In vitro antifungal activities of the tested drugs
The MIC values of the tested drugs used to treat the Aspergillus isolates were ≥ 16 µg/mL for REV, 0.5–4 µg/mL for ITR, 0.5–1 µg/mL for VOR, and 0.5–1 µg/mL for POS (Table 1).
Table 1 Results of MIC and FICI for the combination of REV and antifungal drugs against Aspergillus strains
In vitro interactions of REV and the antifungal agents
When REV and ITR were combined, the MIC values of these two drugs against the clinical isolates decreased to 0.25–8 µg/mL and 0.25–4 µg/mL, The drug combination exhibited synergistic effects (FICI ≤ 0.5) against 20% of the evaluated Aspergillus isolates, comprising 2 A. fumigatus strains, 1 A. flavus strains, and 3 A. terreus strains (Tables 1 and 2).
Table 2 Summary of drug interactions for the combination of REV and antifungal agents
When REV and POS were combined, the MIC values of these two agents decreased to 0.25–8 µg/mL and 0.0625–1 µg/mL, The drug combination exhibited synergistic effects (FICI ≤ 0.5) against 90% of the evaluated evaluated Aspergillus strains, comprising 12 A. fumigatus strains, 11 A. flavus strains, and 4 A. terreus strains (Tables 1 and 2).
When REV and VOR were combined, the MIC values of these two antifungal agents decreased to 0.25 µg/mL and 0.125–1 µg/mL, respectively, and no synergistic or antagonistic effects on Aspergillus isolates were observed (Tables 1 and 2).
In the REV + POS alliance,A. fumigatus: 85.7% isolates (12/14) showed synergy;A. flavus: 91.7% isolates (11/12) showed synergy༛A. terreus: 100% isolates (4/4) showed synergy. POS consistently enhanced REV activity across all species, suggesting broad-spectrum potential.
In the REV + ITR alliance, A. terreus: 75% synergy (3/4 isolates), the highest among species.;A. fumigatus: 14.3% synergy (2/14 isolates)༛A. flavus: 8.3% synergy (1/12 isolates).ITR may have niche utility against A. terreus but limited synergy with REV for other species.
In the REV + VOR alliance, No synergy observed in any isolate (0/30 total); VOR is not a viable partner for REV in these Aspergillus species.
Thus, we conclude that: REV + POS was universally effective (85.7–100% synergy), but most potent against A. flavus (91.7%);REV + VOR failed in all cases, while REV + ITR showed sporadic activity (useful only for A. terreus).The synergy data is now explicitly compared by species, demonstrating that REV + POS is the most promising combination, particularly for A. flavus. The lack of synergy with VOR is also highlighted as a critical negative result.(Fig. 1).
Fig. 1
The Synergistic Rate of REV Combined with Azoles against Aspergillus spp. Note: A, interaction profile of REV combined with ITR, VOR and POS against Aspergillus spp; B, REV + POS interaction profiles across Aspergillus species
Construction of knockout strains for the genes encoding MFS transporters in A. fumigatus
Twelve MFS transporter genes were selected by NCBI database, and 12 MFS knockout strains were successfully constructed by PCR validation and sequencing analysis. The knockdown construction process is shown in Fig 2. Electrophoresis showed that the relevant 12 target genes failed to amplify the bands, while the pyrG gene amplified clear bands, and the electrophoretic profiles of 10 target genes is shown in Fig 3. Target genes AF-MFS32 and AF-MFS35 are shown in Fig 4B; moreover, confirming successful knockout of AF-MFS32 and AF-MFS35, electrophoresis analysis revealed 1.6 kb fragments amplified using AF-MFS32 downstream primers P4 and Awm-F1 and 1.8 kb fragments using AF-MFS35 upstream primers P1 and Carslan-R4 in Fig 4A.
Fig. 2
Schematic diagrams of primer binding sites and gene tissues for gene knockout and knockout verification. A Amplify the upstream and downstream DNA fragments of target geneand amplify the pyrG fragments labeled for screening. B Construct the fusion PCR products (UP, pyrG, DOWN). C Construct knockout confirmatory products to detect whether the gene has been successfully knocked out
Fig. 3
Electrophoretic gel for mutant confirmation. Note: M: DNA5000 Marker; 1, 3, 5, 7, 9, 11, 13, 15, 17, 19: No obvious bands were observed in the amplification of the target gene; 2, 4, 6, 8, 10, 12, 14, 16, 18, 20: Ten of these target genes corresponding to the pyrG fragment
Fig. 4
Verified electrophoretic gel diagram. Note: A: M: DNA5000 Marker; 1: The bands were amplified with primers P4 and Awm-F1 downstream of AF-MFS32; 2: The bands were amplified with primers P1 and Carslan-R4 upstream of AF-MFS35. B:1: The AF-MFS32pyrG fragment; 2: No obvious bands were observed in the amplification of the target gene; 3: No obvious bands were observed in the amplification of the target gene; 4: The AF-MFS35 pyrG fragment
In vitro interaction of REV with antifungal agents in MFS transporter genes knockout strains
When REV, ITR, and VOR were combined, none of the 12 knockout strains of MFS transporter gene showed obvious synergistic activity. When REV and POS were combined, ten of these isolates demonstrated a synergistic activity. However, in the two knockout strains of ΔAF-MFS32 and ΔAF-MFS35, the synergistic effect of REV and POS was reversed. (Table 3)
Table 3 Statistical table of antifungal sensitivity test
Disk diffusion method
The combination of REV and POS exerted a significantly lower inhibitory effect on the ΔAF-MFS32 and ΔAF-MFS35 than on the control WT suggesting a statistically significant difference (P < 0. 05). (Fig 5)
Fig. 5
Results of disk diffusion method. Note: A When REV combined with POS, the inhibition zone of ΔAF-MFS32, ΔAF-MFS35 was significantly smaller than that of control group ΔAF-MFS27. B REV: Revaprazan (8 µg/ml);POS: posaconazole (8 µg/ml). **P < 0.01,***P < 0.005
Rhodamine 6G – Efflux pump activity assay
The experiment to assess the efflux pump activity of knockout strains ΔAF-MFS32, ΔAF-MFS35, and the wild-type strain WT uses Rhodamine 6G as a substrate for the efflux pump. The accumulation and efflux of Rhodamine 6G reflect the pump’s function. According to the time-fluorescence curve, the efflux pump activity of the wild-type strain WT is significantly enhanced when REV and POS are used together compared to when POS is used alone, with a statistically significant difference. In contrast, the differences in efflux pump activity between the knockout strains ΔAF-MFS32 and ΔAF-MFS35 when POS is used alone and when REV and POS are used together are not statistically significant (Fig. 6).
Fig. 6
Rhodamine 6G efflux pump activity. Note: A: When the wild-type strain WT was used together with POS in REV and POS, the efflux pump activity was significantly enhanced compared with that of POS alone, which was statistically significant. B No statistically significant difference in efflux pump activity was observed in the AF-MFS32 knockout strain between POS monotherapy and its combination with REV and POS. C No statistically significant difference in efflux pump activity was observed in the AF-MFS35 knockout strain between POS monotherapy and its combination with REV and POS
Pharmacological dissection of Rhodamine 6G efflux in ΔAF-MFS32 and ΔAF-MFS35 knockout strains
To unambiguously distinguish the types of transporters mediating Rh6G efflux, we further employed pharmacological inhibitors for validation. The experimental results (Fig. 7) demonstrated that in the WT strain, treatment with the proton ionophore CCCP (which abolishes the function of MFS transporters) resulted in a significant suppression of Rh6G efflux activity compared to the DMSO control group (p < 0.01). Subsequent addition of the ABC transporter inhibitor sodium vanadate led to a further significant inhibition of efflux activity (p < 0.05). This confirms that in the wild-type strain, Rh6G efflux is cooperatively mediated by MFS transporters (major contribution) and ABC transporters (minor contribution).
In contrast, both knockout strains, ΔAF-MFS32 and ΔAF-MFS35, exhibited patterns strikingly different from that of the WT. No statistically significant differences were observed between the REV + POS combination treatments in either knockout (p > 0.05). More importantly, CCCP treatment failed to effectively inhibit the efflux activity in both knockout strains (p > 0.05 compared to their respective DMSO controls), and no significant difference was observed between the CCCP and CCCP + Vanadate treatments.
Fig. 7
Pharmacological dissection of Rhodamine 6G efflux in ΔAF-MFS32 and ΔAF-MFS35 knockout strains. Note: (A–C) Time-course analysis of intracellular Rhodamine 6G (Rh6G) accumulation in thewild-type (WT, A), ΔAF-MFS32 (B), and ΔAF-MFS35 (C) strains under different pharmacological treatments. Fluorescence intensity is inversely proportional to efflux pump activity. Treatments: DMSO (vehicle control), CCCP (20 µM, protonophore that collapses the proton motive force and inhibits MFS transporters), and CCCP + Vanadate (50 µM, ABC transporter inhibitor). Data are presented as mean ± SEM (n = 3).**P < 0.01;*P < 0.05
In the WT strain (A), CCCP treatment caused a dramatic increase in Rh6G accumulation (inhibition of efflux), indicating that efflux is primarily dependent on the proton gradient and thus mediated by MFS transporters. Further addition of vanadate significantly increased accumulation, revealing a minor contribution from ABC transporters.The ΔAF-MFS32 mutant (B) exhibited a altered response: CCCP treatment failed to significantly inhibit efflux, and no additional effect was observed with vanadate, suggesting a shift to a non-MFS, non-ABC efflux mechanism.The ΔAF-MFS35 mutant (C) showed complete loss of efflux function, as indicated by consistently high Rh6G accumulation across all treatments, identifying AF-MFS35 as an essential component of the efflux pump.
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A recent Reuters article broke down the essence of the trade ceasefire agreement between the US and China as following:
1. Tariff reduction on Fentanyl related Chinese goods
The US will halve the 20% tariff on Chinese goods related to supplies of fentanyl opioid precursor chemicals coming from China. The reduction to 10% on the duties first imposed in February will cut the overall US tariff rate on Chinese imports to about 47% from 57%, according to US officials.
That total includes duties of approximately 25% imposed on Chinese imports during Trump’s first term in the White House, a reduced 10% “reciprocal” tariff imposed in April, and previous “Most Favoured Nation” tariff rates.
2. Pause on China’s rare earth export controls
China agreed to a one-year pause on export controls after introducing an export ban on rare earth minerals and magnets earlier this year. Rare earth minerals play a vital role in the production of cars, planes, and weapons, and have become Beijing’s most potent and powerful leverage in its trade war with Washington. Those controls would have required export licenses for products with even trace amounts of a larger list of elements and were aimed at preventing use in military products.
The White House stated that China will also issue general licenses for the export of rare earths, gallium, germanium, antimony, and graphite, benefiting US end-users and their suppliers. The White House said that amounted to “the de facto removal of controls China imposed in April 2025 and October 2022.”
China also agreed to suspend all retaliatory tariffs it has announced since March 4, including duties on US chicken, wheat, corn, cotton, sorghum, soybeans, pork, beef, aquatic products, fruits, vegetables, and dairy products.
3. The Trump administration’s Export controls paused
The US agreed to a one-year pause on an expanded Commerce Department blacklist of companies prohibited from buying US technology goods, including semiconductor manufacturing equipment, a move aimed at averting the use of subsidiaries and other firms to bypass export controls.
The expanded blacklist would have automatically included firms more than 50% owned by companies already on the list and would have had the biggest impact on Chinese companies, banning US exports to thousands more Chinese firms.
4. China commits to soybean purchase
The White House stated that China agreed to purchase at least 12 million metric tons of US soybeans in the last two months of 2025, and at least 25 million metric tons of US soybeans in each of the following three years, as well as to resume purchases of US sorghum and hardwood logs.
5. Trump administration pauses new port fees
Beijing agreed to remove measures it had taken in retaliation for Washington’s Section 301 investigation of China’s dominance in the global maritime, logistics, and shipbuilding sectors, and to remove sanctions imposed on various shipping entities.
The Trump administration agreed to a one-year pause for the new port fees imposed on Chinese-built, owned, and flagged ships. The fees, aimed at reviving US commercial shipbuilding, could have added millions of dollars to the cost of each voyage to US ports, with shipping lines, freight forwarders and shippers breathing a loud sigh of relief after the announcement was published.
The port fees took effect on October 14, along with 100% tariffs on Chinese-built ship-to-shore cranes. They quickly disrupted cargo flows, pushing up container rates as shippers sought to avoid China-linked vessels. China has imposed its own fees on US-linked ships, including those from global shippers with 25% US ownership.
The White House stated that it would negotiate with China on the issue in the meantime, while continuing talks with South Korea and Japan on revitalising American shipbuilding.
6. Cooperation on fentanyl trafficking
China agreed to take “significant measures” to end the flow of fentanyl to the US, including moves to halt the shipment of certain precursor chemicals to North America and strictly control exports of other chemicals worldwide.
US Treasury Secretary Scott Bessent told Fox Business Network this week that working groups from the two countries would “set very objective measures” in the coming weeks on reducing flows to measure success in curbing the deadly opioid blamed for tens of thousands of US overdose deaths every year.
When Trump first imposed the fentanyl-related tariffs, officials in his administration said they were wary of ongoing promises by China to help, and that the tariffs would remain in place until Beijing had taken concrete measures. [3]
Global trade reconfiguration gives birth to the US+1 mega-trend
In the aftermath of the COVID-19 Pandemic, the term “China+1” became the hot supply chain take on ensuring a decreased reliance on China as the predominant production and assembly factory of the world.
10 months after the Trump administration took office, it is now clear that the persistent use of tariffs as a geopolitical and trade tool has given birth to an emerging US+1 trend across the world.
As no surprise, China is leading the way in terms of further diversifying its exports to ensure a lesser reliance on the US, recording a decrease in its exports of a whopping -16.9 % during the first nine months of 2025. This trend is even more remarkable given that China recorded a total export growth of 7.1%, proving the resilience of China’s exports.
Source: Reuters
It will naturally be a “forever” discussion whether it is in fact China succeeding in easing reliance on US exports, or whether it is in fact US importers seeking a safe tariff harbour and diversifying imports further. However, with an estimated US economic growth of only 1.8 % in October, economic indicators support the notion that China has gotten the long end of the trade-war stick so far.
The Chinese method has been simple yet effective, and in essence, can be explained as diversifying from developed to emerging markets. It can be fairly argued that this development has been ongoing for years; however, it is clear that the recent trade war has accelerated this development. A recent report from Oxford Economics untangled this effect further, noting that China in recent years has steadily increased exports to ASEAN (Association of Southeast Asian Nations), Latin American and African countries with especially exports to ASEAN countries driving the growth. [4]
Source: Oxford Economics
The timing of this trend is no coincidence, with China reacting immediately to the first round of the US trade war during Trump’s first period in office.
In particular exports of vehicles, communication equipment, and electrical machinery to emerging markets, such as those in ASEAN and Latin America, have risen sharply due to both supply chain diversification and rising local demand for China’s electric vehicles.
The US and Northeast Asia still represent about 32% of China’s total export value (versus 45% in 2017), but their dominance is rapidly fading. This year’s tariff increases have reinforced these redirections. Since February, export growth to ASEAN, India, Africa, and Latin America has been nearly double the pace of contraction in direct shipments to the US, suggesting and confirming that new trade links are gaining traction faster than older ones are eroding.
China pivots away from “Final Consumer Goods Production” label
Breaking the trend further down, it is also clear that while China still holds the title as the “Factory of the World”, it is steadily increasing its exports of intermediate and capital goods. China has been widely recognised as a “final assembler” economy; however, Chinese manufacturers are shifting towards being a key supplier of intermediate products.
Source: Oxford Economics
Since the mid-2010s, other economies have become increasingly reliant on Chinese-made inputs, especially in green industries such as solar and EV mobility.
The implications of China’s multi-year pivot from final consumer goods to capital and intermediate goods means that it is increasingly difficult for global manufacturers to exclude Chinese components and thereby reduce reliance on China. An increased presence in upstream production also makes demand for Chinese exports relatively insulated to tariff shifts.
What the does 2026 crystal ball hold following the US and China trade ceasefire
While lessons learned so far in 2025 indicate that we cannot count on any agreement being definitive, it is likely that there will be a widespread positive effect from the trade war ceasefire. Shippers around the world and not least in the US need a form of stability if the US economy is to kick back into gear.
Neither China, nor US seem to have appetite on an intensified and prolonged trade war and our assessment is that the current status quo, very likely will be the long-term solution. The threat from China of restricting US access to rare earth minerals is so profound and impactful that the US administration has no upside in increasing trade tensions, and conversely China needs a steady and strong export to the largest consuming country in the world.
Accordingly, we also expect a healthy uptick in demand during Q1 much to the relief of both ocean carriers and airlines which you can read more about further down.
The Hamas-Israel ceasefire is a fragile peace with continuous tensions
The ceasefire between Israel and Hamas holds, but the situation remains fragile. Despite diplomatic progress, logistical challenges and security concerns continue to delay the full return of hostages’ remains and the delivery of humanitarian aid.
While Israel and Hamas are committed to the ceasefire terms, including the return of bodies, hostages and the facilitation of aid, the recovery efforts face significant delays due to destroyed infrastructure and ongoing restrictions. Humanitarian organisations report that aid deliveries are still insufficient to meet Gaza’s needs, with key facilities struggling to operate due to limited access.
Reports say that both sides are under pressure to fully comply with the terms of the ceasefire, but with the ongoing internal instability in Gaza and limited progress in easing the humanitarian crisis, the ceasefire remains fragile.
The Houthis have stated that they will refrain from targeting any vessels while the ceasefire holds. However, carriers show no immediate signs of resuming routing through the Red Sea, citing continued concerns about the longevity of the ceasefire. Operationally, it would be very disruptive for ocean carriers to resume Red-Sea routing and then have to change back again later.
We anticipate that, while the ceasefire is long-awaited positive news not only for the people in Gaza and Israel, but also for the broader shipping industry, shipping lines are expected to maintain Cape of Good Hope diversions for at least the next 6 months and well into 2026.
IMO Net Zero Framework vote postponed for a year
As the IMO continues its efforts toward a global climate framework for the shipping sector, the deal is now facing mounting political resistance. While there was initial momentum in favour of the proposal, growing pressure from the US and Saudi Arabia had intensified ahead of the October meeting in London. Both nations lead the push to block the agreement.
Prior to the meeting, Trump made his opposition clear, denouncing the proposed global CO2 levy on shipping as a “fraud tax” and declaring that the US would not comply. In the run-up to the vote, the US administration threatened sanctions, tariffs, port levies, and visa restrictions against countries that supported the deal. This stance had prompted the US to join forces with Saudi Arabia and other oil-producing nations seeking to convince member states to reject or abstain from the vote. “It’s like dealing with the mafia,” a source described as a veteran of IMO negotiations told the Financial Times. “It’s bully tactics. They don’t need to tell you exactly what they’re going to do to you, just make it clear that there will be consequences.” [5]
On 17 October, the IMO announced that members had voted to postpone the Net Zero Framework vote for another year – effectively leaving the initiative in limbo, and supporters of the deal left the meeting disappointed and frustrated. Concluding the conference, the IMO Chairman Harry T Conway stated: ”Delegates, we meet in one year’s time. There is no other business to be discussed.” [6]
The outcome marks a clear setback of the industry’s climate ambitions and, in the short term, a missed opportunity to implement uniform global regulation – “a precondition to securing a level playing field in a global industry,” as Maersk noted in its statement. [7]
While few container shipping lines have commented on the decision publicly, the International Chamber of Shipping (ICS) voiced frustration that the states failed to agree on a path forward, stressing that the industry needs clarity to make long-term investment decisions. Hapag-Lloyd reaffirmed its own decarbonisation targets but warned that the already limited supply of green fuel may be negatively impacted by the decision.
While only a few container shipping lines have commented on the decision publicly, the International Chamber of Shipping (ICS) voiced frustration that the states failed to agree on a path forward, stressing that the industry needs clarity to make long-term investment decisions. Hapag-Lloyd reaffirmed its own decarbonisation targets but warned that the already limited supply of green fuel may be negatively impacted by the decision.
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Global stock markets have fallen sharply amid concerns that a boom in valuations of artificial intelligence (AI) companies could be rapidly cooling.
Markets in the US, Asia and Europe have fallen after bank bosses warned a serious stock market correction could be ahead, after a run of record stock market highs led some companies to appear overvalued.
In the US the tech-focused Nasdaq and the S&P 500 suffered their largest one-day percentage drop in almost a month on Tuesday.
Technology shares pulled the Nasdaq lower, which resulted in it closing 2% down. Meanwhile, there were one-day falls for all of the “magnificent seven” AI-related stocks: including the chipmaker Nvidia, Amazon, Apple, Microsoft, Tesla, Alphabet (the owner of Google) and Meta (the owner of Facebook, Instagram and WhatsApp).
The S&P also closed down just over 1% as it lost ground because of tech stocks, particularly the data analytics company Palantir, which slumped by almost 8% despite having raised its revenue outlook the previous day.
Palantir has also been targeted by a well-known short-seller – who bets on falls in the value of a company.
The investor Michael Burry – who rose to prominence after predicting the 2008 financial crash and inspiring the film The Big Short – bet against Palantir and the chipmaker Nvidia, two of the biggest AI companies, sparking criticism from Palantir’s boss and a stock sell-off.
In an interview on CNBC, Alex Karp, Palantir’s chief executive, criticised Burry and other short-sellers for “trying to call the AI revolution into question”.
Asian markets followed the US falls on Wednesday, recording the sharpest slide in seven months, as the concerns about tech stocks spread, and indices in Japan and South Korea dropped more than 5% from the record highs reached the previous day. In Europe, markets in the UK, France and Germany dropped slightly on Wednesday morning.
The market falls came as the chief executives of Morgan Stanley and Goldman Sachs cautioned there could be a market correction ahead.
They added their voices to that of Jamie Dimon, the head of the US’s largest bank, JP Morgan Chase, who warned in October he was worried markets would crash in the next six months to two years.
Jim Reid, an analyst at Deutsche Bank, said there was a “growing chorusdiscussing whether we might be on the verge of an equity correction”.
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Reid added: “The last 24 hours have brought a clear risk-off move, as concerns over lofty tech valuations have hit investor sentiment.”
Other analysts have raised questions about investment in AI companies, highlighting that the vast majority of investment in AI programmes has been promised to a very small group of tech companies, particularly OpenAI and Nvidia, while there has so far been little return on investment.
The price of bitcoin briefly dipped below $100,000 (£76,764) for the first time since June, as investors withdrew their money from riskier assets such as cryptocurrencies over fears about the economic outlook.
Bitcoin touched a record price of more than $126,000 in early October but went on to fall by 3.7% during the month, resulting in the worst monthly performance by the cryptocurrency in the last decade, according to figures from CoinMarketCap.
