the lateral prefrontal cortex (LPFC) from individual human participants (6-36 years old, males and females; N = 108; 3672 sulci), as well as longitudinal morphological and behavioral data from a subset of child and adolescent participants scanned at two timepoints (6-18 years old; N = 44; 2992 sulci). Manually defining thousands of sulci revealed that LPFC sulcal morphology (depth, surface area, gray matter thickness, and local gyrification index) differed between children (6-11 years old)/adolescents (11-18 years old) and young adults (22-36 years old) cross-sectionally, but only cortical thickness showed both cross-sectional differences between children and adolescents and presented longitudinal changes during childhood and adolescence. Furthermore, a data-driven approach relating morphology and cognition identified that longitudinal changes in cortical thickness of four rostral LPFC sulci predicted longitudinal changes in reasoning performance, a higher-level cognitive ability that relies on LPFC. Contrary to previous findings, these results suggest that sulci may flatten either after this time frame or over a longer longitudinal period of time than previously presented. Crucially, these results also suggest that longitudinal changes in the cortex within specific LPFC sulci are behaviorally meaningful—providing targeted structures, and areas of the cortex, for future neuroimaging studies examining the development of cognitive abilities.Significance StatementRecent work has shown that individual differences in neuroanatomical structures (indentations, or sulci) within the lateral prefrontal cortex (LPFC) are behaviorally meaningful during childhood and adolescence. Here, we describe how specific LPFC sulci develop at the level of individual participants for the first time—from both cross-sectional and longitudinal perspectives. Further, we show, also for the first time, that the longitudinal morphological changes in these structures are behaviorally relevant. These findings lay the foundation for a future avenue to precisely study the development of the cortex and highlight the importance of studying the development of sulci in other cortical expanses and charting how these changes relate to the cognitive abilities those areas support at the level of individual participants.

Understanding brain structure-function relationships, and their development and evolution, is central to neuroscience research. Here, we show that morphological differences in posterior cingulate cortex (PCC), a hub of functional brain networks, predict individual differences in macroanatomical, microstructural, and functional features of PCC. Manually labeling 4511 sulci in 572 hemispheres, we found a shallow cortical indentation (termed the inframarginal sulcus; ifrms ) within PCC that is absent from neuroanatomical atlases yet colocalized with a focal, functional region of the lateral frontoparietal network implicated in cognitive control. This structural-functional coupling generalized to meta-analyses consisting of hundreds of studies and thousands of participants. Additional morphological analyses showed that unique properties of the ifrms differ across the life span and between hominoid species. These findings support a classic theory that shallow, tertiary sulci serve as landmarks in association cortices. They also beg the question: How many other cortical indentations have we missed?

Two recent parallel research tracks link tertiary sulcal morphology—sulci that emerge last in gestation and continue to develop after birth—with functional features of the cerebral cortex and cognition, respectively. The first track identified a relationship between the mid-fusiform sulcus (MFS) in ventral temporal cortex (VTC) and cognition in individuals with Autism Spectrum Disorder (ASD). The second track identified a new tertiary sulcus, the inframarginal sulcus (IFRMS), that serves as a tripartite landmark within the posteromedial cortex (PMC). As VTC and PMC are structurally and functionally different in individuals with ASD compared to neurotypical controls (NTs), here, we integrated these two tracks with a twofold approach. First, we tested if there are morphological differences in VTC and PMC sulci between 50 NTs and 50 individuals with ASD. Second, we tested if tertiary sulcal morphology was linked to cognition in ASD individuals. Our twofold approach replicates and extends recent findings in five ways. First, in terms of replication, the standard deviation (STD) of MFS cortical thickness (CT) was increased in ASDs compared to NTs. Second, MFS length was shorter in ASDs compared to NTs. Third, the CT STD effect extended to other VTC and PMC sulci. Fourth, a subset of VTC and PMC morphological features were correlated between regions in ASD. Fifth, IFRMS depth was negatively associated with ADOS-GS score. These results empirically support a relationship between later-developing, tertiary sulci and ASD, providing a novel framework to study the relationship between brain structure and cognition in additional neurodevelopmental disorders in future studies.Lay SummaryWe observed that some, but not all, morphological features of later-developing tertiary indentations (sulci) in the cerebral cortex differed significantly between neurotypical controls and individuals with autism spectrum disorder (ASD). In ASD, a subset of sulcal morphological features also correlated between brain areas and one feature reflected differences in cognition. Thus, studying these structures provides insight into how individual variability in structure is related to individual variability in cognition in ASD.

Obesity affects the health and well-being of children globally. Despite recommendations to routinely screen children for obesity starting at age 6 years, physicians do not consistently address weight or provide effective weight-management counseling. We developed an interactive session for second-year medical students with foundational knowledge and practical communication skills around partnership and discussion of pediatric healthy weight management. Students were administered a pre-/post-Likert survey to self-assess knowledge, comfort, and confidence in counseling patients and caregivers about weight management. Students' related counseling skills were assessed during a standardized patient encounter of a teen with rapid weight gain. The session successfully increased students' self-assessed knowledge, comfort, and confidence, and resulted in successful application of weight management skills in a simulated patient encounter. Utilization of empathy skills requires continued coaching. We propose incorporation of similar sessions into medical school curricula to address the pediatric obesity epidemic.

Superficial white matter (SWM) represents a significantly understudied part of the human brain, despite comprising a large portion of brain volume and making up a majority of cortical structural connections. Using multiple, high-quality, datasets with large sample sizes (N=2421, age range 5-100) in combination with methodological advances in tractography, we quantified features of SWM volume and thickness across the brain and across the lifespan. We address four questions: (1) How does U-fiber volume change with age? (2) What does U-fiber thickness look like across the brain? (3) How does SWM thickness change with age? (4) Are there relationships between SWM thickness and cortical features? Our main findings are that (1) SWM volume shows unique volumetric trajectories with age that are distinct from gray matter and other white matter trajectories; (2) SWM thickness varies across the brain, with patterns robust across individuals and across the population at the region-level and vertex-level; (3) SWM shows nonlinear changes across the lifespan that vary across regions; and (4) SWM thickness is associated with cortical thickness and curvature. For the first time, we show that SWM volume follows a similar trend as overall white matter volume, peaking at a similar time in adolescence, leveling off throughout adulthood, and decreasing with age thereafter. Notably, the relative fraction of total brain volume of SWM continuously increases with age, and consequently takes up a larger proportion of total white matter volume, unlike the other tissue types that decrease with respect to total brain volume. This study represents the first characterization of SWM features across the lifespan and provides the background for characterizing normal aging and insight into the mechanisms associated with SWM development and decline.

In this paper, we combine evidence from archaeology, landscape, astronomy, and Indigenous oral traditions to propose that Chaco Canyon was established as a regionally influential sun-moon-rain shri...

This paper offers a new interpretation of Chacoan Great Houses, multistoried masonry structures of the 9th-12th century U.S. Southwest, using insights from animist ontologies, cognitive science, cr...

The occurrence of nonlocal objects, raw materials, and ideas in the southwestern United States (U.S. SW) has long been recognized as evidence of interaction between prehispanic peoples of this region and those of greater Mesoamerica. Although many archaeologists have analyzed the directionality and potential means by which these objects and concepts moved across the landscape, few have assessed the degree to which Mesoamerican practices and traditional assemblages remained intact as the artifacts and ideas moved farther from their places of origin. The current study analyzes the distribution and deposition of blue-green stone mosaics, a craft technology that was well established in Mesoamerica by the Late Preclassic period (300 BC–AD 250) and spread to the U.S. SW by the start of the Hohokam Pioneer period (AD 475). We assess the spatial distribution, contextual deposition, and morphology of mosaics at sites within Hohokam Canal System 2, located in the Phoenix Basin of Arizona. We use these data to infer mosaics’ social value and function within Hohokam social structure. Analyses suggest that, although the technology of mosaic making may have originated in Mesoamerica, the contexts and ways in which mosaics were used in the Hohokam regional system were decidedly Hohokam.

T-cells in the tumor microenvironment can often become exhausted and dysfunctional due to chronic and prolonged exposure to antigen. The resulting condition of T cell exhaustion represents an important mechanism of clinical resistance to immune checkpoint blockade. The transcription factor NR4A1 is known to be upregulated in tumor-specific T-cells and is a mediator of T cell dysfunction including driving exhaustion during chronic antigen stimulation of T-cells. Pro-oncogenic activities of NR4A1 have been observed in various solid tumors, including colorectal and breast cancers, and co-expression of NR4A1 with known immune checkpoint markers such as PD-L1 and B7 family members has also been observed in various cancer cell lines. These findings have identified NR4A1 as an important target for overcoming resistance to cancer immunotherapy. We hypothesize that targeted silencing of the NR4A1 and other immunomodulatory genes can reverse T-cell exhaustion and expand the clinical benefit of immune checkpoint blockade in solid tumors resistant to immune therapy. To reverse T-cell exhaustion with a targeted approach, we developed T cell targeting SeekRsTM, which are chimeric RNA therapeutics containing dual-flanking aptamer binders connected by a double-stranded bridge containing siRNA silencers that can target multiple immunomodulatory genes. First-generation aptamer-siRNA chimeras designed with a CTLA-4 targeting aptamer containing a STAT3 siRNA demonstrated effectiveness in silencing its target. Modifications to the structure included the addition of chemically modified nucleotides to improve serum stability. Additionally, dimerization of the structure to form a SeekR dimer molecule greatly improved internalization and target silencing compared to the monomeric chimera. Newly developed SeekRs targeting T cells and designed to silence NR4A1 have effectively downregulated NR4A1 in model cell lines and activated T cells. These results demonstrate that dual targeting SeekRs can be used to specifically deliver siRNA to T cells for targeted silencing that can reverse exhaustion and potentially overcome resistance to cancer immunotherapy in the clinic. Citation Format: Marvin O'Ketch, Jeffrey A. Kiefer, Dnyanesh Rasale, Warren S. Weiner, Lizette A. Castaño, Nathalie A. Azorsa, David W. Lee, Kerry M. Barnhart, Spyro Mousses, David O. Azorsa. Activity of novel RNA therapeutics to overcome resistance to immune checkpoint blockade. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4417.

The transcription factor NRF2 is a master regulator of cellular responses to oxidative stress, contributing to the pathogenesis of autoimmunity, metabolic disorders, and neurodegeneration. Somatic alterations in the NRF2 pathway also contribute to the growth and metastasis of many cancer types including ~30% of lung cancers. Still, the activation of NRF2 has frequently been observed in the absence of known genomic alterations, indicating that other pathways may drive its dysregulation. Further, approaches to target NRF2 pharmacologically have remained elusive. Here, we conducted a screen that identified a small molecule, ML329, exhibiting selective cytotoxicity in cells exhibiting NRF2 dependency and synthetic lethality to NRF2 pathway mutations across 489 cell lines. Surprisingly, we find that melanomas—which rarely have somatic mutations in the NRF2 pathway—were commonly sensitive to ML329. Melanomas were seen to exhibit NRF2-dependent metabolomic and transcriptional programs through the transcriptional activation of the adaptor protein p62/SQSTM1 by the melanocyte master regulator and oncoprotein MITF. This pathway was found to be conserved among all cancers characterized by genomic alterations of the MiT family (MITF, TFEB and TFE3) including subsets of renal cell carcinomas, pediatric sarcomas, and uveal and cutaneous melanomas. Our data identify a previously unrecognized, non-canonical mechanism of NRF2 activation by the MiT family, clarifying the regulation of NRF2 in pathologic and physiologic contexts. Pharmacologic inhibition of NRF2 could be valuable in the treatment of conditions with MITF family dysregulation. Citation Format: Xinbo Luo, Bart Lutterbach, Priya Pancholi, Yeon Sook Choi, Xiao Liu, Phillip Munson, Saqib Faisal, David A. Whipple, Robert A. Smith, Warren S. Weiner, David K. Johnson, Myriam Boukhali, Nicole S. Persky, Matthew G. Rees, Shunsuke Kitajima, David Barbie, Anuradha Roy, Michael Baltezor, Lian Rajewski, William McGuinness, John Haslam, Ananthan Sadagopan, Charles H. Yoon, Cory M. Johannessen, Christine G. Lian, Jason L. Hornick, Srinivas R. Viswanathan, David Liu, Vicki Nienaber, Wilhelm Haas, Frank J. Schoenen, David E. Fisher, Rizwan Haq. A non-canonical MiT/TFE-dependent NRF2 program is a druggable vulnerability in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1706.

In 2013, the U.S. government announced that its nuclear war plans would be “consistent with the fundamental principles of the Law of Armed Conflict” and would “apply the principles of distinction and proportionality and seek to minimize collateral damage to civilian populations and civilian objects.” If properly applied, these legal principles can have a profound impact on U.S. nuclear doctrine. The prohibition against targeting civilians means that “countervalue” targeting and “minimum deterrence” strategies are illegal. The principle of distinction and the impermissibility of reprisal against civilians make it illegal for the United States, contrary to what is implied in the 2018 Nuclear Posture Review, to intentionally target civilians even in reprisal for a strike against U.S. or allied civilians. The principle of proportionality permits some, but not all, potential U.S. counterforce nuclear attacks against military targets. The precautionary principle means that the United States must use conventional weapons or the lowest-yield nuclear weapons that would be effective against legitimate military targets. The law of armed conflict also restricts targeting of an enemy's leadership to officials in the military chain of command or directly participating in hostilities, meaning that broad targeting to destroy an enemy's entire political leadership is unlawful.

The neuroanatomical changes that underpin cognitive development are of major interest in neuroscience. Of the many aspects of neuroanatomy to consider, tertiary sulci are particularly attractive as they emerge last in gestation, show a protracted development after birth, and are either human- or hominoid-specific. Thus, they are ideal targets for exploring morphological-cognitive relationships with cognitive skills that also show protracted development such as working memory (WM). Yet, the relationship between sulcal morphology and WM is unknown—either in development or more generally. To fill this gap, we adopted a data-driven approach with cross-validation to examine the relationship between sulcal depth in lateral prefrontal cortex (LPFC) and verbal WM in 60 children and adolescents between ages 6 and 18. These analyses identified 9 left, and no right, LPFC sulci (of which 7 were tertiary) whose depth predicted verbal WM performance above and beyond the effect of age. Most of these sulci are located within and around contours of previously proposed functional parcellations of LPFC. This sulcal depth model outperformed models with age or cortical thickness. Together, these findings build empirical support for a classic theory that tertiary sulci serve as landmarks in association cortices that contribute to late-maturing human cognitive abilities.

Posterior cingulate cortex (PCC) is an enigmatic region implicated in psychiatric and neurological disease, yet its role in cognition remains unclear. Human studies link PCC to episodic memory and default mode network (DMN), while findings from the non-human primate emphasize executive processes more associated with the cognitive control network (CCN) in humans. We hypothesized this difference reflects an important functional division between dorsal (executive) and ventral (episodic) PCC. To test this, we utilized human intracranial recordings of population and single unit activity targeting dorsal PCC during an alternated executive/episodic processing task. Dorsal PCC population responses were significantly enhanced for executive, compared to episodic, task conditions, consistent with the CCN. Single unit recordings, however, revealed four distinct functional types with unique executive (CCN) or episodic (DMN) response profiles. Our findings provide critical electrophysiological data from human PCC, bridging incongruent views within and across species, furthering our understanding of PCC function.

The Fusiform Face Area (FFA) is a widely studied region causally involved in face perception. Even though cognitive neuroscientists have been studying the FFA for over two decades, answers to foundational questions regarding the structure, function, and connectivity of the FFA from a large (N>1000) group of participants are still lacking. To fill this gap, we quantified structural, functional, and connectivity features of fusiform face-selective regions in 1080 participants in the Human Connectome Project (HCP). After manually defining over 4,000 fusiform face-selective regions, we report five main findings. First, 68.94% of hemispheres have two cortically separate regions (pFus-faces/FFA-1 and mFus-faces/FFA-2). Second, in 26.48% of hemispheres, pFus-faces/FFA-1 and mFus-faces/FFA-2 are spatially contiguous, yet functionally and structurally distinct. Third, pFus-faces/FFA-1 is more face-selective than mFus-faces/FFA-2, and the two regions have distinct functional connectivity fingerprints. Fourth, pFus-faces/FFA-1 is cortically thinner and more heavily myelinated than mFus-faces/FFA-2. Fifth, face-selective patterns and functional connectivity fingerprints of each region were more similar in monozygotic than dizygotic twins and more so than structural gradients. As we share our areal definitions with the field, future studies can explore how structural and functional features of these regions will inform theories regarding how visual categories are represented in the brain.

Similarities and differences in brain structure and function across species is of major interest in systems neuroscience, comparative biology, and brain mapping. Recently, increased emphasis has been placed on tertiary sulci, which are shallow indentations of the cerebral cortex that appear last in gestation, continue to develop after birth, and are largely either human- or hominoid-specific. While tertiary sulcal morphology in lateral prefrontal cortex (LPFC) has been linked to functional representations and cognition in humans, it is presently unknown if LPFC tertiary sulci also exist in non-human hominoids. To fill this gap in knowledge, we leveraged two freely available multimodal datasets to address the following main question: Can LPFC tertiary sulci be defined in chimpanzee cortical surfaces from human predictions? We found that 1-3 components of the posterior middle frontal sulcus (pmfs) in the posterior middle frontal gyrus are identifiable in nearly all chimpanzee hemispheres. In stark contrast to the consistency of the pmfs components, we could only identify components of the paraintermediate frontal sulcus (pimfs) in two chimpanzee hemispheres. LPFC tertiary sulci were relatively smaller and shallower in chimpanzees compared to humans. In both species, two of the pmfs components were deeper in the right compared to the left hemisphere. As these results have direct implications for future studies interested in the functional and cognitive role of LPFC tertiary sulci across species, we share probabilistic predictions of the three pmfs components to guide the definitions of these sulci in future studies.