Most studies of genome organization have focused on intrachromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans-contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands," and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans-acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA-binding proteins interact with one another in trans, especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. We observe that these trans-interacting loci are close to nuclear speckles. These findings support the existence of trans-interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.

Purpose The posterior superior alveolar (PSA) block injection is one of many techniques used to provide profound anesthesia for invasive dental procedures. This technique has a high success rate but is not without complication risks. The purpose of this study was to determine if pulpal anesthesia of the maxillary second molar could be achieved using a reduced needle depth of 10mm or 5mm compared to the traditional needle depth of 16mm.Methods Sixty participants were asked to participate in three sessions. Each session started with a pre neural response test, followed by one randomized needle depth PSA injection, and ending with a post neural response test. The neural response test consisted of two parts, a cold refrigerant and a dental probe, on the buccal and interproximal surface of the maxillary second molar. After receiving a positive neural response, each participant received a posterior superior alveolar block injection using a short (21mm), 27-gauge dental needle with a randomized needle penetration depth of 16mm, 10mm, or 5mm. A post neural response test consisting of the same two parts as the pre-test was conducted on the maxillary second molar to evaluate for profound anesthesia.Results Positive neural responses were obtained from 100% of the participants (n=167) during the pre-tests. Study results demonstrated an 85% success rate at the traditional 16mm needle depth and a 93% and 92% success rates for the reduced needle depths of 10mm and 5mm, respectively. Pulpal anesthesia of the maxillary second molar had been achieved at all three needle depths with no statistically significant difference in the rate of success. Furthermore, there were no adverse events observed.Conclusion The reduced needle depth technique showed promise in achieving desired results of pulpal anesthesia with a reduced risk for complications associated with the PSA block injection. Additional studies are recommended to achieve evidence-based support for this reduced needle depth technique.

Many RNA-binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to their physiological roles in RNA processing and organization. However, this also makes these RBPs prone to pathological misfolding and aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms pathological aggregates associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that highly disordered, hydrophilic, and charged heat-resistant obscure (Hero) proteins may have similar effects. Specifically, Hero proteins can maintain the activity of other proteins from denaturing conditions in vitro, while their overexpression can suppress cellular aggregation and toxicity associated with aggregation-prone proteins. However, it is unclear how these protective effects are achieved. Here, we used single-molecule FRET to monitor the conformations of the aggregation-prone prion-like LCD of TDP-43. While we observed high conformational heterogeneity in wild-type LCD, the ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, and a Hero protein, Hero11, stabilized extended states of the LCD, consistent with their ability to suppress the aggregation of TDP-43. Our results link single-molecule effects on conformation to macro effects on bulk aggregation, where a Hero protein, like a chaperone, can maintain the conformational integrity of a client protein to prevent its aggregation.

ABSTRACTIntroduction:Postpartum hemorrhage (PPH) remains the leading cause of maternal mortality. A new clinical intervention (E-MOTIVE) holds the potential to improve early PPH detection and management. We aimed to develop and pilot implementation strategies to support uptake of this intervention in Kenya, Nigeria, South Africa, and Tanzania.Methods:Implementation strategy development: We triangulated findings from qualitative interviews, surveys and a qualitative evidence synthesis to identify current PPH care practices and influences on future intervention implementation. We mapped influences using implementation science frameworks to identify candidate implementation strategies before presenting these at stakeholder consultation and design workshops to discuss feasibility, acceptability, and local adaptations. Piloting: The intervention and implementation strategies were piloted in 12 health facilities (3 per country) over 3 months. Interviews (n=58), case report forms (n=1,269), and direct observations (18 vaginal births, 7 PPHs) were used to assess feasibility, acceptability, and fidelity.Results:Implementation strategy development: Key influences included shortages of drugs, supplies, and staff, limited in-service training, and perceived benefits of the intervention (e.g., more accurate PPH detection and reduced PPH mortality). Proposed implementation strategies included a PPH trolley, on-site simulation-based training, champions, and audit and feedback. Country-specific adaptations included merging the E-MOTIVE intervention with national maternal health trainings, adapting local PPH protocols, and PPH trollies depending on staff needs. Piloting: Intervention and implementation strategy fidelity differed within and across countries. Calibrated drapes resulted in earlier and more accurate PPH detection but were not consistently used at the start. Implementation strategies were feasible to deliver; however, some instances of limited use were observed (e.g., PPH trolley and skills practice after training).Conclusion:Systematic intervention development, piloting, and process evaluation helped identify initial challenges related to intervention fidelity, which were addressed ahead of a larger-scale effectiveness evaluation. This has helped maximize the internal validity of the trial.

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring.

Rare genetic conditions are challenging for the primary care provider to manage without proper guidelines. This clinical review is designed to assist the pediatrician, family physician, or internist in the primary care setting to manage the complexities of 16p11.2 deletion syndrome. A multidisciplinary medical home with the primary care provider leading the care and armed with up-to-date guidelines will prove most helpful to the rare genetic patient population. A special focus on technology to fill gaps in deficits, review of case studies on novel medical treatments, and involvement with the educational system for advocacy with an emphasis on celebrating diversity will serve the rare genetic syndrome population well.

BackgroundAttention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, for which there are effective pharmacological treatments that improve symptoms and reduce complications. Guidelines published by the National Institute for Health and Care Excellence recommend that primary care practitioners prescribe medication for adult ADHD under shared-care agreements with Adult Mental Health Services (AMHS). However, provision remains uneven, with some practitioners reporting a lack of support.AimThis study aimed to describe elements of support, and their availability/use, in primary care prescribing for adult ADHD medication in England to improve access for this underserved population and inform service improvement.Design and settingCross-sectional surveys were used to elicit data from commissioners, health professionals (HPs), and people with lived experience of ADHD (LE) across England about elements supporting pharmacological treatment of ADHD in primary care.MethodThree interlinked cross-sectional surveys were used to ask every integrated care board in England (commissioners), along with convenience samples of HPs and LEs, about prescribing rates, AMHS availability, wait times, and shared-care agreement protocols/policies for the pharmacological treatment of ADHD in primary care. Descriptive analyses, percentages, and confidence intervals were used to summarise responses by stakeholder group. Variations in reported provision and practice were explored and displayed visually using mapping software.ResultsData from 782 responders (42 commissioners, 331 HPs, 409 LEs) revealed differences in reported provision by stakeholder group, including for prescribing (95% of HPs versus 64% of LEs). In all, >40% of responders reported extended AMHS wait times of ≥2 years. There was some variability by NHS region – for example, London had the lowest reported extended wait time (25%), while East of England had the highest (55%).ConclusionElements supporting appropriate shared-care prescribing of ADHD medication via primary care are not universally available in England. Coordinated approaches are needed to address these gaps.

This week we finally figure out if Dark Souls ripped off Breath of the Wild. We also get really worked up over Bethesda. When is Game Pass coming to PS5, again?

The post RPG Cast – Episode 557: “PS5 Crunchwrap Supreme!” appeared first on RPGamer.

This week we discuss the bacon that broke Anna's back, Kelley shows us the power of the nip-nado, Pascal meets the Bok Choys, Josh is sponsored by revengecrabs.com, and Robert speedruns the produce department.

The post RPG Cast – Episode 567: “Supermarket Cloth Map” appeared first on RPGamer.

Chris embraces our cyberpunk subscription overlords. Josh kills the innkeeper (accidentally). Meanwhile Robert plunges down the .Hack hole.

The post RPG Cast – Episode 610: “No One Should Learn Japanese from Super Robot Wars” appeared first on RPGamer.

Super Mario Party Jamboree (NS) has remained in first place on the retail charts in Japan with sales of 57,522 units, according to Famitsu for the week ending October 27, 2024. 

Farmagia (NS) debuted in eighth place with sales of 4,296 units.

Romancing SaGa 2: Revenge of the Seven (NS) remained in second place with sales of 14,646 units. The PS5 version fell from third to seventh place with sales of 5,097 units.

Call of Duty: Black Ops 6 (PS5) is up one spot to third place with sales of 8,620 units and Mario Kart 8 Deluxe (NS) re-entered the top 10 in fourth place with sales of 5,782 units.

Professional Baseball Spirits 2024-2025 (PS5) is up two spots to fifth with sales of 5,729, and The Legend of Zelda: Echoes of Wisdom (NS) is up two spots to sixth place with sales of 5,492 units.

The Nintendo Switch was the best-selling platform with 60,096 units sold. The PlayStation 5 sold 13,965 units, the Xbox Series X|S sold 2,610 units, and the PlayStation 4 sold 53 units.

Here are the best-selling games in Japan:

1. [NSW] Super Mario Party Jamboree (Nintendo, 10/17/24) – 57,522 (364,484)
2. [NSW] Romancing SaGa 2: Revenge of the Seven (Square Enix, 10/24/24) – 14,646 (85,013)
3. [PS5] Call of Duty: Black Ops 6 (Activision, 10/25/24) – 8,620 (35,567)
4. [NSW] Mario Kart 8 Deluxe (Nintendo, 04/28/17) – 5,782 (6,044,039)
5. [PS5] Professional Baseball Spirits 2024-2025 (Konami, 10/17/24) – 5,729 (84,989)
6. [NSW] The Legend of Zelda: Echoes of Wisdom (Nintendo, 09/26/24) – 5,492 (294,371)
7. [PS5] Romancing SaGa 2: Revenge of the Seven (Square Enix, 10/24/24) – 5,097 (37,254)
8. [NSW] Farmagia (Marvelous, 11/01/24) – 4,296 (New)
9. [NSW] Animal Crossing: New Horizons (Nintendo, 03/20/20) – 4,253 (7,943,533)
10. [NSW] Minecraft (Microsoft, 06/21/18) – 4,242 (3,666,338)

Here is the hardware breakdown (followed by lifetime sales):

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463007/super-mario-party-jamboree-tops-the-japanese-charts/

Nintendo announced it will host a Super Nintendo World Direct livestream on Monday, November 11 at 2:00 pm PT / 5:00 pm ET. You will be able to watch it on YouTube.

The Direct will be roughly 10 minutes and feature the Donkey Kong Country area of Super Nintendo World at Universal Studios Japan.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463031/super-nintendo-world-direct-set-for-november-11/

Nintendo today hosted a Super Nintendo World Direct livestream that featured Shigeru Miyamoto giving a deep dive look into the Donkey Kong Country-themed land.

The new land will feature a family roller coaster, called Mine-Cart Madness, congas you can hit to a rhythm, letters that can found throughout the land that can be scanned on the new Donkey Kong Power-Up Band, character meet and greets, and new food options.

Donkey Kong Country will open at Universal Studios Japan on December 11, 2024, and will also be a part of Super Nintendo World at Epic Universe in Florida when the theme park opens in May 2025.

View the Direct below:

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463038/super-nintendo-world-direct-dives-into-the-donkey-kong-country-themed-land/

Former President Donald Trump said Wednesday that Jan. 6, 2021— the day his supporters occupied Congress in a failed insurrection to try to stop lawmakers from certifying Joe Biden’s election victory—was a “day of love.”

Trump made the baffling claim during a televised election town hall hosted by Univision.

Ramiro González, a construction worker from Tampa, told the meeting he deregistered as a Republican because he found Trump’s “inaction” during both Jan. 6 and the COVID-19 pandemic “disturbing.” He asked Trump to square his controversial behavior during the attack on the U.S. Capitol—and the fact that many of his own former administration officials don’t support him any longer—with why he should be re-elected.

Read more at The Daily Beast.

The Steam Deck is something of a talisman for gaming on Linux, its popularity and penguin-powered SteamOS having almost singlehandedly dragged it past MacOS as the second-most-used operating system among Steam users. Sadly, this also means the Valve handheld is the primary casualty when developers decide to stop bothering with Linux support, as Respawn Entertainment have decided to do for Apex Legends.

Read more

October marked the "biggest" sales month for supermarkets in the UK so far despite food price hikes.

After a star explodes, the resulting supernova remnant collapses in on itself and could begin the cycle again, creating generations of stars enriched with heavy elements

Five satellites due to launch this week could be brighter than most stars, and astronomers fear the growth of such constellations could have a catastrophic impact

How did the supermassive black holes we’re now seeing in the early universe get so big so fast? Astrophysicist Sophie Koudmani is using sophisticated galaxy simulations to figure it out

A nearby star that exploded some 3 million years ago could have removed all dust smaller than a millimetre from the outer solar system

Hours after Donald Trump wins the most conclusive mandate in 40 years, Mitch McConnell engineers a coup against his agenda by calling early leadership elections in the senate.

The Federal Emergency Management Agency supervisor who was fired after she told her staff to skip hurricane-damaged homes with Trump signs in their yards says it wasn't an isolated incident and is a "colossal event."

In an interview with IT World Canada, consulting giant Deloitte highlighted the importance of an ecosystem-based approach to tackle issues around digital equity in Canada and service delivery challenges in the public sector. “Our strong view is that the people of Canada benefit when there’s effective collaboration between public and private organizations, including on critical […]

How private is your internet address? Very, says the Supreme Court of Canada. Police can’t just walk into a company and demand a suspect’s IP address by saying a Canadian resident doesn’t have an expectation of privacy of that information, the court ruled today. An IP address is vital enough that every resident expects it […]

A massive NASA spacecraft is ready to set sail for Jupiter and its moon Europa. The craft, named Europa Clipper, will determine if conditions there could support life.

U.S.-based startup company Heliospect Genomics reportedly is offering wealthy couples embryo screening for IQ and other traits at $50,000 for 100 embryos.

An accurate description of low-density nuclear matter is crucial for explaining the physics of neutron star crusts, according to a team of theoretical physicists led by Argonne National Laboratory’s Dr. Alessandro Lovato.

The post Physicists Find Evidence for Superfluidity in Low-Density Neutron Matter appeared first on Sci.News: Breaking Science News.

The compound creatine, a popular exercise supplement that only occurs naturally in animal products, could one day be produced in edible plants

Recent research shows that anti-inflammatory diets are not as faddish as they might sound, with the power to reduce the risk of heart attacks and some cancers

Most ingredients touted as the key to better health fail to live up to the hype but fibre bucks this trend, with benefits for the whole body, not just the gut

The Biden administration will support a United Nations treaty this week that will create a new cybercrime convention, including China and Russia, which has not sat well with some lawmakers and critics.

Trump would face little to no resistance in confirming his picks for Supreme Court justices in the majority-GOP Congress, but Alito has no plans to step down.

Dallas Mavericks minority owner Mark Cuban returned to the Bluesky social media platform with a post after weeks of contentious X posts.

While other bears battled over fish in a prime spot, Otis would sit off to the side and wait for the fish to come to him. But so far this year, he hasn’t been spotted in Katmai National Park and Preserve

The actor is getting some support from his ex-wife, Lindsay Hartley, and daughter, Bella.

[[ This is a content summary only. Visit my website for full links, other content, and more! ]]

Dry ice is becoming an essential resource for various industries in Lakeland, Florida. Made from carbon dioxide in its solid form, dry ice sublimates directly into gas without leaving any liquid residue. This characteristic makes it a highly effective cooling solution, ideal for transporting perishable goods, supporting medical needs, and industrial cleaning. With the right […]

The post Essential Guide to Choosing the Best Lakeland Dry Ice Supplier for Your Business Needs appeared first on Chart Attack.

Can you get one speaker on Alexa, Google, and Apple's home apps all at once?

The Supreme Court dealt a major legal blow to former White House Chief of Staff Mark Meadows on Tuesday, refusing to move the Georgia election interference charges against him to federal court.

Whoopi Goldberg told her co-hosts Tuesday on ABC's "The View" that she agrees with Vice President Kamala Harris voters who want to avoid family members who voted for President-elect Donald Trump during the holidays.

The post Whoopi Goldberg Endorses Harris Voters Avoiding Holidays with Trump-Supporting Family — ‘It Might Not Be the Time to Gather’ appeared first on Breitbart.

A Kenora, Ont., resident says she wants to see more resources for people who encounter sick or injured animals after seeing a deer in her yard with a tomato cage stuck on its head. Here's how the community has responded to the incident, and what we know about the deer's status.

In a 5-4 decision, the Supreme Court struck down a key provision of the Voting Rights Act of 1965, stating that the legislation was based on now outdated data. The ruling removes the coverage formula that required federal oversight for voting processes in nine states.

In a 5-4 decision in U.S. v. Windsor, the Supreme Court ruled the federal Defense Of Marriage Act unconstitutional. The court rules that supporters of California's Proposition 8 case did not have standing to bring the case to court, which means same-sex marriages in California may resume.

All the kit balancing, squad leading, and lore you could want, if you want it.

Founded by Thaalla Vaishnav and Pramod Uppalapati, ‘The Script Craft’ is backed by Prabhas to nurture new talent and provide emerging writers with valuable opportunities

Mark Cohon, who brought the CFL back to Ottawa with the Redblacks as CFL commissioner, is joining the new Northern Super League as chair of its board of directors.