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Synchronous T-lymphoblastic lymphoma and neuroblastoma in a 3-yr-old with novel germline SMARCA4 and EZH2 variants [RAPID CANCER COMMUNICATION]

T-lymphoblastic lymphoma (T-LLy) is the most common lymphoblastic lymphoma in children and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here, we discuss the case of a previously healthy 3-yr-old male who presented with mediastinal T-LLy with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants. Combination large panel (864 genes) profiling analysis in the context of a precision oncology study revealed two novel likely pathogenic heterozygous variants: SMARCA4 c.1420-1G > T p.? and EZH2 c.1943G > C p.(Ile631Phefs*44). Somatic analysis revealed potential second hits/somatic variants in EZH2 (in the T-LLy) and a segmental loss in Chromosome 19p encompassing SMARCA4 (in the NBL). Synchronous cancers, especially at a young age, warrant genetic evaluation for cancer predisposition; enrollment in a precision oncology program assessing germline and tumor DNA can fulfill that purpose, particularly when standard first-line genetic testing is negative and in the setting of tumors that are not classic for common cancer predisposition syndromes.




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Leukemic presentation and progressive genomic alterations of MCD/C5 diffuse large B-cell lymphoma (DLBCL) [RESEARCH ARTICLE]

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.




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Drosophila Cornmeal-Yeast Food




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Phosphate-Buffered Saline (PBS), pH 7.4




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Sodium Acetate (3 M, pH 5.5)




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Phosphate-Buffered Saline with Tween and BSA (PBSTB)




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Phosphate-Buffered Saline with Tween (0.1%) (PBST)




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Phosphate-Buffered Saline with 1% BSA (PBSB)




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Glycine-HCl (0.1 M, pH 3.0)




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Selection of Affibody Molecules Using Staphylococcal Display

Affibody molecules are small (6-kDa) affinity proteins generated by directed evolution for specific binding to various target molecules. The first step in this workflow involves the generation of an affibody library, which can then be used for biopanning using multiple display methods. This protocol describes selection from affibody libraries using display on Staphylococcus carnosus. Display of affibodies on staphylococci is very efficient and straightforward because of the single cell membrane and the use of a construct with a constitutive promoter. The workflow involves display of affibody libraries on the surface of S. carnosus cells, followed by screening and selection of binders using fluorescence-activated cell sorting (FACS). The transformation of DNA libraries into S. carnosus is less efficient and more complicated than for Escherichia coli. Because of this, staphylococcal display is suitable for affinity maturation or other protein-engineering efforts that are not dependent on very high diversity, and thus magnetic-activated cell sorting (MACS) is often not required before FACS. However, MACS is an option, and MACS procedures used for E. coli can easily be adapted for use in S. carnosus if needed.




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Selection of Affibody Molecules Using Phage Display

Affibody molecules are small (6-kDa) affinity proteins generated by directed evolution for specific binding to various target molecules. The first step in this workflow involves the generation of an affibody library. This is then followed by amplification of the library, which can then be used for biopanning using multiple methods. This protocol describes amplification of affibody libraries, followed by biopanning using phage display and analysis of the selection output. The general procedure is mainly for selection of first-generation affibody molecules from large naive (unbiased) libraries, typically yielding affibody hits with affinities in the low nanomolar range. For selection from affinity maturation libraries with the aim of isolating variants of even higher affinities, the procedure is similar, but parameters such as target concentration and washing are adjusted to achieve the proper stringency.




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Analysis of Sleep and Circadian Rhythms from Drosophila Activity-Monitoring Data Using SCAMP

Sleep is a fundamental feature of life for virtually all multicellular animals, but many questions remain about how sleep is regulated and what biological functions it plays. Substantial headway has been made in the study of both circadian rhythms and sleep in the fruit fly Drosophila melanogaster, much of it through studies of individual fly activity using beam break counts from Drosophila activity monitors (DAMs). The number of laboratories worldwide studying sleep in Drosophila has grown from only a few 20 years ago to hundreds today. The utility of these studies is limited by the quality of the metrics that can be extracted from the data. Many software options exist to help analyze DAM data; however, these are often expensive or have significant limitations. Therefore, we describe here a method for analyzing DAM-based data using the sleep and circadian analysis MATLAB program (SCAMP). This user-friendly software has an advantage of combining several analyses of both sleep and circadian rhythms in one package and produces graphical outputs as well as spreadsheets of the outputs for further statistical analysis. The version of SCAMP described here is also the first published software package that can analyze data from multibeam DAM5Ms, enabling determination of positional preference over time.




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Analysis of Positional Preference in Drosophila Using Multibeam Activity Monitors

The positional preference of an animal can be very informative regarding the choices it makes about how to interact with its environment. The fruit fly Drosophila melanogaster has been used as a robust system for examining neurobiological mechanisms underlying behavior. Fruit fly positional preference can be gathered from TriKinetics Drosophila activity monitors (DAMs), which contain four infrared beams, allowing for tracking the position of individual flies along the length of a tube. Here, we describe a method for using DAM5Ms to examine food preference. Specifically, we show an example in which circadian changes in food preference are compared between different Drosophila species. More information about the evolution of behavior can be gathered by measuring feeding preference relative to time of day. Noni, fruit from Morinda citrifolia, contains octanoic acid, a chemical toxic to many species of Drosophila. D. melanogaster and D. simulans, both food generalists, show high sensitivity to octanoic acid, whereas D. sechellia, a specialist, can tolerate high concentrations. When two different food substrates are provided at each end of a tube, food preference can be inferred at various times of the day, using the sleep and circadian analysis MATLAB program (SCAMP) to extract and analyze positional data from DAM5Ms. Data gathered from these analyses can be used to compare avoidance or attraction to nutrients, tastants, or odors between species and genotypes or after specific different treatments. Additionally, such data can be examined as a function of time of day.




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Neural Stimulation during Drosophila Activity Monitor (DAM)-Based Studies of Sleep and Circadian Rhythms in Drosophila melanogaster

Sleep is a fundamental feature of life for virtually all multicellular animals, but many questions remain about how sleep is regulated by circadian rhythms, homeostatic sleep drive that builds up with wakefulness, and modifying factors such as hunger or social interactions, as well as about the biological functions of sleep. Substantial headway has been made in the study of both circadian rhythms and sleep in the fruit fly Drosophila melanogaster, much of it through studies of individual fly activity using Drosophila activity monitors (DAMs). Here, we describe approaches for the activation of specific neurons of interest using optogenetics (involving genetic modifications that allow for light-based neuronal activation) and thermogenetics (involving genetic modifications that allow for temperature-based neuronal activation) so that researchers can evaluate the roles of those neurons in controlling rest and activity behavior. In this protocol, we describe how to set up a rig for simultaneous optogenetic or thermogenetic stimulation and activity monitoring for analysis of sleep and circadian rhythms in Drosophila, how to raise appropriate flies, and how to perform the experiment. This protocol will allow researchers to assess the causative role in the regulation of sleep and activity rhythms of any genetically tractable subset of cells.




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Activity Monitoring for Analysis of Sleep in Drosophila melanogaster

Sleep is important for survival, and the need for sleep is conserved across species. In the past two decades, the fruit fly Drosophila melanogaster has emerged as a promising system in which to study the genetic, neural, and physiological bases of sleep. Through significant advances in our understanding of the regulation of sleep in flies, the field is poised to address several open questions about sleep, such as how the need for sleep is encoded, how molecular regulators of sleep are situated within brain networks, and what the functions of sleep are. Here, we describe key findings, open questions, and commonly used methods that have been used to inform existing theories and develop new ways of thinking about the function, regulation, and adaptability of sleep behavior.




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Geographic inequalities in need and provision of social prescribing link workers a retrospective study in primary care

BackgroundLong-term health conditions are major challenges for care systems. Social prescribing link workers have been introduced via primary care networks (PCNs) across England since 2019 to address the wider determinants of health by connecting individuals to activities, groups, or services within their local community.AimTo assess whether the rollout of social prescribing link workers was in areas with the highest need.Design and settingA retrospective study of social prescribing link workers in England from 2019 to 2023.MethodWorkforce, population, survey, and area-level data at the PCN-level from April 2020 to October 2023 were combined. Population need before the rollout of link workers was measured using reported lack of support from local services in the 2019 General Practice Patient Survey. To assess if rollout reflected need, linear regression was used to relate provision of link workers (measured by full-time equivalent [FTE] per 10 000 patients) in each quarter to population need for support.ResultsPopulations in urban, more deprived areas and with higher proportions of people from minority ethnic groups had the highest reported lack of support. Geographically these were in the North West and London. Initially, there was no association between need and provision; then from July 2022, this became negative and significant. By October 2023, a 10-percentage point higher need for support was associated with a 0.035 (95% confidence interval = −0.634 to −0.066) lower FTE per 10 000 patients.ConclusionRollout of link workers has not been sufficiently targeted at areas with the highest need. Future deployments should be targeted at those areas.




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Collaborative discussions between GPs and pharmacists to optimise patient medication: a qualitative study within a UK primary care clinical trial

BackgroundThere has been significant investment in pharmacists working in UK general practice to improve the effective and safe use of medicines. However, evidence of how to optimise collaboration between GPs and pharmacists in the context of polypharmacy (multiple medication) is lacking.AimTo explore GP and pharmacist views and experiences of in-person, interprofessional collaborative discussions (IPCDs) as part of a complex intervention to optimise medication use for patients with polypharmacy in general practice.Design and settingA mixed-method process evaluation embedded within the Improving Medicines use in People with Polypharmacy in Primary Care (IMPPP) trial conducted in Bristol and the West Midlands, between February 2021 and September 2023.MethodAudio-recordings of IPCDs between GPs and pharmacists, along with individual semi-structured interviews to explore their reflections on these discussions, were used. All recordings were transcribed verbatim and analysed thematically.ResultsA total of 14 practices took part in the process evaluation from February 2022 to September 2023; 17 IPCD meetings were audio-recorded, discussing 30 patients (range 1–6 patients per meeting). In all, six GPs and 13 pharmacists were interviewed. The IPCD was highly valued by GPs and pharmacists who described benefits, including: strengthening their working relationship; gaining in confidence to manage more complex patients; and learning from each other. It was often challenging, however, to find time for the IPCDs.ConclusionThe model of IPCD used in this study provided protected time for GPs and pharmacists to work together to deliver whole-patient care, with both professions finding this beneficial. Protected time for interprofessional liaison and collaboration, and structured interventions may facilitate improved patient care.




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Using the Electronic Health Record to Facilitate Patient-Physician Relationship While Establishing Care [Innovations in Primary Care]




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A Few Doctors Will See Some of You: The Critical Role of Underrepresented in Medicine (URiM) Family Physicians in the Care of Medicaid Beneficiaries [Original Research]

PURPOSE

Despite being key to better health outcomes for patients from racial and ethnic minority groups, the proportion of underrepresented in medicine (URiM) physicians remains low in the US health care system. This study linked a nationally representative sample of family physicians (FPs) with Medicaid claims data to explore the relative contributions to care of Medicaid populations by FP race and ethnicity.

METHODS

This descriptive cross-sectional study used 2016 Medicaid claims data from the Transformed Medicaid Statistical Information System and from 2016-2017 American Board of Family Medicine certification questionnaire responses to examine the diversity and Medicaid participation of FPs. We explored the diversity of FP Medicaid patient panels and whether they saw ≥150 beneficiaries in 2016. Using logistic regression models, we controlled for FP demographics, practice characteristics, and characteristics of the communities in which they practiced.

RESULTS

Of 13,096 FPs, Latine, Hispanic, or of Spanish Origin (LHS) FPs and non-LHS Black FPs saw more Medicaid beneficiaries compared with non-LHS White and non-LHS Asian FPs. The patient panels of URiM FPs had a much greater proportion of Medicaid beneficiaries from racial and ethnic minority groups. Overall, non-LHS Black and LHS FPs had greater odds of seeing ≥150 Medicaid beneficiaries in 2016.

CONCLUSIONS

These findings clearly show the critical role URiM FPs play in caring for Medicaid beneficiaries, suggesting physician race and ethnicity are correlated with Medicaid participation. Diversity in the health care workforce is essential for addressing racial health inequities. Policies need to address problems in pathways to medical education, including failures to recruit, nurture, and retain URiM students.




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[PERSPECTIVES] {alpha}-Synuclein in Parkinson's Disease: 12 Years Later

α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.




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Stephen Flynn slammed by SNP colleagues over Holyrood bid

Stephen Flynn has been criticised by SNP colleagues after saying he would stay on at Westminster, even if elected to Holyrood.




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Steve Camley on ... Tam Shepherds closing

You can purchase Steven Camley's cartoons by calling 0141 302 7000 or visiting thepicturedesk.co.uk.




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SNP's Stephen Flynn announces bid to become MSP in 2026 election

The SNP's Westminster leader has announced he is to contest a seat at Holyrood – and will ‘double-job’ as an MP and MSP if he wins.




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RPG Cast – Episode 646: “You Have to Butter Your Sphinx”

Kelley carries her Vita with her, but then realizes she can't play the games in public. Josh practices his dramatic Yakuza shirt ripping skills. And Chris uses an AI to generate a new Soul Hackers map.

The post RPG Cast – Episode 646: “You Have to Butter Your Sphinx” appeared first on RPGamer.



  • News
  • Podcasts
  • RPG Cast
  • Mary Skelter: Nightmares
  • Soul Hackers 2
  • Xenoblade Chronicles 3
  • Yakuza: Like a Dragon

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RPG Cast – Episode 716: “Canadian Telephone Game”

Chris is hunting bears, because of course that's what you do. Kelley hangs out with Chadley and the massively annoying individual. Robert is all about that exquisite fraisier cake.

The post RPG Cast – Episode 716: “Canadian Telephone Game” appeared first on RPGamer.




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RPG Cast – Episode 728: “Cats With Jiggle Physics”

Kelley makes a Morgen Wonk. Chris loves the smell of Gundam in the morning. Phil plays some Mathfinder while listening to his favorite new band, Creepy Lego Waifus. The cake has arrived.

The post RPG Cast – Episode 728: “Cats With Jiggle Physics” appeared first on RPGamer.



  • News
  • Podcasts
  • RPG Cast
  • Live A Live
  • SKALD: Against the Black Priory
  • World of Warcraft: Mists of Pandaria

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RPG Cast – Episode 744: “11.5-Bit Graphics”

Chris is unmasked as The Corporate Body. Tam talks about anime and waifus. Kelley is excited about text size. Josh explains the meaning of "time to shipwreck." Subscribe to our latest offering, The Monthly Litterbox.

The post RPG Cast – Episode 744: “11.5-Bit Graphics” appeared first on RPGamer.




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Metaphor Re:Fantazio (PS5)

When I was reviewing Final Fantasy VII Rebirth a few months ago, it looked set to be my Game of the Year. Metaphor: ReFantazio was still a distant concept and, I thought, communication of that concept was anything great. It turns out that I was really underestimating Atlus at the time. It's been eight years since Persona 5, and maybe I had begun to forget its magic, because as a JRPG from the creators of Persona 5, the magic is undoubtedly there in Metaphor: ReFantazio.



When I was younger, I used to watch the Columbo series, where you know the culprit's identity right away at the start. Metaphor: ReFantazio is a bit like that, because the introduction shows the King of Euchronia (Metaphor's fantasy world) being murdered in his sleep by an ambitious aristocrat named Louis, which throws the whole country into turmoil. From there, the protagonist and the comrades he meets all have different reasons for sharing the same goal: to prevent the wicked Louis from seizing the throne.



As simple as it seems, the narrative has its fair share of surprises. This has to do with the tremendous wealth of characters in the game. Due to a certain magic, the race for the throne is turned into an election, in which the protagonists gets to runs. Adding to the eight playable characters, you meet several competitors and followers who back you. All of them have personal stories and strange personalities that make Metaphor's adventure strikingly vivid.

The sub-stories are quite interesting for most part, for they convey a range of different emotions: sometime are heart-breaking, sometime heart-warming or just purely fun, and they'll keep you engaged for hours. They often leave you in suspense, since the structure of the game has you experiencing them little by little. And, just like in Persona, you can spend extensive time with your allies in a whole lot of mini sequences that play a great part in making the cast truly unforgettable.



But that doesn't mean you'll forget about the main story. Metaphor: ReFantazio offers some fascinating chapters. Take for instance the Opera house one, it's a breathtaking chapter very reminiscent of the great Final Fantasy VI, absolutely loaded with memorable sequences, grandiose fights, and striking reveals. And in the end, the whole game is like that. The thirst for more is real, as Atlus always drops a little something to make you eager to progress and feel engaged - a new character, intense combat, a shocking truth, stunning landscapes, etc. Even the most common NPCs sometimes tell a tale that blows your mind. Metaphor: ReFantazio has so much to offer in terms of characters, creativity, and storytelling that I couldn't help feeling overwhelmed at times.



The incongruity of an election in a kingdom ruled by Royals for ages is in reality an occasion for the story to develop elaborate thoughts about democracy and society. The protagonist always carries with him a strange book about an ideal world, where people have equal chances, decide their own fates, and live in harmony. It's a dream-like realm wholly different from Euchronia, which is a medieval regime plagued by injustice, greed, and poverty.

But there are whispers of a past, of a very advanced civilisation that ultimately failed, creating a scenario that raises the question of the relationship between democracy and freedom. There are also different tribes in the game, and it's worth noticing that the protagonist's party has one representative of each tribe, like a call for tolerance in a kingdom known for its inequality. The narrative therefore has powerful philosophic elements - something that only the greatest works in JRPG history possess.

Metaphor: ReFantazio boasts world design like you seldom see, starting with the giant flying rock that has symbolized it since reveal. Here again Atlus' creativity is absolutely inspired. The designers left their comfort zone and came up with an innovative take on characters, meaning that they ditched the classical human hero or heroine. You befriend an elf-like girl, a bat-like character or a maiden with a third eye, but no real typical human. The result is a party that literally breathes fantasy, a bit like Final Fantasy Tactics Advance did in its time. Humans exist, though, but on the opposite side of the divide.

These so-called Humans are twisted and awfully misshapen creatures roaming Euchronia as dangerous enemies. Atlus went beyond the boundaries of the bizarre with these designs and the result is amazing. I could also mention the funny Runner, a land vessel with legs that the party owns. Just travelling with it feels incredible. There are numerous examples like this, but in short the world is packed with wonders that I've never seen in a game before.

As for combat, Metaphor: ReFantazio is a good old turn-based JRPG, where strategy and careful planning matter. Characters wield the power of Archetypes, abstract figures that party members turn into when attacking. Archetypes are essentially jobs, hence my mention of Final Fantasy Tactics above. You can equip a character with an archetype, and they then acquire attack and passive skills specific to that archetype. For example, the Gunner can deal what is called "pierce" damage from behind, the Warrior heavy "slash" damage with its greatsword, and the Mage masters the natural elements.

There are also very complex Archetypes like the Masked Dancer, which can wear different masks to mimic other Archetypes, or the all-powerful Summoner, who masters absolutely ever type of damage once you acquire the corresponding stones (needless to say, these are incredibly difficult to come by). Unlike Persona 5, every character can equip any archetype, so you can choose the allies you like the most. Besides that, the currently-equipped Archetype can also inherit a couple of skills or spells from another, allowing for very elaborate lineups.

Combat isn't simplistic or easy; basic skills won't do much against bosses or even the relatively big enemies within dungeons. For these, the player must analyze how Archetypes can cooperate. Two Healers can, for example, cast a light spell on all opponents, while a single healer only targets one. Three magic-type archetypes lets the Mage unleash the mightiest fire spell available, which comes in handy at times. Such cooperation skills take more than one turn crystal (as turns are represented in game), but you can save turn crystals by exploiting the enemy's weakness, like you can in Shin Megami Tensei and its spin-offs.

The possibilities offered by Archetypes are fantastic and their complexity goes well beyond anything I've experienced from Atlus thus far. You have several types of Archetypes that work against a set weakness (three Archetype lineages have fire spells, for example). So you can choose the ones that fit your current goal or preferences. Boss fights are no joke and it's a renewed pleasure to overcome the various (tough) challenges after devising the right strategy. Metaphor: ReFantazio also lives up to Persona 5 in two particular aspects: main dungeons are never short of surprises, and the presentation of the battle menu is once again fantastic.



Like in Persona, Metaphor: ReFantazio is played in limited time. There's an in-game calendar with deadlines set to clear the main dungeons. So you can't have everyone master every archetype - you need to choose and use every day wisely. Unlike Persona 5, which gives you fixed Personas that you have to figure out how to use optimally, building characters and Archetypes in Metaphor: ReFantazio must be planned well ahead of time. This a fundamental difference between the two and the reason why this new IP elevates Atlus' core gameplay conceits, which were already very good. Exploration is important and quite entertaining too: you can tackle tricky secondary dungeons, discover special shops, or visit your followers. 

The latter provide perks, like increased slots for inherited skills, greater experience gain and, most importantly, the ability to unlock advanced Archetypes. The Healer can become the Cleric, for instance, with far superior healing capabilities, and you can become a General after being a Commander, gaining powerful ice skills in addition to the potent fire skills the latter had.

The whole game must be seen as a wide array of possibilities, with the player finding their own way to victory with their choices and favorite characters. As far as I'm concerned, this feels rewarding beyond anything I expected. Overflowing with content, the game is very long (around 70 hours), even with Atlus allowing you save time (any low-level enemy on the map can be beaten instantly without entering a turn-based battle, and you'll still gain experience and materials). 



The visuals are Metaphor's clear weakness. The game modeling isn't what you'd expect from a PS5 game in 2024, and I'd say it's fairly underwhelming for PS4 too. The backgrounds aren't very sharp and you see aliasing here and there. Secondary dungeons look very common; actually, they don't look like much of anything really. And there are several towers to explore across Euchronia, but the interior of each tower looks the exact same everytime. This kind of reuse of assets is fairly disappointing for a game of this magnitude. I shiver at the thought of what Metaphor: ReFantazio could have looked like with a Final Fantasy-sized budget. I expect it would have been my first perfect score, but it looks like I'll need to withhold that one once again.

One aspect that does score perfect marks is the original music score. Here again, I was pretty sure that Final Fantasy VII Rebirth would be my soundtrack of the year, but Metaphor's music blows it away completely. Atlus' sound team has crafted vibrant choruses befitting the heroic fantasy genre, but with such unorthodox compositions that it felt fresh to my ears. Other vocals and melodies are bewitching to the point they lift your spirit in battle or dungeons. And there's the strange theme of Virga island, with its weird vocals and hypnotic murmurs. It sounds like a tribal chant from afar, a bit like what Genshin Impact achieved with the Natlan soundtrack two months ago. The music is a splendid journey in itself.   

Metaphor: ReFantazio is the type of game you feel was made to achieve something greater than just sales. It's a completely new world, boasting an immense wealth of gameplay, characters, locations, and music, redefining heroic fantasy like no JRPG has done for decades. Atlus' latest title is also a fantastic challenge for turn-based combat and strategy lovers, with highly enjoyable and rewarding dungeons. Put another way, Metaphor: ReFantazio is the golden age of fantasy JRPGs, revived from the ashes in all its majesty, no less.

During the day, Thomas is a normal account manager. But at night he becomes Ryuzaki57, an extreme otaku gamer hungry for Japanese games (preferably with pretty girls in the main role). He spends a lot of time on F2P RPGs, but never misses the lastest interesting releases. Feel free to contact on twitter at @Ryuz4ki57

Full Article - https://www.vgchartz.com/article/463032/metaphor-refantazio-ps5/




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Watch Liam Payne’s Phenomenal ‘X-Factor’ Audition That Made Him a Star

YouTube Screenshot

A collective gasp echoed like a thunderclap in a valley in our Daily Beast newsroom late Wednesday afternoon at the news that singer Liam Payne, who became famous as a member of the group One Direction, died at age 31.

TMZ reports that Payne fell from a hotel balcony in Argentina, where he had reunited with bandmates at 1D-er Niall Horan’s concert. He had, according to the site, been behaving “erratically,” earlier in the day, and was spotted smashing a laptop in the hotel lobby and having to be carried back to his room. He had been in headlines on gossip blogs over tension with his ex-fiancée Maya Henry, who, TMZ says, alleged “he'd left her after asking her to get an abortion.”

In the shock of his death, fans couldn’t ignore the eerie nature that Payne had just connected with his One Direction bandmates. Dark questions emerge when a celebrity dies so young: What role did the often horrific toll of fame have on a person like Payne, who has been open about addiction and suicidal ideation? But there’s also an impulse to go back to the roots of a person’s talent, to revisit what it was that we all fell in love with—and was their passion—in the first place.

Read more at The Daily Beast.




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Choose between cyberpunk and magic in Zephon, the new 4X from the Warhammer 40,000 – Gladius devs

Warhammer 40,000: Gladius - Relics Of War developers Proxy Studios have just released Zephon, a new 4X strategy game set in a manky, post-apocalyptic world. It's got hexagonal maps, flesh trees, gangly Evangelion-grade giants, "otherworldly hymns of decay", nuclear bombs, and a player-led "blend of magic and cyberpunk" that extends from the city architecture to the research component. All of which is my cup of giblets. Here's the launch trailer.

Read more




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Trump ignites furor with claim past presidents didn’t console military families by phone

Watch Video | Listen to the Audio

JUDY WOODRUFF: Now: new questions surrounding the deaths of four Green Berets in the Western African nation of Niger and the role of the president as consoler in chief.

John Yang has the story.

JOHN YANG: Sending young Americans into harm’s way can be the most serious decision a president makes. Consoling the families of the fallen has become the latest controversy to engulf President Trump.

To bolster his claim that he does more than his predecessors, Mr. Trump today invoked the dead son of his chief of staff, retired Marine general John Kelly.

PRESIDENT DONALD TRUMP: To the best of my knowledge, I think I have called every family of somebody that’s died. Now, as far as other representatives, I don’t know. I mean, you could ask General Kelly, did he get a call from Obama?

JOHN YANG: Kelly’s 29-year-old son, Robert, a Marine lieutenant, was killed in 2010 when he stepped on a land mine in Afghanistan, an episode Kelly rarely talks about publicly. Kelly and his wife did attend a 2011 Memorial Day breakfast President Obama hosted for Gold Star families.

President Trump ignited the furor when he was asked about his public silence on four Green Berets killed two weeks ago in Niger.

PRESIDENT DONALD TRUMP: If you look at President Obama and other presidents, most of them didn’t make calls. A lot of them didn’t make calls. I like to call when it’s appropriate, when I think I’m able to do it.

JOHN YANG: Reporters pressed him to back up the claim.

PRESIDENT DONALD TRUMP: I don’t know. That’s what I was told. All I can do — all I can do is ask my generals.

JOHN YANG: The response from former Obama officials was swift and forceful.

Former Attorney General Eric Holder tweeted this photo and insisted: “Stop the damn lying. I went to Dover Air Force base with 44 and saw him comfort families,” a reference to one of Mr. Obama’s late-night trips to pay his respects to troops killed in Afghanistan.

Mr. Obama and President George W. Bush often visited wounded warriors at Walter Reed and Bethesda hospitals, a practice Mr. Trump has continued. In February, the president and his daughter Ivanka went to Dover for the return of the remains of a Navy SEAL killed in Yemen, the first casualty of his administration.

So far this year, the Pentagon says 16 Americans have been killed in action. Another 17 sailors died in accidents. In the first year of the Obama presidency, 344 were killed in action.

During last year’s campaign, Mr. Trump publicly feuded with the Khans, the parents of a Muslim American soldier killed in Iraq, after they criticized him at the Democratic Convention.

Today, the Khans said: “President Trump’s selfish and divisive actions have undermined the dignity of the high office of the presidency.”

The current controversy comes as questions are being raised about how and why the four soldiers died in Niger.

Senator Jack Reed is the top Democrat on the Armed Services Committee.

SEN. JACK REED, D-R.I.: I think the administration has to be much more clear about our role in Niger and our role in other areas in Africa and other parts of the globe.

JOHN YANG: The Pentagon is investigating the deaths. Reportedly among the questions, did commanders adequately assess the risk, and was there ready access to medical support?

Today, President Trump called the families of the four dead Green Berets.

For the PBS NewsHour, I’m John Yang.

The post Trump ignites furor with claim past presidents didn’t console military families by phone appeared first on PBS NewsHour.




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A small asteroid hit Earth and burned up over the Philippines

A newly spotted asteroid named 2024 RW1 burned up in the atmosphere over the South Pacific, creating a spectacular bright flash in the sky over the Philippines just hours after first being detected




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Cloud atlas of Mars reveals an atmosphere unlike our own

Using images captured by the European Space Agency’s Mars Express spacecraft, researchers have created a cloud atlas of Mars, to better understand the climate of the Red Planet




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Astronomy Photographer of the Year showcases world's best space images

See the world's best space images from the Astronomy Photographer of the Year 2024 award




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The astrophysicist who may be about to discover how the universe began

Astronomer Jo Dunkley is planning to use the Simons Observatory to snare evidence for inflation, the theory that the universe expanded at incredible speed after its birth




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The astrophysicist unravelling the origins of supermassive black holes

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




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Period atmosphere is best part of game set on turbulent oil rig

In Still Wakes the Deep, you play as a Glaswegian electrician on a 1970s oil rig. The well-crafted setting gives way to horror, but I wish I could linger in mundanity for longer, says Jacob Aron




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Smartphone flaw allows hackers and governments to map your home

A newly identified smartphone vulnerability can reveal the floor plans of where you are and what you are doing - and it is possible that companies or intelligence agencies are already making use of it




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AI tweaks to photos and videos can alter our memories

It has become trivially easy to use artificial intelligence to edit images or generate video to remove unwanted objects or beautify scenes, but doing so leads to people misremembering what they have seen




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It's parents who are anxious about smartphones, not their children

Smartphones have indeed created an "anxious generation", but it isn't young people, it is their parents, argues neuroscientist Dean Burnett




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Hackers can turn your smartphone into an eavesdropping device

Motion sensors in smartphones can be turned into makeshift microphones to eavesdrop on conversations, outsmarting security features designed to stop such attacks




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Nobel prize for physics goes to pair who invented key AI techniques

The 2024 Nobel prize in physics has gone to John Hopfield and Geoffrey Hinton for discoveries that enabled machine learning and are key to the development of artificial intelligence models like ChatGPT




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6G phone networks could be 9000 times faster than 5G

Next-generation phone networks could dramatically outperform current ones thanks to a new technique for transmitting multiple streams of data over a wide range of frequencies




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I've been boosting my ego with a sycophant AI and it can't be healthy

Google’s NotebookLM tool is billed as an AI-powered research assistant and can even turn your text history into a jovial fake podcast. But it could also tempt you into narcissism and nostalgia, says Jacob Aron




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AI can use tourist photos to help track Antarctica’s penguins

Scientists used AI to transform tourist photos into a 3D digital map of Antarctic penguin colonies – even as researchers debate whether to harness or discourage tourism in this remote region




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Spies can eavesdrop on phone calls by sensing vibrations with radar

An off-the-shelf millimetre wave sensor can pick out the tiny vibrations made by a smartphone's speaker, enabling an AI model to transcribe the conversation, even at a distance in a noisy room




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My iPhone says I have 14 viruses. What should I do next?

Getting virus alerts on your iPhone? Tech expert Kurt “CyberGuy" Knutsson helps you learn how to handle fake scam alerts and boost security.



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How to easily record phone calls on your iPhone

Apple has introduced a native call recording feature as part of Apple Intelligence with its release of iOS 18.1. It's easier than ever to document conversations.



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Powerboat racing returns to south coast as speedsters compete for famous Beaverbrook trophy