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Purpose: The purpose is to demonstrate the existence of the parallel line sign (PLS), a dark line parallel to the sacroiliac joint (SIJ), and determine its prevalence, characteristics, and associations. Methods: 200 consecutive SIJ MRIs referred by rheumatologists were retrospectively reviewed for the presence of the PLS. Presence and extent of imaging features of sacroiliitis (bone marrow edema, fatty infiltration, erosions, sclerosis, and ankylosis) were evaluated. Results: Prevalence of PLS was 11.5% (23/200), with 9 subjects having bilateral PLS, resulting in 32 SIJs showing a PLS. Every PLS involved the synovial portion of the SIJ, and almost all (31/32, 96.9%) involved the iliac (rather than sacral) side of the SIJ. Every PLS occurred with at least one established imaging feature of sacroiliitis. Presence of a PLS was associated with higher prevalence of erosions (78.3% vs 36.7% in those without PLS, P < .001), greater extent of SIJ involvement by erosions (3.6 ± 1.3 vs 2.3 ± 1.1 quadrants of the SIJ involved, P < .001), and higher density of erosions per centimeter (88.9% vs 46.2% with >2 erosions/cm, P = .001). There was higher prevalence of bone marrow edema, fatty infiltration, and sclerosis in those with PLS compared to those without PLS ( P = .001, P < .001, and P = .006, respectively). Extent of involvement by any of these features was not significantly different between the two groups ( P = .22, P = .16, and P = .46, respectively). Conclusions: The PLS is associated with imaging features of chronic sacroiliitis, especially erosions. Knowledge of the existence of the PLS may help avoid misdiagnosis of an insufficiency fracture and increase confidence in the diagnosis of sacroiliitis.

In North America, public-private partnerships (P3s) are increasingly using pre-development agreements to enhance collaboration between the public and private sectors. Known colloquially as “progressive P3s”, these agreements allow the private sector to help scope and shape the structure of projects at the front end. However, concerns about their efficacy persist. Our Commentary contextualizes this ongoing debate by outlining the potential benefits and pitfalls of this new approach to P3s. We conclude that both practitioners and academics have a crucial role to play in our experience with and understanding of the progressive P3 experiment.

The InSight lander rests on a regolith-covered, Hesperian to Early Amazonian lava plain in Elysium Planitia within a ∼27-m-diameter, degraded impact crater called Homestead hollow. The km to cm-scale stratigraphy beneath the lander is relevant to the mission's geophysical investigations. Geologic mapping and crater statistics indicate that ∼170 m of mostly Hesperian to Early Amazonian basaltic lavas are underlain by Noachian to Early Hesperian (∼3.6 Ga) materials of possible sedimentary origin. Up to ∼140 m of this volcanic resurfacing occurred in the Early Amazonian at 1.7 Ga, accounting for removal of craters ≤700 m in diameter. Seismic data however, suggest a clastic horizon that interrupts the volcanic sequence between depths of ∼30 and ∼75 m. Meter-scale stratigraphy beneath the lander is constrained by local and regional regolith thickness estimates that indicate up to 10–30 m of coarse-grained, brecciated regolith that fines upwards to a ∼3 m thick loosely-consolidated, sand-dominated unit. The maximum depth of Homestead hollow, at ∼3 m, indicates that the crater is entirely embedded in regolith. The hollow is filled by sand-size eolian sediments, with contributions from sand to cobble-size slope debris, and sand to cobble-size ejecta. Lander-based observations indicate that the fill at Homestead hollow contains a cohesive layer down to ∼10–20 cm depth that is visible in lander rocket-excavated pits and the HP3 mole hole. The surface of the landing site is capped by a ∼1 to 2 cm-thick loosely granular, sand-sized layer with a microns-thick surficial dust horizon., Journal of Geophysical Research: Planets, 127 (4), ISSN:0148-0227, ISSN:2169-9097

The small ubiquitin-like modifier (SUMO) family is composed of five members, SUMO1, the highly similar SUMO2/SUMO3, SUMO4 and the tissue-specific SUMO5 (SUMO1P1). Sequence variation in SUMO4 is thought to prevent its maturation, resulting in an un-conjugatable SUMO isoform, and consequently, its functions are poorly understood. Here we show for the first time that SUMO4 promotes DNA double-strand break signalling in a manner distinct from SUMO1 or SUMO2/3. We show that SUMO4 function depends on interaction with partner proteins through SUMO interacting motifs and, on its inability, to be conjugated. We show that SUMO4 promotes the activity of the SUMO protease SENP1. In the absence of SUMO4, reduced SENP1 catalytic activity results in hyperSUMOylation that unbalances the recruitment of several DSB repair factors, including RAP80. These data reveal that SUMO4 acts as a buffer for the SUMOylation system.

The E3 ubiquitin ligase RNF168 is a rate-limiting component of DNA double-strand break signalling that acts to amplify histone ubiquitylation. The confining of RNF168 chromatin spreading around DNA break sites has been related to constraining its expression levels and to the removal of ubiquitin-conjugates to which it binds. Here we identify a new mechanism that suppresses RNF168 amplification at chromatin. We show that depletion of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) or mutation of the Pin1-binding site of RNF168 increases DNA-damage site accumulation of RNF168 to supraphysiological levels without impacting RNF168 expression levels. Pin1 promotes SUMOylation of RNF168 by SUMO2/3, and a SUMO conjugation site on RNF168 is required to restrict RNF168 accumulations. We find Pin1-SUMO mediated-regulation of RNF168 is associated with cellular radioresistance. These data demonstrate that the regulation of chromatin ubiquitylation is actively suppressed by modification of RNF168 to counteract excessive RNF168-ubiquitin spreading.

Introductory paragraphCells lacking several DNA repair proteins, including those promoting homologous recombination (HR), are sensitive to polymerase theta (Polθ) repression1–4. Polθ drives theta-mediated end joining (TMEJ) and suppresses HR but what mediates its synthetic lethal relationships is unclear. Here we examine murine Brca1C61G/C61G 53bp1-/-cells and find they are largely HR proficient by using RNF168 and RAD52. They exhibit no more TMEJ than 53bp1-/- cells yet are more sensitive to targeting of Polθ. We find that RAD52 recruitment to damaged chromatin is increased following Polθ depletion. RAD52 accumulation and cellular sensitivity to Polθ repression can be curbed by the RAD51-binding regions of BARD1 and BRCA2, and sensitivity of BRCA1/2 depleted cells to Polθ repression is suppressed by RAD52 inhibition. 53bp1-/- cells exhibit a smaller increase in RAD52 recruitment following Polθ repression and also become resistant to Polθ repression following RAD52 inhibition. Thus, RAD52 mediates sensitivity to targeting Polθ in these contexts.

Monoclonal antibodies (MAb) to members of the Small Ubiquitin-like modifier (SUMO) family are essential tools in the study of cellular SUMOylation. However, many reagents are poorly validated, and the choice of which antibody to use for which detection format is without an evidence base. Here we test twenty-four anti-SUMO monoclonal antibodies for sensitivity and specificity to SUMO1-4 in monomeric and polymeric states in dot-blots, immunoblots, immunofluorescence and immunoprecipitation. We find substantial variability between SUMO MAbs for different conjugation states, detection of increased SUMOylation in response to thirteen different stress agents and as enrichment reagents for analysis of SUMOylated RanGAP1 or KAP1. All four anti-SUMO4 monoclonal antibodies tested cross-reacted with SUMO2/3, and several SUMO2/3 monoclonal antibodies cross-reacted with SUMO4. ~10% of tested monoclonal antibodies produced specific results across multiple applications.

Protein conjugation with the Small Ubiquitin-like Modifier SUMO1 or the related SUMO2/3 drive changes to protein behaviour. Many substrates are found modified by both SUMO1 and SUMO2/3, while others are modified by one or the other. How isoform specificity is directed is poorly understood. Here we examine modification of the catalytic component of the human SUMO Activation Enzyme, SAE2. We find that an acetylated K164-SAE2 analogue preferentially activates SUMO2 in competition with SUMO1, and that K164-SAE2 discriminates paralogues through their C-terminal regions. We find that K164-SAE2 is deacetylated during mitosis. Mitotic defects in cells expressing an acetylated K164-SAE2 analogue can be corrected by over-expression of SUMO1, suggesting SUMO1 conjugation driven by the deacetylated enzyme supports mitotic fidelity. These surprising data reveal that modification of the SUMO-activating enzyme can bias SUMO paralogue conjugation.

Despite the awareness that uncertainty impacts projects with long time horizons, public-private partnership (PPP) research has not extensively examined the operations phase of such projects where interactions between public and private counterparties will be frequent and long-term while subject to a changing environment. Accordingly, two distinct but related investigations examining how governance strategies can address uncertainty in PPP projects are presented. The first identified contractual mechanisms for risk sharing formed during the shaping phase of a broad set of PPP projects; a majority of these mechanisms were strategically designed to address risks as they unfold so counterparty project managers can rely on current information and circumstances during risk resolution. The second explored the emergence of relational mechanisms over time, which revealed that project managers had to consistently adjust established relational approaches to respond to unforeseen events in PPPs. The findings of both studies illustrate the necessity for responsiveness and complementarity of contractual and relational mechanisms in PPPs. Further, the mechanisms uncovered demand project management agility and flexibility as well as improved relational strategies, which is aligned with the emphasis on learning and adaptation in the broader, contemporary project management literature. Consequently, principles from project management 2.0 such as empowering competent project managers and shared global awareness are likely to enhance responsive PPP governance and warrant further exploration.

The cellular response to genotoxic DNA double strand breaks (DSBs) uses a multitude of post-translational modifications to localise, modulate and ultimately clear DNA repair factors in a timely and accurate manner. Ubiquitination is well established as vital to the DSB response, with a carefully co-ordinated pathway of histone ubiquitination events being a central component of DSB signalling. Other ubiquitin-like modifiers (Ubl) including SUMO and NEDD8 have since been identified as playing important roles in DSB repair. In the last five years ∼20 additional Ub/Ubl proteases have been implicated in the DSB response. The number of proteases identified highlights the complexity of the Ub/Ubl signal present at DSBs. Ub/Ubl proteases regulate turnover, activity and protein–protein interactions of DSB repair factors both catalytically and non-catalytically. This not only ensures efficient repair of breaks but has a role in channelling repair into the correct DSB repair sub-pathways. Ultimately Ub/Ubl proteases have essential roles in maintaining genomic stability. Given that deficiencies in many Ub/Ubl proteases promotes sensitivity to DNA damaging chemotherapies, they could be attractive targets for cancer treatment.

Transportation infrastructure is critical to any community. Disturbances such as natural hazards can hinder transportation infrastructure performance impacting a community’s quality of life through disruptions in service and effects on interdependent systems. Ecological systems are robust and resilient and have similarities with infrastructure systems. Diversity is a fundamental element of ecological resilience and is recognized as an important factor in transportation resilience. However, measures of transportation diversity are not well-developed. Accordingly, this paper adapts the ecological diversity concepts of richness and evenness to develop an approach to characterize transportation system diversity and distinguishes the approach from existing methods. Measures of transportation functional richness and evenness are derived and applied to New York City at the zip code level. The results facilitate identification of zip codes in New York City with varying levels of transportation diversity. Those zip codes with low diversity generally have limited availability (low richness) and disproportionate distribution (low evenness) of alternative transportation modes. Further, these zip codes are potentially susceptible to system disturbances as a consequence of routine disruptions or natural hazards. For instance, many low diversity zip codes are in hurricane evacuation zones. Limited complementarity in the transportation system of these zip codes will likely impact evacuations during hurricanes and recovery to pre-disturbance performance levels. Ultimately, the transportation diversity approach presented should lead to better understanding of transportation system characteristics such as inherent and augmented complementarity, which will enhance transportation system performance in urban communities.

The NASA InSight Lander on Mars includes the Heat Flow and Physical Properties Package HPThe online version contains supplementary material available at 10.1007/s11214-022-00941-z.

Communal rainwater harvesting (RWH) systems allow a community to collect rainwater from multiple roofs, store and treat it in a central location, and then distribute it back to the communit...

BACKGROUND: First discussed by Dr. Robert Maigne in the late 1980s, Maigne Syndrome is an often unrecognized and treatable cause of low back pain. It can be separated into two distinct entities. The central variant is a result of nerve afferent input secondary to changes of facet joint arthropathy at the thoracolumbar junction. The peripheral variant is a result of impingement of the medial branch of the superior cluneal nerve, which arises from the posterior rami of the lower thoracic and upper lumbar nerve roots, and results in similar clinical symptoms and signs. OBJECTIVE: To review the current literature for a comprehensive description of Maigne Syndrome, its diagnosis and management. METHODS: Evidence was gathered using two main medical databases, namely PubMed and Google Scholar. Search terms included ‘Maigne’s Syndrome’, ‘Maigne facet’, ‘thoracolumbar junction syndrome’, ‘cluneal nerve entrapment’, ‘posterior iliac crest trigger point’, ‘pseudosciatica’, as well as various permutations of these terms. RESULTS: The initial search generated 52 articles. These were screened, and duplicate and irrelevant articles were removed. Using the remaining articles, and with evaluation of their cited references, we selected 28 articles for review. Most of these consisted of case reports, many of which were published in rehabilitation, chiropractic and medical journals. The papers explored topics such as anatomy, cluneal nerve imaging, and treatment of nerve entrapment and facet related back pain syndromes, and have been included in this review, which is, to the best our knowledge, the most comprehensive description of Maigne Syndrome to date. CONCLUSION: The keys to the diagnosis of Maigne Syndrome include an awareness of the mechanical causes of back dominant pain, an understanding of the relevant anatomy, a specific clinical examination, and focused radiological guided anesthetic blocks. Treatment is available, and as in all back-pain etiologies, is most effective in the early stages of the disease.

The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1–PALB2 interaction, is required for fork protection. BRCA1–BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1–BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1–BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1–BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection. BRCA1–BARD1 has a role in replication fork protection that is mediated by a mechanism of phosphorylation-targeted isomerization of BRCA1 and is independent of the canonical interaction between BRCA1 and PALB2.

IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilized protein that accumulates at target promoters but fails to induce RNA-Pol-II elongation and subsequent transcription of target genes. Consequently, the anti-proliferative activity of IRF1 is lost in cell lines expressing T181A mutant. Further, cell lines with dysfunctional Fbxw7 are less sensitive to IRF1 overexpression, suggesting an important co-activator function for this ligase complex. As T181 phosphorylation requires both DNA binding and RNA-Pol-II elongation, we propose that this event acts to clear ‘spent’ molecules of IRF1 from transcriptionally engaged target promoters.

SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.